Randomized controlled trial

Reporting of industry funded study outcome data: comparison of confidential and published data on the safety and effectiveness of rhBMP-2 for spinal fusion.

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Abstract

Objective To investigate whether published results of industry funded trials of recombinant human bone morphogenetic protein 2 (rhBMP-2) in spinal fusion match underlying trial data by comparing three different data sources: individual participant data, internal industry reports, and publicly available journal publications and conference abstracts.

Data collection and synthesis The manufacturer of rhBMP-2 products (Medtronic; Minneapolis, MN) provided complete individual participant data and internal reports for all its studies of rhMBP-2 in spinal fusion. We identified publications and conference abstracts through comprehensive literature searches. We compared outcomes provided in the individual participant data against outcomes reported in publications. For effectiveness outcomes, we compared meta-analyses of randomised controlled trials based on each of the three data sources. For adverse events, meta-analysis of the published aggregate data was not possible and we compared the number and type of adverse events reported between data sources.

Results 32 publications reported outcomes from 11 of the 17 existing manufacturer sponsored studies. For individual randomised controlled trials, 56% (9/16) to 88% (15/17) of effectiveness outcomes known to have been collected were reported in the published literature. Meta-analyses of effectiveness data were almost identical for pain outcomes and similar for fusion across the three data sources. A minority of adverse event data known to have been collected were reported in the published literature. Several journal articles reported only “serious,” “related,” or “unanticipated” adverse events, without defining these terms. Others reported a small proportion of the collected adverse event categories. Around 23% (533/2302) of the total adverse events collected in published randomised controlled trials have been reported in the literature, with randomised controlled trials evaluating the licensed preparation (Infuse) reporting around 11% (122/1108) of collected adverse events.

Conclusions The published literature only partially represents the total data known to have been collected on the effects of rhBMP-2. This did not lead to substantially different results for meta-analysis of effectiveness outcomes. In contrast, reporting of adverse event data in trial publications was inadequate and inconsistent to the extent that any systematic review based solely on the publicly available data would not be able to properly evaluate the safety of rhBMP-2. Analysis of individual participant data enabled the most complete, detailed, and in-depth analysis and was not more resource intensive than extracting, collating, and analysing aggregate data from multiple trial publications and conference abstracts. Confidential internal reports presented considerably more adverse event data than publications, and in the absence of individual participant data access to these reports would support more accurate and reliable investigation, with less time and effort than relying on incomplete published data.

Discussion

Controversy around use of recombinant human bone morphogenetic protein 2 (rhBMP-2) in spinal fusion began with suggestions that inadequate peer review and editorial oversight were responsible for an apparent absence of adverse events from early peer reviewed publications of industry sponsored studies. A subsequent investigation led by the editor in chief of The Spine Journal14 found fewer reported adverse events in academic publications of industry sponsored studies than in related study data available in FDA summaries and public meeting documents. The FDA materials available for that investigation appear to be partial outcome data from a subset of industry funded studies evaluating Infuse/LT-CAGE, Infuse/MASTERGRAFT, and AMPLIFY rhBMP-2 matrix preparations. Our investigation was able to explore this issue in greater depth having individual participant data on all recorded effectiveness and safety outcomes as well as internal reports provided for all Medtronic funded studies of rhBMP-2 for spinal fusion. Given their previous confidentiality, high degree of detail, and availability for all known studies, we consider the combination of individual participant data and internal reports to be the most comprehensive and trustworthy source of Medtronic trial evidence available to date.

Source: BMJ

Local Therapies for Unresectable Primary Hepatocellular Carcinoma.

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Objectives. To characterize the comparative effectiveness and harms of various local hepatic therapies for patients with unresectable primary hepatocellular carcinoma (HCC) who are not candidates for surgical resection or liver transplantation. Local hepatic therapies include those related to ablation, embolization, and radiotherapy. Data sources. We searched MEDLINE® and Embase® from January 2000 to July 2012. We also searched for gray literature in databases with regulatory information, clinical trial registries, abstracts and conference papers, as well as information from manufacturers. Review methods. We sought studies reporting two final health outcomes—overall survival and quality of life—and various adverse events related to the different interventions. Data were dually abstracted by a team of four reviewers. A third reviewer resolved conflicts when necessary. We assessed the quality of individual studies and graded the strength of the body of evidence according to prespecified methods. Results. We identified 1,707 articles through the literature search, excluded 1,665 at various stages of screening, and included 42 articles. To these we added 6 hand-searched articles for a total of 48 articles included in this review. Our searches of gray literature sources did not yield any additional published studies. The included literature was comprised of 6 randomized controlled trials (RCTs), 4 nonrandomized comparative studies, 35 case series, and 3 case reports. One RCT was rated as good, three were rated as fair, and two were rated as poor quality. We included 13 local hepatic therapies in this review; however, there was sufficient comparative evidence (three RCTs) to assess only one direct comparison: radiofrequency ablation (RFA) versus percutaneous ethanol injection (PEI)/percutaneous acetic acid injection (PAI). Three-year survival when treated with RFA was superior to that for PEI/PAI for unresectable HCC, with a moderate grade of evidence. Time to progression (TTP) and local recurrence were better for RFA than PEI/PAI, but length of stay (LOS) was longer after RFA than PEI/PAI. Strength of evidence for all other comparisons was rated insufficient. There was a low level of evidence to support longer overall survival following RFA than PEI/PAI for the subgroup of patients with larger lesion size. Conclusions. Of the 13 interventions included in this report, only 1 comparison had sufficient evidence to receive a rating above insufficient. There was moderate strength of evidence demonstrating better overall survival at 3 years, a low level of evidence supporting improved overall survival for patients with larger lesion sizes, and low strength of evidence for improved TTP and local control for RFA than PEI/PAI for the treatment of unresectable HCC. A low level of evidence also supports a longer LOS following RFA than PEI/PAI. For all other outcomes and comparisons, there is insufficient evidence to permit conclusions on the comparative effectiveness of local hepatic therapies for unresectable HCC. Additional RCTs are necessary for all comparisons. Focusing on comparisons with RFA may allow for the greatest integration of new data with the current body of evidence.

Oncology – Radiation

An apparently exhaustive (and exhausting) review. However, the authors ultimately include only 42 of 1707 papers identified in their literature search (plus 6 identified by hand search). I am aware of at least 3 other publications (of prospective case series), published within the time span reviewed, which I would consider meet the criteria for inclusion. Why they were excluded is not apparent since the full list of publications screened is not given. Others may be aware of additional publications in their own area of special interest which have not been included in the review. Nevertheless, it is not likely that any number of additional papers, other than unidentified randomised trials, would change the conclusions of the authors; there is a lack of well conducted studies, and of randomized trials in particular.

Source: Agency for Healthcare Research and Quality (US); 2013 May

 

Comparative Effectiveness Research in Oncology.

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Although randomized controlled trials represent the gold standard for comparative effective research (CER), a number of additional methods are available when randomized controlled trials are lacking or inconclusive because of the limitations of such trials. In addition to more relevant, efficient, and generalizable trials, there is a need for additional approaches utilizing rigorous methodology while fully recognizing their inherent limitations. CER is an important construct for defining and summarizing evidence on effectiveness and safety and comparing the value of competing strategies so that patients, providers, and policymakers can be offered appropriate recommendations for optimal patient care. Nevertheless, methodological as well as political and social challenges for CER remain. CER requires constant and sophisticated methodological oversight of study design and analysis similar to that required for randomized trials to reduce the potential for bias. At the same time, if appropriately conducted, CER offers an opportunity to identify the most effective and safe approach to patient care. Despite rising and unsustainable increases in health care costs, an even greater challenge to the implementation of CER arises from the social and political environment questioning the very motives and goals of CER. Oncologists and oncology professional societies are uniquely positioned to provide informed clinical and methodological expertise to steer the appropriate application of CER toward critical discussions related to health care costs, cost-effectiveness, and the comparative value of the available options for appropriate care of patients with cancer.

Source: the oncologist

Intravenous or nebulised magnesium sulphate versus standard therapy for severe acute asthma (3Mg trial): a double-blind, randomised controlled trial.

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Background

Previous studies suggested intravenous or nebulised magnesium sulphate (MgSO4) might improve respiratory function in patients with acute asthma. We aimed to determine whether intravenous or nebulised MgSO4 improve symptoms of breathlessness and reduce the need for hospital admission in adults with severe acute asthma.

Methods

In our double-blind, placebo-controlled trial, we enrolled adults (aged ≥16 years) with severe acute asthma at emergency departments of 34 hospitals in the UK. We excluded patients with life-threatening features or contraindication to study drugs. We used a central randomisation system to allocate participants to intravenous MgSO4 (2 g in 20 min) or nebulised MgSO4 (three 500 mg doses in 1 h) alongside standard therapy including salbutamol, or placebo control plus standard therapy alone. We assessed two primary outcome measures in all eligible participants who started treatment, according to assigned treatment group: the proportion of patients admitted to hospital within 7 days and breathlessness measured on a 100 mm visual analogue scale (VAS) in the 2 h after initiation of treatment. We adjusted for multiple testing using Simes’s method. The trial stopped before recruitment was completed because funding expired. This study is registered, number ISRCTN04417063.

Findings

Between July 30, 2008, and June 30, 2012, we recruited 1109 (92%) of 1200 patients proposed by the power calculation. 261 (79%) of 332 patients allocated nebulised MgSO4 were admitted to hospital before 7 days, as were 285 (72%) of 394 patients allocated intravenous MgSO4 and 281 (78%) of 358 controls. Breathlessness was assessed in 296 (89%) patients allocated nebulised MgSO4, 357 (91%) patients allocated intravenous MgSO4, and 323 (90%) controls. Rates of hospital admission did not differ between patients treated with either form of MgSO4 compared with controls or between those treated with nebulised MgSO4 and intravenous MgSO4. Change in VAS breathlessness did not differ between active treatments and control, but change in VAS was greater for patients in the intravenous MgSO4 group than it was in the nebulised MgSO4 group (5·1 mm, 0·8 to 9·4; p=0·019). Intravenous or nebulised MgSO4 did not significantly decrease rates of hospital admission and breathlessness compared with placebo: intravenous MgSO4 was associated with an odds ratio of 0·73 (95% CI 0·51 to 1·04; p=0·083) for hospital admission and a change in VAS breathlessness of 2·6 mm (—1·6 to 6·8; p=0·231) compared with placebo; nebulised MgSO4 was associated with an odds ratio of 0·96 (0·65 to 1·40; p=0·819) for hospital admission and a change in VAS breathlessness of −2·6 mm (—7·0 to 1·8; p=0·253) compared with placebo.

Source: lancet

 

 

Short-term vs Conventional Glucocorticoid Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease: The REDUCE Randomized Clinical Trial.

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International guidelines advocate a 7- to 14-day course of systemic glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the optimal dose and duration are unknown. OBJECTIVE To investigate whether a short-term (5 days) systemic glucocorticoid treatment in patients with COPD exacerbation is noninferior to conventional (14 days) treatment in clinical outcome and whether it decreases the exposure to steroids. DESIGN, SETTING, AND PATIENTS REDUCE (Reduction in the Use of Corticosteroids in Exacerbated COPD), a randomized, noninferiority multicenter trial in 5 Swiss teaching hospitals, enrolling 314 patients presenting to the emergency department with acute COPD exacerbation, past or present smokers (>/=20 pack-years) without a history of asthma, from March 2006 through February 2011. INTERVENTIONS Treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled, double-blind fashion. The predefined noninferiority criterion was an absolute increase in exacerbations of at most 15%, translating to a critical hazard ratio of 1.515 for a reference event rate of 50%. MAIN OUTCOME AND MEASURE Time to next exacerbation within 180 days. RESULTS Of 314 randomized patients, 289 (92%) of whom were admitted to the hospital, 311 were included in the intention-to-treat analysis and 296 in the per-protocol analysis. Hazard ratios for the short-term vs conventional treatment group were 0.95 (90% CI, 0.70 to 1.29; P = .006 for noninferiority) in the intention-to-treat analysis and 0.93 (90% CI, 0.68 to 1.26; P = .005 for noninferiority) in the per-protocol analysis, meeting our noninferiority criterion. In the short-term group, 56 patients (35.9%) reached the primary end point; 57 (36.8%) in the conventional group. Estimates of reexacerbation rates within 180 days were 37.2% (95% CI, 29.5% to 44.9%) in the short-term; 38.4% (95% CI, 30.6% to 46.3%) in the conventional, with a difference of -1.2% (95% CI, -12.2% to 9.8%) between the short-term and the conventional. Among patients with a reexacerbation, the median time to event was 43.5 days (interquartile range [IQR], 13 to 118) in the short-term and 29 days (IQR, 16 to 85) in the conventional. There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean cumulative prednisone dose was significantly higher (793 mg [95% CI, 710 to 876 mg] vs 379 mg [95% CI, 311 to 446 mg], P < .001), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently. CONCLUSIONS AND RELEVANCE In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD.

Source: JAMA

 

Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy..

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To explore the safety and efficacy of external trigeminal nerve stimulation (eTNS) in patients with drug-resistant epilepsy (DRE) using a double-blind randomized controlled trial design, and to test the suitability of treatment and control parameters in preparation for a phase III multicenter clinical trial.

METHODS: This is a double-blind randomized active-control trial in DRE. Fifty subjects with 2 or more partial onset seizures per month (complex partial or tonic-clonic) entered a 6-week baseline period, and then were evaluated at 6, 12, and 18 weeks during the acute treatment period. Subjects were randomized to treatment (eTNS 120 Hz) or control (eTNS 2 Hz) parameters.
RESULTS: At entry, subjects were highly drug-resistant, averaging 8.7 seizures per month (treatment group) and 4.8 seizures per month (active controls). On average, subjects failed 3.35 antiepileptic drugs prior to enrollment, with an average duration of epilepsy of 21.5 years (treatment group) and 23.7 years (active control group), respectively. eTNS was well-tolerated. Side effects included anxiety (4%), headache (4%), and skin irritation (14%). The responder rate, defined as >50% reduction in seizure frequency, was 30.2% for the treatment group vs 21.1% for the active control group for the 18-week treatment period (not significant, p = 0.31, generalized estimating equation [GEE] model). The treatment group experienced a significant within-group improvement in responder rate over the 18-week treatment period (from 17.8% at 6 weeks to 40.5% at 18 weeks, p = 0.01, GEE). Subjects in the treatment group were more likely to respond than patients randomized to control (odds ratio 1.73, confidence interval 0.59-0.51). eTNS was associated with reductions in seizure frequency as measured by the response ratio (p = 0.04, analysis of variance [ANOVA]), and improvements in mood on the Beck Depression Inventory (p = 0.02, ANOVA).
CONCLUSIONS: This study provides preliminary evidence that eTNS is safe and may be effective in subjects with DRE. Side effects were primarily limited to anxiety, headache, and skin irritation. These results will serve as a basis to inform and power a larger multicenter phase III clinical trial. CLASSIFICATION OF EVIDENCE: This phase II study provides Class II evidence that trigeminal nerve stimulation may be safe and effective in reducing seizures in people with DRE.

Source: Neurology

No magic answer for Achilles tendinopathy.

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“Although they are trendy money spinners, best evidence shows little effectiveness”—An attention grabbing subheading to an editorial by Nic Maffulli in the BMJ commenting on an intriguing randomised controlled trial (RCT) from New Zealand on the use of autologus blood injections in treating Achilles tendinopathy. It doesn’t work.

Evidence based sports medicine was radical new thinking when Tom Best and I first began to think about it. Care of the athlete had evolved empirically. Few asked questions. For example, when our university research group first began to study ice, perhaps the most commonly used treatment in soft tissue injury, there was little quality evidence to inform treatment; the duration of each application, over what period of time, the temperature of the ice (melting iced water is 0 degrees Celcius),  if it mattered if you were fat or thin etc. Clinicians then began to ask about the evidence for the tests used in clinical examination, the effectiveness of prevention, the appropriate management of common conditions. Where we thought there was certainty, there was little evidence. This RCT on Achilles tendinopathy is an important trial because it asked serious questions about a treatment that had become commonplace yet seemingly evidence free.

Much of what we think is fact in sport is hype, based often on weak science, but mostly on extrapolation from observation. People in sport are forever looking for that extra added magic ingredient to set them apart. Complicit and gullible because they want to believe.  They follow the training programme, wear the headband, chase the logo the champions wear. It is no surprise that they take the drink, buy the supplement, wear the shoe, or do the exercise endorsed by champions. Ever susceptible, suggestible—looking for an easy way, its human nature.  So, it was no surprise to see the hype surrounding yet another product on the margin. This was the next big thing—an injection to cure one of the most common and troublesome injuries.

Its great to see good quality research and more is needed. But, research is expensive and its almost impossible to justify research in sports medicine when competing for funds with cancer, cardiology, and other core medical topics.  There is an evidence vacuum and in sports medicine there is huge pressure to do something. And, always someone looking for the magic answer.

Sourc: BMJ

 

 

Selective Amygdalohippocampectomy vs. Anterior Temporal Lobectomy for Epilepsy

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In a meta-analysis of nonrandomized studies, seizure-free outcome was greater after ATL than after SAH.

 

In the surgical treatment of intractable medial temporal lobe epilepsy (MTLE), an important unanswered question is whether seizure-free outcome is better with standard anterior temporal lobe resection (ATL) or with a more restrictive procedure, selective amygdalohippocampectomy (SAH). In theory, SAH might mitigate some neuropsychological deficits that are associated with ATL. However, seizure freedom also has important psychosocial benefits. To examine this question, researchers conducted an exhaustive systematic review and meta-analysis of published studies on seizure outcomes following either ATL or SAH. They identified 13 studies that compared the two procedures. Nearly all studies were from individual centers, and follow-up was carried out by clinic visits or telephone calls by investigators or unspecified individuals. Duration of outcome measures ranged from 1 year to a median of 10.9 years. Only three studies separated follow-up according to procedure type; in two, follow-up was an average of 14 to 26 months longer for ATL; in the third, follow-up was an average of 2 months longer for SAH. Other differences in study populations were not specified.

From 11 studies that provided dichotomous outcomes (Engel class I vs. Engel class II–IV), 583 participants had SAH and 620 had ATL. Seizure-free outcome was significantly greater with ATL at final follow-up (relative risk, 1.32; risk difference, 8%; number needed to treat, 13). Results were similar with a more conservative random effects model, in the subset of studies with standardized outcome duration, and among patients with only hippocampal sclerosis. Cumulative addition of studies to the meta-analysis demonstrated a stable RR estimate starting before the most recent three studies were added. Five studies providing data on surgical complications in 392 after ATL and 309 after SAH showed no significant difference.

Comment: This thorough meta-analysis exploited a sufficiently large number of cases, roughly balanced between anterior temporal lobe resection and selective amygdalohippocampectomy (SAH), to provide meaningful information regarding the difference in seizure-free outcomes. This study is particularly valuable because a randomized, controlled trial (RCT) — which the authors say is “justified” — is unlikely to be funded. And yet, an RCT is a compelling proposal if only to address the need for balance in each treatment arm of known variables that affect seizure outcome. Further, only an RCT can answer whether the central postulated benefit of SAH — reduced neuropsychological deficits — exists.

 

Source: Journal Watch Neurology

 

 

Cross-stage and combination treatment for Barcelona Clinic of Liver Cancer stage B (intermediate stage) hepatocellular carcinoma.

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The American Association for the Study of Liver Diseases (AASLD) has approved practice guideline for patients with hepatocellular carcinoma (HCC) staging, originally developed by the Barcelona Clinic of Liver Cancer.1 The guidelines recommend that liver transplantation, surgical resection, and local ablation therapy, including percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA), can all be considered as curative treatments for patients in the very early and early stages (stages 0 and A). Patients classified in the intermediate stage (stage B) should be treated by transcatheter arterial chemoemolization (transarterial chemoembolization [TACE]). Sorafenib, a multikinase inhibitor with both anti-angiogenic and antiproliferative properties, has been shown to prolong the median overall survival and the median time to progression (TTP) compared to placebo in two randomized, controlled trials (RCT).2,3 Thus, in the 2010 revision of the AASLD guidelines, it was proposed as the current standard of care (SOC) for patients in advanced-stage (stage C) HCC.

In actual fact, among the 22 recommendations in the AASLD guidelines for the management of HCC, only five (21%) can be categorized as supported by level I evidence, according to evidence-based medicine clinical practice guidelines. These five recommendations supported by level I evidence are: (i) HCC surveillance is recommended in high-risk patients; (ii) comparison between results of PEI and RFA; (iii) benefit of TACE; (iv) effects of sorafenib; and (v) no benefit of tamoxifen, anti-androgens, octreotide, or hepatic artery ligation/embolization. The proportion of level I evidence in this HCC guideline is lower than for AASLD chronic hepatitis B (CHB) practice guideline (28/90, or 31%).1 One reason for this is the acknowledged greater difficulty to conduct RCT for HCC than for CHB. Therefore, only adopting results from RCT is not feasible or practical for HCC management. Instead, information from well-conducted longitudinal outcomes research is important, although this notionally only provides level II evidence.

In this issue of the Journal of Gastroenterology and Hepatology, Kim et al. reported observations on 264 patients with stage B HCC who received TACE. Approximately one-third (n = 97) were free of progressive disease (PD[–]) during the first 6 months after TACE, and only one-eighth (n = 33) were PD(–) after a mean 18-month follow up.4 Although TACE is the only recommended treatment in AASLD guidelines for stage B patients, its efficacy remains unsatisfactory. We need more optimal treatment for patients with stage B HCC. In particular, we need to know whether cross-stage or combination use of existing treatment modalities can improve clinical outcomes.

The first issue is whether curative treatment could be used in the management for stage B patients. Conservative Milan criteria and expanded University of California, San Francisco (UCSF) criteria are the two most widely accepted indications for liver transplantation for patients with HCC.5 Some cases of stage B HCC might meet UCSF criteria and undergo liver transplantation. Although surgical resection is the treatment of choice for stage 0/A cases, it is impossible to conduct a RCT comparing this traditional treatment and placebo. The same argument applies to stage B patients. Several clinical outcome studies, including our own,6 have provided evidence of benefit from surgical resection for stage B patients. In particular, such studies provide undeniable evidence that stage B HCC patients selected for surgical resection obtained better survival than those who were treated by TACE. Several recent reviews in surgical literature also showed a better overall survival in cases with surgical resection than in those treated by non-surgical therapies, even though these patients were beyond stage 0/A7. However, surgical resection should not be the ordinary choice to treat stage B patients, as its application is limited to several factors. These include patients’ choice, liver functional reserve, skillful surgeons, and experienced hospitals for postoperative care.

Treating multiple nodular HCC patients with nodule numbers slightly more than three by RFA can sometimes be feasible.8 A meta-analysis of 10 RCT showed TACE combined with percutaneous ablation therapy, especially PEI, improved overall survival for large HCC.9 Mid-term outcomes of an RCT also showed that RFA combined with TACE was more effective than RFA alone in extending the ablated area; it required fewer treatment sessions and decreased local tumor progression rate for patients with intermediate-sized HCC.10 However, current settings for RFA or for combination treatment of TACE and RFA in the treatment of stage B patients are the same as for surgical resection. Therefore, the indications for the above treatment modalities in stage B patients should be documented in the future guidelines.

However, oral medication can be used more conveniently and widely than either surgical or percutaneous procedures. The only approved molecular target therapeutic agent, sorafenib, is currently recommended as the SOC for patients with stage C HCC. Several RCT have been or are being conducted to prove the benefits of combining sorafenib and SOC for patients with earlier stages.

A phase I trial has clarified possible adverse effects experienced by patients treated with a combination of TACE and sorafenib. The incidence of these is generally comparable with those with sorafenib alone; an exception is grade III thrombocytopenia, which might be more frequently noted in the former group.11 Phase II trials also showed that the combination of sorafenib and drug-eluting bead–TACE in patients with unresectable HCC is safe and well tolerated, with a majority of toxicities related to sorafenib. Preliminary data concerning efficacy are also promising.12 In an interim analysis of a phase III RCT in patients before transplantation, a potential superiority in TTP was disclosed in patients with combined treatment of TACE and sorafenib over TACE alone;13 the final results are anticipated soon. Another phase III RCT conducted in Japan and Korea concluded that sorafenib did not significantly prolong TTP in patients who responded to TACE. The result might have been due to delays in starting sorafenib after TACE and/or a low daily dose of sorafenib.14 Furthermore, two ongoing large-scaled RCT in stage B patients, that is, the Eastern Cooperative Oncology Group 1208 and Sorafenib or Placebo in Combination with Transarterial Chemoembolization for Intermediate-Stage Hepatocellular Carcinoma (SPACE), are currently exploring the benefits of combination therapy.

If the results of the afore-mentioned RCT favor combination treatment, should all patients be treated with a combination of TACE and sorafenib instead of TACE alone? The answer is absolutely “no”. Although TACE is now categorized as a non-curative treatment, some patients can be very well controlled or even cured by it. Thus, we should identify those patients with “TACE refractory” or “TACE failure” and then switch to sorafenib monotherapy, or add this agent to ongoing TACE.

Kim et al. proposed the term “stage progression” (SP),4 which they defined as the development of either vascular invasion or extrahepatic metastasis, or progression from stage B to stage C HCC during the course of TACE treatment. Their conclusion is that SP might be the end-point of TACE, so that cases with SP can be defined as “TACE refractory”. However, on the basis of the AASLD guidelines, stage C should not represent TACE refractory, and it is actually defined as out of the indications of TACE. “SP-free survival” should be the end-point of TACE in current practice. Thus, declaring that SP is representative as TACE refractory must be too late. They also concluded that the development of progression or the need for three sessions of TACE within the first 6 months could be predictive of TACE refractoriness. This finding is closer to the situation of “TACE refractory”.

The above issue has been documented in the 2010 version the Japan Society of Hepatology (JSH) guidelines,8 who clearly defined TACE failure or refractory as: (a) an intrahepatic lesion; (a-i) more than two consecutive incomplete necroses (depositions of lipiodol < 50%) are seen by response evaluation computed tomography (CT) within the treated tumors 4 weeks after adequately-performed TACE; (a-ii) more than two consecutive appearances of a new lesion (recurrence) are seen in the liver by response evaluation CT at 4 weeks after adequately-performed TACE; (b) appearance of vascular invasion; (c) appearance of extrahepatic spread; and (d) tumor marker: continuous elevation of tumor markers, even immediately after TACE. The JSH also gave the following recommendation: as hepatic arterial infusion chemotherapy is not effective for TACE failure patients, molecular-targeted therapy is the first choice of treatment.

Cases with tumor progression, followed by intensive TACE, should switch to sorafenib. Kudo and Ueshima reported 15 cases with complete response by sorafenib,15 and two of 90 cases in their center achieved complete response. In a literature review, more than 10 case reports like this can be found from PubMed. We have also experienced a case with complete response. It is believed that if patients are not suitable for TACE, the treatment modality should be switched to sorafenib. However, the indication of combination therapy of TACE and sorafenib is still controversy now. There was not evidence enough to use the combination therapy in all stage B patients initially as a purpose in preventing TAE refractory/failure. Repeated TACE could give significant survival benefits to metastatic HCC patients with conserved liver function and intrahepatic HCC T3 stage.16 Combination therapy should be considered in patients who can get any benefit from TACE for tumor control. However, TACE still has some serious adverse effects, such as deteriorating liver function and intolerance of post-TACE syndrome. For TACE-refractory cases without any contraindications of combination therapy of TACE and sorafenib, an RCT to compare sorafenib with and without TACE should be conducted to elucidate the difference between switching and adding on. Both overall survival and quality of life should be assessed in these studies.

In summary, the combination treatment of TACE and sorafenib is currently a hot issue. In the future, it could become an option for SOC for stage B HCC cases and might improve patient survival. However, more information from RCT and outcome research, such as the interesting data reported by Kim et al. in this issue,4 is required.

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References

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Impact of autologous blood injections in treatment of mid-portion Achilles tendinopathy: double blind randomised controlled trial.

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Abstract

Objective To assess the effectiveness of two peritendinous autologous blood injections in addition to a standardised eccentric calf strengthening programme in improving pain and function in patients with mid-portion Achilles tendinopathy.

Design Single centre, participant and single assessor blinded, parallel group, randomised, controlled trial.

Setting Single sports medicine clinic in New Zealand.

Participants 53 adults (mean age 49, 53% men) with symptoms of unilateral mid-portion Achilles tendinopathy for at least three months. Participants were excluded if they had a history of previous Achilles tendon rupture or surgery or had undergone previous adjuvant treatments such as injectable therapies, glyceryl trinitrate patches, or extracorporeal shockwave therapy.

Interventions All participants underwent two unguided peritendinous injections one month apart with a standardised protocol. The treatment group had 3 mL of their own whole blood injected while the control group had no substance injected (needling only). Participants in both groups carried out a standardised and monitored 12 week eccentric calf training programme. Follow-up was at one, two, three and six months.

Main outcome measures The primary outcome measure was the change in symptoms and function from baseline to six months with the Victorian Institute of Sport Assessment-Achilles (VISA-A) score. Secondary outcomes were the participant’s perceived rehabilitation and their ability to return to sport.

Results 26 participants were randomly assigned to the treatment group and 27 to the control group. In total, 50 (94%) completed the six month study, with 25 in each group. Clear and clinically worthwhile improvements in the VISA-A score were evident at six months in both the treatment (change in score 18.7, 95% confidence interval 12.3 to 25.1) and control (19.9, 13.6 to 26.2) groups. The overall effect of treatment was not significant (P=0.689) and the 95% confidence intervals at all points precluded clinically meaningful benefit or harm. There was no significant difference between groups in secondary outcomes or in the levels of compliance with the eccentric calf strengthening programme. No adverse events were reported.

Conclusion The administration of two unguided peritendinous autologous blood injections one month apart, in addition to a standardised eccentric training programme, provides no additional benefit in the treatment of mid-portion Achilles tendinopathy.

 

What is already know on this topic

  • Several studies have suggested that the injection of autologous blood can be helpful in the treatment of various tendinopathies
  • Autologous blood injections are a relatively common treatment, despite a lack of high quality evidence supporting their use in the management of Achilles tendinopathy
  • The use of peritendinous autologous blood injections does not reduce pain or improve function in those with mid-portion Achilles tendinopathy when they are combined with an eccentric training programme.

What this study adds

Discussion

Summary of principal findings

To our knowledge, this is the first double blinded, randomised, controlled trial investigating the efficacy of autologous blood injections as a treatment for mid-portion Achilles tendinopathy in addition to a standardised eccentric training programme. Both groups showed a steady and clinically meaningful improvement in the mean VISA-A scores throughout the study. The addition of two peritendinous autologous blood injections administered one month apart, however, was unlikely to have resulted in additional clinically meaningful improvements in pain or in ability to return to activity.

Comparisons with the literature

The only other available published study investigating the use of autologous blood injections to treat Achilles tendinopathy concluded that injections produced a moderate improvement in symptoms.24 This previous study lacked blinding and allocation concealment, administered a variable number of injections, included participants with unilateral and bilateral symptoms, and had a high dropout rate. The sample size recruited for our study was large enough to preclude possible clinical benefits and harm and was also similar to that in other randomised trials that used the change in VISA-A score as the primary outcome measure (40-75 participants).24 28 29 The monitoring of eccentric training was also similar to that used by some other investigators,28 30 though others did not mention steps taken to monitor compliance.29 31 Good compliance probably contributes to a participant’s clinical improvement.25 Without accurate monitoring, any benefit attributable to the intervention might actually be caused by disparity between groups in the compliance with eccentric training or would at least increase the variation of the results. It is also likely that there would be increased variation in measurement between participants.

Explanations and clinical implications

The use of autologous blood injections to treat tendinopathy has become particularly popular in recent years, despite the apparent lack of quality evidence supporting their use.19 20 24 32 33 Our findings suggest that the application of autologous blood injections as described has no clear clinically beneficial effect, and based on this finding we cannot recommend their future use. There are, however, several other possible explanations for the outcome. Firstly, the needling process itself might have created sufficient bleeding in the control participants to induce a healing response. Secondly, administering injections closer together would have enhanced any potential benefit from maintaining a steady state effect of growth factors present in the blood.17 19 The lack of ultrasound guidance, or the injections being directed peritendinously rather than intratendinously, could have affected the outcome. From our experience however, most autologous blood injections administered in New Zealand are delivered peritendinously. Several reports of benefit from unguided injections in tendinopathy support this type of administration.24 32 33 34 35 36 There are also numerous studies indicating that peritendinous injections of differing substances can provide benefit in the treatment of Achilles tendinopathy.24 36 37 38 The intratendinous injection of platelet rich plasma, a derivative of whole blood, has been investigated in the treatment of mid-portion Achilles tendinopathy with mixed results to date.39 The proposed mechanism of action of autologous blood injections and platelet rich plasma is similar, but the former is cheaper as it does not require specific preparation and a smaller volume of blood is taken from participants. The negligible clinical effect of autologous blood injections in this study, and the mixed results of platelet rich plasma, suggest that these forms of injection therapy are not useful for the treatment of mid-portion Achilles tendinopathy. Eccentric training is already recognised as a good treatment option for Achilles tendinopathy,15 25 28 and both groups showed a clinical improvement as a result of the eccentric training component. It was therefore difficult to show an additive clinically meaningful effect of autologous blood injections. We did not use any type of substance in the injections in the control group, whereas most other studies used injections of normal saline28 40 41 42or local anaesthetic.43 44 There is recent evidence to suggest that higher levels of extracellular sodium suppress transient receptor potential V1 (TRPV1) activity, a non-selective cation channel present in nociceptors that helps to integrate pain perception.45We considered that injecting normal saline could itself result in reduced pain sensation, and as such, not strictly act as a control intervention. Indeed, the group allocation prediction analysis shows that participants were unable to determine which group that they had been randomised to, suggesting that with the use of our control intervention, we were able to maintain adequate blinding.

Strengths and limitations of the study

Strengths of this study were the high participation rate (95%) and low dropout rate (6%). The participants reflected a wide range of society with ages ranging from 27 to 76 and sex being evenly matched with 53% men and 47% women. There was, however, an under-representation of minority ethnic groups, with 91% of the participants identifying themselves as European and the 9% remaining as New Zealand Maori. A further strength was the use of the validated primary outcome measure, the VISA-A questionnaire, which was completed in the presence of the single blinded assessor. We also used daily monitoring of eccentric training compliance with a written log, which could have encouraged good compliance and showed that there were no differences between the groups in the eccentric training aspect of the management.

Future research

We conclude that the administration of unguided peritendinous autologous blood injections does not confer an additional benefit to rehabilitation outcomes resulting from a standardised eccentric training programme. Follow-up studies could involve the injections being given intratendinously under ultrasound guidance, a shorter time interval between injections, or an increase in the volume of injected blood. It would also be beneficial to have a third treatment group who undertake an eccentric training programme only, without injection. While such derivations would aid in estimation of the effect of the needling itself, it would be without blinding and therefore susceptible to placebo effects. A fourth treatment with autologous blood injections in the absence of eccentric training would help to determine whether any benefit is obtained from injections in isolation.

Source: BMJ