Summary Background Results from a previous phase 3 study suggested that prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs overall survival compared ...with no prophylactic cranial irradiation in patients with extensive-disease small-cell lung cancer. However, because of the absence of brain imaging before enrolment and variations in chemotherapeutic regimens and irradiation doses, concerns have been raised about these findings. We did a phase 3 trial to reassess the efficacy of prophylactic cranial irradiation in the treatment of extensive-disease small-cell lung cancer. Methods We did this randomised, open-label, phase 3 study at 47 institutions in Japan. Patients with extensive-disease small-cell lung cancer who had any response to platinum-based doublet chemotherapy and no brain metastases on MRI were randomly assigned (1:1) to receive prophylactic cranial irradiation (25 Gy in ten daily fractions of 2·5 Gy) or observation. All patients were required to have brain MRI at 3-month intervals up to 12 months and at 18 and 24 months after enrolment. Randomisation was done by computer-generated allocation sequence, with age as a stratification factor and minimisation by institution, Eastern Cooperative Oncology Group performance status, and response to initial chemotherapy. The primary endpoint was overall survival, analysed in the intention-to-treat population. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000001755, and is closed to new participants. Findings Between April 3, 2009, and July 17, 2013, 224 patients were enrolled and randomly assigned (113 to prophylactic cranial irradiation and 111 to observation). In the planned interim analysis on June 18, 2013, of the first 163 enrolled patients, Bayesian predictive probability of prophylactic cranial irradiation being superior to observation was 0·011%, resulting in early termination of the study because of futility. In the final analysis, median overall survival was 11·6 months (95% CI 9·5–13·3) in the prophylactic cranial irradiation group and 13·7 months (10·2–16·4) in the observation group (hazard ratio 1·27, 95% CI 0·96–1·68; p=0·094). The most frequent grade 3 or worse adverse events at 3 months were anorexia (six 6% of 106 in the prophylactic cranial irradiation group vs two 2% of 111 in the observation group), malaise (three 3% vs one <1%), and muscle weakness in a lower limb (one <1% vs six 5%). No treatment-related deaths occurred in either group. Interpretation In this Japanese trial, prophylactic cranial irradiation did not result in longer overall survival compared with observation in patients with extensive-disease small-cell lung cancer. Prophylactic cranial irradiation is therefore not essential for patients with extensive-disease small-cell lung cancer with any response to initial chemotherapy and a confirmed absence of brain metastases when patients receive periodic MRI examination during follow-up. Funding The Ministry of Health, Labour and Welfare of Japan.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Summary Background Etoposide and irinotecan are key drugs in the treatment of small-cell lung cancer. We did this study to investigate whether combined chemotherapy with cisplatin, etoposide, and ...irinotecan was superior to topotecan monotherapy as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer. Methods We did this open-label, multicentre, randomised phase 3 trial at 29 institutions in Japan. Patients with small-cell lung cancer that responded to first-line treatment but showed evidence of disease relapse or progression at least 90 days after completion of the first-line treatment were eligible to participate. Enrolled patients were randomly assigned (1:1) to receive combination chemotherapy with cisplatin plus etoposide plus irinotecan or topotecan alone. Randomisation was done via the minimisation method with biased-coin balancing for Eastern Cooperative Oncology Group performance status, disease stage at enrolment, and institution. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m2 on days 1 and 8, intravenous etoposide 60 mg/m2 on days 1–3, and intravenous irinotecan 90 mg/m2 on day 8, with granulocyte colony-stimulating factor given by hypodermic injection every day starting from day 9 of the first course (except on the days anticancer drugs were given). Topotecan therapy consisted of four courses of intravenous topotecan 1·0 mg/m2 on days 1–5, every 3 weeks. The primary endpoint was overall survival in the intention-to-treat population, which was analysed with a one-sided α of 5%, and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number UMIN000000828. Findings Between Sept 20, 2007, and Nov 30, 2012, 180 patients were enrolled, with 90 assigned to each treatment group. The median follow-up for censored patients was 22·7 months (IQR 20·0–35·3). Overall survival was significantly longer in the combination chemotherapy group (median 18·2 months, 95% CI 15·7–20·6) than in the topotecan group (12·5 months, 10·8–14·9; hazard ratio 0·67, 90% CI 0·51–0·88; p=0·0079). The most common grade 3 or 4 adverse events were neutropenia (75 83% patients in the combination chemotherapy group vs 77 86% patients in the topotecan group), anaemia (76 84% vs 25 28%), and leucopenia (72 80% vs 46 51%). Grade 3 or 4 febrile neutropenia was more common in the combination chemotherapy group than in the topotecan group (28 31% vs six 7%), as was grade 3 or 4 thrombocytopenia (37 41% vs 25 28%). Serious adverse events were reported in four (4%) patients in the topotecan group and nine (10%) in the combination chemotherapy group. Two treatment-related deaths (one each of pneumonitis and pulmonary infection) occurred in the topotecan group and one (febrile neutropenia with sepsis) occurred in the combination chemotherapy group. Interpretation Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered the standard second-line chemotherapy for selected patients with sensitive relapsed small-cell lung cancer. Funding National Cancer Center and the Ministry of Health, Labour and Welfare of Japan.
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Primary graft dysfunction (PGD) is one of the most common causes of early death after orthotopic heart transplantation. Mechanical circulatory support devices are required for severe forms of PGD. ...Venoarterial extracorporeal membrane oxygenation (VA-ECMO) and temporary ventricular assist device (VAD) support have both been reported to be useful for severe PGD.
Between January 2007 and December 2015, 597 patients received a heart transplant at our center. Of those, severe PGD developed in 44 patients (7.4%), and they received a continuous-flow external VAD (n = 17) or VA-ECMO (n = 27) support within 24 hours after transplant. We compared early and late outcomes between groups.
Baseline characteristics were similar between groups. Implantation of the temporary VAD required longer cardiopulmonary bypass time compared with VA-ECMO (323 ± 86 minutes vs 216 ± 65 minutes, p < 0.0001). Patients who received a VAD were more likely to have longer support time (14 ± 17 days vs 5.2 ± 3.9 days, p = 0.011), a higher incidence of major bleeding requiring chest reexploration (77% vs 30%, p = 0.0047), and a higher incidence of renal failure requiring renal replacement therapy (53% vs 11%, p = 0.0045) after surgery. Overall hospital mortality was 27%. In-hospital mortality for VAD and VA-ECMO patients were 41% and 19%, respectively (p = 0.16). Ten patients (59%) were weaned from VAD support, and 24 (89%) were weaned from VA-ECMO support after adequate graft function recovery (p = 0.03). The 3-year post-transplant survival was 41% in the VAD group and 66% in the VA-ECMO group (p = 0.13).
For severe PGD, support with VA-ECMO appears to result in better clinical outcomes compared with VAD.
Right heart failure (RHF) is an unresolved issue during continuous-flow left ventricular assist device (LVAD) support. Little is known about the incidence and clinical significance of late RHF during ...LVAD support.
Between May 2004 and December 2013, 336 patients underwent continuous-flow LVAD implantation. Of these, 293 patients (87%) discharged with isolated LVAD support were included in this study. Late RHF was defined as HF requiring re-admission and medical or surgical intervention after initial surgery.
Late RHF occurred in 33 patients (11%) at a median of 99 days after discharge (range 19 to 1,357 days). Freedom from late RHF rates were 87%, 84% and 79% at 1, 2 and 3 years, respectively. RHF recurred in 15 patients. Three patients required right ventricular assist device insertion. Univariable Cox proportional hazards regression model showed diabetes mellitus (HR 2.05, 95% CI 1.03 to 4.06, p = 0.04), body mass index >29 (HR 2.47, 95% CI 1.24 to 4.94, p = 0.01) and blood urea nitrogen level >41 mg/dl (HR 2.19; 95% CI 1.10 to 4.36; p = 0.025) as significant predictors for late RHF. Estimated on-device survival rates at 2 years were 73% in the RHF group and 82% in the non-RHF group (p = 0.20). However, overall survival at 2 years was significantly worse in patients who developed late RHF (60% vs 85%, p = 0.016). This reduction was mostly attributed to worse overall outcomes in the bridge-to-transplant (BTT) population.
Late RHF is common after continuous-flow LVAD implantation, but does not affect survival during LVAD support. However, it is associated with worse overall outcomes in the BTT population.
The use of a right ventricular assist device (RVAD) becomes necessary for severe right ventricular (RV) failure after left ventricular assist device (LVAD) insertion. Although temporary support could ...lead to successful RVAD weaning in certain patients, the data remain scarce.
We retrospectively reviewed 398 patients who underwent implantable LVAD insertion between January 2000 and December 2012. Of these patients, 44 (11%) required unplanned RVAD support due to severe RV failure after LVAD insertion. For comparison, 37 patients who underwent planned biventricular assist device (BiVAD) insertion were identified during the same study period. We analyzed the early and late outcomes in these patients.
The mean duration of RVAD support was 21 ± 23 days. Of the 44 patients, 21 (49%) were weaned from the RVAD (weaning group), whereas 23 (51%) required continued biventricular support (failure group). The failure group had ongoing end-organ dysfunction after RVAD insertion. Hospital mortality was significantly lower in the weaning group (24%) and in the planned BiVAD group (30%) as compared to the failure group (74%, p = 0.0009). The 6-month actuarial survival rate was 75% in the weaning group, 62% in the planned BiVAD group and 13% in the failure group (p < 0.0001). Successful bridge to transplant was achieved in 14 patients (67%) in the weaning group as compared with 8 patients (35%) in the failure group (p = 0.03). On multivariate logistic regression analyses, pre-operative white blood cell (odds ratio OR 1.3, 95% confidence interval CI 1.04 to 1.50, p = 0.016) and creatinine (OR 0.26, 95% CI 0.079 to 0.88, p = 0.03) levels were significant predictors for RVAD removal.
Among patients who developed acute RV failure after LVAD insertion, only half could be weaned from the temporary RVAD support. An alternative strategy is necessary in patients who require continuous RVAD support.
Stroke is one of the leading complications during continuous flow-left ventricular assist device (CF-LVAD) support. Risk factors have been well described, although less is known regarding treatment ...and outcomes. We present a large single-center experience on stroke outcome and transplant eligibility by stroke sub-type and severity in CF-LVAD patients.
Between January 1, 2008, and April 1, 2015, 301 patients underwent CF-LVAD (266 HeartMate II HM I, Thoratec Corp, Pleasanton, CA; 35 HeartWare HVAD, HeartWare International Inc, Framingham, MA). Stroke was defined as a focal neurologic deficit with abnormal neuroimaging. Intracerebral hemorrhage (ICH) definition excluded sub-dural hematoma and hemorrhagic conversion of an ischemic stroke (IS). Treatment in IS included intra-arterial embolectomy when appropriate; treatment in ICH included reversal of coagulopathy. Stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS). Outcomes were in-hospital mortality and transplant status.
Stroke occurred in 40 patients: 8 ICH (4 HM II, 4 HVAD) and 32 IS (26 HM II, 6 HVAD). Among 8 ICH patients, there were 4 deaths (50%), with NIHSS of 18.8 ± 13.7 vs 1.8 ± 1.7 in survivors (p = 0.049). Among 32 IS patients, 12 had hemorrhagic conversion and 5 were treated with intra-arterial embolectomy. There were 9 deaths (28%), with NIHSS of 16.2 ± 10.8 vs 7.0 ± 7.6 in survivors (p = 0.011). Among the 32 IS patients, 12 underwent transplant, and 1 is awaiting transplant. No ICH patients received a transplant.
In-hospital mortality after stroke is significantly affected by the initial neurologic impairment. Patients with IS appear to benefit the most from in-hospital treatment and often make sufficient recovery to be able to progress to transplant.
Summary Background Four cycles of etoposide plus cisplatin and accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard of care for limited-stage small-cell lung cancer (SCLC). ...Irinotecan plus cisplatin significantly improved overall survival compared with etoposide plus cisplatin for extensive-stage SCLC. We compared these regimens for overall survival of patients with limited-stage SCLC. Methods We did this phase 3 study in 36 institutions in Japan. Eligibility criteria included age 20–70 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and adequate organ functions. Eligible patients with previously untreated limited-stage SCLC received one cycle of etoposide plus cisplatin (intravenous etoposide 100 mg/m2 on days 1–3; intravenous cisplatin 80 mg/m2 on day 1) plus AHTRT (1·5 Gy twice daily, 5 days a week, total 45 Gy over 3 weeks). Patients without progressive disease following induction therapy were randomised (1:1 ratio, using a minimisation method with biased-coin assignment balancing on ECOG performance status 0 vs 1, response to induction chemoradiotherapy complete response plus near complete response vs partial response and stable disease, and institution) to receive either three further cycles of consolidation etoposide plus cisplatin or irinotecan plus cisplatin (intravenous irinotecan 60 mg/m2 on days 1, 8, 15; intravenous cisplatin 60 mg/m2 on day 1). Patients, physicians, and investigators were aware of allocation. The primary endpoint was overall survival after randomisation; primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00144989 , and the UMIN Clinical Trials Registry, number C000000095. Findings 281 patients were enrolled between Sept 1, 2002, and Oct 2, 2006. After induction etoposide plus cisplatin and AHTRT, 258 patients were randomised to consolidation etoposide plus cisplatin (n=129) or irinotecan plus cisplatin (n=129). In the etoposide plus cisplatin group, median overall survival was 3·2 years (95% CI 2·4–4·1). In the irinotecan and cisplatin group, median overall survival was 2·8 years (95% CI 2·4–3·6); overall survival did not differ between the two groups (hazard ratio 1·09 95% CI 0·80–1·46, one-sided stratified log-rank p=0·70). The most common adverse events of grade 3 or 4 were neutropenia (120 95% in the etoposide plus cisplatin group vs 101 78% in the irinotecan plus cisplatin group), anaemia (44 35% vs 50 39%), thrombocytopenia (26 21% vs six 5%), febrile neutropenia (21 17% vs 18 14%), and diarrhoea (two 2% vs 13 10%). There was one treatment-related adverse event leading to death in each group (radiation pneumonitis in the etoposide plus cisplatin group; brain infarction in the irinotecan plus cisplatin group). Interpretation Four cycles of etoposide plus cisplatin and AHTRT should continue to be the standard of care for limited-stage SCLC. Funding National Cancer Center and the Ministry of Health, Labour, and Welfare of Japan.
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The prevalence, intensity, safety, and efficacy of oral anticoagulation (OAC) in addition to dual antiplatelet therapy (DAPT) in “real-world” patients with atrial fibrillation (AF) undergoing ...percutaneous coronary intervention (PCI) have not yet been fully evaluated. In the Coronary REvascularization Demonstrating Outcome Study in Kyoto registry cohort-2, a total of 1,057 patients with AF (8.3%) were identified among 12,716 patients undergoing first PCI. Cumulative 5-year incidence of stroke was higher in patients with AF than in no-AF patients (12.8% vs 5.8%, p <0.0001). Although most patients with AF had CHADS2 score ≥2 (75.2%), only 506 patients (47.9%) received OAC with warfarin at hospital discharge. Cumulative 5-year incidence of stroke in the OAC group was not different from that in the no-OAC group (13.8% vs 11.8%, p = 0.49). Time in therapeutic range (TTR) was only 52.6% with an international normalized ratio of 1.6 to 2.6, and only 154 of 409 patients (37.7%) with international normalized ratio data had TTR ≥65%. Cumulative 5-year incidence of stroke in patients with TTR ≥65% was markedly lower than that in patients with TTR <65% (6.9% vs 15.1%, p = 0.01). In a 4-month landmark analysis in the OAC group, there was a trend for higher cumulative incidences of stroke and major bleeding in the on-DAPT (n = 286) than in the off-DAPT (n = 173) groups (15.1% vs 6.7%, p = 0.052 and 14.7% vs 8.7%, p = 0.10, respectively). In conclusion, OAC was underused and its intensity was mostly suboptimal in real-world patients with AF undergoing PCI, which lead to inadequate stroke prevention. Long-term DAPT in patients receiving OAC did not reduce stroke incidence.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objectives To facilitate venoarterial extracorporeal membrane oxygenation (ECMO) insertion for cardiogenic shock, we recently adopted a strategy of using a 15F arterial cannula in all patients, ...rather than 1 designed to maximize flow. We aimed to compare the clinical outcomes of these 2 strategies. Methods In this retrospective study, 101 consecutive patients supported with ECMO via femoral cannulation between March 2007 and March 2013 were divided into 2 groups: Group L (17F-24F arterial cannula to accommodate full flow ie, cardiac index of 2.5 L/m2 /min; n = 51) and Group S (15F arterial cannula; n = 50). The primary outcomes of interest were patients' overall status at 24 hours of support and cannulation-related adverse events. Results There were no significant differences in patient demographics, etiology of cardiogenic shock, or severity of illness before ECMO initiation between the 2 groups. Group L had significantly higher ECMO flow than Group S (flow index at 24 hours: 2.2 ± 0.7 vs 1.7 ± 0.3 L/m2 /min; P < .001). However, there was no significant difference in use of vasoactive medication/hemodynamic parameters/laboratory parameters. Group L had higher incidence of cannulation-related adverse events (35% vs 22% in Group S P = .14), particularly in cannulation site bleeding (28% vs 10% P = .03). Thirty-day survival was 55% in Group L versus 52% in Group S ( P = .77). Bleeding complication occurred in 53% in Group L versus 32% in Group S ( P = .03). Conclusions Compared with the use of larger cannulas, ECMO with a 15F arterial cannula appears to provide comparable clinical support with reduced bleeding complications.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Both the physiological and pathological functions of cardiovascular organs are closely related to circadian rhythm, an endogenously driven 24-h cycle. Heart rate, blood pressure, and ...endothelial function show diurnal variations within a day. The onset of cardiovascular disorders such as acute coronary syndrome, atrial arrhythmia, and subarachinoid hemorrhage also exhibits diurnal oscillation. Recent progress in studying the functions and molecular mechanisms of the biological clock brought forth the idea that intrinsic circadian rhythms are tightly related to cardiovascular pathology. The center of the biological clock exists in the suprachiasmatic nucleus in the hypothalamus. In addition to this central clock, each organ has its own biological clock system, termed the peripheral clock. Each cardiovascular tissue or cell, including heart and aortic tissue, cardiomyocyte, vascular smooth muscle cell, and vascular endothelial cell also has intrinsic biological rhythm. Until recently, little was known about the roles of peripheral clocks in cardiovascular organs. However, studies using genetically engineered mice revealed their contributions during the process of disease progression. Loss of synchronization between the internal clock and external stimuli can induce cardiovascular organ damage. Discrepancy in the phases between the central and peripheral clocks also seems to contribute to progression of the disorders. Elucidation of the precise roles of biological clocks in cardiovascular organs will provide us with more profound insights into the relevance of the circadian rhythm in cardiac pathology. Moreover, identification of the modalities with which we can manipulate the phase of each peripheral clock will enable us to establish a novel chronotherapeutic approach. This time-of-day based strategy may innovate a new paradigm in the prevention and treatment of cardiovascular disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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