Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial.

BACKGROUND: The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients. METHODS: In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing. FINDINGS: Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0-19·7) and followed up for a median of 9·9 months (4·3-12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11-24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-related adverse events (any grade in ≥10% patients) were infusion-related reaction (73 [29%]; all grade 1-2) and fatigue (40 [16%]). Grade 3 or worse treatment-related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event related to treatment with avelumab, and one treatment-related death occurred (pneumonitis). INTERPRETATION: Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis. FUNDING: Merck KGaA, and Pfizer Inc.

Long-term Outcomes of Chemoradiation for Muscle-invasive Bladder Cancer in Noncystectomy Candidates. Final Results of NRG Oncology RTOG 0524-A Phase 1/2 Trial of Paclitaxel + Trastuzumab with Daily Radiation or Paclitaxel Alone with Daily Irradiation.

BACKGROUND: Chemo-radiation is a well-established alternative to radical cystectomy in patients with muscle-invasive bladder cancer. Many patients due to age or medical comorbidity are unfit for either radical cystectomy, or standard cisplatin- or 5-fluorouracil-based chemoradiation, and do not receive appropriate treatment with curative intent. We treated patients with a less aggressive protocol employing seven weekly doses of paclitaxel and daily irradiation. In those whose tumors showed overexpression of her2/neu, seven weekly doses of trastuzumab were also administered. OBJECTIVE: To report the long-term survival outcomes and toxicity results of the of NRG Oncology RTOG 0524 study. DESIGN, SETTING, AND PARTICIPANTS: Seventy patients were enrolled and 65 (median age: 76 yr) were deemed eligible. Patients were assigned to daily radiation and weekly paclitaxel + trastuzumab (group 1, 20 patients) or to daily radiation plus weekly paclitaxel (group 2, 45 patients) based on tumor her2/neu overexpression. Radiation was delivered in 1.8 Gy fractions to a total dose of 64.8 Gy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was unresolved treatment-related toxicity. The secondary endpoints were complete response rate, protocol completion rate, and disease-free and overall survival. RESULTS AND LIMITATIONS: Protocol therapy was completed by 60% (group 1) and 76% (group 2); complete response rates at 12 wk were 62% in each group. Acute treatment-related adverse events (AEs) of grade ≥3 were observed in 80% in group 1 and 58% in group 2. There was one treatment-related grade 5 AE in group 1. Unresolved acute treatment-related toxicity was 35% in group 1 and 31% in group 2. The median follow-up was 2.3 yr in all patients and 7.2 yr in surviving patients. Overall survival at 5 yr was 25.0% in group 1 and 37.8% in group 2 (33.8% overall). At 5 yr, disease-free survival was 15.0% in group 1 and 31.1% in group 2. CONCLUSIONS: In a cohort of patients with muscle-invasive bladder cancer who are not candidates for cystectomy or cisplatin chemotherapy, chemoradiation therapy offers a treatment with a significant response rate and 34% 5-yr overall survival. While there were many AEs in this medically fragile group, there were few grade 4 events and one grade 5 event attributable to therapy. PATIENT SUMMARY: Patients with invasive bladder cancer who cannot tolerate surgery were treated with radiation and systemic therapy without surgically removing their bladders. Most patients tolerated the treatment, were able to keep their bladders, and showed a significant treatment response rate.

The use of analgesia in mountain rescue casualties with moderate or severe pain.

OBJECTIVES: To assess the effectiveness of analgesia used in mountain rescue (MR) in casualties with moderate or severe pain. To determine if a verbal numeric pain score is practical in this environment. To describe the analgesic strategies used by MR. DESIGN: Prospective, descriptive study. SETTING: Fifty-one MR teams in England and Wales. The study period was 1 September 2008 to 31 August 2010. PARTICIPANTS: 92 MR casualties with a pain scoreof 4/10 or greater. MAIN OUTCOME: 38% of casualties achieved a pain reduction of 50% or greater in their initial score at 15 min and 60.2% had achieved this at handover. RESULTS: The initial pain score was 8 (median), reducing to 5 at 15 min and 3 at handover. The mean pain reduction was 2.5 ± 2.4 at 15 min and 3.9 ± 2.5 at handover. 80 casualties (87%) were treated with an opioid and seven had two different opioids administered. Seven main strategies were identified in which the principal agent was entonox, intramuscular opioid, oral analgesia, fentanyl lozenge, intranasal or intravenous opioid. The choice of strategy varied with the skills of the casualty carer. CONCLUSIONS: Pain should be assessed using a pain score. When possible, intravenous opioid is the gold standard to achieve early and continuing pain control in patients with moderate or severe pain. Entonox and oral analgesics, as sole agents, have limited use in moderate or severe pain. Intranasal opioid and fentanyl lozenge are effective, and appropriate in MR. Research priorities include bioavailability in different environmental conditions and patient's satisfaction with their pain management.

Suspension syndrome: a scoping review and recommendations from the International Commission for Mountain Emergency Medicine (ICAR MEDCOM).

BACKGROUND: Suspension syndrome describes a multifactorial cardio-circulatory collapse during passive hanging on a rope or in a harness system in a vertical or near-vertical position. The pathophysiology is still debated controversially. AIMS: The International Commission for Mountain Emergency Medicine (ICAR MedCom) performed a scoping review to identify all articles with original epidemiological and medical data to understand the pathophysiology of suspension syndrome and develop updated recommendations for the definition, prevention, and management of suspension syndrome. METHODS: A literature search was performed in PubMed, Embase, Web of Science and the Cochrane library. The bibliographies of the eligible articles for this review were additionally screened. RESULTS: The online literature search yielded 210 articles, scanning of the references yielded another 30 articles. Finally, 23 articles were included into this work. CONCLUSIONS: Suspension Syndrome is a rare entity. A neurocardiogenic reflex may lead to bradycardia, arterial hypotension, loss of consciousness and cardiac arrest. Concomitant causes, such as pain from being suspended, traumatic injuries and accidental hypothermia may contribute to the development of the Suspension Syndrome. Preventive factors include using a well-fitting sit harness, which does not cause discomfort while being suspended, and activating the muscle pump of the legs. Expediting help to extricate the suspended person is key. In a peri-arrest situation, the person should be positioned supine and standard advanced life support should be initiated immediately. Reversible causes of cardiac arrest caused or aggravated by suspension syndrome, e.g., hyperkalaemia, pulmonary embolism, hypoxia, and hypothermia, should be considered. In the hospital, blood and further exams should assess organ injuries caused by suspension syndrome.

Should helicopters have a hoist or 'long-line' capability to perform mountain rescue in the UK?

OBJECTIVES: To determine how far mountain rescue casualties in the UK have to be carried and the impact of adding a hoist or 'long-line' to helicopters operating in this environment. DESIGN: Retrospective analysis of mountain rescue incidents. SETTING: Pre-hospital, mountain rescue service based in Patterdale, English Lake District. PARTICIPANTS: Casualties between 1 January 2006 and 31 December 2008 that required stretcher evacuation. Casualties directly accessible by a road ambulance were excluded. MAIN OUTCOME: The horizontal and vertical distance of the evacuation route to an agreed helicopter-landing site, and its technical character. Direct access to the incident site by a helicopter with a hoist or long-line capability was determined. RESULTS: 119 casualties were identified. The median horizontal and vertical evacuation distances were 250 m and -30 m respectively. The proposed manual carrying distances were ≤100 m in 33/119 (28%), between 101 and 400 m in 60/119 (50%) and >400 m in 26/119 (22%) of casualties. 13/119 (11%) casualties were in a position where direct access to the incident site would not have been possible with a helicopter equipped with a hoist or long-line. 31/119 (26%) casualties required a technical evacuation with the use of ropes. CONCLUSIONS: Using the criteria that all casualties requiring a technical rescue or >400 m evacuation route to an appropriate helicopter-landing site, 34% of casualties could have been rescued using a hoist or long-line with an expected reduction in the pre-hospital time. Helicopters working in UK mountain rescue should be equipped to international standards.

Physiological demands of mountain rescue work.

OBJECTIVE: To characterise the physical fitness of mountain rescue (MR) volunteers and the physical demands of a typical MR callout. METHODS: Eight MR volunteers (age ± SD: 45.5 ± 8.9 years) completed a laboratory-based treadmill exercise test to exhaustion. One week later subjects completed a field-based simulated callout to retrieve a casualty by stretcher. In both studies exercise intensity was evaluated by determination of oxygen uptake and other cardiovascular measures. RESULTS: The maximal oxygen uptake of the participants was 53 ml/kg/min (95% CI 45 to 60). In an unassisted callout, a typical rucksack load was 17% of body mass. Ascent time was 56 min (95% CI 40 to 72), of which 82% (95% CI 66% to 98%) was completed at hard or very hard intensity (above the respiratory compensation point). Descent time with a stretcher was 58 min (95% CI 52 to 64), of which only 6% (95% CI -4% to 16%) was completed at hard or very hard intensity. Correlations between heart rate and oxygen uptake were similar (p=0.254 by analysis of variance) during laboratory (r=0.72) and field testing, especially for the ascent (r=0.75). CONCLUSIONS: Mountain rescuers generally have high levels of physical fitness and are required to perform at very hard intensity for the majority of the ascent to a casualty. Heart rate is a simple yet valid measure of exercise intensity in MR personnel. These findings highlight important information on the unique physical demands faced by MR volunteers and provide direction for future research, volunteer selection and training.

Quality Indicators for Avalanche Victim Management and Rescue.

Decisions in the management and rescue of avalanche victims are complex and must be made in difficult, sometimes dangerous, environments. Our goal was to identify indicators for quality measurement in the management and rescue of avalanche victims. The International Commission for Mountain Emergency Medicine (ICAR MedCom) convened a group of internal and external experts. We used brainstorming and a five-round modified nominal group technique to identify the most relevant quality indicators (QIs) according to the National Quality Forum Measure Evaluation Criteria. Using a consensus process, we identified a set of 23 QIs to measure the quality of the management and rescue of avalanche victims. These QIs may be a valuable tool for continuous quality improvement. They allow objective feedback to rescuers regarding clinical performance and identify areas that should be the foci of further quality improvement efforts in avalanche rescue.

Effects of training time and feedback on ventilation skills in lay rescuers.

OBJECTIVE: Lay rescuers have difficulties acquiring ventilation skills during training. Non-feedback manikins are still widely employed, although skill acquisition is suboptimal. We analysed if a longer training time and verbal feedback, given by an instructor, improved ventilation skill acquisition with non-feedback manikins. METHODS: Forty-three high school students without prior medical training participated in this prospective randomised trial. Under one-to-one instructor guidance, 25 volunteers were trained on a manikin with a mouth-to-mask device for 10 min, and 18 volunteers for 20 min. After training, volunteers were assessed and verbal feedback was given: ventilate more if the mean tidal volume <0.5 L, ventilate less if >0.7 L or ventilate the same for 0.5-0.7 L. The volunteers were then reassessed. RESULTS: At the assessment, tidal volume, minute volume, peak airway pressure, ventilation rate and stomach inflation rate were comparable between the 10 and 20 min groups. After verbal feedback, at reassessment both groups increased tidal volume (assessment 0.75+/-0.24 vs reassessment 0.80+/-0.16 l/min; p=0.007), minute volume (9.1+/-3.0 vs 10.0+/-2.4 l/min; p=0.001), peak airway pressure (17.0+/-5.2 vs 18.3+/-3.4 cmH(2)O; p=0.003) and stomach inflation rate (67 vs 88%; p=0.02), while ventilation rate (12.3+/-2.1 vs 12.6+/-2.3 ventilations/min; p=NS) remained comparable. CONCLUSIONS: Both 10 and 20 min ventilation training times resulted in comparable skills. Volunteers hyperventilated the manikin and produced excessive stomach inflation in this model. This increased even further after verbal feedback.

Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: 2-year updated efficacy and safety analysis.

BACKGROUND: Anti-programmed cell death ligand 1 (PD-L1)/programmed cell death 1 antibodies have shown clinical activity in platinum-treated metastatic urothelial carcinoma, resulting in regulatory approval of several agents, including avelumab (anti-PD-L1). We report ≥2-year follow-up data for avelumab treatment and exploratory subgroup analyses in patients with urothelial carcinoma. METHODS: Patients with previously treated advanced/metastatic urothelial carcinoma, pooled from two cohorts of the phase Ib JAVELIN Solid Tumor trial, received avelumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity or withdrawal. End points included best overall response and progression-free survival (PFS) per RECIST V.1.1, overall survival (OS) and safety. Post hoc analyses included objective response rates (ORRs) in subgroups defined by established high-risk/poor-prognosis characteristics and association between time to response and outcome. RESULTS: 249 patients received avelumab; efficacy was assessed in 242 postplatinum patients. Median follow-up was 31.9 months (range 24-43), and median treatment duration was 2.8 months (range 0.5-42.8). The confirmed ORR was 16.5% (95% CI 12.1% to 21.8%; complete response in 4.1% and partial response in 12.4%). Median duration of response was 20.5 months (95% CI 9.7 months to not estimable). Median PFS was 1.6 months (95% CI 1.4 to 2.7 months) and the 12-month PFS rate was 16.8% (95% CI 11.9% to 22.4%). Median OS was 7.0 months (95% CI 5.9 to 8.5 months) and the 24-month OS rate was 20.1% (95% CI 15.2% to 25.4%). In post hoc exploratory analyses, avelumab showed antitumor activity in high-risk subgroups, including elderly patients and those with renal insufficiency or upper tract disease; ORRs were numerically lower in patients with liver metastases or low albumin levels. Objective response achieved by 3 months versus later was associated with longer OS (median not reached (95% CI 18.9 months to not estimable) vs 7.1 months (95% CI 5.2 to 9.0 months)). Safety findings were consistent with previously reported 6-month analyses. CONCLUSIONS: After ≥2 years of follow-up, avelumab showed prolonged efficacy and acceptable safety in patients with platinum-treated advanced/metastatic urothelial carcinoma, including high-risk subgroups. Survival appeared longer in patients who responded within 3 months. Long-term safety findings were consistent with earlier reports with avelumab treatment in this patient population.

The impact of avalanche rescue devices on survival.

BACKGROUND: Within Europe and North America, the median annual mortality from snow avalanches between 1994 and 2003 was 141. There are two commonly used rescue devices: the avalanche transceiver, which is intended to speed up locating a completely buried person, and the avalanche airbag, which aims to prevent the person from being completely buried. OBJECTIVE: This retrospective study aimed to evaluate whether these avalanche rescue devices had an effect on mortality. METHODS: The study population was 1504 persons who were involved in 752 avalanches either in Switzerland from 1990 to 2000 and from 2002 to 2003 (1296 persons, 86.2%) or in Austria from 1998 to 2004 (208 persons, 13.8%). RESULTS: Persons equipped with an avalanche airbag had a lower chance of dying (2.9% versus 18.9%; P=0.026, OR 0.09, n=1504). In persons who were completely buried, without visible or audible signs at the surface and who did not rescue themselves (n=317), we found a lower median duration of burial (25min versus 125min; P<0.001) and mortality (55.2% versus 70.6%; P<0.001, OR 0.26) in those using an avalanche transceiver than in those not using the device. CONCLUSIONS: Our data showed that both the avalanche airbag and the avalanche transceiver reduce mortality. However, to improve the evaluation of rescue devices in the future, the data collection procedures should be reviewed and prospective trials should be considered, as the reliability of retrospective studies is limited.

Basic life support ventilation in mountain rescue. Official recommendations of the International Commission for Mountain Emergency Medicine (ICAR MEDCOM).

Cardiopulmonary resuscitation in the mountains usually has to be performed under difficult and hostile circumstances and sometimes for extended periods of time. Therefore, mountain rescuers should have the ability and the appropriate equipment to perform prolonged, efficient, and safe ventilation. Members of the International Commission for Mountain Emergency Medicine (ICAR MEDCOM) discussed the results of a literature review, focusing on the advantages and disadvantages of common ventilation techniques in basic life support and their training methods with specific respect to use in mountain rescue, and recommendations were proposed. Bystanders fear the potential risk of infection and lack the willingness to perform mouth-to-mouth ventilation, though the risk of infection is low. Mouth-to-mouth ventilation remains the standard technique for bystander ventilation and, in the absence of a barrier device, bystanders should not hesitate to ventilate a patient by this technique. For mountain rescue teams, we encourage the use of a barrier device for artificial ventilation. Mouth-to-mask ventilation devices are most likely to fulfill the requirements of being safe, simple, and efficient in the hands of a basic-trained rescuer. The use of a mouth-to-mask ventilation device is recommended for out-of-hospital ventilation in the mountains and should be part of the mountain rescuer's standard equipment. Bag-valve-mask ventilation is efficient, if performed by well-trained rescuers, but it leads to a low ventilation quality in the hands of a less experienced rescuer. It should be emphasized that regular training every 6 to 12 months is necessary to perform proper ventilation.

Pattern and severity of injury in avalanche victims.

In avalanche accidents, the significance of major trauma as a cause of morbidity and mortality is controversial. The aim of this retrospective study is to determine the severity and pattern of injury in avalanche victims admitted to the University Hospital of Innsbruck between 1996 and 2005. A total of 49 significant injuries were found in 105 avalanche victims; the most frequent were of the extremities (n = 20), the chest (n = 18), and the spine (n = 7). In contrast, cerebral (n = 2), abdominal visceral (n = 1), and pelvic trauma (n = 1) were rare. The severity of injury was minor or moderate in most patients, with only 9 (8.6%) being severely or critically injured. Of 105 (34.3%) avalanche victims, 36 died. Autopsy was performed in 30 of 36 nonsurvivors. The cause of death in the remaining 6 victims was concluded from clinical, radiological, and electrophysiological findings. Trauma was responsible for deaths of only 2 avalanche victims (5.6%); both had cervical spine fractures with dislocation leading to death. One death was due to hypothermia, whereas the remaining 33 fatalities (91.7%) were due to asphyxia. The incidence of life-threatening or lethal trauma was well below 10%. Asphyxia is by far the most important reason for death. Deaths from trauma were solely due to isolated cervical injuries, demonstrating that the cervical spine may be a region at particular risk in avalanche victims.

Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732.

PURPOSE: To determine, in a randomized comparison, whether the addition of paclitaxel to etoposide and cisplatin improves the time to progression and overall survival in patients with extensive small-cell lung cancer (SCLC) compared with standard etoposide and cisplatin and to compare the regimens' toxicity. PATIENTS AND METHODS: Eligible patients (N=587) with untreated extensive SCLC were randomly assigned to receive either cisplatin 80 mg/m2 on day 1 and etoposide 80 mg/m2 on days 1 through 3 administered every 3 weeks for six cycles (EP) or cisplatin 80 mg/m2 on day 1, paclitaxel 175 mg/m2 over 4 hours on day 1, and etoposide 80 mg/m2 on days 1 to 3 followed by recombinant human granulocyte colony-stimulating factor on days 4 to 18 administered every 3 weeks for six cycles (PET). RESULTS: Reporting of demographics, response, and survival included 565 patients, of whom 282 were randomly assigned to receive EP and 283 were assigned to receive PET. Overall response rates were 68% for the EP arm and 75% for the PET arm. Median failure-free survival time was 5.9 months for the EP arm and 6 months for the PET arm (P = .179). Median overall survival time was 9.9 months for patients on EP and 10.6 months for patients on PET (P = .169). Toxic deaths occurred in 2.4% of the patients on EP and 6.5% of patients on PET. CONCLUSION: PET did not improve the time to progression or survival in patients with extensive SCLC compared with EP alone and was associated with unacceptable toxicity.

Comparison of mouth-to-mouth, mouth-to-mask and mouth-to-face-shield ventilation by lay persons.

OBJECTIVE AND METHODS: A prospective randomised study on 70 volunteers without previous first aid education (42 males, 28 females, mean age 17) was performed to compare mouth-to-mouth ventilation (MMV, n = 24) versus mouth-to-pocket-mask ventilation (MPV, n = 25) and mouth-to-face-shield ventilation (MFV, n =21), and to evaluate if an instruction period of 10 min would be sufficient to teach lay persons artificial ventilation. Every volunteer performed three ventilation series using a bench model of an unprotected airway. RESULTS: MMV and MPV show higher mean tidal volume (TV) than MFV (values of series 3: 976 +/- 454 and 868 +/- 459 versus 604 +/- 328 ml, P = 0.002 and P = 0.025, respectively). We found a higher inter-individual variation in TV than in previous studies (P = 0.031). The recommended TV of 700-1000 ml was reached in only 23%, most frequently with MPV (MMV 16.7%, MPV 32%, MFV 19%) but the difference was not significant (P = 0.391). However, we found a significantly higher percentage with a TV below 700 ml with MFV (MMV 33.3%, MPV 36%, MFV 66.7% P = 0.047) and a significantly higher percentage of TV exceeding 1000 ml with MMV (MMV 50%, MPV 32%, MFV 14.3%) (P = 0.039). "Stomach" inflation was highest with MMV (79.2%) followed by MPV (52%) and MFV (42.9%) (P = 0.034). We found further differences between the sexes; males produced a higher TV (P = 0.003) and a higher percentage of stomach inflation (P = 0.029). CONCLUSION: MPV showed the best ventilation quality. It resulted in a more adequate TV than MMV and MFV and lower stomach inflation than MMV. Only a relatively low percentage of ventilations were within the recommended range for TV and this may be related to the short training duration. We found different performances between the sexes, a high inter-individual variation and mainly a low ventilation quality. Therefore, further studies have to focus more on teaching duration, sex differences and ventilation quality.

Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study.

PURPOSE: The impact of azacytidine (Aza C) on the quality of life of 191 patients with myelodysplastic syndrome was assessed in a phase III Cancer and Leukemia Group B trial (9221). PATIENTS AND METHODS: One hundred ninety-one patients (mean age, 67.5 years; 69% male) were randomized to receive either Aza C (75 mg/m(2) subcutaneous for 7 days every 4 weeks) or supportive care, with supportive care patients crossing over to Aza C upon disease progression. Quality of life was assessed by centrally conducted telephone interviews at baseline and days 50, 106, and 182. Overall quality of life, psychological state, and social functioning were assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and the Mental Health Inventory (MHI). RESULTS: Patients on the Aza C arm experienced significantly greater improvement in fatigue (EORTC, P =.001), dyspnea (EORTC, P =.0014), physical functioning (EORTC, P =.0002), positive affect (MHI, P =.0077), and psychological distress (MHI, P =.015) over the course of the study period than those in the supportive care arm. Particularly striking were improvements in fatigue and psychological state (MHI) in patients treated with Aza C compared with those receiving supportive care for patients who remained on study through at least day 106, corresponding to four cycles of Aza C. Significant differences between the two groups in quality of life were maintained even after controlling for the number of RBC transfusions. CONCLUSION: Improved quality of life for patients treated with Aza C coupled with significantly greater treatment response and delayed time to transformation to acute myeloid leukemia or death compared with patients on supportive care (P <.001) establishes Aza C as an important treatment option for myelodysplastic syndrome.

Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B.

PURPOSE: Patients with high-risk myelodysplastic syndrome (MDS) have high mortality from bone marrow failure or transformation to acute leukemia. Supportive care is standard therapy. We previously reported that azacitidine (Aza C) was active in patients with high-risk MDS. PATIENTS AND METHODS: A randomized controlled trial was undertaken in 191 patients with MDS to compare Aza C (75 mg/m(2)/d subcutaneously for 7 days every 28 days) with supportive care. MDS was defined by French-American-British criteria. New rigorous response criteria were applied. Both arms received transfusions and antibiotics as required. Patients in the supportive care arm whose disease worsened were permitted to cross over to Aza C. RESULTS: Responses occurred in 60% of patients on the Aza C arm (7% complete response, 16% partial response, 37% improved) compared with 5% (improved) receiving supportive care (P <.001). Median time to leukemic transformation or death was 21 months for Aza C versus 13 months for supportive care (P =.007). Transformation to acute myelogenous leukemia occurred as the first event in 15% of patients on the Aza C arm and in 38% receiving supportive care (P =.001). Eliminating the confounding effect of early cross-over to Aza C, a landmark analysis after 6 months showed median survival of an additional 18 months for Aza C and 11 months for supportive care (P =.03). Quality-of-life assessment found significant major advantages in physical function, symptoms, and psychological state for patients initially randomized to Aza C. CONCLUSION: Aza C treatment results in significantly higher response rates, improved quality of life, reduced risk of leukemic transformation, and improved survival compared with supportive care. Aza C provides a new treatment option that is superior to supportive care for patients with the MDS subtypes and specific entry criteria treated in this study.

Delayed and intermittent CPR for severe accidental hypothermia.

INTRODUCTION: Cardiac arrest (CA) in patients with severe accidental hypothermia (core temperature <28 °C) differs from CA in normothermic patients. Maintaining CPR throughout the prehospital period may be impossible, particularly during difficult evacuations. We have developed guidelines for rescuers who are evacuating and treating severely hypothermic CA patients. METHODS: A literature search was performed. The authors used the findings to develop guidelines. RESULTS: Full neurological recovery is possible even with prolonged CA if the brain was already severely hypothermic before CA occurred. Data from surgery during deep hypothermic CA and prehospital case reports underline the feasibility of delayed and intermittent CPR in patients who have arrested due to severe hypothermia. CONCLUSIONS: Continuous CPR is recommended for CA due to primary severe hypothermia. Mechanical chest-compression devices should be used when available and CPR-interruptions avoided. Only if this is not possible should CPR be delayed or performed intermittently. Based on the available data, a patient with a core temperature <28 °C or unknown with unequivocal hypothermic CA, evidence supports alternating 5 min CPR and ≤5 min without CPR. With core temperature <20 °C, evidence supports alternating 5 min CPR and ≤10 min without CPR.