Addressing the research methodology challenges in rare cancers

The world of rare cancers is a strange one. For patients there is no such thing as rarity – ‘I’ve got this disease and that’s not rare is it?’ For doctors there are specific challenges, mostly around the absence of evidence which gives some certainty to their recommendations and decisions. This is what makes research so important in rare diseases.

At the same time research is difficult. Getting adequate numbers of patients to include in a study which can deliver a level of significance which points to certainty is a challenge. You either need to take a long time over the study or you need to widen the catchment to attract as many patients as you can from as many treatment centres as you can. Both of these issues carry costs, create challenges in consistency of observance of protocols, and maintaining the quality of the data gathered becomes complicated.

It is therefore encouraging to see the article in the latest edition of the European Journal of Cancer addressing the subject. It looks at the practical challenges of trial design in rare cancers from the experience of the International Rare Cancers Initiative. This is a project involving NCI (USA), EORTC (Europe) and Cancer Research UK (with the NIHR Cancer CRN) to develop key studies in very rare diseases.

The lead authors are Jan Bogaerts and Matt Sydes. Jan is the EORTC’s senior methodologist and Matt has a similar role with the MRC’s Clinical Trials Unit. The long list of authors includes the PIs on the various studies and other key trial designers, with Prof Matt Seymour from NCRI/NCRN as final author.

As a description of the decision-making in trial design for rarer cancers it is a masterpiece. The problems and the solutions tested to address them are described in detail (enough for a statisticiain in most cases). This is a recommended read for anyone involved in clinical trial development. It is a free download.

Three of the eight trials developed so far are in sarcomas – two uterine and one for Ewings sarcoma. There are other trials in development and these include one for Desmoplastic Small Round Cell Tumour (DSRCT), a sarcoma of late teenage years. DSRCT affects perhaps 15 patients each year in the UK and there are no treatments with proven efficacy for those who relapse after surgery.

http://bit.ly/172QovL

While considering the challenges of research in rarer cancers a superb analysis of the issues was recently published in Annals of Oncology. This too is well worth the read. The principle authors include Dr Paolo Casali and Prof Jean-Yves Blay. The consensus group working with them on the paper includes a wide range of professionals and patient group representatives.

http://bit.ly/1DokNBn

 

Quality Standard sets new challenges

The publication of the Quality Standard for Sarcoma by NICE open up a new set of dialogues in how to improve the standards of sarcoma care in England and Wales. The NICE standing committee on quality recruited six members of the sarcoma community to advise it and to be part of the decision structure during the development of the standards so, hopefully, they are rooted in the realities of daily provision of care and treatment. The standards can be found at: www.nice.org.uk/guidance/qs78/chapter/list-of-quality-statements

The first standard calls for clear pathways in diagnosis. This is something for the wider NHS to develop, informed and supported by sarcoma MDTs. There was discussion about the value of local diagnostic services and a real example of development work from Yorkshire where DGH ultrasound operators play an important part in the diagnostic pathway. Other areas are also making important steps in improving GP awareness, for example. The hope is that other commissioners and NHS managers will look at how local services can develop, working with their local sarcoma MDT.

The second standard re-affirms the requirement in the NICE IOG that all sarcomas should be treated in consultation with a sarcoma MDT. It does it however in slightly different terms and gives a Sarcoma Advisory Group (the local oversight group in the NHS) the power to determine which treatments for which groups of patients can be managed outside a sarcoma MDT. In the case of children, for example, the decisions will be easy because the current systems work well. In the case of gynaecological sarcomas those in the gynae community who are reluctant to refer their patients (often until it is too late for any benefit to be gained) can be brought into line (we hope).

Statement number three is an important one for the development of the sarcoma treatment network. Sarcoma MDTs must make public their skills and the pathways they observe. Clearly this will be valuable information for patients. It should become obvious that having a multitude of different sarcoma oncologists in different locations all treating a few gynae patients (for example) is not a proper way forward. Every MDT will need to decide what it handles and what it refers on and to whom – very much in the same way that they may diagnose a bone tumour but pass it on to one of the recognized bone centres. I hope we will see development of regional experts in some areas, giving one centre a critical mass on which to develop a specific expertise. This can only help patients in the longer term. It might also be good for some careers. It is important that MDTs recognise their strengths and where they may be weaker and do not try to maintain a “we can do everything” stance. The NHS England Sarcoma CRG will have a role here, alongside SAGs.

The next statement can be linked to the previous one. Retroperitoneal sarcoma patients have their best chance of survival with radical surgery at the first intervention. There is currently a trial underway to see whether radiotherapy may improve that. There have been too many patients treated conservatively, followed by recurrence and decline. Data from international series also show that high volume centres which can develop expertise, offer real benefit. The NICE rules forbade the quality standard from being specific about this but the Quality Statement is an open invitation to professional associations, the NHS England Sarcoma CRG and to commissioners to put in place structures which meet the Quality Standard and improve outcomes.

Statement number five recognises that there may be unplanned resections of sarcomas but once diagnosed patients must be referred for treatment to a sarcoma MDT. Most limb/trunk tumours will be diagnosed and treated by a surgeon who is a core member of an MDT but in other anatonical sites it is not enough for a diagnosis to be made and surgery to go ahead locally. The sarcoma MDT must be brought in to discuss the treatment plan (Statement 2) and for planned surgery in the anatomical specialty the sarcoma MDT must nominate the surgeon as an extended member of the MDT.

The final statement makes it a requirement that there is a nominated key worker for every sarcoma patient. This includes patients whose care and treatment is co-ordinated through a site MDT (such as Upper GI or Gynae). It makes it an imperative that in agreeing that a site MDT can look after a patient this statement is observed by the site MDT. There is also the implication that a single person in a sarcoma MDT is not adequate for this role. Illness, holidays, training all take people away from their duties and it is essential that patients do not lose this kind of contact. So trained cover is a minimum requirement.

At first sight these standards look quite gentle. Close examination shows that there are some big nitty-gritty issues hidden in them, as I am sure you can see, and it will be something of a challenge to attitudes and behaviour to make this work. The sarcoma network in England has been slowly coming together and with the BSG now properly constituted and ready to take some actions and decisions, together with a Sarcoma CRG which is clinically led and has a role with commissioners, we have a structure which could initiate action and deliver new benefit to patients.

Cast into oblivion

Among the cancer drugs refused continuing funding through the revised Cancer Drugs Fund are three treatments for sarcoma, one of the groups of rare cancers.

Sarcoma patients are used to discrimination through rarity – they have suffered for decades. When a drug company decides to test its new treatments in sarcoma it is welcomed, but few drugs survive the trials process. When one does survive, showing benefit to patients, it is fair to expect it to be accepted by funding bodies such as the NHS.

Two recent drugs that have come through this process are pazopanib (Votrient) for advanced soft tissue sarcoma and regorafenib (Stivarga) for 3rd line use with GIST. Another drug, pegylated doxorubicin (Caelyx) had shown real value for the treatment of cardiac sarcoma patients.

The first two have been refused appraisals by NICE because it is judged they are applicable to so few patients that the costs would be disproportionate. The third will never be appraised by NICE because it is an off-label treatment for which a licensed indication is unlikely when only a handful of patients are treated each year.

All have now been refused funding by the Cancer Drugs Fund. I estimate that they account for between £1 to £2m of the CDF budget and more than 10% of the refused drugs.

They have no other route to NHS approval. They represent half of the new generation drugs licensed for sarcoma. Patients have been benefiting but now, using criteria valid for commoner cancers but not for rare situations, they have been de-listed.

This is blatant discrimination against rarity.