Too Many Scans for Aggressive Lymphoma in Clinical Trials

Alexander M. Castellino, PhD

February 26, 2015

Clinical trials do not mirror what is done in clinical practice when it comes to the number of scans required for patients with aggressive lymphoma. For patients who are well, in complete remission, and are treated with curative intent, increasing the number of scans to determine disease progression (as required in clinical trial protocols) is unnecessary and increases risk for second primary malignancies without providing any benefits, say a group of clinicians from Australia.

These concerns are expressed by medical oncologists Eliza A. Hawkes, MD, and Geoff Chong, MD, and hematologist Andrew Grigg, MD, all from the Olivia Newton-John Cancer Research Institute, Austin Hospital and Eastern Health, Melbourne, writing in a letter to the editor published online on February 17 in the Journal of Clinical Oncology.

What prompted this letter? Medscape Medical News posed the question to Dr Hawkes.

"The data have been building for a while that there is a lack of benefit with surveillance scans," Dr Hawkes said. Specifically, two recent reports prompted Dr Hawkes and colleagues to argue against the number of scans clinical trials require of patients with aggressive lymphoma.

First was a presentation at the 2014 Annual Congress of the European Haematology Association. An analysis of 4874 patients with non-Hodgkin's lymphoma who were treated with curative intent showed that patients who received more than eight CT scans were at a greater than twofold risk of developing second primary malignancies. The report is now published.

The second was a published report that provided support against routine surveillance scans. In 776 patients with diffuse large B-cell lymphoma (DLBCL), researchers reported that for patients who were in remission after treatment, fewer than 2% of relapses were detected on routine surveillance scans before clinical presentation.

Clinical Practice Versus Clinical Studies

According to Dr Hawkes, data such as these cited have been responsible for clinicians reducing the number of scans in routine surveillance in clinical practice. She also cited the recommendations from several organizations that have curtailed surveillance scans.

The British Columbia Cancer Agency guidelines on follow-up of high-grade lymphoma in Canada recommend no surveillance CT scans. The European Society of Medical Oncology recommends only three scans in follow-up. For high-grade lymphomas, the National Comprehensive Cancer Network recommends surveillance scans every 6 months for 2 years, and then as clinically needed.

Bruce D. Cheson, MD, head of hematology, Georgetown University Hospital and Lombardi Comprehensive Cancer Center, in Washington, DC, agrees with Dr Hawkes and colleagues.

He also indicated that the new Lugano Classification — the standard response criteria adopted universally for lymphoma — speaks against surveillance scans ( J Clin Oncol. 2014;32:3059-68).

Yet, the US Food and Drug Administration (FDA), which influences clinical trials design, recommends scans every 3 or 6 months in long-term trials of up to 5 years that treat patients with aggressive lymphoma with curative intent, especially when the primary endpoint is progression-free survival (PFS).

Dr Cheson believes that the requirement of the FDA for the PFS endpoint mandates the number of scans built into study protocols. Patients in clinical trials are monitored closely and more frequently than in clinical practice, he noted.

However, Dr Hawkes is emphatic that well patients who are treated with curative intent and who are in complete remission do not require routine scans even in clinical trials. She agrees with Dr Cheson that patients should be monitored closely and that clinical features are unsatisfactory in confirming relapses; therefore, any clinical suspicion should be confirmed on a CT or PET-CT. However, in well patients, scans should not replace clinical assessment.

Dr Hawkes and colleagues are so ardent against surveillance scans that they refused to participate in one DLBCL study that required 11 surveillance CT scans owing to the justification from the sponsor that the "FDA requires these for a regulatory trial," rather than a clinical need.

They point out that their participation in two other studies requiring 12 surveillance scans — one a T-cell lymphoma trial and the other a Hodgkin's lymphoma trial — occurred before the two crucial reports that prompted their letter.

"We would argue that a more practical, safer, and cheaper approach within clinical trials would be to reflect current clinical practice and adopt the use of clinical assessment rather than routine scanning in well patients, reserving imaging for those with concerning clinical features," Dr Hawkes and colleagues write in their letter.

She further supports her argument with a United Kingdom study of 1080 patients with DLBCL in which patients received only two routine scans in follow-up. The results for PFS, which was not the primary endpoint of the study, were similar to those reported in other studies.

Dr Hawkes told Medscape Medical News: "PFS is not an ideal endpoint for evaluation of first-line curative treatment, given a proportion of patients have a further chance of cure with subsequent therapies, and studies should preferentially utilize overall survival."

The scan requirements are also influencing patient enrollment in clinical trials. With information on the potential of second primary malignancies now included in informed consent forms, "patients are refusing to participate in studies or enrolling but refusing to comply with the imaging requirements," the researchers point out in their letter. Dr Cheson agrees that patients are falling off clinical trials. However, the outcomes are not greatly affected, he believes.

Imaging technology such as CT exposes patients to radiation doses that put them at risk for malignancies. Even the FDA agrees. In 2010, it launched the Initiative to Reduce Unnecessary Radiation Exposure from Medical Imaging.

Yet the arm of the FDA that has oversight of clinical trial design is taking an opposing view in mandating an excessive number of scans in clinical trial protocols.

Is it possible to reconcile these discrepancies for surveillance scan requirements in clinical trials that do not mirror clinical practice?

Dr Cheson told Medscape Medical News that sponsors need to work together with regulatory agencies to minimize the number of scans required. Dr Hawkes and colleagues write: "Within clinical trials, the FDA and the trial sponsors with whom they negotiate need to reassess the rationale for what we believe to be clinically unnecessary and potentially unsafe imaging requirements."

A response in the Journal of Clinical Oncology, which Dr Cheson also coauthored, indicated: "Hawkes et al present a well-argued case that imaging surveillance provides minimal benefit for patients who achieve a complete response after treatment for aggressive lymphoma. Patients with a complete response and those with a complete metabolic response have a low relapse rate."

"Most relapses are detected clinically, and only a tiny proportion are detected on imaging before clinical symptoms, signs, or abnormal blood tests develop that result in considerable financial and other costs," the responders add.

The authors and respondents have disclosed no relevant financial relationships.

J Clin Oncol. Published online Feb. 17, 2015. Full text

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