Bridging the gap between the randomised clinical trial world and the real world by combination of population-based registry and electronic health record data: A case study in haemato-oncology

Randomised clinical trials (RCTs) are considered the basis of evidence-based medicine. It is recognised more and more that application of RCT results in daily practice of clinical decision-making is limited because the RCT world does not correspond with the clinical real world. Recent strategies aiming at substitution of RCT databases by improved population-based registries (PBRs) or by improved electronic health record (EHR) systems to provide significant data for clinical science are discussed. A novel approach exemplified by the HemoBase haemato-oncology project is presented. In this approach, a PBR is combined with an advanced EHR, providing high-quality data for observational studies and support of best practice development. This PBR + EHR approach opens a perspective on randomised registry trials.     

Chemo-radiotherapy in locally advanced rectal cancer: What is the optimal strategy?

The management of locally advanced rectal cancers, although has remarkably improved in the last years, still remains a challenge. The results of recent European randomised trias have marked a paradigm shift from the postoperative to preoperative CRT approach. However, this approach do not impact on the occurrence of distant metastases, disease-free survival and overall survival, underlining the need for a more intensified approach. Moreover, the data of retrospective analysis have evidenced that an other critical point is the selection of patients for whom a risk-adapted pre and postoperative treatment should be delivered, considering that locally advanced rectal tumours are a widely heterogeneous group of tumours. Therefore, a refinements of a multimodality therapy by an integrated approach of a highly skilled multidisciplinary team is needed for a further improvement of clinical management.     

Two questions about the analysis and interpretation of randomised trials

This non-technical tutorial focus on two questions about the analysis of data from randomised trials. Which is the more appropriate analysis of data from a randomised trial – an unadjusted analysis or an adjusted one? When a result is not statistically significant is it nevertheless appropriate to comment on its direction?     

Patterns of mortality after prolonged follow-up of a randomised controlled trial using granulocyte colony-stimulating factor to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma

The effect of utilising granulocyte colony-stimulating factor (G-CSF) to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma (NHL) on long-term mortality patterns has not been formally evaluated. We analysed prolonged follow-up data from the first randomised controlled trial investigating this approach. Data on 10-year overall survival (OS), progression-free survival (PFS), freedom from progression (FFP) and incidence of second malignancies were collected for 80 patients with aggressive subtypes of NHL, who had been randomised to receive either VAPEC-B chemotherapy or VAPEC-B+G-CSF. Median follow-up was 15.7 years for surviving patients. No significant differences were found in PFS or OS. However, 10-year FFP was better in the G-CSF arm (68 vs 47%, P=0.037). Eleven deaths from causes unrelated to NHL or its treatment occurred in the G-CSF arm compared to five in controls. More deaths occurred from second malignancies (4 vs 2) and cardiovascular causes (5 vs 0) in the G-CSF arm. Although this pharmacovigilance study has insufficient statistical power to draw conclusions and is limited by the lack of data on smoking history and other cardiovascular risk factors, these unique long-term outcome data generate hypotheses that warrant further investigation.     

The issue of lymphadenectomy during laparoscopic gastrectomy for gastric carcinoma

Surgical resection remains the mainstay of treatment for gastric cancer. Laparoscopic assisted gastrectomy has failed to gain universal acceptance as an alternative to the open approach for a number of reasons, one of which includes the issue of oncological radicality in terms of lymph node dissection. Nodal status, which is one of the most crucial and independent predictors of patient survival, therefore has been examined both in single institutional trials and also in randomised controlled trials especially on early gastric cancer. The issue of oncological adequacy for laparoscopic lymph node harvesting for advanced gastric cancer remains a contentious issue because of the unique challenges it poses in terms of complexity, safety and time, and also the lack of randomised controlled trials in this area. It is thus imperative that good quality multicentre randomised controlled trials are designed to investigate the benefits of extended lymphadenectomy in the setting of laparoscopic surgery, especially for advanced gastric cancer and its impact on both short and long term survival.     

Rationale and techniques of intra-operative hyperthermic intraperitoneal chemotherapy

BACKGROUND: In recent years surgical cytoreduction followed by intra-operative hyperthermic intraperitoneal chemotherapy (HIPEC) was introduced as treatment modality in patients with peritoneal surface malignancy. In the current review the rational for this approach, the prerequisites and the different techniques used are discussed. METHODS: A literature search through PubMed was performed. RESULTS: Pharmacokinetic studies have shown an important dose advantage for intraperitoneal versus intravenous application. Hyperthermia enhances the penetration of cytostatic drugs into tumour tissue and also shows synergism with various cytostatic drugs. The penetration depth of drugs into tissue is limited, therefore HIPEC can only be effective in patients with minimal residual disease after (aggressive) surgery. HIPEC can be conducted in various ways, without clear proven advantage of one method over the others. Local complications after this combined treatment approach are mainly surgery related. Intraperitoneal chemotherapy may cause systemic toxicity, dependent on the drug used. In randomised studies cytoreductive surgery followed by HIPEC has proven its value in the prevention of peritoneal dissemination in gastric cancer. Phase II data on HIPEC in peritoneal carcinomatosis of colorectal origin and pseudomyxoma peritonei are promising, but randomised studies are still not available. CONCLUSION: Aggressive surgical cytoreduction and HIPEC in patients with peritoneal surface malignancy has a clear rational and seems to have clinical value.     

Peritoneal carcinomatosis of colorectal origin

Peritoneal carcinomatosis is, after liver metastases, the second most frequent cause of death in colorectal cancer patients and at the present time, is commonly inserted and treated as a stage IV tumour. Because there is no published data that outlines the impact of new therapeutic regimens on survival of patients with peritoneal surface diffusion, the story of carcinomatosis can be rewritten in light of a new aggressive approach based on the combination of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Also if these treatment perhaps allow to obtain better results than standard therapies, we suggest, that a large prospective randomised control trial is needed to compare long-term and progression-free survival under the best available systemic therapy with or without cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.     

Effects of patient selection on the applicability of results from a randomised clinical trial (EORTC 10853) investigating breast-conserving therapy for DCIS

Selection of patients for randomised clinical trials may have a large impact on the applicability of the study results to the general population presenting the same disorder. However, clinical characteristics and outcome data on non-entered patients are usually not available. The effects of patient selection for the EORTC 10853 trial investigating the role of radiotherapy in breast conserving therapy for ductal carcinoma in situ have been studied, in an analysis of all patients treated for ductal carcinoma in situ in five participating institutes. The reasons for not entering patients were evaluated and treatment results of the randomised patients were compared to those not entered. A total of 910 patients were treated for ductal carcinoma in situ. Of these, 477 (52%) were ineligible, with the size of the lesion being the main reason for ineligibility (30% of all ductal carcinoma in situ). Of the 433 eligible patients, 278 (64%) were randomised into the trial. The main reasons for non-entry of eligible patients were either physicians' preference for one of the treatment arms (26%) or patients' refusal (9%). These percentages showed significant variation among the institutes. At 4 years follow-up, those patients not entered in the trial and treated with local excision and radiotherapy, had higher local recurrence rates than the patients randomised in the trial and treated with the same approach, (17 vs 2%, P=0.03). The patients treated with local excision alone had equal local recurrence rates (11% in both groups). Selection of patients may explain the differences in outcome of the randomised patients, and those not-entered. Thus, the results of this trial may not be applicable to all patients with ductal carcinoma in situ.     

A randomised trial of robotic and open prostatectomy in men with localised prostate cancer

ABSTRACT: BACKGROUND: Prostate cancer is the most common male cancer in the Western world however there is ongoing debate about the optimal treatment strategy for localised disease. While surgery remains the most commonly received treatment for localised disease in Australia more recently a robotic approach has emerged as an alternative to open and laparoscopic surgery. However, high level data is not yet available to support this as a superior approach or to guide treatment decision making between the alternatives. This paper presents the design of a randomised trial of Robotic and Open Prostatectomy for men newly diagnosed with localised prostate cancer that seeks to answer this question. METHODS: 200 men per treatment arm (400 men in total) are being recruited after diagnosis and before treatment through a major public hospital outpatient clinic and randomised to 1) Robotic Prostatectomy or 2) Open Prostatectomy. All robotic prostatectomies are being performed by one surgeon and all open prostatectomies are being performed by one other surgeon. Outcomes are being measured pre-operatively and at 6 weeks and 3, 6, 12 and 24 months post-surgery. Oncological outcomes are being related to positive surgical margins, biochemical recurrence +/ the need for further treatment. Non-oncological outcome measures include: pain, physical and mental functioning, fatigue, summary (preference-based utility scores) and domain-specific QoL (urinary incontinence, bowel function and erectile function), cancer specific distress, psychological distress, decision-related distress and time to return to usual activities. Cost modelling of each approach, as well as full economic appraisal, is also being undertaken. DISCUSSION: The study will provide recommendations about the relative benefits of Robotic and Open Prostatectomy to support informed patient decision making about treatment for localisedprostate cancer; and to assist in treatment services planning for this patient group. Trial Registration ACTRN12611000661976.     

Advances in the therapy of gastroenteropancreatic-neuroendocrine tumours (GEP-NETs)

Neuroendocrine tumours (NET) of the digestive tract comprise a broad range of malignancies. The therapeutic approach to these tumours has not evolved as it did in other tumour types in the last two decades. The deeper knowledge of the underlying molecular biology behind the growth of neuroendocrine cells has brought much information to light. We now know that somatostatin analogues may not only be considered as symptomatic treatment but also as antitumour agents. Sunitinib, a tyrosine kinase (TK) inhibitor with antiangiogenic and antitumoural properties, has been shown to induce significant improvement in progression-free survival in a randomised trial conducted in well-differentiated pancreatic islet-cell NETs. The relevance of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway seems to be crucial in gastroenteropancreatic (GEP)-NETs. In fact, mTOR inhibitors have shown activity in uncontrolled trials, and large, randomised trial results will be available shortly. In this article, we summarise the most recent available data on medical therapy for GEPNETs.     

Evaluation of novel radiotherapy technologies: what evidence is needed to assess their clinical and cost effectiveness,and how should we get it?

Technical innovations in radiation oncology--eg, intensity-modulated radiotherapy, stereotactic radiotherapy, and particle therapy--can be developed rapidly and introduced into the clinic even when costs associated with their use are much higher than those for conventional radiotherapy. Although clinical benefit is expected on the basis of superior biological and physical characteristics, data for clinical effectiveness of new radiotherapy techniques are scarce. Evidence from randomised clinical trials would be ideal but such studies focus mostly on new drugs. High investment costs and modifications over time make evaluation of novel radiotherapy technologies in clinical trials more complex. Here, we propose an algorithm for evaluation of the clinical and cost effectiveness of novel radiotherapy technologies. We suggest situations when randomised trials might be feasible and the type of trial that should be undertaken when they are not. Furthermore, we discuss the usefulness of dose-distribution models for estimation of expected clinical benefit and for selection of the patients' population with the highest expected benefit. Economic modelling, including the approach of real options analysis, can inform whether implementation of a technology should begin (based on available evidence) or be delayed (until further data are available), and it can indicate the best trial design and required sample size.     

Can the published data tell us about the effectiveness of neoadjuvant chemotherapy for locally advanced cancer of the uterine cervix?

The effect of neoadjuvant chemotherapy on survival of patients with locally advanced cervical cancer was investigated by conducting a systematic review and meta-analysis of the published data. Of the 21 randomised trials that we identified, only 15 were published. Furthermore, 2-year survival data could be extracted from only seven trial reports and 3-year survival from only nine trial reports. Meta-analyses of the published data at 2 and 3 years are neither clearly in favour of neoadjuvant chemotherapy nor control (2 years: odds ratio (OR)=1.09, 95% confidence interval (CI)=0.83–1.45, P=0.37; 3 years: OR=0.96, 95% confidence interval (CI)=0.73–1.25, P=0.45). Being restricted to only some of the data from a relatively small fraction of the randomised trials, these analyses potentially suffer from a number of biases and are therefore inconclusive. The only reliable way to judge the value of neoadjuvant chemotherapy in this disease is to perform a meta-analysis of centrally collected, updated, individual data on all patients from all known randomised trials. Such an analysis is currently being carried out by an international collaborative group.     

Preoperative treatment impact for ultralow rectal carcinoma sphincter preservation]

Sphincter preservation for low rectal carcinoma must be evaluated with a plurifactoriel approach. Multicentric randomised studies are unable to demonstrate a relationship between complete tumoral response and conservative sphincteric rate. Intersphincteric resection technique is becoming a main factor to transform conservative indication. Complete tumoral response should not be the only purpose of future trials.     

Radiation therapy of mesothelioma: the Heidelberg experience and future aspects

Pleural mesothelioma is a rare but fatal tumour. Numerous attempts to find effective treatment approaches have, in general, been disappointing. To date, the most promising treatment is surgery, or surgery in combination with radio and chemotherapy as a part of a multidisciplinary approach. Preliminary results from clinical trials evaluating intensity modulated radiotherapy are encouraging. Further randomised trials are proposed.     

When Should we Irradiate the Primary in Metastatic Lung Cancer?

Metastatic lung cancer encompasses a heterogenous group of patients in terms of burdens of disease, ranging from patients with extensive metastases to those with a limited number of metastatic lesions (oligometastatic disease). Histopathological heterogeneity also exists within two broad categories, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), portraying different patterns and evolution of disease. Local consolidative therapy to the primary tumour and metastatic sites, including surgery and/or radical dose radiotherapy, is increasingly being used to improve survival outcomes, particularly in the context of oligometastatic disease, with or without the use of molecular targeted therapy and immunotherapy. Recently, randomised studies in oligometastatic NSCLC have shown that local consolidative therapy may confer a survival advantage. This review explores whether treating just the primary tumour with radiotherapy may similarly produce improved clinical outcomes. Such a treatment strategy may carry less potential toxicity than treating multiple sites upfront. The biological rationale behind the potential benefits of treating just the primary in metastatic malignancy is discussed. The clinical evidence of such an approach across tumour sites, such as breast and prostate cancer, is also explored. Then the review focuses on treating the primary in NSCLC and SCLC with radiotherapy, by first exploring patterns of failure in metastatic NSCLC and second exploring evidence on survival outcomes from studies in metastatic NSCLC and SCLC. It is challenging to draw conclusions on the clinical benefit of treating the primary cancer in isolation from the evidence available. This highlights the need to collect data within the ongoing clinical trials on the clinical outcome and toxicity of radiotherapy delivery to primary thoracic disease specifically. This challenge also identifies the need to design future clinical trials to produce randomised evidence for such an approach.     

Practical Bayesian adaptive randomisation in clinical trials

While randomisation is the established method for obtaining scientifically valid treatment comparisons in clinical trials, it sometimes is at odds with what physicians feel is good medical practice. If a physician favours one treatment over another based on personal experience or published data, it may be more appropriate ethically for that physician to use the favoured treatment, rather than enrolling patients on a randomised trial. Still, the randomised trial may later show the physician's favoured treatment to be inferior. This paper reviews a statistical method, Bayesian adaptive randomisation, that provides a practical compromise between the scientific ideal of conventional randomisation and choosing each patient's treatment based on a personal preference that may prove to be incorrect. The method will first be illustrated by a simple hypothetical example, then by a recent trial in which patients with unresectable soft tissue sarcoma were adaptively randomised between two chemotherapy regimens.     

Definitive and neoadjuvant radiochemotherapy of squamous cell carcinoma of the oesophagus

In cases of advanced carcinoma of the oesophagus with no metastatic spread, a concurrent radiochemotherapy can improve the patient's prognosis in comparison to radiotherapy alone. This approach increases the treatment-related toxicity, in particular haematological side effects. Therefore therapy must be adapted to the general condition of the patient, demanding an intensive supportive treatment and monitoring of the patient. At present the optimal radiation dose and the role of brachytherapy for the reduction of the still high rate of local recurrences has not been determined. The value of neoadjuvant radiochemotherapy for operable or inoperable tumours is unclear. Meta-analyses did show an improvement of the prognosis, however most of the randomised studies found improvement only for the recurrence rate but not for survival. The reasons for this are numerous; however, the high postoperative lethality after radiochemotherapy in some studies is conspicuous. Conversely, the initial results of randomised studies show that operative measures could possibly be forgone if a complete remission is achieved by concurrent radiochemotherapy. Nevertheless, this approach must also be regarded critically, as the local recurrence rate after radiochemotherapy alone is high and long-term results are not available.     

早期子宫内膜样癌的放射治疗

早期子宫内膜样癌患者术后是否应接受辅助盆腔外照射目前尚存争议。现有的3项随机对照临床试验提供的循证医学证据显示,术后盆腔外照射能够显著降低局部复发率,但无益于提高患者远期生存率。总结文献结果,早期子宫内膜样癌患者首先应根据手术分期判断复发风险,从而进一步决定是否需要术后辅助放疗。     

Cytoreductive surgery plus hyperthermic perioperative chemotherapy to treat peritoneal metastases from colorectal cancer: standard of care or an experimental approach?

Peritoneal carcinomatosis is a common presentation in patients with metastatic colorectal cancer and the overall survival is poor. In most patients, the disease remains limited to the peritoneal cavity. Therefore, investigators have applied cytoreductive surgery and hyperthermic perioperative chemotherapy as the standard approach for selected patients with peritoneal metastases from colorectal cancer. Overall, very promising long-term survival has been shown in a subset of patients with a limited extent of peritoneal disease before treatment. Whether randomised, controlled trials are needed to definitively show the magnitude of benefit, if any, of this approach is an important question. This Debate outlines the arguments on each side of this issue.