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Risk management in cancer clinical trials – new recommendations for imaging biomarkers
In recent years, there has been rapid growth in the use of molecular and functional imaging for clinical cancer research. Experts have focused their attention on devising risk management methodologies to optimize the use of such modalities. However, the rapid pace of progress in technology and new insights into cancer mean that risk management itself is permanently under re-development.
RECIST: driven by growth of imaging techniques
At present, the most widely used tool to assess treatment response and risk versus benefit in clinical trials is known as RECIST (Response Evaluation Criteria In Solid Tumors).
The original RECIST criteria date to the year 2000, following a collaborative effort between the US National Cancer Institute (NCI), the European Organization for Research and Treatment of Cancer (EORTC) and the Cancer Institute at Canada Clinical Trials Group.
RECIST was the first major effort since World Health Organization definitions in 1979, published in the WHO Handbook. By the early 1990s, the WHO definitions began to confront major limitations, above all with respect to changes in the size and minimal number of ‘measurable’ lesions. In turn, the key reason for this was the rapid development and growth of new imaging techniques such as CT and MRI, as well as confusion about how to integrate their far more precise data into response assessments.
Criteria are tumour-centric, not patient-centric
RECIST criteria define when treatment leads to tumours improving, stabilizing or progressing. They are principally intended to evaluate tumour response as a prospective endpoint in clinical trials. Although concurrent benefits are obtained by clinicians who use imaging studies to determine the success of a particular therapy and whether to continue or discontinue it, this is not the intention of RECIST. Indeed, one of the most significant elements of RECIST is that the criteria are tumour-centric, rather than patient-centric.
NCI guidelines in mid-2000s
The mid-2000s witnessed some technology-specific imaging guidelines for clinical trials. The best known of these followed workshops by the Cancer Imaging Program of the US National Cancer Institute.
They included guidelines on dynamic contrast MRI (DCE-MRI) and on the use of 18F Fludeoxyglucose (FDG) PET as an indicator of therapeutic response in clinical trial patients.
2009: RECIST 1.0 upgraded to 1.1
The RECIST criteria were updated in 2009. While the original set are now commonly known as RECIST 1.0, the revised criteria are called RECIST 1.1.
The reasons for the revisions were manifold. During the 2000s, numerous prospective analyses confirmed the validity of substituting uni-dimensional for bi-dimensional or even three-dimensional criteria. In spite of some exceptions (such as mesothelioma), uni-dimensional criteria seemed to perform adequately in solid tumour studies up to phase II.
However, several questions had also arisen over the past decade and these demanded further clarity. Key questions, which the revised RECIST guidelines address, include:
- whether it was possible to assess fewer than ten lesions without affecting the overall assigned response for patients
- making an assessment of lymph nodes
- ways to apply RECIST in randomized phase III trials where progression rather than response is the primary endpoint (especially for patients who do not demonstrate measurable disease)
- the applicability of RECIST in trials of targeted non-cytotoxic drugs
- the need for response confirmation
Qualified endorsement of FDG-PET
Finally, RECIST 1.1 provides guidelines on newer imaging technologies, especially FDG-PET (where preliminary efforts on its use as a “qualified biomarker” had already been made by the Cancer Imaging Program of the US National Cancer Institute in 2006).
Although RECIST 1.1 cautions that FDG-PET response assessments need additional study, the revised criteria do note that “it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible ‘new’ disease). RECIST 1.1 also provides an algorithm to identify new lesions from FDG-PET imaging.
As mentioned previously, one of the key questions considered by the Working Group revising RECIST was to determine whether it was appropriate “to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI.” The Working Group concluded that there was (still) not enough standardization or evidence “to abandon anatomical assessment of tumour burden.” The only exception was to use FDG-PET imaging as an adjunct to determination of progression, and pursue appropriate clinical validation studies for new technologies.
Imaging hybrids such as PET-CT, however, remain strongly qualified. The revised criteria state that “the low dose or attenuation correction CT portion of a combined PET–CT is not always of optimal diagnostic CT quality for use with RECIST measurements.”
Immunotherapy poses specific challenges
Almost in parallel to the RECIST revision, another recent initiative has sought to take into account the fast-emerging new field of immunotherapy.
Immunotherapy is also known as biological therapy and biotherapy and uses the body’s immune system to produce anti-tumour effects and fight cancer. It works by either stimulating a patient’s immune system to attack cancer cells or providing the immune system with what it needs, such as antibodies, to fight cancer.
Examples of immunotherapeutic agents include monoclonal agents, cancer vaccines and man-made versions of cytokines, the chemical agent in immune cells.
However, the clinical response to an immunotherapeutic agent can sometimes manifest only after “an initial increase in tumour burden or the appearance of new lesions (progressive disease).” In other words, such drugs would fail in clinical trials which measured response using WHO or RECIST criteria, because they fail to take account of the time gap in many patients between initial treatment and the apparent action of the immune system to reduce the tumour burden. Such a failure would occur in spite of the fact that these drugs ultimately prolonged life.
irRC Criteria
The so-called irRC (Immune-Related Response Criteria) consists of a set of published rules for evaluating anti-tumour responses with immunotherapeutic agents. It seeks to define when tumours respond, stabilize or progress during treatment. irRC was developed by a team of researchers from the US and Austria, France, Germany and Italy on the basis of experience with the CTLA-4 function blocking antibody ipilimumab in phase II trials in patients with advanced melanoma. Other immunotherapeutic anti-cancer drugs to have recently been approved in the US and Europe include pembrolizumab, sipuleucel-T and nivolumab. These drugs offer considerable promise for patients with advanced lung cancer, prostate cancer, renal cell carcinoma and melanoma.
Molecular and functional imaging
The advent of new drugs offering new promise for some of the toughest cancers is likely to continue in the coming years. Meanwhile, imaging biomarkers are expected to provide invaluable information on disease staging and characterization. Increasingly, researchers are enthused about the fact that molecular and functional imaging permits the detection or absence of response within days after the onset of treatment. In turn, early stage detection makes it feasible for non-responding patients to avoid unnecessary toxicity associated with therapy.
The development and and use of imaging biomarkers, however, is a complex process with complex data acquisition methods as well as specific regulatory issues for the trialling of new imaging agents. Quality control issues associated with image processing and the use of multi-vendor software are major, additional challenges – which can impact on data standardization. Such problems are clearly going to be more acute in the case of multicentre international trials.
Improving the use of imaging biomarkers
At the end of 2015, experts from Europe and the US published a paper in ‘Lancet Oncology’, aimed at “improving the implementation and utilization of imaging biomarkers in cancer clinical trials.” The authors represented the EORTC and the United States NCI – both of which have been associated with RECIST – as well as the European Society of Radiology (ESR) and the European Association of Nuclear Medicine (EANM).
The authors explicitly noted the promise of novel imaging modalities on disease staging and characterization and the rapid detection interval offered by molecular and functional imaging. Their aim is to “propose a practical risk-based framework and recommendations on imaging biomarker-driven trials that allows identification of risks at trial initiation so that resources can be better allocated and key tasks prioritized.” The paper also recognizes the “essential roles” played in clinical trials by other stakeholders such as “regulatory bodies, pharmaceutical companies, and patients.”
Dr Yan Liu, lead author of the paper and the Head of Translational Research, Radiotherapy and Imaging at EORTC, noted that cancer clinical trials have always sought to find a right balance between maximizing data quality and minimizing cost. Here, he said, “risk management can be an extremely helpful tool, because it can help us to prioritize, reduce costs, and decrease attrition rates.”
The Risk Assessment Plan would be best realized via a multi-disciplinary team which includes imaging experts, oncologists, as well as study project managers.
It should be reviewed and updated throughout a trial.
Towards personalized medicine
The need for robust risk management approaches in imaging was illustrated shortly before publication of the above paper in ‘Lancet Oncology’. On December 9, scientists at the University of Manchester and the Institute of Cancer Research in London announced development of a new oxygen-enhanced MRI test which mapped areas of hypoxia (or oxygen deprivation) within tumours – often a sign that a cancer is growing aggressively. The aim of the test is to enable doctors identify more dangerous tumours before they spread around the body – and tailor treatment accordingly.
Researchers used the technology to produce hypoxia maps within tumours in mice. It is now being further developed through clinical studies of cancer patients. According to study co-author, Dr. James O’Connor of the University of Manchester: “There is currently no validated, affordable and widely available clinical imaging technique that can rapidly assess the distribution of tumour hypoxia.” He hoped that oxygen-enhanced MRI will not only help identify the most dangerous tumours, but also assist in the monitoring of treatment response.
On his part, Nell Barrie of Cancer Research UK noted that “this early-stage research in mice will help to find new ways to use existing scanning technology to monitor and personalize each patient’s treatment …”.
Workflow optimization: a technological challenge
Hospitals have witnessed successive waves of information and
communications technology (ICT) adoption over the past two decades. This has been driven by the rapid pace of development in the fields of computing and the Internet, device miniaturization and mobility. One of the biggest challenges for deployment of new technology in hospitals consists of workflow.
Workflow and health ICT success
Workflow can determine the success or failure of health ICT projects at hospitals for a simple reason: the lower the compatibility of a new system with a clinician
Esaote MyLab: Ultrasound imaging technology tailored for the user
As a leading player in the diagnostic ultrasound market, active since 1983, Esaote has a long experience in developing and fine-tuning ultrasound systems and probes for a broad range of clinical segments.
MyLab Ultrasound solutions are shaped to answer the most demanding clinical needs in many applications: from abdominal to vascular, including musculoskeletal, internal medicine, cardiology, obstetrics and gynecology, as well as interventional ultrasound guidance.
Esaote puts a high effort in designing systems that offer top image quality for confident diagnosis from difficult-to-scan patients up to fully detailed superficial image resolution. This has been achieved over the years through advanced research, with several patents and publications, and effective implementations on the system and also on the probe side, the latter offering a broad choice of in-house made transducers ranging from traditional phased, linear, convex and endocavity to dedicated solutions for surgery and intervention. The Esaote probe family has recently been extended with the brand new High Frequency Hockey Stick probe IH 6-18 and the Biopsy dedicated 0 degree insertion convex transducer SI2C41.
Customizable buttons on the probe body enhance comfort and increase possibilities.
Advanced hemodynamic evaluation tools such as XFlow and HD CFM, tissue stiffness evaluation with ElaXto as well as Virtual Navigator for easy-to-perform real-time fusion imaging are just a few examples of Esaote advanced technologies tailored to meet any requirements up to the most demanding ones.
Virtual Biopsy and Needle Enhancement technology are valuable tools to facilitate needle insertions for simple biopsies as well as percutaneous treatments.
Top level Contrast Enhanced Ultrasound (CEUS) as well as advanced cardiovascular tools such as the 4D XStrain volumetric cardiac deformation analysis tool and the Radiofrequency-based Intima Media Thickness (QIMT) and Arterial Stiffness (QAS) measurement tools are featured, reflecting the
Video laryngoscopy – ease of use and quick training drive acceptance
Introduced in the early 2000s, video laryngoscopy marks the first major development in airway management since the advent of laryngeal mask airways. In 2012, Ron Walls, then the Neskey Family Professor of Emergency Medicine at Harvard Medical School provoked considerable controversy after he
Point-of-care testing in the BRICS
In spite of clusters of world class hospitals in high-end districts of major cities, the BRICS group of large emerging markets (Brazil, Russia, India, China and South Africa) are handicapped by rudimentary healthcare infrastructure in outlying regions and in their countrysides. In addition, even in central urban areas, the growth of new lifestyle diseases threatens to swamp existing facilities.
?Spare parts? for human beings: narrowing the gap between vision and reality
It sounds simple, but remains wishful thinking:
Does CT cause cancer? Assumptions questioned by new evidence
One of the biggest medical controversies in recent years concerns claims about radiation risks from CT (computed tomography) imaging. Although experts have questioned certain facets of such claims, an especially powerful riposte was published in an article late last year in the ‘American Journal of Clinical Oncology’. The authors took great pains to explain that the “widespread belief” about a link between medical imaging and cancer was founded on “an unproven” and “illegitimate” theoretical model, dating to the 1940s.
Media fuels emotion, fear
The emotive nature of the CT and cancer debate may be best illustrated by an Op-Ed in the ‘New York Times’ on January 31, 2014. Its authors are two Professors at the University of California, San Francisco Medical Center – radiologist Rebecca Smith-Bindman and cardiologist Rita Redberg.
The headline of the article, in one of the world’s most influential publications, clearly seeks to draw maximum attention. “We Are Giving Ourselves Cancer,” it says. The opening paragraph continues in the same vein, closing with the observation that “we” are “silently irradiating ourselves to death.” So too does the final sentence of the Op-Ed – that “we” must find ways to use CTs “without killing people in the process.”
Expert oversights
Professors Redberg and Smith-Bindman acknowledge that “medical imaging can be lifesaving.” Their principal argument is that once rare, CTs have now become routine and that the “current high rate of scans” do not correlate to “better health outcomes.” The reasons for growth in CT use are both good and bad: “desire for early diagnoses, higher quality imaging technology,” as well as the “financial interests of doctors and imaging centers.” However, the authors do not even attempt an informed guess about whether good motives outweigh the bad.
In contrast, they state conclusively that there is “evidence of its harms.” This evidence consists of two clinical studies in Britain and Australia where the risks of CT, they say, were “directly demonstrated,” especially in children.
One of their biggest oversights was to avoid mentioning the conclusions of the two studies. Both, in fact, took great care to qualify their verdicts.
Key studies in Britain and Australia qualify judgements
The British study, published in ‘Lancet’ in August 2012, was titled ‘Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study’. It used data on 175,000 children and young adults and found a three-fold increase in the risk of brain tumoUrs and leukemia. However, the cumulative 10-year risk was one excess case of leukemia and one excess case of brain tumour per 10,000 head CT scans.
On its part, the Australian study was published in the ‘British Medical Journal’ in May 2013 and titled ‘Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians.’ The authors found a 24% increase in childhood cancer risk over a 10-year period – from 39 per 10,000 young people to 45, after a CT scan. These findings were, like the British study, put in perspective by an accompanying editorial: the incidence of cancer in children “is extremely small and so a 24% increase makes this risk just slightly less small.” In addition, the authors observed that almost 60% of CT scans were of the brain and “in some cases the brain cancer may have led to the scan rather than vice versa.”
Indeed, unlike the ‘New York Times’ Op-Ed, the two studies provided a balanced view. Above all, they took great care to avoid drawing alarmist conclusions.
The need for balance
The British study stated that “immediate benefits of CT outweigh the long-term risks in many settings and because of CT’s diagnostic accuracy and speed of scanning …, it will remain in widespread practice for the foreseeable future.” Lead author Mark S. Pearce of Newcastle University’s Institute of Health and Society echoed this forcefully, noting that “CT can be highly beneficial for early diagnosis, for clinical decision-making, and for saving lives. However, greater efforts should be made to ensure clinical justification and to keep doses as low as reasonably achievable.”
The Australian study, too, concluded that practitioners “will increasingly need to weigh the undoubted benefits of CT scans in clinical practice against the potential risks to justify each CT scan decision.”
Dosage: wide margins for error
Meanwhile, one of the biggest issues of concern with CT is a lack of clarity – and some uncertainty – about dosage and exposure. The British study, for example, underscored that the increase in risk followed “two or three CT scans of the head” under “current scanner settings” for brain tumours and “five to 10 head CT scans” for leukemia.
Radiologists have in fact not reached a consensus on how to define a dose, according to Michael McNitt-Gray, an associate professor of radiological sciences at the University of California, Los Angeles. Doses per indication vary by institution and by patient size. As a result, no national average is available.
An additional problem is that effective, organ-specific doses relate to how much radiation the body absorbs. However, CT scanners do not report the absorbed fraction, says McNitt-Gray. Instead, they report only what the machine emits, which is less than what is absorbed by the body.
Australian study urges validation of risk model
Nevertheless, in general, there is widespread agreement that CT scans should be limited to situations with a definite clinical indication and that scans should be optimiZed to provide a diagnostic CT image at the lowest possible radiation dose. The editorial accompanying the Australian study in the ‘British Medical Journal’ called for further validation of risk models, and stated that “more accurate risk assessment “can be performed to “better inform imaging decisions.”
Missing nuances
Such nuances seem to have been missed out by the Op-Ed in the ‘New York Times’.
A “single CT scan,” the authors wrote, “exposes a patient to the amount of radiation that epidemiologic evidence shows can be cancer-causing.” They also asserted that CT radiation was “100 to 1,000 times higher than conventional X-rays.”
Their certainty stands in some contrast to a quote from the British study used to justify the authors’ views: The “amount of radiation delivered during a single CT scan,” it said, “can still vary greatly and is often up to 10 times higher than that delivered in a conventional X-ray procedure.”
French study in 2014 raises new doubts
In October 2014, nine months after the ‘New York Times’ Op-Ed, a French study of 67,274 children raised further doubts about the strength of the correlation between CT and childhood cancer. The objective of the study, published in the ‘British Journal of Cancer’, was to estimate how cancer-predisposing factors (PFs) affected assessment of radiation-related risk in CTs.
The authors found that adjusting for PF “reduced the excess risk estimates related to cumulative doses from CT scans” and that “no significant excess risk was observed in relation to CT exposures.” The study concluded that there was a need “to avoid overestimation of the cancer risks associated with CT scans.”
The 2009 NCI study
Aside from the British and Australian studies, an authoritative and oft-cited source for most of the alarms about CT have their origins in a 2009 report from the US National Cancer Institute (NCI). This report was referenced by the authors of the ‘New York Times’ Op Ed, in their statement that “CT scans conducted in 2007 will cause a projected 29,000 excess cancer cases and 14,500 excess deaths over the lifetime of those exposed.”
BEIR and Lifetime Attributable Risk
The NCI figures were based on the US National Research Council’s Biological Effects of Ionizing Radiation (BEIR) report in 2006 and estimated the mean number of radiation-related incident cancers with 95% uncertainty limits (UL).
The so-called BEIR VII model generates what it calls lifetime attributable risk (LAR) factors. These estimate the likelihood of cancer in hypothetical individuals as a function of dose. Multiplying LAR by the number of people exposed to a given dose yields an estimate of expected cancers from that exposure in the population.
BEIR VII was also used by Smith-Bindman, one of the authors of the ‘New York Times’ Op-Ed, who used it in a study of four San Francisco facilities to estimate that one cancer might appear for every 270 middle-aged women undergoing CT coronary angiography, and that women aged 20 who underwent the procedure had twice the risk as middle-aged women.
BEIR and linear no-threshold: assumptions challenged
The so-called BEIR VII model postulates that there is no safe level of ionizing radiation exposure. As a result, it is assumed that carcinogenic effects follow a linear dose response – which means that even the smallest exposure carries some level of cancer risk. It is precisely this baseline assumption which has been challenged by a recent article in the ‘American Journal of Clinical Oncology’. The article, published in November 2015, is titled ‘The Birth of the Illegitimate Linear No-Threshold Model: An Invalid Paradigm for Estimating Risk Following Low-dose Radiation Exposure.’
BEIR VII is based on the linear no-threshold (LNT) model. However, risk estimates based on LNT “are only theoretical” and “have never been conclusively demonstrated by empirical evidence,” according to lead author James Welsh, Professor in the Department of Radiation Oncology of Loyola University Chicago Stritch School of Medicine.
Dosing fruit flies after 70 years
The article painstakingly re-examines the original studies, dating back over 70 years, which led to adoption of LNT. The experiments involved exposure of fruit flies to various doses of radiation, and concluding there was no ‘safe’ level of radiation – the basis of the LNT model which is used to this day. However, such a conclusion was unwarranted as the experiments had not been done at truly low doses and there is growing evidence that the human body has evolved the ability to repair damage from low-dose radiation – such as that which occurs naturally in the environment.
Indeed, as the authors argue, the first study to expose fruit flies to low-dose radiation was conducted only in 2009 and its findings did not support the LNT model. Other sources too suggest that the dose-response relationship between radiation and somatic mutation has a threshold, and that biological defence mechanisms come into play at low radiation levels.
Abandoning LNT
Use of the LNT model, according to the authors of the article in the ‘American Journal of Clinical Oncology’, dissuades many physicians from using appropriate imaging techniques and “discourages many in the public from getting proper and needed imaging, all in the name of avoiding any radiation exposure.” They conclude that the LNT model “should finally and decisively be abandoned.”