Dr. Collette spoke as part of the Friday morning session on prostate cancer at the 10th European Multidisciplinary Congress on Urological Cancers (EMUC18) in Amsterdam. She offered a biostatistician’s perspective in the two-hour session that also included pathologists, urologists, radiation and medical oncologists and research scientists. Dr. Collette is the senior manager in charge of statistics and independent data monitoring at the European Organisation for Research and Treatment of Cancer (EORTC).

Good evidence in challenging times

Tasked with offering a view on evidence gathering in 2025, Dr. Collette spoke of trials taking place in a “fast-changing, high-tech and economically challenging environment.” She pointed out five major themes: which drugs work (best), which sequence, the impact of modern imaging, new technologies and the emergence of big data.

On drug trials: “Typically, trials end up adding to existing treatments. Their controlling arm is usually placebo, and the trial is focused on rapid authorization before the long-term information is available.” Collette cited the PROSPER trial, praising its results. Nevertheless, she considers it striking that information about the patient’s quality of life is only collected until the time of progression, without any information available for a complete assessment of the treatment.

“Trials should be designed not just to achieve clearance for the drug or treatment in question, but ultimately to inform healthcare systems on which treatment is effective for the patient and worth the investment. We need to move on from drug-centered to patient-centered trials.”

In order to determine which drugs work best, parallel and comparative studies are needed. Collette quoted the STAMPEDE trial as a good example of a flexible, adaptive trial that compares different treatment options in different arms that could be added or stopped early. “This leads to practice-changing results in a much shorter time than sequential trials. This requires pharmaceutical companies to work together, and here academia can play a role.”

With regards to new technologies: “There is a danger of a catch-22 situation: people need to buy the technology to test it, but are compelled to use it once the investment has been made.”

The application of big data in cancer research has its potential in the near future, as well as some challenges, according to Prof. Collette: “Big data in oncology is obviously not on the scale of Google’s use of data, or social media. It can also not be monitored on a day-by-day basis, unlike conditions that can be monitored through wearable devices like blood pressure or heart rate.”

“Furthermore, there is the challenge of new laws. We are currently trying to negotiate an exception to the GDPR rules that impact our trials by preventing us from sharing data or in some cases even invalidating existing data.”

In summary, for generating good evidence in the coming decade: “Patient-centric trials are the future, as are multi-stakeholder collaborations with more than one company. Effective digitalization of our results will lead to bigger data for researchers.”

Predictive statistics

The morning continued with a session on controversies and contradictions in the staging of prostate cancer. This mainly took the form of an hour-long multidisciplinary case discussion concerning a 69 year-old man with hypertension and a PSA of 14.7, a family history of PCa but no suspicious lesions after a DRE was performed. Sixteen cores were taken in a random TRUS biopsy. A panel of six experts debated the course of action.

Preceding the case discussion was a presentation by Dr. Daniel Sjoberg (New York City, USA), biostatistician of Memorial Sloan Kettering Cancer Center who in the past also worked to develop the 4Kscore.

“Recently, there has been a huge increase in modern markers for prostate cancer,” Dr. Sjoberg began. “We are starting to move beyond the ROC curve, which is insufficient for making a useful clinical prediction. We need make a more pragmatic assessment of these markers.”

Dr. Sjoberg lined out three qualities that make a good biomarker: discrimination, calibration and ultimately clinical utility.

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Speakers included urologists, pathologists, medical oncologists and a urological researcher, each giving the audience of around 50 different insights on bladder cancer treatment from their respective specialities. Urologist Prof. Hein Van Poppel (Leuven, BE) and pathologist Prof. Montironi (Ancona, IT) chaired the session, although the latter was briefly replaced by Prof. Antonio Lopez-Beltran (Lisbon, PT) (also a pathologist) in his absence.

Update on BCa Treatments

The symposium started with a broad and up-to-the-minute update on BCa treatment by medical oncologist Prof. Susanne Osanto (Leiden, NL). Prof. Osanto first gave an overview of the current treatment options for bladder cancer, listing some recent developments and their implications for treatment. She then highlighted some trends that point to the future of the field: the increasing importance of the molecular pathologist.

“Molecular profiling will become increasingly relevant for choosing the right treatment for our patients,” Osanto said. “They already offer prognostic or predictive markers. In future, mutations will be actionable. In 2014, Nature published a so-called ‘genomic landscape of bladder cancer’, featuring many subsets and profiles. It is not yet known if the data are strong enough, and validation will be required. This will be an expensive process.”

Looking ahead, Prof. Osanto pointed to an increased use of checkpoint inhibitors (metastatic 2L and 1L, neo and adjuvant space and even in non-muscle invasive bladder cancer). Combinations of chemo- and immunotherapy and in future systemic therapy will be used in metastatic and high-risk non-muscle invasive and invasive or metastatic bladder cancer.

“All these strategies in muscle and non-muscle invasive bladder cancer should also be tested in upper urinary tract cancers,” Prof. Osanto emphasised.

Pathology

A significant part of the Symposium was then dedicated to the pathologist’s perspective, as Dr. Maurizio Colecchia (Milan, IT) explained their methods and standards. The International Collaboration on Cancer Reporting (ICCR) has established international standards for evaluation and reporting.

“Our goals are to provide accurate macroscopic and microscopic evaluation of features with diagnostic, prognostic and therapeutic value. We then offer personalised pathology reports based on the latest international standards (ICCR). Additional tissue studies including molecular investigations for personalized therapies are strongly recommended.”

Prof. Van Poppel then raised the surgeon’s perspective, eliciting clear and practical advice from Dr. Colecchia and the other pathologists. Prof. Lopez-Beltran explained the necessity for both the ‘freshness’ of the tissue sample and its shape. “Urologists need to realise how to best deliver the specimen. I ask the clinicians in my centre to give a cut, transversal or otherwise. This allows the formalin to fully penetrate the sample, which should not be too big or surrounded by layers of fat.”

Prof. Lopez-Beltran proceeded to give an overview of changes in the bladder resulting from treatment for non-muscle invasive bladder cancer, including BCG, mitomycin-C, and also ketamine, which might have been taken in a recreative setting. Prof. Montironi then did the same for muscle-invasive.

Potential of immuno-oncology

Medical oncologist Prof. Andrea Necchi (Milan, IT) gave a talk on the role of checkpoint inhibition in bladder cancer, introduced as a particularly hot topic by Prof. Van Poppel.

Necchi gave a wide-ranging overview of the latest developments in the field of immuno-oncology (IO), citing the latest studies as presented at ESMO 2018 in Munich only days before. The first data regarding neoadjuvant use of pembrolizumab and chemotherapy for locally advanced urothelial cancer (C. Holmes et al) were briefly summarised by Necchi, who gave the personal recommendation. “In selected patients, we should really be brave and continue immunotherapy instead of complicating the process with chemotherapy. Patients are also often happy to not receive chemotherapy.”

Speaking generally and looking to the near future, Necchi pointed out that pathologic response rates observed in single-agent IO studies are promising: “but we need to confirm the association with long-term improved outcomes.”

“Chemotherapy plus IO combinations are now even more attractive in neoadjuvant setting. IO, on its own or combined, is poised to make a significant impact in the management of localised muscle-invasive disease. This requires the right trial design.”

Prof. Van Poppel latched onto Prof. Necchi’s point about recommending single rather than combined immunotherapy. Necchi conceded that there was also a commercial dimension at play between the academic perspective and the perspective of the companies. “The bigger trials are initiated by companies that have an interest in offering chemotherapy options and these trials are currently pushing developments in that direction.”

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“The POUT trial is the first randomised trial in this niche area. It has shown an absolute improvement of 16% (95% CI:2-30%) in disease free survival (DFS) at two years in favour of chemotherapy and a similar benefit for metastasis-free survival (MFS). Data collection for overall survival is ongoing. We have had retrospective data in this area; now we have robust data to guide treatment and to change practice,” said Dr. Birtle.

The study won the first prize for Best Abstract in Oncology at the 33rd Annual EAU Congress held in Copenhagen, Denmark early this year.

The POUT study

The POUT trial was coordinated by the Clinical Trials and Statistics Unit at The Institute of Cancer Research (ICR-CTSU) and between May 2012 and November 2017, 261 patients were randomised to receive either chemotherapy (131) or surveillance (129) at 57 hospitals across the UK. POUT examined the role of post nephro-ureterectomy (NU) treatment for UTUC and whether adjuvant chemotherapy improves DFS for patients with histologically confirmed TCC pT2-pT4 pN0-3 M0 or pTany N1-3 M0, WHO PS 0-1 who were fit to receive chemotherapy.

The POUT findings concluded that adjuvant platinum based chemotherapy should be considered as a new standard of care; it is tolerable for patients and improved MFS in UTUC. Recruitment to the POUT trial was terminated early because of efficacy was met in favour of chemotherapy; follow up for overall survival continues.

Potential and possibilities

In terms of possible new breakthroughs in the coming years, Dr. Birtle anticipates that there could be data on adjuvant treatment with checkpoint inhibitors: “We will have data on adjuvant treatment with checkpoint inhibitors in bladder cancer –  the studies are not powered sufficiently for the UTUC cohorts as these were added post hoc so they won’t truly answer how effective check point inhibitors are in UTUC adjuvantly. Similarly, studies in metastatic urothelial cancer will read out, comparing immuno-oncology (IO) versus chemotherapy versus a combination.” Dr. Birtle is currently working on a successor trial to POUT.

Working together

According to Dr. Birtle, the lack of access to data is crucial for researchers since it leads to bottlenecks and delays the progress of current trials, which in turn affects the speed of offering curative therapies to cancer patients. She added, “The barriers among countries (even pre-Brexit) makes true collaborations challenging. We don’t want competing trials, we want to run studies together across countries to give us data to move onto the next trial. Pooling our individual biobanks so that we can mine the wealth of translational work is vital.”

“POUT is a triumph of UK collaboration. 71 UK sites were opened and 57 recruited at least one patient.  We need to make sure that other countries can join together and reduce bureaucracy so that we can recruit to important trials quickly and improve options for patients. We should all view research as the core business as it improves what we can do for patients. It should never be seen as an optional extra.”

On multidisciplinary team (MDT) work, she commented that forums and events like the EMUC significantly contributes to a more effective network among cancer specialists. “Meetings like this are so important – not just to keep up to date but to hear what is going on, what the next stages might be, and to network with colleagues so that we can join in cutting-edge research at an early stage.”

EMUC as a platform

At EMUC18, the POUT update will be taken up during the session “New trials update: What we need to know.” Also to be presented during this session are key updates on the CARMENA, STAMPEDE, PRECISION and HORRAD trials. Biostatistician Laurence Collette (BE), surgical oncologist Ganesh Palapattu (US), and radiation oncologist Alberto Bossi (FR) will chair the session which will be held on Saturday, 10 November.

Annually held as a platform for scientific updates and professional networking for urological cancers experts, EMUC focuses on improving MDT work and is organised by three of Europe’s frontline professional associations – the European Society for Medical Oncology (ESMO), the European Association of Urology (EAU), and the European SocieTy for Radiotherapy & Oncology (ESTRO).

EMUC18’s Scientific Programme will address clinical and research issues with the interactive sessions to be led by opinion leaders, expert lecturers and speakers from across Europe and North America. From decision-making dilemmas to future prospects in drug development, participants will not only contribute to the discussion through direct voting but can also join workshops, special courses, hands-on training and other specialist forums.

Want to know more about EMUC18? For additional information on the Scientific Programme, Venue and Registration, visit the meeting website.

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