Tag Archive for: Clinical Trial

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Editorial: New robots – cost, connectivity and artificial intelligence

The amazing Da Vinci system, is about to face some market competition from other international companies with their own versions of next generation robots [1]. In order to challenge the current gold standard, these systems will need to be at least as good if not better. The alternative is to be significantly cheaper thus attracting a wider variety of institutions who could currently not afford the Da Vinci. Open consoles, 3D enhanced vision, lighter instruments and greater portability will be recurring themes in these new systems. There is even some renewed interest in automation that goes back to the days of John Wickham, who passed away just short of his 90th birthday (https://www.bjuinternational.com/bjui-blog/light-years-ahead-john-wickham-1927-2017/). The STAR robot can suture bowel better than a human hand in an animal model [2]. The water jet robot (Procept Biorobotics) takes inspiration from Wickham’s PROBOT and may prove to be a viable alternative to TURP or HOLEP but without the steep learning curve [3].

The Revo-i, a Korean robot, has completed the first clinical testing in 17 patients undergoing Retzius sparing robotic assisted radical prostatectomy (RARP). It is an example of real-life reporting where even in experienced hands, three patients underwent blood transfusion and the positive margin rate was 23% [4]. One could speculate whether the approach itself or the adoption of a new robotic system reflected the results of this paper? Either way we can expect to see more such first in man reports over coming years as new robots become available.

These new machines have the potential to reduce the cost of robotic surgery to be similar to that of laparoscopy although the initial hardware outlay may still be substantial. Cambridge Medical Robotics (CMR), UK have plans to introduce competitive cost models which cover maintenance, instruments and even assistants as a comprehensive package. This may make robotics attractive to multidisciplinary expansion, amongst high volume open and laparoscopic surgeons.

The two other aspects in the world of new robots that are causing excitement are artificial intelligence (AI) and faster digital communication. The concept of AI is not new, going back to genius of Alan Turing, who with his decoding skills had a major impact on the outcome of World War II. Machine Learning (ML) is a subset of AI, using decision-making computer algorithms to grasp and respond to specific data. For example, a prostate recognition algorithm could make the machine learn whether a given image is that of a prostate cancer or not, thus reducing the variability in MRI readings by radiologists. The video recordings of surgeons performing RARP can now be converted through a “black box” into Automated Performance Metrics (APMs) and demonstrate paradoxical findings in that not all high volume surgeons are necessarily those with the best outcomes [5]. With Google moving into surgical robotics in collaboration with J&J, data capture and ML are likely to hold promise for the future.

The UK government amongst others has declared significant investment of > £1billion in AI, with a view to engaging with new talent and remaining a world leader in this emerging field. Led by Dame Wendy Hall (https://www.gov.uk/government/publications/growing-the-artificial-intelligence-industry-in-the-uk) this ambitious project outlines a vision of appointing new researchers from the UK and overseas in all forms of AI, while maintaining the sensitivities around data trust and ethics. However, a word of caution in that AI faces difficulty with reproducibility as a result of unpublished codes in over 90% of articles written on the subject [6].

Surgery may be further democratised in coming years with the advent of low latency ultrafast 5G connectivity. The Internet of Skills could make remote robotic surgery and mentorship easily accessible, irrespective of the location of the expert surgeon [7]. The impact of these developments on patient care will be of considerable interest to the wider surgical community.

Prokar Dasgupta FKC, Editor-in-Chief BJUI

MRC Centre for Transplantation, NIHR Biomedical Research Centre, King’s College London, UK

 

References

  1. Rassweiler JJ, Autorino R, Klein J et al. Future of robotic surgery in urology. BJU Int 2017; 120: 822-841. doi:10.1111/bju.13851
  2. Shademan A, Decker RS, Opfermann JD, Leonard S, Krieger A, Kim PC. Supervised autonomous robotic soft tissue surgery. Sci Transl Med 2016;8:337ra64
  3. Gilling P, Reuther R, Kahokehr A, Fraundorfer M. Aquablation – image‐guided robot‐assisted waterjet ablation of the prostate: initial clinical experience. BJU Int 2016; 117: 923-9.
  4. Chang KD, Abdel Raheem A, Choi Y D, Chung BH, Rha KH. Retzius‐sparing robot‐assisted radical prostatectomy using the Revo‐i robotic surgical system: surgical technique and results of the first human trial. BJU Int 2018; 122: 441-448
  5. Chen J, Oh PJ, Cheng N, Shah A, Montez J, Jarc A, Guo L, Gill IS, Hung AJ. Utilization of automated performance metrics to measure surgeon performance during robotic vesicourethral anastomosis and methodical development of a training tutorial. J Urol. 2018 May 21. pii: S0022-5347(18)43237-5. doi: 10.1016/j.juro.2018.05.080. [Epub ahead of print] PMID: 29792882
  6. Hutson M. Artificial intelligence faces reproducibility crisis. Science 16 Feb 2018: Vol. 359, Issue 6377, pp. 725-726
  7. Kim SS, Dohler M, Dasgupta P. The Internet of Skills: use of fifth‐generation telecommunications, haptics and artificial intelligence in robotic surgery. BJU Int 2018; 122: 356-359

 

Article of the Month: Retzius-sparing RARP using the Revo-i: results of the first human trial

Every Month, the Editor-in-Chief selects an Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Retzius-sparing robot-assisted radical prostatectomy using the Revo-i robotic surgical system: surgical technique and results of the first human trial

 

Ki Don Chang*†, Ali Abdel Raheem*‡, Young Deuk Choi* , Byung Ha Chung* and Koon Ho Rha*

*Department of Urological Science Institute, Yonsei University College of Medicine, Seoul, †Department of Urology, Urological Science Institute, Yonsei Wonju University College of Medicine, Wonju, Korea, and ‡Department of Urology, Tanta University Medical School, Tanta, Egypt

Abstract

Objective

To evaluate the safety and proficiency of the Revo‐i® robotic platform (Meere Company Inc.) in the treatment of prostate cancer (PCa).

Patients and Methods

A prospective study was carried out on 17 patients with clinically localized PCa treated between 17 August 2016 and 23 February 2017 at our urology department using the Revo‐i. Patients underwent Retzius‐sparing robot‐assisted radical prostatectomy (RS‐RARP). The primary objective was to describe the RS‐RARP step‐by‐step surgical technique using the Revo‐i. In addition, the safety of the Revo‐i was assessed according to intra‐operative and the postoperative complications within 30 days of surgery. Early oncological outcomes were also assessed according to surgical margin status and biochemical recurrence (BCR). Continence was defined as use of no or only one pad. Surgeons’ satisfaction with the Revo‐i was assessed using the Likert scale.

Results

All surgeries were completed successfully, with no conversion to open or laparoscopic surgery. The median patient age was 72 years. The median docking time, console time, urethrovesical anastomosis time and estimated blood loss were 8 min, 92 min, 26 min and 200 mL, respectively. One patient was transfused intra‐operatively as a result of blood loss of 1 500 mL. Postoperatively, two patients received blood transfusion, and there were no other serious/major complications. The median hospital stay was 4 days. At 3 months, four patients had positive surgical margins, one patient had BCR, and 15 patients were continent. Most of surgeons were satisfied with the Revo‐i performance.

Conclusions

The first human study for the treatment of patients with localized PCa using the Revo‐i robotic surgical system was carried out successfully. The peri‐operative, early oncological and continence outcomes are encouraging. Further prospective studies are warranted to support our preliminary results.

Video: Retzius-sparing RARP using the Revo-i – results of the first human trial

Retzius-sparing robot-assisted radical prostatectomy using the Revo-i robotic surgical system: surgical technique and results of the first human trial

 

Abstract

Objective

To evaluate the safety and proficiency of the Revo‐i® robotic platform (Meere Company Inc.) in the treatment of prostate cancer (PCa).

Patients and Methods

A prospective study was carried out on 17 patients with clinically localized PCa treated between 17 August 2016 and 23 February 2017 at our urology department using the Revo‐i. Patients underwent Retzius‐sparing robot‐assisted radical prostatectomy (RS‐RARP). The primary objective was to describe the RS‐RARP step‐by‐step surgical technique using the Revo‐i. In addition, the safety of the Revo‐i was assessed according to intra‐operative and the postoperative complications within 30 days of surgery. Early oncological outcomes were also assessed according to surgical margin status and biochemical recurrence (BCR). Continence was defined as use of no or only one pad. Surgeons’ satisfaction with the Revo‐i was assessed using the Likert scale.

Results

All surgeries were completed successfully, with no conversion to open or laparoscopic surgery. The median patient age was 72 years. The median docking time, console time, urethrovesical anastomosis time and estimated blood loss were 8 min, 92 min, 26 min and 200 mL, respectively. One patient was transfused intra‐operatively as a result of blood loss of 1 500 mL. Postoperatively, two patients received blood transfusion, and there were no other serious/major complications. The median hospital stay was 4 days. At 3 months, four patients had positive surgical margins, one patient had BCR, and 15 patients were continent. Most of surgeons were satisfied with the Revo‐i performance.

Conclusions

The first human study for the treatment of patients with localized PCa using the Revo‐i robotic surgical system was carried out successfully. The peri‐operative, early oncological and continence outcomes are encouraging. Further prospective studies are warranted to support our preliminary results.

Video: Stereotactic ablative body radiotherapy for inoperable primary kidney cancer

Stereotactic ablative body radiotherapy for inoperable primary kidney cancer

Abstract

Objective

To assess the feasibility and safety of stereotactic ablative body radiotherapy (SABR) for renal cell carcinoma (RCC) in patients unsuitable for surgery. Secondary objectives were to assess oncological and functional outcomes.

Materials and Methods

This was a prospective interventional clinical trial with institutional ethics board approval. Inoperable patients were enrolled, after multidisciplinary consensus, for intervention with informed consent. Tumour response was defined using Response Evaluation Criteria In Solid Tumors v1.1. Toxicities were recorded using Common Terminology Criteria for Adverse Events v4.0. Time-to-event outcomes were described using the Kaplan–Meier method, and associations of baseline variables with tumour shrinkage was assessed using linear regression. Patients received either single fraction of 26 Gy or three fractions of 14 Gy, dependent on tumour size.

Results

Of 37 patients (median age 78 years), 62% had T1b, 35% had T1a and 3% had T2a disease. One patient presented with bilateral primaries. Histology was confirmed in 92%. In total, 33 patients and 34 kidneys received all prescribed SABR fractions (89% feasibility). The median follow-up was 24 months. Treatment-related grade 1–2 toxicities occurred in 26 patients (78%) and grade 3 toxicity in one patient (3%). No grade 4–5 toxicities were recorded and six patients (18%) reported no toxicity. Freedom from local progression, distant progression and overall survival rates at 2 years were 100%, 89% and 92%, respectively. The mean baseline glomerular filtration rate was 55 mL/min, which decreased to 44 mL/min at 1 and 2 years (P < 0.001). Neutrophil:lymphocyte ratio correlated to % change in tumour size at 1 year, r2 = 0.45 (P < 0.001).

Conclusion

The study results show that SABR for primary RCC was feasible and well tolerated. We observed encouraging cancer control, functional preservation and early survival outcomes in an inoperable cohort. Baseline neutrophil:lymphocyte ratio may be predictive of immune-mediated response and warrants further investigation.

Editorial: Stereotactic radiotherapy for primary renal cell carcinoma: time for larger-scale prospective studies

A number of important trends in kidney cancer diagnosis have emerged in recent decades, including the increasing detection of renal tumours in older patients with more comorbidities. In the UK in 2012–2014, 50% of new cases were diagnosed in people aged 70 years and over. Whilst many of these lesions are incidental small renal masses suitable for active surveillance, the dilemma of how to manage the higher-risk lesion (rapid growth kinetics, larger size, symptomatic lesion) is increasingly encountered. Surgical management may pose an unacceptable risk of morbidity, mortality or dialysis, yet these patients may live long enough to experience the consequences of disease progression. Thermal ablation is an option for small cortical tumours (≤3 cm), but there are limitations for larger or centrally located tumours.

In this issue of BJUI, Siva and colleagues [1] report promising early efficacy and toxicity data using stereotactic ablative body radiotherapy (SABR) for the treatment of primary RCC in this difficult cohort. SABR is a non-invasive treatment that delivers very high doses of radiation over one to five outpatient sessions. It uses advanced motion management, radiation planning and image guidance techniques to ensure delivery of an ablative dose with millimetre precision. Survival benefits with stereotactic radiosurgery have been demonstrated in patients with solitary brain metastases [2], and SABR is now an accepted standard of care for patients with medically inoperable early-stage lung cancer [3]. Randomized phase III trials are currently under way, testing SABR against standard of care in primary prostate (clinicaltrials.gov ID NCT01584258) and liver cancer (NCT01730937) and in the oligometastatic setting (NCT02759783). Historically considered radio-resistant, both pre-clinical and clinical data now support the sensitivity of RCC to high-dose per fraction radiotherapy, as used in SABR [4].

The study by Siva and colleagues is one of the largest, early-phase, prospective studies of SABR for primary RCC to date, accruing 37 patients with cT1a–cT2a RCC not suitable for other therapies. Importantly, this was not a cohort of incidentally detected small renal masses. The majority (65%) of tumours were >4 cm (median 4.8 cm), were growing on surveillance or symptomatic, and were biopsy-proven. The inclusion of enlarging T1a tumours is not unreasonable. A recent analysis of patients with localized T1a kidney cancer from the Surveillance, Epidemiology and End Results (SEER) Medicare data reported an excess of kidney cancer deaths for non-surgically managed patients aged >75 years, highlighting how difficult it can be to find the right balance between active and expectant management in this group [5]. Indeed 11% of patients in the present study by Siva et al. developed distant metastases by 2 years.

In the present study, tumours <5 cm received a single 26-Gy fraction of SABR, whilst tumours >5 cm received 42 Gy over three fractions. Whilst acknowledging a number of uncertainties in modelling, this should equate to an equivalent biological dose in excess of 100 Gy. The authors found that delivering this SABR regimen was feasible and well tolerated with one grade 3 toxicity (transient fatigue) and no grade 4–5 toxicities. Most patients sustained only transient minor side effects (78%) or no treatment-related side effects (18%). The mean baseline estimated GFR was 55 mL/min, which decreased to 44 mL/min at 1 year, and was maintained for those with 2 years follow-up.

Similarly, short-term efficacy appears promising. With a median follow-up of 24 months, freedom from local progression at 2 years was 100%, with one patient subsequently progressing locally with concurrent distant metastases 28 months after treatment. Local progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. This is a pragmatic definition and takes into account the challenges in interpreting standard imaging after SABR and the difficulties in obtaining and interpreting repeat biopsies in this cohort. Similarly to the study by Sun et al. [6] it appears that stable or partial radiological responses will predominate in the early years after SABR and, unlike thermal ablation, changes in enhancement patterns can be very slow to evolve.

Longer-term follow-up is required to confirm these promising tumour control and nephron preservation rates, in addition to evaluating longer-term late effects. To that end, the present study has provided a platform for the authors to launch an international phase II clinical trial under the auspices of the TransTasman Radiation Oncology Group (TROG 15.03 FASTRACK, clinicaltrials.gov ID NCT02613819). Larger-scale prospective studies are essential to confirm the efficacy and safety of this non-invasive, nephron-sparing, ablative technique and provide further information to help refine patient selection and develop better biomarkers of response.

David I. Pryor *† and Simon Wood†‡

 

*Department of Radiation Oncology, Princess Alexandra Hospital, Wooloongabba, School of Medicine, University of Queensland, Brisbane, and Department of Urology, Princess Alexandra Hospital, Wooloongabba, Qld, Australia

 

References

 

1 Siva S. Stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial. BJU Int 2017; 120: 62330
 

 

2 Andrews DW, Scott CB , Sperduto PW et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with  one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet (London, England) 2004; 363: 166572

 

4 De Meerleer G, Khoo V, Escudier B et al. Radiotherapy for renal-cell carcinoma. Lancet Oncol 2014; 15: e1707

 

 

6 Sun MR, Brook A, Powell MF et al. Effect of stereotactic body radiotherapy on the growth kinetics and enhancement pattern of primary renal tumors. AJR Am J Roentgenol 2016; 206: 54453

 

Article of the Week: Stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial

Every week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial

 

Shankar Siva*,, Daniel Pham*, Tomas Kron*,, Mathias Bressel*, Jacqueline Lam*, Teng Han Tan*, Brent Chesson*, Mark Shaw*, Sarat Chander*, Suki Gill*,Nicholas R. Brook§, Nathan Lawrentschuk*,, Declan G. Murphy*,† and Farshad Foroudi*,

 

*Peter MacCallum Cancer Centre, Melbourne, Vic., Australia, † Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic. Australia, Sir Charles Gairdner Hospital, Nedlands Perth, WA, Australia, §Royal Adelaide Hospital, Adelaide, SA, Australia, and Olivia Newton John Cancer Centre, Heidelberg, Vic., Australia

 

Abstract

Objective

To assess the feasibility and safety of stereotactic ablative body radiotherapy (SABR) for renal cell carcinoma (RCC) in patients unsuitable for surgery. Secondary objectives were to assess oncological and functional outcomes.

Materials and Methods

This was a prospective interventional clinical trial with institutional ethics board approval. Inoperable patients were enrolled, after multidisciplinary consensus, for intervention with informed consent. Tumour response was defined using Response Evaluation Criteria In Solid Tumors v1.1. Toxicities were recorded using Common Terminology Criteria for Adverse Events v4.0. Time-to-event outcomes were described using the Kaplan–Meier method, and associations of baseline variables with tumour shrinkage was assessed using linear regression. Patients received either single fraction of 26 Gy or three fractions of 14 Gy, dependent on tumour size.

Results

Of 37 patients (median age 78 years), 62% had T1b, 35% had T1a and 3% had T2a disease. One patient presented with bilateral primaries. Histology was confirmed in 92%. In total, 33 patients and 34 kidneys received all prescribed SABR fractions (89% feasibility). The median follow-up was 24 months. Treatment-related grade 1–2 toxicities occurred in 26 patients (78%) and grade 3 toxicity in one patient (3%). No grade 4–5 toxicities were recorded and six patients (18%) reported no toxicity. Freedom from local progression, distant progression and overall survival rates at 2 years were 100%, 89% and 92%, respectively. The mean baseline glomerular filtration rate was 55 mL/min, which decreased to 44 mL/min at 1 and 2 years (P < 0.001). Neutrophil:lymphocyte ratio correlated to % change in tumour size at 1 year, r2 = 0.45 (P < 0.001).

Conclusion

The study results show that SABR for primary RCC was feasible and well tolerated. We observed encouraging cancer control, functional preservation and early survival outcomes in an inoperable cohort. Baseline neutrophil:lymphocyte ratio may be predictive of immune-mediated response and warrants further investigation.

April Editorial: The BJUI’s clinical trials initiative

The BJUI supports clinical trials. Plain, simple, and with some new strategies.

Randomised clinical trials (RCTs) are the highest level of evidence-based medicine. We know this to be true, but we also know that RCTs are a challenge to fund, accrue patients, execute, and follow to endpoints. From a statistician’s point of view, RCTs provide unbiased estimates of the effects of different treatments. From a clinician’s point of view, RCTs provide the grandest of experiments in nature – a true test of option A vs option B. We are thrilled when one option beats the other. We can be satisfied if the options are equivalent, at least knowing the matter is settled and move on to the next question. Either way, the story lines can be rich with ongoing debate, drama, and analysis: were the cohorts truly equivalent? Was the study population generalisable? Were the treatments contemporary? Were there unintended harms/toxicities?

Allow us to illustrate some examples of what we propose to our readers. In 2003, Thompson et al. [1] published the famous Prostate Cancer Prevention Trial in the New England Journal of Medicine: ‘The influence of finasteride on the development of prostate cancer’. This landmark study has been cited 2541 times, according to Google Scholar. Looking further at impact, one can go to the www.swog.org site and query the protocol ‘SWOG-9217’ and see that over 150 publications have been produced using this dataset (16 in 2016!). Several publications pre-dated the primary endpoint paper and discussed trial design, the dilemma of chemoprevention, and updates to trial progress. Post primary endpoint, publications have looked at multiple strategies – costs, the high-grade findings, longer-term follow-up, biopsy findings from the placebo arm, etc. Just last year, the UK made its mark on the prostate cancer world with the landmark Prostate Testing for Cancer and Treatment (ProtecT) study [2]. Again, we see the primary endpoint paper in the New England Journal of Medicine, but secondary endpoint papers, such as the quality-of-life outcomes are in the BJUI [3], and a mortality outcome analysis for trial screen failures in European Urology [4].

The BJUI can support clinical trial efforts through multiple pathways. Certainly, we would love to receive a primary endpoint paper from an important RCT in urology. We can also have impact by featuring important secondary endpoint papers, trial design papers (preferably ones that read like a good review article, with the trial proposed as the ‘answer’ to the dilemma), as well as smaller/early phase I–II trials that are stand-alone pieces of key knowledge. Figure 1 shows a possible flow chart of a RCT with each box representing possible publication points. In addition to content in the BJUI, our webpage Blogs section has a ‘rapid response team’ to start immediate dialogue on important RCTs published in other journals. For example with the recent Yaxley et al. [5] trial in the Lancet, our blogs section, led by Declan Murphy, had over 10 000 views and over 50 follow-up comments. So clearly, our readers care about RCTs.

apr-ed

Figure 1. A possible flow chart of a randomised clinical trial (RCT) with each box representing possible publication points. QOL, quality of life; f/u, follow-up.

Finally, the BJUI can help with RCTs in two more ways. For the reader, we will highlight RCT-related papers in their native sections (i.e. oncology, functional, education) with a special ‘Trials’ headline, and will invite experts to comment on the significance of the study. For reviewers and authors, we will be critical on RCT design, such that flaws are identified, and papers not given inflated significance. It is frustrating to receive papers that lack adequate reporting on what researchers did, RCT-related papers submitted to the BJUI frequently fail to adhere to the 2010 Consolidated Standards of Reporting Trials (CONSORT) guidance for reporting RCTs, which potentially leads to major revisions, if not outright rejection. The CONSORT requirements are on our author submission guidelines, but ideally these are read and adhered to in advance, as many are not possible to correct after the fact. Recently, we have also added that all RCTs must be registered (i.e. clinicaltrials.gov or similar) before the first patient is enrolled.

John W. Davis, Associate Editor, Urological Oncology* and
Graeme MacLennan, Consulting Editor, Statistics and Trials

*MD Anderson Cancer Center, Houston, TX, USA and University of Aberdeen, Aberdeen, UK


References

How to Cite this article

Davis, J. W. and MacLennan, G. (2017), The BJUI‘s clinical trials initiative. BJU International, 119: 503. doi: 10.1111/bju.13837

 

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