Robert J. Hayashi, MD, Division of Pediatric
Hematology/Oncology, Department of Pediatrics, Washington University
School of Medicine, Siteman Cancer Center, St. Louis Children’s
Hospital, St. Louis, MO.
Standard management of pediatric Non-Hodgkin’s Lymphoma (NHL) patients
have included an initial assessment of the disease at presentation to
establish it’s extent. This “staging” process has historically
assigned patients using traditional classifications which were
established decades ago when, like other pediatric malignancies, the
more extensive involvement of the cancer for a patient directly
correlated with the patient’s long term survival[1]. Advances in
radiologic technology have evolved in the way the disease extent was
evaluated, moving from conventional radiographs, to computerized
tomography (CT) to magnetic resonance imaging (MRI) to most recently
positron emission tomography (PET)[2]. Despite the development and
use of PET scans for decades for various cancer diagnoses, the role of
PET scans for NHL remains unclear[3]. Indeed, its value for many
conditions is its ability to assess the response to initial therapy and
establish the patient’s risk stratification guiding the remaining
treatment plan[4]. Such efforts have not occurred in clinical trials
of NHL and thus we are left to examine case series and try to discern
its value for this disease.
Advances in the management of NHL have resulted in tremendous
improvements in long-term, overall survival for all disease groups. As
the outcomes continue to improve, with the event free survival (EFS) of
some subgroups of NHL approaching or even exceeding 90%, the power of
traditional prognostic factors have waned in their
significance[5-7]. In this issue, Kroeze, et al[8]describes their experience with PET scans in a relatively large cohort
of B cell lymphoblastic lymphoma patients. Their retrospective review
reveals that several patients had findings which led to a different
clinical stage than what was derived using other imaging modalities.
Some patients had a higher stage using PET compared to conventional CT’s
or MRI’s while others would have been assigned a lower stage if PET were
used as the primary imaging modality. Given that discrepancies in the
clinical stage between PET scans and other imaging modalities have been
observed by others, the authors advocate for the use of PET scans in
staging NHL patients. Although this seems very reasonable, given the
current state of the management of NHL in children, one must first
reflect on the current success of up front therapy, the salvage rate for
patients of recurrent disease, and the state of our understanding of how
PET scans may assist in the risk stratification of patients.
The original Ann Arbor and Murphy staging classifications have struggled
to maintain their relevance with the advancements of modern day therapy
for NHL. Indeed, staging for mature B cell lymphoma has relied more on
other staging classifications (FAB/LMB, BFM) which incorporates the
ability to resect limited disease and serum LDH values to assign the
final stage of the patient. The validity of such staging has been
established by a series of trials both in the US and internationally
adhering to a consistent backbone of therapy (FAB/LMB) which allows us
to discern how clinical stage holds up with the stepwise modifications
of treatment with each subsequent multi-center trial[9]. However,
even in this case, as the EFS for mature B cell lymphoma is well over
90%, we are left to reflect upon how different stages correlate to
outcomes using modern therapy[6].
NHL continues to struggle in defining the role of PET scan in
establishing risk categories. There are many reasons for this. Firstly,
NHL is a relatively rare condition and many trials have taken years to
design and execute and are thus often ill equipped to answer ancillary
study questions such as the role of PET scans in staging disease or the
its role in assessing response to therapy. Secondly, studies which
require national participation to accrue sufficient numbers of patients
may not have the radiology resources to answer the clinical question
making such imaging studies “optional” virtually eliminating the
possibility that the data generated could be evaluated with any
scientific rigor. Finally, NHL often presents abruptly, with rapidly
growing tumors in compromising locations (i.e. mediastinal masses), so
that baseline imaging is often not feasible and thus not practical for a
patient in a tenuous clinical situation. Thus, with the absence of a
baseline exam to use to assess responses to therapy short of a complete
metabolic response, designing studies to examine the use of PET scans
remain challenging.
Moving forward, we need to assess the value of refining staging
assessments with the current state of treatment in NHL. Current clinical
trials have often merged stages together (Low stage; I-II verses high
stage III-IV) making distinctions between stages less critical. Recently
completed trials in NHL have failed to demonstrate that clinical stage
has prognostic importance[5, 7]. Modern therapies often result in
vigorous responses, often leading to complete remission in a short
period of time, making rapidity of response a variable that fails to
segregate patients into meaningful groups that can be used to assess
prognosis. Thus, even though if PET imaging may change the clinical
stage relative to conventional imaging, its use may not impact clinical
trial design or patient outcome.
Finally, in most clinical scenarios, despite the successes of upfront
therapy, the ability to salvage relapsed disease remains a major
clinical challenge, with the majority of patients failing to achieve
long term survival once relapse occurs[10]. Thus, there is currently
little utility to refine the means of identifying low stage disease with
more sensitive imaging techniques as deescalating therapy for perceived
favorable prognostic patients may not be practical until better salvage
regimens become available.
Thus, the future of the use of PET scan in NHL remains to be determined.
Proposals to investigate its use should probably be restricted to large
scale clinical trials where a critical mass of patients receiving
uniform imaging in the face of rigorous protocol driven therapy can
generate data to assess whether more refined disease evaluations or the
extent of initial response to therapy can identify patients for risk
stratification for future prospective trials. Hopefully such efforts
will come to fruition to clarify the role of PET scans in this disease.
References:
1. Murphy, S.B., et al., Non-Hodgkin’s lymphomas of childhood: an
analysis of the histology, staging, and response to treatment of 338
cases at a single institution. J Clin Oncol, 1989. 7 (2): p.
186-93.
2. Rosolen, A., et al., Revised International Pediatric
Non-Hodgkin Lymphoma Staging System. Journal of Clinical Oncology,
2015. 33 (18): p. 2112-2118.
3. Sandlund, J.T., et al., International Pediatric Non-Hodgkin
Lymphoma Response Criteria. J Clin Oncol, 2015. 33 (18): p.
2106-11.
4. Keller, F.G., et al., Results of the AHOD0431 trial of response
adapted therapy and a salvage strategy for limited stage, classical
Hodgkin lymphoma: A report from the Children’s Oncology Group. Cancer,
2018. 124 (15): p. 3210-3219.
5. Lowe, E.J., et al., Brentuximab vedotin in combination with
chemotherapy for pediatric patients with ALK+ ALCL: results of COG trial
ANHL12P1. Blood, 2021. 137 (26): p. 3595-3603.
6. Minard-Colin, V., et al., Rituximab for High-Risk, Mature
B-Cell Non-Hodgkin’s Lymphoma in Children. N Engl J Med, 2020.382 (23): p. 2207-2219.
7. Hayashi, R.J., et al., Successful Outcomes of Newly Diagnosed T
Lymphoblastic Lymphoma: Results From Children’s Oncology Group
AALL0434. J Clin Oncol, 2020. 38 (26): p. 3062-3070.
8. Kroeze, E., 18F FDG-PET/CT imaging in diagnostic work-up of
pediatric precursor B-cell lymphoblastic lymphoma. Pediatr Blood
Cancer, 2023. in press .
9. Cairo, M.S., et al., Advanced stage, increased lactate
dehydrogenase, and primary site, but not adolescent age (≥ 15 years),
are associated with an increased risk of treatment failure in children
and adolescents with mature B-cell non-Hodgkin’s lymphoma: results of
the FAB LMB 96 study. J Clin Oncol, 2012. 30 (4): p. 387-93.
10. Devine, K.J., et al., How I approach B-lymphoblastic lymphoma
in children. Pediatr Blood Cancer, 2023. 70 (8): p. e30401.
Correspondence to: Robert J. Hayashi, MD, Division of Pediatric
Hematology/Oncology, Department of Pediatrics, Washington University
School of Medicine, 660 S. Euclid Ave. St. Louis, MO 63110, E-mail:
hayashi_r@wustl.edu