What Are the iRECIST Criteria for Immunotherapy?

Immunotherapy is a cancer treatment that harnesses the body’s own immune system to fight tumors. To measure the effectiveness of these therapies, doctors use a specialized set of guidelines known as iRECIST. These criteria provide a standardized framework to assess how tumors respond, which is necessary because immunotherapies can induce response patterns that differ from traditional chemotherapy. The iRECIST guidelines, developed by the RECIST working group, ensure this evaluation is consistent across clinical trials and in patient care, helping researchers and oncologists compare treatments and make informed decisions.

Evolution from RECIST to iRECIST

The need for specialized criteria arose because tumors react to immunotherapy differently than to conventional chemotherapy. The established guidelines, Response Evaluation Criteria in Solid Tumors (RECIST 1.1), were developed based on tumor shrinkage patterns seen with cytotoxic drugs. RECIST 1.1 defines disease progression as a significant increase in tumor size or the appearance of new lesions, which would often lead to stopping the treatment.

With immunotherapy, however, unique response patterns like pseudoprogression were observed. This is a pattern where a tumor may initially appear to grow larger or new lesions may emerge before the tumor ultimately shrinks. This flare effect is thought to be caused by an influx of immune cells into the tumor, which can temporarily increase its size on imaging scans.

Using RECIST 1.1 alone, this temporary inflammation could be misinterpreted as true disease progression, potentially causing doctors to prematurely discontinue a beneficial treatment. The development of iRECIST was a direct response to this challenge, providing a way to account for these atypical responses. It allows for continued treatment and subsequent evaluation to determine if the initial growth was pseudoprogression or actual disease advancement.

Key Definitions in iRECIST

A central feature of iRECIST is its introduction of new terminology to describe tumor response, distinguishing between unconfirmed and confirmed disease progression. This is a departure from the more definitive progression calls made under RECIST 1.1.

A key term is “immune Unconfirmed Progressive Disease” (iUPD). A patient is categorized as having iUPD when they meet the standard RECIST 1.1 criteria for progressive disease, such as a significant increase in tumor size or the appearance of a new lesion. Instead of immediately stopping treatment, iRECIST recommends that if the patient is clinically stable, treatment may continue pending a follow-up assessment.

This leads to the concept of “immune Confirmed Progressive Disease” (iCPD). Progression is only confirmed if a subsequent scan, typically performed 4 to 8 weeks after the iUPD designation, shows further worsening. If the follow-up scan shows tumor shrinkage or stabilization, the iUPD designation is rescinded and re-categorized as “immune Stable Disease” (iSD) or “immune Partial Response” (iPR). The other main category is “immune Complete Response” (iCR), where all target lesions have disappeared.

Tumor Assessment and Response Evaluation

The process of evaluating tumor response using iRECIST begins with a baseline assessment before treatment starts. Clinicians use imaging scans to identify and measure tumors, selecting specific “target lesions” that are measurable and will be tracked throughout treatment. A maximum of five target lesions can be selected, with no more than two per organ, while other tumors are classified as “non-target lesions” and monitored qualitatively.

Follow-up assessments are performed at regular intervals to monitor changes in these lesions. When a new lesion appears during treatment, it is handled differently under iRECIST. Instead of automatically signaling progressive disease, the new lesion is categorized and measured separately as a “New Lesion-Target” or assessed qualitatively as a “New Lesion Non-Target,” while the original target lesions are monitored independently.

The overall response is determined by considering the changes in all lesion categories: the original target lesions, non-target lesions, and any new lesions. For instance, even if a new lesion appears (triggering an iUPD), the original target lesions might be shrinking. An overall response of iCPD is only assigned if there is continued growth in the lesion category that first triggered the iUPD, providing a more comprehensive approach to determining progression.

Clinical Implications of iRECIST

The adoption of iRECIST has significant implications for clinical practice and research. It allows for the continuation of treatment in patients who might show initial signs of progression but are otherwise clinically stable, preventing the premature cessation of a potentially effective therapy. This framework helps oncologists make more informed decisions regarding patient care.

In clinical trials, iRECIST standardizes how responses to new immunotherapies are measured and reported. This consistency is essential for comparing the efficacy of different drugs and combination therapies across various studies. By ensuring that data on tumor response is collected uniformly, researchers can build large data warehouses to further validate and refine the iRECIST guidelines.

For patients and their families, a basic understanding of iRECIST can help them better comprehend the treatment journey with immunotherapy. It explains why a doctor might continue treatment even if a scan shows some tumor growth, providing context for the “watch and wait” approach. This can alleviate anxiety and foster better communication between patients and their healthcare providers.