Received: 7 October 2019 Revised: 16 December 2019 Accepted: 17 December 2019

DOI: 10.1002/hon.2708

REVIEW

Radiotherapy in mantle cell lymphoma: A literature review

Sharon Ben Barouch1 | John Kuruvilla1 | Richard W. Tsang1 | Eva Yashphe2 |

Nadav Sarid2

1
Division of Medical Oncology and
Hematology, Princess Margaret Cancer Centre, Abstract
Department of Medicine, University of Mantle cell lymphoma (MCL) is a B-cell malignancy, comprising between 3% and
Toronto, Toronto, Ontario, Canada
2 10% of all adult-onset non-Hodgkin lymphomas. MCL is considered incurable with
Institute of Hematology, Tel Aviv Sourasky
Medical Center, affiliated to the Sackler current treatment modalities and most patients require multiple lines of treatment
Faculty of Medicine, Tel Aviv University,
during their lifetime. MCL is very sensitive to radiotherapy (RT), even when deliv-
Tel Aviv, Israel
ered in low doses. In limited-stage MCL, RT can enable the de-escalation of
Correspondence
systemic therapy. RT monotherapy is a valid option for frail patients. In advanced-
Nadav Sarid, MD, Institute of Hematology,
Tel Aviv Sourasky Medical Center, stage disease, RT is very potent mode of palliation, even in heavily pretreated and
6 Weizmann Street, Tel Aviv 6423906, Israel.
chemo-resistant patients. Furthermore, it can provide a respite during which sys-
Email: [email protected]
temic treatment is unnecessary. In general, RT has a favorable toxicity profile and
Peer Review
can be repeated as necessary for local relapse or distant disease. This effective,
The peer review history for this article is
available at https://publons.com/publon/10. safe, and relatively inexpensive modality of therapy has been underutilized
1002/hon.2708.
for patients with MCL. In this review, we will outline the use of RT for limited
and advanced-stage disease and its potential application in combination with
novel drugs.

KEYWORDS

mantle cell lymphoma, non-Hodgkin lymphoma, radiotherapy

1 | I N T RO DU CT I O N sensitive to radiotherapy (RT) over a wide intensity range of 4 to

45 Gy, even in heavily pretreated and chemo-resistant patients.
Mantle cell lymphoma (MCL) is one of the mature B-cell non-Hodgkin However, this effective, minimally toxic, and relatively inexpensive
lymphomas (NHL), comprising between 3% and 10% of adult-onset modality of therapy has generally been underutilized in MCL. In this
NHL.1 Over 95% of cases involve a translocation between the IGH review, we will outline the use of RT for localized and advanced
and cyclin D1 genes. It mostly occurs in older individuals (median age MCL. Total body irradiation as part of a conditioning regimen pre-
60 years) and has a male predominance. The majority of patients pre- ceding ASCT has been reviewed elsewhere and will not be discussed
sent with advanced-stage disease with extranodal involvement and here.6
1
follow an aggressive course. Intensified chemo-immunotherapy
induction with autologous stem cell transplantation (ASCT) and the
introduction of novel agents have improved the outcome for these 2 | LIM I TE D - ST AGE M CL
patients. Nevertheless, MCL is considered incurable with current
treatment modalities. Disease relapse is almost universal, and most Recent years have witnessed a decline in limited-stage MCL diagno-
patients require multiple lines of treatment during their lifetime.2 ses, because of the growing sensitivity of staging modalities. Surveil-
Mutation in the ataxia telangiectasia–mutated (ATM) gene is lance, Epidemiology, and End Result (SEER) records reported that
3
found in 43% of MCL cases. 5.8% of all MCL patients between 2004 and 2007 were diagnosed
ATM is a key regulator of the cellular response to DNA double- with limited-stage disease, as opposed to 30.5% between 1992
strand breaks induced by irradiation.4,5 Accordingly, MCL is highly and 1999.7

Hematological Oncology. 2020;1–6. wileyonlinelibrary.com/journal/hon © 2019 John Wiley & Sons Ltd 1
2 BEN BAROUCH ET AL.

2.1 | The role of RT in limited-stage MCL only (N = 12, 7%). The median radiation dose was 36 Gy (range,
24-46 Gy). R-CHOP (rituximab, cyclophosphamide, doxorubicin, vin-
Table 1 summarizes the results of publications describing RT use for cristine, and prednisone) was the most commonly employed regimen
early-stage MCL. Leitch et al8 retrospectively reported on 21 patients (57%). The 10-year freedom from progression (FFP) and OS were 42%
with stage I or II low-bulk MCL (less than 10 cm), with a median age and 64%, respectively. Treatment failure at the original disease site
of 68 years and a male predominance (54%). Twelve (46%) patients was mostly observed among the patients who received chemotherapy
had stage I disease. Seventeen patients received RT at a dose of 30 to alone. The univariate analysis demonstrated a trend towards lower
35 Gy as part of their initial therapy, and none of the patients FFP in patients with stage II compared with stage I disease (P = .062).
received rituximab. The 5-year progression free survival (PFS) was On the multivariate analysis, the RT dose and treatment modality
better for the patients who received RT compared with those who did (chemotherapy alone, RT alone, or combined chemotherapy and RT)
not (73% vs 13%, P = .01). Similarly, there was a trend towards did not significantly affect FFP or OS.
improved overall survival (OS) among those who received RT (71% vs Bernard et al11 undertook a retrospective study of 21 patients
25%, P = .13). The latter patients experienced relapse mostly outside with limited-stage MCL, treated between 1990 and 2007, with a
of the radiation field, while relapse among the patients who received median age of 60 years and a male predominance (76%). Eight
chemotherapy alone occurred at the site of initial disease and at dis- patients (38%) had stage I disease. Most (81%) of the patients
tant sites as well. The 5-year PFS for patients with stages I and II was received combined modality treatment (mainly CHOP+/−R and RT).
73% and 20%, respectively (P = .10). Since the numbers of patients Only one patient underwent ASCT. The median dose of RT was
included in this trial are small and the chemotherapy regimens that 35 Gy. The median PFS and OS were 3.2 and 6.4 years, respectively.
had been used would now be considered out of date, it is difficult to Specifically, the median PFS for stages I and II were 10.8 and
draw any firm conclusions regarding the benefit of including RT in 2.8 years, respectively. RT and no-RT modalities were not compared.
the initial treatment as opposed to employing chemotherapy-only The Nordic Lymphoma Group observational study included 1389
regimens. patients with MCL.12 Forty-three patients (3.6%), all of whom pres-
Guru et al9 evaluated the role of RT in patients with stage I and II ented with stage I and II disease, received RT as primary treatment
MCL by performing a retrospective analysis of the SEER database with a curative intent and showed an estimated 3-year survival of
between 1992 and 2010. A total of 657 patients (57% stage I; median 93%. Eleven patients (0.9%) were treated with RT as palliative first-
age, 68 years) were eligible for analysis, and 178 of them (27%) were line therapy, and their estimated 3-year OS was 56%. The added value
treated with initial RT. The median OS was 103 months in the RT of RT was not evaluated.
group compared with 66 months in the no-RT group (P = .002). There
was no information on PFS. These data should be interpreted with
caution considering the lack of information on the patients' baseline 3 | DI SCU SSION
characteristics as well as on concomitant treatment.
In contrast to the publications of Leitch et al8 and Guru et al,9 Since MCL is principally a systemic disease, curative intent with RT is
Dabaja et al10 found no significant difference in outcome for limited- essentially unrealistic. Therefore, watchful waiting is a reasonable
stage MCL as a function of RT. Thirteen institutions from the Interna- approach in asymptomatic patient with low disease burden.13 Studies
tional Lymphoma Radiation Oncology Group contributed data on that looked at RT in limited-stage MCL are few, retrospective; some
179 patients, treated between 1990 and 2013. The median age at report on a small number of patients; some describe outdated chemo-
diagnosis was 63 years, 78% were men, 54% had stage I disease, and therapy regimens. Moreover, they conflict with each other with
17% had bulky disease (defined as a lesion greater than 5 cm). The respect to the question of whether regimens that also include RT are
patients were grouped according to treatment as follows: chemother- superior to chemotherapy alone. When treatment is indicated, RT can
apy only (with or without rituximab; N = 44, 25%), chemotherapy allow the administration of an abbreviated and a de-intensified course
followed by RT (N = 99, 55%), RT only (N = 24, 13%), or observation of chemotherapy, with the effect of maximizing disease control and

TABLE 1 Publications of radiotherapy for early-stage mantle cell lymphoma

Study Year of Publication Design Patients, n Radiation Dose, Gy Local RR, % PFS OS
Leitch et al8 2003 Retro 26 30-35 94 5 y, 45% 5 y, 68%
Guru et al9 2014 Retro 657 N/A N/A N/A With RT, 103 mo
No RT, 66 mo
Dabaja et al10 2017 Retro 179 36 N/A 10 y, 42% 10 y, 64%
Bernard et al11 2013 Retro 21 35 100 3.2 y 6.4 y
12
Abrahamsson et al 2014 Retro 43 N/A N/A N/A 3 y, 93%

Abbreviations: N/A, not available; OS, overall survival; PFS, progression free survival; Retro, retrospective; RT, radiotherapy; RR, response rate.
BEN BAROUCH ET AL. 3

minimizing systemic toxicity, as demonstrated by Bernard et al,11 who M'kacher et al,4 who demonstrated that the molecular pathways in
described a median PFS of 10.8 years for stage I MCL patients treated MCL cell lines that are activated in response to RT are distinct from
with a combined modality approach (RT + CHOP+/−R) without ASCT. those affected during response to chemotherapy.
All the above-cited papers consistently described better out- In 2014, Haque et al15 retrospectively reviewed 39 MCL patients
comes for patients in stage I disease as opposed to those in stage II (68 symptomatic sites) treated with involved site RT (ISRT). Most of
disease. Since stage II disease tends to relapse systemically more the patients were males, with median age of 71 years, and most (88%)
quickly than stage I, RT is probably less contributory for those had stage III or IV disease. Twenty-nine patients (74%) had received
patients. greater than or equal to 3 systemic regimens before RT. The median
Lastly, RT monotherapy may be an excellent alternative approach maximal tumor size was 3.5 cm (range, 1.3-9.6). The median RT dose
for patients who are poor candidates for chemotherapy. Dabaja was 30.6 Gy (range, 18-40). The overall local RR was 94%, with a CR
10
et al reported that 58% (14/24) of patients with early-stage MCL of 69%. Almost all patients (95%) reported symptom relief following
treated with RT alone did not relapse, not only locally but also on dis- RT. Local relapse in the previously irradiated area occurred at nine
tant sites at median follow-up of 60 months. sites (13%) after a median of 7 months (range, 2-21) post-RT.
The concept of low-dose IFRT (LD-IFRT) for palliation was intro-
duced in 1994 by Ganem et al and further validated by Girinsky
4 | ADVANCED-STAGE MCL et al.21,22 White et al16 published a 2 × 2-Gy study restricted to
patients with MCL. Fourteen patients (25 disease sites) were treated
To date, five publications have specifically addressed the topic of RT with palliative intent for recurrent or relapsed (R/R) MCL. Most
14-18
for patients with systemic MCL (Table 2). In those studies, most patients (86%) were males, with a median age at treatment of
of the patients were elderly and heavily pretreated, thus reflecting 69 years, and were diagnosed with advanced-stage disease (85%).
“real-world” experience. Other reported series included MCL patients The median gross tumor volume was 33 cc (range, 1.7-1620). Follow-
among heterogeneous NHL populations.19,20 ing 2 × 2-Gy RT, the overall local RR was 88%, with a CR of 68%. The
median time to best response was 79 days, and a symptomatic
response was achieved in 94% of patients. Local failure was subse-
4.1 | Local control and symptom relief quently observed at 12 sites (48%), with a median time of 10 months
to relapse (range, 1-26).
One of the first attempts to determine the quality and duration of Neville et al17 retrospectively analyzed IFRT for MCL. Twenty-
local response to RT in patients with MCL comes from the Memorial five patients received RT to 60 sites. Most patients were males (84%),
Sloan-Kettering Cancer Center.14 Twenty-one patients (38 different with a median age of 64 years, and most (64%) had stage III or IV dis-
sites), with a median age of 68 years, were treated with involved field ease. There was marked heterogeneity in the dose regimens used,
RT (IFRT). Seventeen patients (81%) had stage IV or relapsed disease, ranging from 3 to 36 Gy (mean 17.4 Gy). The RR was 85% for all sites,
with an average of 2 prior lines of treatment. Most (71%) target with a 72% CR rate. Local control at 12 and 24 months was 80% and
lesions were 5 cm or larger. The mean IFRT dose was 30 Gy (range, 63%, respectively. Symptomatic improvement occurred after IFRT for
10-45). The overall local response rate (RR) was 100%, with a com- most (93%) of the sites.
plete response (CR) rate of 64% and an average time to response of
20 days. Of the treated sites that were initially associated with pain or
discomfort, 94% exhibited symptomatic relief after IFRT. Thirteen 4.2 | Chemotherapy break
sites (34%) showed local progression, with a median time to progres-
sion of 10 months (range, 1-39) after completion of IFRT. No correla- Although RT is administered locally, it can provide a time window dur-
tion was found between pre-IFRT systemic therapy or response and ing which systemic treatment is unnecessary. Haas et al reported
local response to IFRT. This is in keeping with the in vitro findings of median time to in-field or out-field progression of 9 months in

TABLE 2 Publications of radiotherapy for advanced-stage mantle cell lymphoma

Year of Radiation Symptoms Local Local Local Systemic PFS,

Study Publication Design Patients, n Dose, Gy Relief, % RR, % CR, % PFS, mo mo OS
Rosenbluth et al14 2006 Retro 21 30 94 100 64 10 N/A 1 y, 55%
Haque et al15 2014 Retro 39 30 95 94 69 7 N/A 73 mo
White et al16 2016 Retro 14 4 94 88 68 10 10 N/A
17
Neville et al 2015 Retro 25 17 93 85 72 N/A 6.2 74.3 mo
Ning et al18 2019 Retro 19 4 N/A 86 81 4 mo, 85% 7.9 1 y, 90%

Abbreviations: CR, complete response; N/A, not available; OS, overall survival; PFS, progression free survival; Retro, retrospective; RT, radiotherapy; RR,
response rate.
4 BEN BAROUCH ET AL.

17 MCL and 13 diffuse large B-cell lymphoma (DLBCL) with R/R dis- II and site-dependent toxic effects in patients with MCL treated with
ease.19 White et al reported a median duration of chemotherapy conventional dose RT, with no cases of grade III toxicity. Haque
16
break of 10 months (range, 0-80) after LD-IFRT for R/R MCL, while et al15 reported very good tolerability of conventional-dose RT among
Neville et al recorded a median systemic PFS of 6.2 months following MCL patients. They observed that 84.6% of patients had either no
RT.17 Ning et al18 reported that six patients with R/R MCL treated toxicities or only grade I toxic effects, 7.7% had grade II toxicities, and
with LDRT, without concurrent systemic treatment, achieved a fewer than 10% of patients developed grade III reactions.
median treatment break of 7.9 months (range, 0.4-16.4 months) prior In a series of NHL patients treated with LDRT (24% MCL) by
to restarting chemotherapy. Haas et al,19 no toxicity was evident, while White et al16 report only
Other published series covering a wide range of NHL histologies two cases of acute grade I toxicity following LDRT. In yet another
also report having obtained significant chemotherapy breaks following series, Neville et al17 observed that after RT, ranging from 3 to 36 Gy,
local RT to the larger sites of disease. However, MCL was more likely acute toxicities were all grade ≤ 2.
to progress systemically when compared with indolent NHL histolo- Ning et al18 report on low-dose RT (4 Gy) with/without concur-
23
gies; Chan et al evaluated NHL patients following LDRT and rent chemotherapy in R/R MCL. There were no RT-related toxicities,
reported that 48% were free from systemic progression at 1 year. even among 76 sites treated with concurrent chemotherapy. Many
Lymphomas with an indolent histology, eg, follicular lymphoma patients had sensitive organs sites (bowel, oropharynx, orbit, and spi-
(FL) and marginal zone lymphoma (MZL), were less likely to progress nal cord) radiated, without safety issue.
systemically than those with an aggressive histology, eg, MCL or These safety data are in keeping with findings of the FORT trial,25
DLBCL (P = .018). Russo et al20 reported a 54% freedom from further which randomly compared standard with LDRT for FL and MZL. Only
treatment for distant failures after LD-IFRT for heterogeneous NHL 3% and 1% of sites in the 24 and 4 Gy groups had grade III or IV acute
patients, with a median follow-up of 2 years. MCL was again associ- toxicity, respectively, while grade I or II toxicity was seen in 57% and
ated with a shorter median time to re-treatment for distant disease 25% of sites in the 24 and 4 Gy groups, respectively.
progression (P < .0001).

5 | CONCOMITANT RT AND NOVEL

4.3 | Re-treatment AGENTS

The feasibility of delivering repeated RT (treatment with two or more Ning et al18 recently made an important contribution by reporting on
courses of RT, either conventional or LDRT) was documented in sev- LDRT (4 Gy) given concurrently with systemic treatment, mainly novel
eral NHL series.20,24 Repeated RT was given for distal progression or agents. They provided this treatment with nonpalliative intent for R/R
to the original site, as an exclusive therapeutic modality, or alternating MCL, with the goal of achieving prolonged remission. Significantly,
19
with immune-chemotherapies. Haas et al demonstrated that LD- they succeeded in documenting the effectiveness of LDRT for
IFRT re-treatment, for non-FL patients, achieved a RR of 100%. Ning patients who had already been introduced to ibrutinib.
et al18 described four MCL recurrences after LDRT that were salvaged Nineteen patients with R/R MCL had 98 sites treated with 4 Gy
with further RT (three with LDRT). from 2014 through 2018. The median follow-up from the initial LDRT
was 15.4 months. The median tumor size was 2.8 cm (range,
0.9-11.5 cm). Patients had received a median of 7 courses of chemo-
4.4 | Low vs standard-dose RT therapy since diagnosis, and 58% were ibrutinib refractory.
Of the 98 sites, LDRT was delivered with concurrent chemother-
17
Neville et al also reported the outcomes of patients with MCL apy for 76%. Common regimens consisted of rituximab and
treated with a wide spectrum of RT doses, ranging from 3 to 36 Gy. lenalidomide, followed by venetoclax and obinutuzumab. Each patient
Local failure was most common with the 4-Gy protocol, and time to had a median of 2 treated sites (range, 1-27 sites). The overall RR and
local progression was also dependent upon RT dose. These findings CR was 86% and 81%, respectively, for all 98 treated sites, with
25
are in line with the FORT study, a prospective, randomized, phase median time to CR of 2.7 months post-LDRT. The CR rate was not
3 trial that compared 4 Gy with a standard dose of 24 Gy in patients associated with ibrutinib-refractory disease, prior chemotherapy
with FL and MZL. The overall RR was higher in the 24 Gy group (91% courses, tumor size, or blastoid variant. The freedom from local recur-
vs 81%, P = .00095), as well as local PFS (hazard ratio 3.42, median rence at 2 and 4 months was 88.8% and 84.5%, respectively. The PFS
follow-up of 26 mo; P < .0001). and OS at 1 year following LDRT were 55% and 90%, respectively.

4.5 | Safety 6 | DI SCU SSION

Overall, the reported toxicity after local RT, especially LDRT, appears RT achieves excellent local RR (80%-100%) and a high palliation rate
to be very mild. Rosenbluth and Yahalom14 report mostly grade I and in advanced-stage MCL, even in cases of ibrutinib-refractory and
BEN BAROUCH ET AL. 5

chemo-refractory disease.14,18 In advanced-stage MCL for which RT is Lymphoma. 2012;53(8):1488-1493. https://doi.org/10.3109/10428194.

not given with intent to cure, we favor LDRT over higher doses, which 2012.656628.
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