Evidence-based Medicine in Oncology: Molecular Imaging's Expanding Role

Evidence has clearly shown the impact of PET/CT imaging in initial treatment strategies—diagnosis and initial staging as well as in the subsequent treatment strategies—treatment monitoring and restaging/detection of suspected recurrence in various cancers. The molecular imaging community needs to work with industry and regulators to emphasize that patient-focused care benefits everyone.

Evidence-based medicine (EBM) seeks to homogenize patient groups and disease biology by seeking to categorize and define them by a single parameter. The beauty of molecular imaging is its ability to visualize and characterize the heterogeneity that exists in most diseases in most patients, says Rodney J. Hicks, MD, professor at the departments of medicine and radiology, the University of Melbourne, and director of the centre for molecular imaging and head of molecular imaging and targeted therapeutics laboratory at the Peter MacCallum Cancer Centre in Melbourne, Australia.

Impact of PET in oncology

There are numerous examples to show evidence of the role played by PET/CT in oncology imaging. In diagnosis, for example, it has been shown through prospective studies that it is appropriate to obtain PET/CT scan even before the biopsy for a suspected lung cancer, says Michael Steinberg, MD, the president-elect of American Society for Radiation Oncology (ASTRO) and professor and chair of the department of radiation oncology at the David Geffen School of Medicine at University of California, Los Angeles.

Molecular imaging with PET/CT appears to be the modality of choice for regular and systematic assessments of tumor metabolic activity and detecting resistance at the earliest opportunity, shares Sandip Basu, MBBS, head of nuclear medicine academic programme of the radiation medicine centre at Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe, Mumbai, India. A classical example of this is gastrointestinal stromal tumor patients being treated with imatinib mesylate, says Basu.

The ability to document the presence of a molecular target or the downstream effects of signaling through that pathway before treatment and their abrogation during treatment are likely to be one of the most important future applications of molecular imaging, says Hicks. A major focus of his research is in development and validation of novel molecular targeted therapeutic agents including various antibody and small molecule receptor kinase inhibitors and radiopeptides.

There also is evidence to show that PET/CT is superior to CT alone in radiation therapy planning for many head and neck cancer patients. By using the PET/CT for planning of the radiation therapy, you not only get the cross-sectional anatomy seen on CT, but also the metabolic activity noted on the PET scan, shares Steinberg. For example, a CT scan of lymph nodes in head and neck isn’t called positive until it is greater than a centimeter while a PET/CT can show uptake in a normal sized lymph node, suggesting the presence of cancers in those areas which may allow a radiation oncologist to redefine the dose plan.

Evidence development also is ongoing on new tracers that reflect other molecular processes where FDG is either unhelpful or limited by physiological uptake. Hicks group uses the amino acid analogue ¹⁸F-fluoroethyltyrosine (FET) for brain tumor imaging; the proliferation marker ¹⁸F-fluorothymidine (FLT) to assess bone marrow reserves and distribution in heavily pretreated cancer patients being considered for further chemotherapy or radiotherapy; the choline analogue 18F-fluorocholine (FCH) for patients with rising prostate specific antigen levels but negative conventional imaging; and ⁶⁸Ga DOTA-octreotate for staging and therapeutic response assessment in patients with neuroendocrine tumor. “We have used ¹⁸F-fluoroazomycin arabinoside (FAZA) for hypoxia imaging in clinical trials and potential apoptosis imaging agents and a new melanoma imaging agent are in pre-clinical trials,” he adds.

‘When, how often, in what sequence’

The key policy and economic questions for oncology imaging are “when, how often and in what sequence should advanced imaging in patients with suspected or confirmed cancers be done and what methods are feasible to address this question in a timely manner?” poses Bruce E. Hillner, MD, chair of the National Oncologic PET Registry (NOPR) working group and professor and eminent university scholar in the department of internal medicine at Virginia Commonwealth University in Richmond, Va.

“Technology is constantly changing and the use of a prospective registry is something ideal for radiation oncology,” says Steinberg. “The major challenges in EBM are the funding of studies and getting patients to participate in studies particularly when randomization is required.” He says he believes that all stakeholders including the payors, providers and medical device vendors need to pay for the gathering of evidence or else medicine will not progress on an evidence-based path. “Non-government insurance companies for the most part do not fund these studies, yet they create a Catch 22 by denying coverage due to lack of evidence. From a contractual point of view, of course they are correct in not participating in the gathering of medical evidence, but what I am suggesting as part of their social contract in being part of the healthcare continuum, is that they should be required to participate in the development of medical evidence,” says Steinberg.

Australian scenario

The methodology used for NOPR was actually pioneered in prospective studies performed at the Peter MacCallum Cancer Centre in Melbourne, Australia, in the late 1990s and early 2000s, says Rodney J. Hicks, MD, head of molecular imaging and targeted therapeutics laboratory at the Centre. These were adapted from pioneering but retrospective studies performed by Peter E. Valk, MD, soon after the introduction of whole-body PET scanning. In 1999, the Medicare Services Advisory Committee (MSAC), the main national body responsible for assessing medical technology in Australia received applications from Wesley Hospital, in Brisbane, Australia, and the Peter MacCallum Cancer Institute, seeking extension of Medicare funding for the use of PET. This led to a National Review of PET that has been the subject of much controversy with its findings challenged by Hicks and others in a number of Senate hearings. Nevertheless, the Australian government did fund a National PET Data Collection Project to evaluate the clinical impact of PET in a number of diseases and those indications that have been added to the Medicare schedule.

However, some indications studied have been taken off, erroneously in Hicks opinion, because they failed to perform adequately for the indication evaluated. For example, the restaging of esophageal cancer after neoadjuvant chemoradiation is no longer allowed because FDG PET/CT has been shown to have imperfect accuracy compared to pathology in identifying residual disease. What the regulators and the “experts” appointed to review the data don’t realize is that we never do the post-treatment scan to confirm a complete pathological response, which is beyond the spatial or contrast resolution capability of any imaging technology, but rather to exclude the presence of progressive disease outside the radiation treatment volume (which occurs in more than 25 percent of cases), making surgery futile, he comments. There is much concern over the most recent recommendations to limit lymphoma patients to two scans and to only allow restaging in patients with confirmed relapse. FDG PET/CT has become a routine staging and therapeutic monitoring tool in lymphoma with high management impact and clinicians can’t even conceive of managing high-risk patients without this information in my facility, Hicks adds.

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Success Story: The National Oncologic PET Registry (NOPR)

	Michael Steinberg, MD, President-elect of the American Society for Radiation Oncology (ASTRO) and Professor and Chair of the Department of Radiation Oncology at the David Geffen School of Medicine at University of California, Los Angeles

“The National Oncologic PET Registry (NOPR) is a wonderful example of physician/industry [collaboration] and in this case a government payor getting involved in developing evidence on the value and efficacy of PET/CT in oncology,” says Michael Steinberg, MD, president-elect of the American Society for Radiation Oncology (ASTRO) and professor and chair of the department of radiation oncology at the David Geffen School of Medicine at University of California, Los Angeles.

In the 1990s, the U.S. Centers for Medicare & Medicaid Services (CMS) adopted a new evidence-based approach for making coverage determinations that requires peer-reviewed scientific evidence to document that new technology leads to changes in patient management and to improved health outcomes for Medicare beneficiaries. Starting from January 2005, PET scans were covered by Medicare for diagnosis, staging, and restaging for esophageal, head and neck, non-small cell lung carcinoma, and colorectal cancers, and lymphoma and melanoma (excluding regional lymph node evaluation). Reimbursement for PET also was approved for specific indications in breast, cervical, and thyroid cancers. Coverage for all other cancers and indications required participation in the Coverage with Evidence Development (CED) program.

In response to this CMS policy, the Academy of Molecular Imaging (AMI) in collaboration with the American College of Radiology Imaging Network (ACRIN) developed a CED program known as the NOPR, a nationwide prospective medical registry that started May 8, 2006, and is designed to systematically collect clinical and demographic data on the usefulness and impact of PET and PET/CT in previously noncovered cancer types and indications.

NOPR published results from 22,975 studies at 1,178 centers over a one year period in May 2008 issue of the Journal of Clinical Oncology. The investigators reported that PET or PET/CT resulted in a change in intended patient management in 36.5 percent of cancer cases. In a subsequent study published in the December 2008 issue of the Journal of Nuclear Medicine, the NOPR investigators reported on the relationship between cancer type and impact of PET on intended management. The study included data from 40,863 PET studies done at 1,368 centers. Physicians changed their intended management in 38 percent of cases by using PET or PET/CT and the frequencies ranged from 48.7 percent for myeloma to 31.4 percent for non-melanoma skin cancer.

The impact of PET or PET/CT on expected management during cancer treatment using NOPR data was published in the January 2009 issue in the journal Cancer. Data were available from 8,240 patients who had 10,497 treatment-monitoring PET or PET/CT scans at 946 centers; these studies were used to monitor chemotherapy alone (82 percent), radiation therapy alone (6 percent), or combined-modality treatment (12 percent). Ovarian, pancreatic, and lung cancers accounted for 37 percent of the cohort. In 54 percent of scans, the pre-PET or PET/CT summary stage was metastatic disease. The physicians indicated that PET or PET/CT enabled 91 percent of their patients to avoid future tests. Post-PET or PET/CT intended management led to switching to another therapy in 26 percent to 28 percent, adjustment of the dose or duration of therapy in 16 percent to 19 percent and switching from therapy to observation/supportive care in 6 percent.

As of March 31, 2009, NOPR had compiled data for 130,167 patients with 1,891 U.S. PET facilities participating. Partly due to data gathered by NOPR, in April 2009 CMS announced a new coverage framework for PET and PET/CT to combine diagnosis and initial staging into “initial treatment strategy,” and restaging/detection of suspected recurrence and treatment monitoring into “subsequent treatment strategy.” The new national coverage determination expanded coverage to lift the CED requirement for initial treatment evaluation for nearly all tumors, while maintaining data collection for subsequent treatment evaluations for a range of solid tumors. On August 4, CMS issued a decision memo stating that the national coverage determination manual will be changed to remove the current absolute restriction of coverage to ‘only one’ FDG PET  scan, and local Medicare administrative contractors will have discretion to cover (or not cover) any additional FDG PET  or PET/CT scan for initial treatment strategy in solid tumors and myeloma.

Radiation therapy planning and reimbursement
Expanded coverage is a significant gain, but the single-scan limit for initial treatment evaluation is problematic for radiation therapy planning. “That’s a problem we run into and not so much with Medicare but with non-government payors and also Medicaid in some states,” says Steinberg.

The first scan for diagnosis or staging is performed differently from a technical point of view than the second scan required for radiation therapy planning. In the planning scan, the CT scan and the PET scan need to be co-registered at the same time and done with millimeter precision. The scan must be done in the exact treatment position or it would be inaccurate, says Steinberg.

In radiation therapy, we don’t perform in-treatment interval PET scans to get the response partially because the radiation itself increases the metabolic uptake, notes Steinberg. There are guidelines noting what interval one should do a PET scan for follow up after radiation therapy. In some diseases it makes sense to get the PET scans at closer intervals, particularly when a salvage intervention is possible. In other diseases where you don’t have salvage intervention or the pace of the disease is slower, the interval should be longer, suggests Steinberg.

“In head and neck cancer for example, we wait eight to 12 weeks before obtaining a baseline PET/CT scan and we tend to go a bit longer rather than shorter as we don’t want to see evidence of the previous treatment—surgical or radiation,” shares Steinberg. If there is no disease then we would probably wait six months to do a physical exam, but if we continue to see residual disease, a PET/CT scan might be ordered again in six to eight weeks because you may need a surgical intervention, notes Steinberg. Where the conflict comes in is when the evidence that the insurance company perceives does not come together with the clinical judgment of the treating physician. Somewhere in between is the balance of clinical judgment and existing evidence together to decide when an individual patient needs an individual repeat scan, says Steinberg.

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Is there a link between EBM & Personalized Medicine?

	Sandip Basu, MBBS, Head of Nuclear Medicine Academic Programme of the Radiation Medicine Centre at Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe in Mumbai, India

The answer is yes, says Rodney J. Hicks, MD, professor at the departments of medicine and radiology, the University of Melbourne, and director of the Centre for Molecular Imaging and head of Molecular Imaging and Targeted Therapeutics Laboratory at the Peter MacCallum Cancer Centre in Melbourne, Australia, but it requires a total realignment of perspective. “We need highly personalized selection and monitoring of patients within clinical trials to establish the evidence that will guide the treatment of individual patients,” says Hicks. He prefers to call it science-based medicine.

Sandip Basu, MBBS, head of nuclear medicine academic programme of the radiation medicine centre at Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe, Mumbai, India, believes that a synergistic and probably incremental link between EBM and personalized medicine will ultimately improve patient management. “Tailoring therapeutic approaches and regimens by molecular imaging, with PET/CT at its forefront, would enable disease management at the individual level and this modification would hopefully further strengthen the evidence-based approach in oncology,” he wrote in an article published online August 10, 2010, in Nature Reviews Clinical Oncology.

There is an inherit conflict between personalized medicine and an inflexible approach to evidence-based medicine, says Michael Steinberg, MD, president-elect of the American Society for Radiation Oncology (ASTRO) and professor and chair of the department of radiation oncology at the David Geffen School of Medicine at University of California, Los Angeles. In rare diseases, large, high-level trials cannot be run. Steinberg takes it one step further, using prostate cancer as an example. Prostate cancer is in actuality not one disease but many diseases. Right now prostate cancer is categorized by various risk groups based on the histology, the prostate specific antigen measurement at presentation and the clinical exam findings.

In the future, Steinberg believes we will be using genomics or proteomics to identify many different types of prostate cancer with different natural histories and response to treatment. Developing evidence in a traditional way then becomes very difficult and complex. Large registries will be needed to gather evidence which would require sufficient infrastructure at the individual offices, hospital departments and academic medical centres, he says.

The way of the future
The availability of a plethora of molecular targeting agents will increase the scope for molecular imaging specialists to be directly engaged in multidisciplinary cancer care, Hicks predicts. “Molecular medicine is coming and molecular imaging is its natural partner. It draws together the link from genetic defect through aberrant protein function to cellular transformation and development of a lesion.”

Genomics and proteomics are the primary data, but molecular and anatomical imaging techniques are the integrating devices, shares Hicks.

Drugs that are effective in only a subgroup of patients will be less expensive to validate in clinical trials and more likely to get to market if cohort enrichment can be achieved through judicious use of molecular imaging and correlative tissue biomarkers, adds Hicks. This will benefit the patients, healthcare providers, and the pharmaceutical industry because the drugs that come to market will be cheaper because development time and costs will be lower. Therapies will be better selected, planned and monitored. This will reduce futile treatment and limit toxicity in patients, adds Hicks.

The molecular imaging community needs to work with industry and regulators to emphasize that patient-focused care benefits everyone, says Hicks. “We have a choice. We need to gather evidence, prove efficacy, gather information about cost to prove value and that’s where the future is,” sums Steinberg.