Recommendations for imaging tumor response in neurofibromatosis clinical trials

Abstract

Objective: Neurofibromatosis (NF)-related benign tumors such as plexiform neurofibromas (PN) and vestibular schwannomas (VS) can cause substantial morbidity. Clinical trials directed at these tumors have become available. Due to differences in disease manifestations and the natural history of NF-related tumors, response criteria used for solid cancers (1-dimensional/RECIST [Response Evaluation Criteria in Solid Tumors] and bidimensional/World Health Organization) have limited applicability. No standardized response criteria for benign NF tumors exist. The goal of the Tumor Measurement Working Group of the REiNS (Response Evaluation in Neurofibromatosis and Schwannomatosis) committee is to propose consensus guidelines for the evaluation of imaging response in clinical trials for NF tumors.

Methods: Currently used imaging endpoints, designs of NF clinical trials, and knowledge of the natural history of NF-related tumors, in particular PN and VS, were reviewed. Consensus recommendations for response evaluation for future studies were developed based on this review and the expertise of group members.

Results: MRI with volumetric analysis is recommended to sensitively and reproducibly evaluate changes in tumor size in clinical trials. Volumetric analysis requires adherence to specific imaging recommendations. A 20% volume change was chosen to indicate a decrease or increase in tumor size. Use of these criteria in future trials will enable meaningful comparison of results across studies.

Conclusions: The proposed imaging response evaluation guidelines, along with validated clinical outcome measures, will maximize the ability to identify potentially active agents for patients with NF and benign tumors.

Figure 1. Comparison of measurement sensitivity to detect change in tumor size

Axial short TI inversion recovery MRI images show a large paraspinal, abdominal, and pelvic plexiform neurofibroma at 3 time points (top to bottom: baseline, 12 months, 27 months) measured by 3 methods (left to right: 1D/RECIST, 2D/WHO, 3D/volumetric criteria). Progressive disease was detected after 27 months by RECIST criteria, after 12 months by WHO criteria, and after 6 months by the proposed volumetric criteria (20% volume increase, not shown). At the time of 2D progression, the volume increase was 57%, and by the time of 1D progression, the volume had more than doubled. RECIST = Response Evaluation Criteria in Solid Tumors; WHO = World Health Organization.

Figure 2. Examples of PN volume change over time

Small incremental changes are demonstrated in a complex large abdominal and flank plexiform neurofibroma (PN) with consistent upward trend through several investigational treatments (A). Extended disease stabilization of a back PN in a patient receiving peginterferon alfa-2b (B). PN growth accelerated upon discontinuation of treatment and slowed again when the patient restarted peginterferon alfa-2b. While in most cases PN growth is linear over extended periods, some measurement variation is not uncommon, as demonstrated by the example of a large neck and chest PN (C). The first observer performed the volumetric analysis prospectively and a second observer repeated the analysis at the end of the observation period while blinded to the chronological order of the scans.

Figure 3. Considerations for the selection of target lesions for volumetric assessment

Volumetric analysis is only feasible on lesions with well-defined borders. The superficial flank plexiform neurofibroma (PN) shown on axial (A) and coronal (B) short TI inversion recovery MRI lacks tissue contrast (arrowheads) and it is not suitable for volume measurement. Edema within a tumor or surrounding tissue affects the lesion volume (C, D). Image C shows a facial PN 2 months after debulking surgery. The tumor volume gradually decreased over the next 10 months until the complete resolution of postsurgical changes (D). Metal in the imaging field results in image distortion on MRI (arrows), and the position of metal artifact may vary between scans (E, F).

Figure 4. Progression in target and nontarget lesions

The diffuse face and neck plexiform neurofibroma shown on axial short TI inversion recovery MRI has a well-circumscribed nodular component on the left side. The complete volume of the lesion increased from 1,870 mL at the first time point (A) to 2,015 mL (8% increase) at the second time point (B) to 2,283 mL (22% increase) on the final evaluation (C). Concurrently, the volume of the nodular component increased from 28.2 mL to 34.3 mL (22% increase) and then to 63.0 mL (84% increase). Determination of disease progression depends on whether the entire lesion or the nodular component is selected as the target lesion at trial entry.