Reexamining the RECIST Criteria and the Need
for a Paradigm Shift in Assessment Guidelines
An overarching theme to virtually all of the studies examining
the issue of treatment beyond progression is the
focus on RECIST criteria and the need to reevaluate practical
implications of their use. As Wolchok suggest in
their report, increasing clinical experience indicates that
traditional response criteria may not be sufficient to fully
characterize activity in the new era of targeted therapies
and/or biologics. The RECIST criteria were initially published
nearly 20 years ago and the guidelines were updated
10 years ago.6 The criteria have become so much a
part of practice and have guided the methods used in
clinical trials. What can replace them? The precepts embodied
by the RECIST criteria suggest why new thinking
needs to be considered. For example, for cytotoxic
agents, the guidelines assume that an early increase in
tumor growth and/or the appearance of new lesions signal
progressive disease. Thus, for cytotoxic agents, the
term “progression” became synonymous with drug failure
and cessation of the current treatment
is recommended once PD is
detected.
In contrast to the rationale for discontinuing
the use of cytoxic agents,
the calculus for immunotherapeutic
agents is markedly different. With
chemotherapy, for example, stable disease
(SD) is often transient and not considered
indicative of true antitumor
activity.6 With immunotherapy SD may
be viewed as an indicator of a meaningful
therapeutic effect. Wolchok et al also
provide a valuable backdrop with which
to analyze whether the traditional RECIST
criteria need to be revisited. In
studies with cytokines, cancer vaccines,
and monoclonal antibodies (such as ipilimumab)
“It is our practice generally
to continue immunotherapy
beyond the first progression,
if patients are tolerating the
drug and are found to have
clinical benefit (after explain -
ing the potential flare
phenomenon). If progressive
dis ease is observed a second
time then immunothera-
peutic agents should be
discontinued.”
complete response, partial response (PR), and
SD have been shown to occur after an increase in tumor
burden characterized as PD by the RECIST criteria.
A pivotal point in the evolution of new criteria occurred
when approximately 200 oncologists, immunotherapists
and regulatory experts met in a series of
workshops in 2004 and 2005. The result of these workshops
was a new line of thinking about immunotherapeutic
agents in cancer.18 Wolchok et al present novel
criteria, called immune-related response criteria (irRC)
that can better capture the response patterns observed
with some immunotherapies. Among the criteria suggested
in this report:
• An increase in tumor burden or the appearance of new
lesions points toward the need for appropriate followup
at a subsequent point to confirm progressive
disease.
• Treatment should be continued as tumors may begin
to shrink during this interval.
• Patients treated with immune therapy whose performance
status is stable and whose laboratory values have
not significantly deteriorated, as well as those with
moderate tumor growth on physical exam or radiographic
72 Kidney Cancer Journal
imaging, should be considered for repeat
confirmation scans. These scans should be done before
progressive disease is defined and the immunotherapeutic
agent is discontinued.
It is our practice generally to continue immunotherapy
beyond the first progression, if patients are tolerating the
drug and are found to have clinical benefit (after explaining
the potential flare phenomenon). If progressive disease
is observed a second time then immunotherapeutic
agents should be discontinued. The key message is that
TBP refers to treatment beyond first progression; because
the tail of the survival curve does not support continued
immunotherapy after a second progression, we recommend
discontinuation of immunotherapeutic agents.
Conclusion
The criteria for the continued use of immune checkpoint
inhibitors beyond progression are changing as recent
analyses begin to show a translational impact on clinical
practice. The concept of tumor flare or
pseudoprogression is increasingly important
to consider in patient assessment.
Based on data from pooled
analyses and other reports in a broad
range of tumors, including RCC, the traditional
RECIST criteria have been reexamined
and, if followed, may not
provide patients with the potential clinical
benefit they could receive with continuation
of treatment beyond first
progression. A new set of guidelines, the
immune-related response criteria, need
further prospective evaluation to determine
the extent to which their application
could be associated with sustained
benefit and improved overall survival.
This topic also underscores the unmet
need to develop radiographic bio-marker studies to better
assess early tumor changes after the introduction of immune
checkpoint inhibitors. Such imaging modalities
should ideally include tracking T-cell infiltration of tumors/
tumor metabolism/tumor microenvironment in
parallel to the RECIST based assessments. Although it is
not possible to conduct a prospective trial to definitively
address many questions regarding TBP, if there are adequate
resources to address this in a prospective trial, a
randomized discontinuation trial would provide important
perspectives.
References
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http://www .nccn.org/professionals/physician_gls/f_guidelines .asp.
Accessed September 16, 2016.
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Group. Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis,
treatment and follow-up. Ann Oncol. 2014;25(suppl 3):iii49-iii56.
4. Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1
ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic
factors of human ovarian cancer. Proc Natl Acad Sci USA. 2007;104(9):
3360-3365.