Strategies For Future Trials Research Articles

The Effects of red Blood Cell Transfusion on Tissue Oxygenation and the Microcirculation in the Intensive Care Unit: A Systematic Review.

The transfusion of red blood cells (RBCs) is a common intervention in intensive care unit (ICU) patients, yet the benefits are far from clear in patients with moderate anemia (eg, hemoglobin (Hb) levels of 7-10 g/dL). Determining which of these patients benefit, and how to even define benefit, from transfusion is challenging. As the intended physiological benefit underpinning RBC transfusion is to improve tissue oxygenation, several studies utilizing a wide range of assessment techniques have attempted to study the effects of transfusion on tissue oxygenation and microcirculatory function. The objective of this systematic review was to determine whether RBC transfusion improves tissue oxygenation/microcirculatory indices in the ICU population, and to provide an introduction to the techniques used in these studies. Eligible studies published between January 1996 and February 2017 were identified from searches of PubMed, Embase, Cinahl, ScienceDirect, Web of Science, and The Cochrane Library. Seventeen studies met inclusion criteria, though there was significant heterogeneity in study design, patient population, assessment techniques and outcomes reported. Overall, the majority of studies (11 of 17) concluded that transfusion did not generally improve tissue oxygenation or microcirculation. Inter-individual effects were highly variable, however, and closer review of sub-groups available in 9 studies revealed that patients with abnormal tissue oxygenation or microcirculatory indices prior to transfusion had improvement in these indices with transfusion, irrespective of assessment method. This finding suggests a new strategy for future trials in the ICU: utilizing tissue oxygenation/microcirculatory parameters to determine the need for transfusion rather than largely arbitrary hemoglobin concentrations.

Locally Advanced and Metastatic Gastric Cancer

The management of gastric cancer remains a challenge. In recent years, the most important advances have been achieved in the adjuvant setting for patients with locally advanced disease, where significant survival benefits have been demonstrated for both perioperative chemotherapy and adjuvant chemoradiotherapy. These findings have changed the standard of care for patients with resectable disease. In the setting of metastatic gastric cancer, the development of new cytotoxic regimens must consider the balance between efficacy and toxicity in patients whose overall prognosis is poor. Major advances in recent years include the development of orally administered fluoropyrimidine analogues, which can be used in place of intravenous fluorouracil, and the addition of newer agents such as oxaliplatin and docetaxel, which have demonstrated efficacy in patients with advanced disease. Targeted therapies have had a major impact on the management of certain malignancies, and while their evaluation in the treatment of advanced gastric cancer remains early, it is likely that these agents will continue to be developed and studied in combination with chemotherapy. This article reviews recent advances in the use of chemotherapy for advanced gastric cancer. Targeted therapies, their mechanisms of action and emerging data supporting their use in gastric cancer are also discussed. The two randomized phase III trials supporting adjuvant therapy for locally advanced, resectable gastric cancer are discussed in detail, together with strategies for future trials in this area. Overall, there remains optimism that further incremental gains will be achieved with future studies combining chemotherapy, radiotherapy and targeted therapies, both in the adjuvant and metastatic disease settings.

Phase I Trial of Sphingosomal Vincristine (SV, Marqibo®) and Dexamethasone in Relapsed or Refractory Acute Lymphocytic Leukemia (ALL).

Delivery of standard therapeutics in formulations which allow increased drug delivery with equivalent or less toxicity may improve outcome. Vincristine is an essential component of ALL therapy. Its cytotoxicity occurs in a time and dose-dependent manner, but the dose needs to be capped at 2 mg to prevent severe neurotoxicity. SV is a form of vincristine encapsulated in sphingomyelin liposomes or “sphingosomes” with an increased circulation half-life of 12 hours compared with 6–12 minutes for free vincristine. In vivo, SV has more anti-tumor activity than free vincristine in mice bearing P388 and L1210 leukemias. A previous study of single agent SV 2.0 mg/m2 given every 2 weeks (without dose capping) was conducted in 16 patients (pts) with relapsed or refractory ALL. Objective responses were observed in 14% (1 complete response [CR], 1 partial response [PR]); 36% had transient reduction in marrow leukemia infiltrate with very minimal toxicity (Thomas et al., Cancer 106:1641, 2006). An increase in dose intensity was considered the strategy for future trials. A standard 3 + 3 phase I study of weekly escalating doses of SV (1.5 mg/m2, 1.825 mg/m2, 2 mg/m2, 2.25 mg/m2, 2.4 mg/m2) with pulse dexamethasone (D) 40 mg daily days 1–4 and 11–14 was initiated. Pts with active grade 2 or greater central or peripheral neuropathy (PN) were excluded. Pts were evaluated for dose-limiting toxicities (DLT) after 1 course (defined as 4 weekly doses of SV + D). To date, 36 pts with relapsed/refractory ALL were enrolled. Median age was 34 years (range, 21–62). Median number of prior salvage regimens was 2 (range, 1–3); all pts had prior vincristine. SV was discontinued early for progressive disease (n=5), death due to sepsis (n=3) or other toxicities (n=3). Thus, twenty-five pts (71%) completed 1 full course and were considered evaluable. DLTs were observed at the 2.4 mg/m2 dose level (grade 3 PN, seizure with intracranial hemorrhage, grade 4 hepatotoxicity). The tentative MTD is 2.25 mg/m2 (expansion of cohort ongoing). Expected toxicities included infections related to neutropenia, grade 1–3 constipation, grade 1–2 PN and transient grade 1–3 elevations in hepatic transaminases related to azole antifungal prophylaxis. Six pts (24%) achieved CR (2 at 1.5 mg/m2, 1 at 1.825 mg/m2, 2 at 2.25 mg/m2, 1 at 2.4 mg/m2), 1 a PR (at 2.25 mg/m2), and 3 (12%) hematological improvements (of platelets at 1.825 mg/m2 and 2 mg/m2 or clearance of marrow blasts at 2.25 mg/m2). Five responders proceeded to allogeneic stem cell transplant. In conclusion, SV with pulse dexamethasone demonstrated encouraging activity in relapsed or refractory ALL. Phase II and III studies of SV in ALL are planned.

Quality of life in patients treated for head and neck cancer: A follow-up study 7 to 11 years after radiotherapy

Purpose : To compare health-related quality of life factors in 845 head and neck cancer patients randomized to receive either conventional radiotherapy (2 Gy, 5 days-a-week) or a hypofractionated regimen (2.35 Gy, 4 days-aweek), a follow-up study was carried out 7 to 11 years after treatment in the surviving patients, representing 30% of the original patient number. Methods and Materials : The cancer-specific EORTC Core Quality of Life Questionnaire (30 item version; the EORTC QLQ-C30) and a 19 item head and neck cancer-specific questionnaire were mailed to the 245 surviving patients of the trial. The EORTC QLQ-C30 is comprised of six multi-item function scales, three symptom scales, and six single items which assess both symptoms and economic consequences of the disease. Two hundred and four patients (83%) completed the questionnaire. The two groups of patients ( N = 103 and N = 101) treated by different fractionating schedules, were comparable with regard to sociodemographic variables, tumor site, treatment variables (including different types of surgical treatment), and secondary primary cancers. Patients in the conventional group had more advanced disease and a higher recurrence rate compared to patients in the hypofractionated group. Results : Unexpectedly, patients in the hypofractionated group, reported similar or better quality of life compared to patients in the conventional fractionated group. Patients in both groups described a high level of symptoms, like dryness in the mouth and mucus production. Clinical and sociodemographic variables did not explain variance in social function, emotional function or fatigue, except for the type of surgery performed, which significantly influenced the patients' emotional function. Conclusion : Long-term survivors of head and neck cancer reported a high level of disease and treatment related symptoms. Emotional function was significantly influenced by the type of surgical procedure. Strategies for future trials in head and neck cancer should continue to attempt to stress conservative surgical approaches and coordinated adjuvant therapy to maximize local regional control and quality of life. Functional and emotional outcome are important parameters which should prospectively be evaluated in future clinical trials in head and neck cancer.