Early Tumour Shrinkage: A Tool for the Detection of Early Clinical Activity in Metastatic Renal Cell Carcinoma.

BACKGROUND: The predictive role of objective remission remains undefined for targeted agents in metastatic renal cell carcinoma (mRCC); however, early tumour shrinkage (eTS) was shown to be predictive and/or prognostic for overall survival (OS) and progression-free survival (PFS) in mRCC in several small studies. OBJECTIVE: To evaluate the degree of eTS following systemic therapy that may predict survival in mRCC. DESIGN, SETTING, AND PARTICIPANTS: Data from 4334 patients with mRCC in phase 2 and 3 clinical trials between 2003 and 2013 were pooled for analyses. Early tumour shrinkage was assessed based on percentage change in sum of the longest diameters of target lesions at first postbaseline scan. Patients were categorised by a more or equal versus less optimal threshold of eTS, assessed using receiver operating characteristic (ROC) analysis. OS and PFS in patients with eTS were summarised using the Kaplan-Meier method. INTERVENTION: Axitinib, bevacizumab, interferon α, sorafenib, sunitinib, or temsirolimus. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured optimal thresholds of eTS and eTS as a predictor of OS or PFS. RESULTS AND LIMITATIONS: Optimal threshold of eTS for the prediction of OS and PFS was determined to be approximately 10%. In Cox proportional hazards models, compared with patients without eTS, those with eTS had significantly longer OS (hazard ratio [HR]: 0.615; p<0.0001; median: 28.5 vs 16.0 mo) and PFS (HR: 0.628; p<0.0001; median: 10.5 vs 5.3 mo). The major limitation was the retrospective nature of our analysis, including different lines and types of therapy, although subset analyses detected a similar predictive pattern for eTS across all lines and types of therapy. CONCLUSIONS: Early tumour shrinkage ≥10% at first postbaseline assessment could serve as a putative early end point in patients with mRCC. A prospective evaluation of eTS in clinical trials is warranted. PATIENT SUMMARY: Early tumour shrinkage may be used to identify patients with metastatic renal cell carcinoma who would benefit from treatment with antitumour agents. TRIAL REGISTRATION: The clinical trials are registered on ClinicalTrials.gov (NCT00267748, NCT00338884, NCT00835978, NCT00065468, NCT00083889, NCT00631371, NCT00920816, NCT00077974, NCT00137423, NCT00054886, NCT00678392, and NCT00474786).

Depth of remission is a prognostic factor for survival in patients with metastatic renal cell carcinoma.

BACKGROUND: Response remains an important endpoint in clinical cancer trials. However, the prognostic utility of best tumor response in metastatic renal cell carcinoma (mRCC) remains vague. OBJECTIVE: To define the prognostic relevance of the depth of remission in mRCC. DESIGN, SETTING, AND PARTICIPANTS: Pooled data from the Pfizer database for 2749 patients from phase 2 and 3 clinical trials in mRCC were analyzed. Tumor shrinkage was categorized according to the best percentage change in the sum of the largest diameter of target lesions. Outcome was computed using Kaplan-Meier curves and correlation was assessed via Cox regression, including a 6-mo landmark. INTERVENTION: Sunitinib, sorafenib, axitinib, temsirolimus, or temsirolimus and interferon-α. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Categorized tumor shrinkage, overall survival (OS), progression free survival (PFS). RESULTS AND LIMITATIONS: Major tumor shrinkage of 60% or more occurred in approximately 10% of patients and was associated with median OS of 54.5 mo. OS expectations steadily decreased with depth of remission (26.4, 16.6, 10.4, and 7.3 mo). The association was maintained when stratified by type of therapy, line of therapy, and performance status. Cox proportional regression analyses for the 6-mo landmark confirmed the prognostic relevance of major tumor shrinkage (hazard ratio 0.29, 95% confidence interval 0.22-0.39; p<0.001). The major limitation of our study is the variability of imaging intervals among studies. CONCLUSIONS: This is the first and largest analysis of best tumor response in mRCC. We demonstrate that depth of remission is an independent prognostic factor in mRCC. PATIENT SUMMARY: It remains unknown whether tumor shrinkage during therapy is needed to achieve clinical activity in metastatic renal cell carcinoma. Our analysis shows that the magnitude of tumor shrinkage correlates with better survival in patients. This observation may be used as a clinical research tool in future trials. TRIAL REGISTRATION: NCT00054886, NCT00077974, NCT00267748, NCT00338884, NCT00137423, NCT00083889, NCT00065468, NCT00678392.

Patient relevant endpoints in oncology: current issues in the context of early benefit assessment in Germany.

UNLABELLED: The German AMNOG healthcare reform includes a mandatory early-benefit-assessment (EBA) at launch. As per German social code, EBA is based on registration trials and includes evaluation of the patient-relevant effect of the new medicines compared to an appropriate comparator as defined by the Federal Joint Committee (G-BA). Current EBA decisions released have unveiled issues regarding the acceptance of some patient-relevant endpoints as G-BA and IQWiG are grading the endpoints, focusing on overall survival as the preferred endpoint in oncology.A taskforce of experienced German outcomes research, medical, health-technology assessment and biostatistics researchers in industry was appointed. After agreement on core assumptions, a draft position was prepared. Input on iterative versions was solicited from a panel of reviewers from industry and external stakeholders.Distinctive features of registration trials in oncology need to be considered when these studies form basis for EBA, especially in cancer-indications with long post-progression survival; and with several consecutive therapeutic options available post-progression. Ethical committees, caregivers and patients often demand cross-over-designs diluting the treatment-effect on overall survival. Regulatory authorities require evaluation of morbidity-related study endpoints including survival of patients without their disease getting worse (i.e., progression-free survival). Also, progression requires treatment-changes, another strong indicator for its relevance to patients.Based on specific guidelines and clinical trial programs that were developed to be consistent with regulatory guidance, endpoints in oncology are thoroughly evaluated in terms of their patient-relevance. This extensive knowledge and experience should be fully acknowledged during EBA when assessing the patient-relevant benefit of innovative medicines in oncology. JEL CODES: D61; H51; I18.

Management of sunitinib-related adverse events: an evidence- and expert-based consensus approach.

BACKGROUND: The advance of medical treatment in renal cell carcinoma (RCC) has fostered the development of diverse continuous oral therapies with tyrosine kinase inhibitors (TKI), among these sunitinib remains the mainstay of therapy for most of the patients. Based on its clinical activity, disease control over a period of 11 months can be expected with sunitinib treatment. Given this prolonged period of exposure to sunitinib, adverse events tend to reoccur and can possibly decrease the quality of life in our patients. Hence, development of modalities to detect, treat and cope with such adverse events has become a major focus for physicians and patients. Today, numerous publications address these questions and offer advice from experienced centers. However, these reviews summarize single or oligo-center experiences. METHODS AND RESULTS: Our approach is based (1) on an extensive review and analysis of available evidence from literature and (2) a structured consensus survey among 12 German experts in the field who treated at least 30 patients each with a TKI. CONCLUSIONS: Derived from this process, this paper gives an overview on Sunitinib therapy management recommendations deducted from published evidence and consensus agreement among experts.

Development of a transoral fundoplication device and related experimental research.

This paper describes a device and surgical techniques developed between 1999 and 2003 to enable an entirely transoral approach to fundoplication. The Endofundoplication System (EFS) system consisted of a multifunctional flexible tube for oral introduction (18 mm) as the key component, with a specially designed retroverted grasper that was used to grasp the lower esophageal sphincter (LES) area of the esophagus, for invaginating the LES into the stomach and folding the gastric wall onto the wall of the intraabdominal esophagus. The EFS system was finally studied in a consecutive series of animal experiments in the domestic pig (n = 10). In nine out of the ten cases the procedure could be successfully completed and the animals survived six weeks according to the study protocol. The clinical follow-up of the nine animals went without problems. The animals behaved normally the first day after the procedure and tolerated regular diet very well. No signs of pain or any abdominal pathology were found in the clinical follow-up. Follow-up by endoscopy and fluoroscopy showed a subsequent postoperative migration of fasteners within the tissue. After autopsy and macroscopic inspection of the gastroesophageal junction (GEJ), we found firm tissue indurations around the fasteners. This may indicate that the fastener as a foreign body leads to a sufficient amount of scar tissue formation to contribute to permanent fixation of the tissue layers. The basic advantage of the EFS technique was seen by our group in the fact that it comes closer to the shape and function of a classical fundoplication than any other techniques proposed at the time we did our development. The nipple valve created by the EFS technique is, however, geometrically not identical to any existing fundoplication technique and is not directly comparable to any such procedure.

Artificial tactile sensing in minimally invasive surgery - a new technical approach.

The loss of tactile sensation is a commonly known drawback of minimally invasive surgery (MIS). Since the advent of MIS, research activities in providing tactile information to the surgeon are still ongoing, in order to improve patient safety and to extend the indications for MIS. We have designed a tactile sensor system comprising a tactile laparoscopic grasper for surgical palpation. For this purpose, we developed a novel tactile sensor technology which allows the manufacturing of an integrated sensor array within an acceptable price range. The array was integrated into the jaws of a 10mm laparoscopic grasper. The tactile data are transferred wirelessly via Bluetooth and are presented visually to the surgeon. The goal was to be able to obtain information about the shape and consistency of tissue structures by gently compressing the tissue between the jaws of the tactile instrument and thus to be able to recognize and assess anatomical or pathological structures, even if they are hidden in the tissue. With a prototype of the tactile sensor system we have conducted bench-tests as well as in-vitro and in-vivo experiments. The system proved feasibility in an experimental environment, it was easy to use, and the novel tactile sensor array was applicable for both palpation and grasping manoeuvres with forces of up to 60N. The tactile data turned out to be a useful supplement to the minimal amount of haptic feedback that is provided by current endoscopic instruments and the endoscopic image under certain conditions.

Independent testing of soft tissue visco-elasticity using indentation and rotary shear deformations.

Numerous techniques exist to measure the mechanical properties of soft tissues in vivo, such as mechanical stretching, indentation or shearing, as well as elastographic methods employing ultrasound or other imaging modes. Many groups have reported properties which do not necessarily correspond with each other due to differences in choice of technique, tissue model or other variations. This work deliberately makes use of the two independent modes of indentation and rotary shear, on the same material samples, employing similar modeling approximations, to attempt to determine the common, underlying material properties. This paper introduces the ROSA-2 rotary shear instrument, and presents its mechanical characteristics, as well as presenting validation experiments that were performed to verify non-slip contact with tissue. Measurements made with it are compared with those acquired with the TeMPeST l-D indentation instrument. Initial testing showed reasonably agreement when testing silicone gel samples, over a restricted range of frequencies. When testing bovine liver samples in vitro and porcine liver in vivo, significant discrepancies were found. The potential sources of these differences will be discussed, as will directions for ongoing work.