The Challenges of Evaluating Tumor Response With The Evolution of Novel Biologics

Local response to treatment is usually defined following the World Health Organization (WHO) criteria as follows: complete response (CR): complete disappearance of all known disease and no new lesions; partial response (PR): 50% reduction in total tumor load of all measurable lesions; stable disease (SD): does not qualify for CR/PR or; progressive disease (PD): 25% increase in size of one or more measurable lesions or the appearance of new lesions. In short, successfully treated lesions should disappear or shrink in size and definitely not grow larger.

WHO

The accurate evaluation of response to treatment is imperative in cancer therapy research, as an objective response may become a surrogate marker of improved survival. Reliable and reproducible criteria universally applicable to allow comparisons between different study groups is key.

Local response to treatment is usually defined following the World Health Organization (WHO) criteria as follows: complete response (CR): complete disappearance of all known disease and no new lesions; partial response (PR): 50% reduction in total tumor load of all measurable lesions; stable disease (SD): does not qualify for CR/PR or; progressive disease (PD): 25% increase in size of one or more measurable lesions or the appearance of new lesions. In short, successfully treated lesions should disappear or shrink in size and definitely not grow larger.

RECIST, EASL and mRECIST

Specific application of the WHO criteria, however, varied between study groups to such an extent that reliable, reproducible comparison of their results could not always be made. A working group, formed with the objective of unifying the criteria utilized in this response assessment, led to development of the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines published by the National Cancer Institute in 2000 and revised in 2009 (version 1.1). These rely on the measurement of the greatest dimension of all target lesions, and response is categorized as a complete response (CR) (the disappearance of all target lesions), a partial response (PR) (a decrease of 30% in the sum of the greatest dimension of target lesions), progressive disease (PD) (an increase 20% in the sum of the greatest dimension of target lesions (minimum 5 mm) and/or the appearance of new lesions and/or unequivocal progression of existing non-target lesions), and stable disease (SD) (not enough shrinkage nor sufficient increase to qualify as a PR or as PD, respectively.

While easier to adjudicate, RECIST’s reliance only on linear determinations of tumor diameter is a limitation, since tumor necrosis due to treatment is not distinctly evaluated. Non-enhancing tumoral areas reflect tissue necrosis after treatment, whereas viable neoplastic cells are recognized by areas of residual enhancement inside treated lesions. In practice, extensive tumor necrosis may not be paralleled by a reduction in diameter of the lesion. Dependence upon the RECIST criteria alone would miss a CR in cases like this. Indeed, more than one report has noted similar limitations of the RECIST criteria in evaluating response for tumors such as prostate, non-small cell lung cancer, GIST tumors, sarcomas and neuroendocrine tumors.

A histological type where this is particularly true is Hepatocellular Carcinoma (HCC). Total percentage tumor necrosis is the objective of all effective locoregional therapies widely used for HCC, including ablation and intra-arterial procedures like chemoembolization. This reduction in viable tumor burden correlates better with survival than does tumor response as defined by RECIST. The Barcelona 2000 EASL clinical guidelines recommended that assessment of tumor response should be performed taking into account the reduction in viable tumor burden as recognized by non-enhancing areas demonstrated on dynamic CT or magnetic resonance imaging studies. This criterion is used widely by the majority of groups studying HCC and a proposal to formally amend RECIST was published in 2010. This Modified RECIST criteria (mRECIST) would include evaluation of the arterial enhancement of target lesions.

Cheson

RECIST, EASL and mRECIST are specified without reference to individual imaging modalities. CT is commonly available and accurate in measuring size and extent of disease so it is the most commonly used. The Cheson criteria used for response assessment in Lymphoma have been predominantly based on CT measurements of disease in the lymph nodes, spleen and bone marrow. Lymphoma, with its infiltrative patterns of disease, does not always present as discrete nodules or masses to measure. Normal size lymph nodes may in fact be abnormal and bone marrow involvement without cortical bone destruction is hard to detect even with contrast enhanced CT. Lymphoma staging accuracy improves when CT imaging data is fused with the functional metabolic information obtained with FDG-PET imaging. Almost 10% of patients examined with fused PET-CT were found to have additional disease, compared to conventional CT, resulting in assignment to a more advanced stage at diagnosis. After treatment, up to 40% of Lymphoma patients will have residual bulk disease on CT scan that may or may not represent viable tumor. The Cheson criteria include a category CRu (Complete Response uncertain) to address some of these patients. Since most CRu patients don’t have residual disease in these masses, CT scanning has limited value in predicting clinical outcome. Almost all CRu and many PR patients can be reclassified as complete responders if they have PET-CT scans that are negative. Even MR imaging, which has advantages over CT when assessing bone marrow and central nervous system involvement, does not approach this power in identifying clinical pertinent response after treatment.

Novel Biologics

With the arrival of biologic therapies, additional concerns about the reliability of imaging response evaluation criteria will emerge. Consider development of just antibody-based therapeutic products. Novel monoclonal antibodies have been entering clinical study at a rate of over 40 per year since 2007. A dozen monoclonal antibodies are currently in Phase 3 studies targeting neoplasms. The majority of these treatments have demonstrated cytostatic, rather than cytotoxic, properties, such that significant tumor volume reduction after treatment may not occur, and RECIST would not reveal the efficacy of these agents. This has been seen with bevacizumab in metastatic colorectal cancer, erlotinib in non-small cell lung cancer and temsirolimus in renal cancer.

Dramatically, sorafenib, the only systemic agent that has shown any benefit in survival for patients with HCC, does not shrink tumor volumes. As most of these agents act through the inhibition of angiogenesis, an assessment of a lesions’s devitalization could more accurately judge tumor response, and avoid the rejection of a potential treatment based on an underestimation of its true anti-tumor activity.

Assessment of treatment efficacy by measuring tumor shrinkage alone is no longer adequate. Absence of viability is the target as measured by vascular enhancement, glucose metabolic activity or some new method pending development. The WHO criteria can be further refined by focusing on the estimation of the reduction in viable residual tumor as the optimal method to assess the local response to treatment.

Contrast enhanced Spiral CT and MRI are the best currently readily available and reproducible methods to measure target lesion viability for response assessment. CT-PET fusion studies will also play an ever more important role as that technology becomes readily available. Capitalizing on these imaging studies and maximizing their role in determining utility for investigational agents will require that a combination of response evaluation criteria be incorporated into clinical study design. Legacy criteria like RECIST and Cheson will continue to be important to standardize response to treatment, while the newer more functional imaging techniques will improve detection of sites of involvement, provide metabolic tissue characterization and improve correlation to clinical outcome.

As the identification of objective responses becomes more critical and imaging acquisition protocols and assessments become increasingly complex, their optimization for each individual trial will become more important as well.

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Volume 6, Issue 9: Guidance for Sponsors: The Challenges of Evaluating Tumor Response With The Evolution of Novel Biologics

Originally written by legacy Intrinsic Imaging Medical Director