Overall Survival in Patients with Endometrial Cancer Treated with Dostarlimab plus Carboplatin-Paclitaxel in the Randomized ENGOT-EN6/GOG-3031/RUBY Trial.

BACKGROUND: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer. At the first interim analysis, the trial met one of its dual-primary endpoints with statistically significant progression-free survival benefits in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. PATIENTS AND METHODS: RUBY is a phase 3, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer who were randomly assigned (1:1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual-primary endpoint. RESULTS: A total of 494 patients were randomized (245 in dostarlimab arm; 249 in placebo arm). In the overall population, with 51% maturity, RUBY met the dual-primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death (HR = 0.69; 95% CI, 0.54-0.89; P = 0.0020) in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32; 95% CI, 0.17-0.63; nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair proficient/microsatellite stable (MMRp/MSS) population (HR = 0.79; 95% CI, 0.60-1.04; nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis. CONCLUSIONS: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful overall survival benefit in the overall population of patients with primary advanced or recurrent endometrial cancer while demonstrating an acceptable safety profile.

Medical education and law: withholding/withdrawing treatment from adults without capacity.

BACKGROUND: Law is increasingly involved in clinical practice, particularly at the end of life, but undergraduate and postgraduate education in this area remains unsystematic. We hypothesised that attitudes to and knowledge of the law governing withholding/withdrawing life-sustaining treatment from adults without capacity (the WWLST law) would vary and demonstrate deficiencies among medical specialists. AIMS: We investigated perspectives, knowledge and training of medical specialists in the three largest (populations and medical workforces) Australian states, concerning the WWLST law. METHODS: Following expert legal review, specialist focus groups, pre-testing and piloting in each state, seven specialties involved with end-of-life care were surveyed, with a variety of statistical analyses applied to the responses. RESULTS: Respondents supported the need to know and follow the law. There were mixed views about its helpfulness in medical decision-making. Over half the respondents conceded poor knowledge of the law; this was mirrored by critical gaps in knowledge that varied by specialty. There were relatively low but increasing rates of education from the undergraduate to continuing professional development (CPD) stages. Mean knowledge score did not vary significantly according to undergraduate or immediate postgraduate training, but CPD training, particularly if recent, resulted in greater knowledge. Case-based workshops were the preferred CPD instruction method. CONCLUSIONS: Teaching of current and evolving law should be strengthened across all stages of medical education. This should improve understanding of the role of law, ameliorate ambivalence towards the law and contribute to more informed deliberation about end-of-life issues with patients and families.

Palliative care, double effect and the law in Australia.

Care and decision-making at the end of life that promotes comfort and dignity is widely endorsed by public policy and the law. In ethical analysis of palliative care interventions that are argued potentially to hasten death, these may be deemed to be ethically permissible by the application of the doctrine of double effect, if the doctor's intention is to relieve pain and not cause death. In part because of the significance of ethics in the development of law in the medical sphere, this doctrine is also likely to be recognized as part of Australia's common law, although hitherto there have been no cases concerning palliative care brought before a court in Australia to test this. Three Australian States have, nonetheless, created legislative defences that are different from the common law with the intent of clarifying the law, promoting palliative care, and distinguishing it from euthanasia. However, these defences have the potential to provide less protection for doctors administering palliative care. In addition to requiring a doctor to have an appropriate intent, the defences insist on adherence to particular medical practice standards and perhaps require patient consent. Doctors providing end-of-life care in these States need to be aware of these legislative changes. Acting in accordance with the common law doctrine of double effect may not provide legal protection. Similar changes are likely to occur in other States and Territories as there is a trend towards enacting legislative defences that deal with the provision of palliative care.

Two steps forward, one step back: advance care planning, Australian regulatory frameworks and the Australian Medical Association.

The Australian Medical Association has recently adopted a policy position concerning advance care planning, which is generally supportive of extending patient self-determination beyond the loss of decision-making capacity. It calls for uniform national legislation for legally enforceable advance health directives (AHD), and statutory protection for practitioners who comply with valid AHD, or who do not comply on several grounds. Analysis of the grounds for non-compliance indicate that they undermine patient autonomy, and aspects of the policy are inconsistent with current common law and statutory regimes that allow an adult to complete a legally binding AHD. The policy therefore threatens the patient self-determination, which it endorses, and places doctors who participate in advance care planning at legal risk.

A model for decision making at the end-of-life: Queensland and beyond.

This paper addresses when it is legal to withdraw or withhold medical treatment that is needed to keep a patient alive. It draws on cases and legislation from the common law world (including Australia, England and New Zealand) and considers the various legal tests applied in the different jurisdictions. Two of the most common tests employed in this situation are the "best interests of the patient" test and the "substituted judgment" test. Some jurisdictions also include other criteria as well, such as a requirement that withdrawing or withholding of medical treatment is "not inconsistent with good medical practice". This paper analyses these different legal tests, and after identifying the factors that are judged to be legally relevant to consider when deciding to withdraw or withhold treatment, outlines a preferred model. This model addresses who the relevant decision maker should be, and the criteria that should govern their decision. It suggests that family members are better equipped and more appropriate to act as decision makers than health professionals, and also questions the appropriateness of responsible medical opinion as the decisive factor in such cases, preferring instead an approach more consistent with the principles of self determination. The model also proposes a method for resolving any disputes that arise.

Overriding advance refusals of life-sustaining medical treatment.

The law recognises the right of a competent adult to make an advance refusal of life-sustaining medical treatment. This right is based on the principle of self-determination which dictates that a competent adult is entitled to make decisions about the kind of treatment he or she wants to receive or not to receive. However, the right to refuse life-sustaining treatment in advance is not unqualified. There are circumstances in which a health professional or a court will be entitled to disregard an advance directive and provide the life-sustaining medical treatment. This intervention is justified on the grounds of the State's interest in preserving life. Although self-determination prevails over the State's interest in life, the courts have held that an adult's wishes need only be respected if the adult has expressed them clearly and there is otherwise no uncertainty. This paper explores in some detail the common law and statutory excuses available to health professionals in Australia who do not wish to comply with directions in an advance directive to refuse life-sustaining medical treatment. At common law, the inquiry revolves around whether the adult intended his or her refusal to apply to the circumstances that have subsequently arisen. The paper considers the different situations in which it might be argued that an adult completed an advance directive but did not intend it to apply, thus permitting a health professional to disregard it. In contrast, the relevant Australian statutes specify a number of excuses that expressly allow a health professional not to follow an advance directive, or prohibit him or her from following it. The paper then compares the common law with those jurisdictions that have enacted legislation and critiques the different excuses available. The paper concludes by asserting that the law generally strikes the correct balance between requiring an advance directive to be followed but not enforcing a direction to refuse life-sustaining medical treatment where there is some doubt about whether it presents the adult's views. However, there are two riders to this proposition. The first is the tendency of the judiciary to err unduly in favour of the sanctity of life when it is called upon to interpret whether an advance directive can be regarded as representing the adult's wishes in the situation that subsequently arose. Secondly, comment is made about the recognition in one statutory jurisdiction of an excuse that permits a health professional to provide treatment contrary to an advance refusal based on good medical practice.

Evidence for colorectal cancer micrometastases using reverse transcriptase-polymerase chain reaction analysis of MUC2 in lymph nodes.

Poor survival in patients following resection for early stage colorectal cancer is thought to be due in part to the presence of occult micrometastases at the time of surgery. The MUC2 mucin gene is highly expressed in the colon and associated colorectal tumors and may be a candidate marker for colorectal cancer micrometastases. We have used RT-PCR to detect expression of MUC2 mRNA transcripts in order to identify possible lymph node micrometastases in node negative (Stage I and II, or Dukes A and B) colorectal cancer patients. A total of 396 nodes (histologic stage N0) from 34 colon and nine rectal cancers were studied by RT-PCR analysis with nested primers for MUC2 (an average of 7.6 nodes per case). In the primary tumors, 42/43 (98.1%) were positive for MUC2 by RT-PCR. Evidence of the presence of MUC2 was demonstrated in nodes from 0 of 10 (0%) patients with Tis or T1, one of six (16.7%) from T2, 10 of 25 (40.0%) from T3, and one of two (50%) from T4 tumors. MUC2 RT-PCR was negative in six nodes from three patients with non-malignant colon disease and positive in histologically positive lymph nodes from six of six (100%) stage III colon cancers. In this study, using RT-PCR to detect the presence of MUC2 transcripts, we have found preliminary evidence for possible micrometastatic disease in approximately a third of histologically negative N0 colorectal cancer patients. The increased presence of MUC2 expression also correlated with more advanced T stage. We conclude that MUC2 RT-PCR may be a sensitive and specific marker for occult micrometastases. This technique has the potential to identify a group of colorectal cancer patients at risk for early cancer recurrence.

Metabolism of the carcinogen N-hydroxy-N-2-fluorenylacetamide by rat peritoneal neutrophils.

The in vitro metabolism of a locally carcinogenic N-hydroxy-N-2-fluorenylacetamide (N-OH-2-FAA) by rat peritoneal polymorphonuclear leukocytes (PMNL), chiefly neutrophils, elicited with intraperitoneal injections of proteose peptone, was examined. At 10(6) PMNL/ml in media containing halide (X-), 0.14 M Cl- +/- 0.1 mM Br- (without Ca++ and Mg++), addition of 10 nM phorbol myristate acetate (PMA) resulted in generation of superoxide anion and H2O2. Subsequent cetyltrimethylammonium Cl- (Cetac) addition at 0.002% effected myeloperoxidase (MPO) activity release. PMNL treated with PMA and/or Cetac did not metabolize N-OH-2-FAA (30 microM). However, 1-2 pulses of H2O2 (50 microM) after Cetac addition resulted in oxidation of N-OH-2-FAA to N-acetoxy-2-FAA (< 0.5 microM) and 2-nitrosofluorene (2-NOF) (1-2 microM). In the presence of Br- 2-NOF was increased (3-5 microM). The results are consistent with oxidation of N-OH-2-FAA by MPO/H2O2 and MPO/H2O2/X- via two pathways: one electron oxidation leading to N-acetoxy-2-FAA and 2-NOF, and X(-)-dependent oxidation to 2-NOF. N-Acetoxy-2-FAA (10 microM) incubated with PMNL under similar conditions was converted non-enzymatically to 4-OH-2-FAA (< or = 5 microM) and enzymatically to N-OH-2-FAA (< or = 3 microM). In the presence of H2O2, smaller amounts of these products were formed. Formation of N-OH-2-FAA was prevented by paraoxon (0.1 mM) suggesting O-deacetylase activity. However, accountability for N-acetoxy-2-FAA decreased with time, presumably because of binding to cellular macromolecules. With H2O2 addition, 2-NOF (10 microM) was converted to 0.5 or 0.25 microM 2-nitrofluorene by active PMNL or heat-inactivated cell lysates, respectively. Low recoveries of 2-NOF were also attributed to binding. The results suggest that PMNL may be involved in activation of the carcinogenic N-arylhydroxamic acids in vivo.