Vol 28, No 5 (2023)
Research paper
Published online: 2023-08-09

open access

Page views 324
Article views/downloads 288
Get Citation

Connect on Social Media

Connect on Social Media

Results of consolidative radiotherapy for relapsed diffuse B-cell lymphoma

Geovanne Pedro Mauro12, Mario Ribeiro Neto13, Heloisa A. Carvalho12
Rep Pract Oncol Radiother 2023;28(5):601-607.

Abstract

Background: Recurrent diffuse large B-cell lymphoma (DLBCL) is a disease with high mortality. The standard of care involves autologous stem-cell transplantation (ASCT), which is not always feasible. We investigated the impact of radiotherapy as part of the salvage treatment for patients with relapsed disease.

Materials and methods: retrospective study of patients with recurrent DLBCL after chemotherapy and consolidative radiotherapy at a single institution. All patients were included if radiation was part of the first treatment.

Results: Of 359 patients assessed between 2010 and 2017, 65 (18.1%) presented a recurrence, but only 62 received further treatment and were included in the study. Mean overall survival was 18.6 months since diagnosis and progression-free survival after first progression (PFS2) was 7.7 months. Patients were divided into two groups according to whether they did (24.8%) or did not (75.8%) receive radiation as part of their salvage treatment. Patients that did not receive R-CHOP (rituximab plus cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone) in the first line were treated more with radiation in the second line (p = 0.02). Six patients with in-field relapse were re-irradiated. Only 4 patients received ASCT as part of their treatment for relapsed disease. There was no difference in outcomes.

Conclusion: There is a place for radiotherapy in the treatment of relapsed DLBCL, particularly when patients do not receive ASCT. Radiotherapy is well-tolerated. More trials to assess the role of radiotherapy for these patients are needed.

research paper

Reports of Practical Oncology and Radiotherapy

2023, Volume 28, Number 5, pages: 601–607

DOI: 10.5603/rpor.96866

Submitted: 05.02.2023

Accepted: 28.07.2023

© 2023 Greater Poland Cancer Centre.

Published by Via Medica.

All rights reserved.

e-ISSN 2083–4640

ISSN 1507–1367

Results of consolidative radiotherapy for relapsed diffuse B-cell lymphoma

Geovanne Pedro Mauro12Mario Ribeiro Neto12Heloisa de Andrade Carvalho12
1Department of Radiology and Oncology, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
2Hospital Japonês Santa Cruz, Sao Paulo, Brazil

Address for correspondence: Geovanne Pedro Mauro, Department of Radiology and Oncology, Radiotherapy, Faculdade de Medicina da Universidade de São Paulo, Avenida Doutor Arnaldo, 251 – Cerqueira César, São Paulo, SP, Brazil. Zip Code 01255-000, tel: (+11) 3893-2000; e-mail: geovanne95@gmail.com

This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially

Abstract
Background: Recurrent diffuse large B-cell lymphoma (DLBCL) is a disease with high mortality. The standard of care involves autologous stem-cell transplantation (ASCT), which is not always feasible. We investigated the impact of radiotherapy as part of the salvage treatment for patients with relapsed disease.
Materials and methods: Retrospective study of patients with recurrent DLBCL after chemotherapy and consolidative radiotherapy at a single institution. All patients were included if radiation was part of the first treatment.
Results: Of 359 patients assessed between 2010 and 2017, 65 (18.1%) presented a recurrence, but only 62 received further treatment and were included in the study. Mean overall survival was 18.6 months since diagnosis and progression-free survival after first progression (PFS2) was 7.7 months. Patients were divided into two groups according to whether they did (24.8%) or did not (75.8%) receive radiation as part of their salvage treatment. Patients that did not receive R-CHOP (rituximab plus cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone) in the first line were treated more with radiation in the second line (p = 0.02). Six patients with in-field relapse were re-irradiated. Only 4 patients received ASCT as part of their treatment for relapsed disease. There was no difference in outcomes.
Conclusion: There is a place for radiotherapy in the treatment of relapsed DLBCL, particularly when patients do not receive ASCT. Radiotherapy is well-tolerated. More trials to assess the role of radiotherapy for these patients are needed.
Key words: non-Hodgkin lymphoma; refractory lymphoma; radiotherapy
Rep Pract Oncol Radiother 2023;28(5):601–607

Introduction

Disease relapse is still an important outcome for patients treated for diffuse large B-cell lymphoma (DLBCL). Almost one quarter of patients will have disease progression after the completion of the first treatment and will be treated for relapsed disease [1], and treatment is not always curative [2]. The standard of care for these patients, which is high-dose chemotherapy followed by autologous stem-cell transplantation (ASCT), with or without irradiation, is not feasible for a large portion of patients [3], even in controlled trials.

In this setting, radiotherapy can be used either for local control or as a palliative treatment. The role of radiation in the standard treatment for these patients was established almost thirty years ago [3], in the first PARMA trial. In addition, radiation has been investigated in the setting before [4] and after [5, 6] ASCT, with good results. Even after other important randomized trials that omitted radiotherapy, such as the CORAL trial [7], the use of radiation has been recurrently investigated, since that trial presented high rates of relapse in sites that would have been treated with radiotherapy.

This study was designed to assess the use of radiotherapy for relapsed DLBCL in a single university hospital and to describe the population for whom this treatment has been favored.

Materials and methods

This was a retrospective study of patients diagnosed with DLBCL and treated with radiotherapy between July 2010 and July 2017 who presented recurrent disease. Patients that did not receive second line/salvage treatment were excluded.

Demographic and treatment characteristics were assessed. Demographic variables included age, performance status (Eastern Cooperative Oncology Group ECOG scale), stage, the presence of bulky disease, B symptoms, extranodal disease and human immuno-deficiency virus (HIV) status. The revised International Prognostic Index (R-IPI) was applied and updated in all patients. Treatment variables included the use of radiotherapy in second-line treatment, doses and fields, second-line chemotherapy, autologous stem-cell transplantation (ASCT) as consolidative treatment and the use of total body irradiation (TBI) as a conditioning agent. Afterwards, patients were divided in two groups for subsequent analyses: one including those patients that received radiotherapy for the recurrence, and the other including those who did not.

Overall survival (OS) was assessed from the date of diagnosis. Second progression-free survival (PFS2), considered as any recurrence after salvage treatment, was assessed from the date of first progression to the date of second progression.

Statistical analysis consisted of descriptive, and frequencies analyses, with comparisons between groups by the Fisher’s Exact test. For the oncological outcomes and survivals, the Kaplan-Meier method was used with the Log-rank test for univariate analysis. Significance was set at 5% (p 0.05).

Results

In the studied period, 359 patients were retrieved and, after charts evaluation, 65 (18.1%) presented disease progression, but only 62 (17.3%) that received further treatment were included in the study. Most patients were male (61.3%) and mean age at first diagnosis was 56.7 years. The most common chemotherapy regimens used as second line were ICE (ifosfamide, carboplatin, and etoposide) and IVAC (etoposide, cytarabine, ifosfamide, mesna and methotrexate). Table 1 and Table 2 describe, respectively, demographic and treatment characteristics. The respective characteristics and comparisons of the two groups: one that received radiotherapy as part of second line treatment and the other that did not are presented in Table 3. The use of radiation in the second-line setting was correlated only to the use of chemotherapy regimens other than R-CHOP (rituximab plus cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone) in the first-line treatment (p = 0.020).

Table 1. Overall demographic description

Variable

Number (n)

(%)

Age at diagnosis (years), mean (range)

56.7 (2472)

Age (at diagnosis)

< 60

36

58.1

≥ 60

26

41.9

Sex

Male

38

61.3

Female

24

38.7

ECOG performance status at diagnosis

01

51

82.3

24

11

17.7

Stage (Lugano system at first presentation)

1

4

6.5

2

7

11.3

3

10

16.1

4

41

66.1

R-IPI (at diagnosis)

Very good

2

3.2

Good

22

35.5

Poor

38

61.3

Bulky disease

Present

48

77.4

Absent

14

22.6

Extranodal disease

Present

52

83.9

Absent

10

16.1

B symptoms

Present

49

79.0

Absent

13

21.0

HIV

Negative

56

90.3

Positive

6

9.7

Table 2. Treatment characteristics

Variable

Number (n)

(%)

First-line

First-line chemotherapy regimen

R-CHOP

50

80.6

Others

12

19.4

Number of chemotherapy cycles in the first line

≤ 6

24

38.7

> 6

38

61.3

Toxicity to first-line chemotherapy

03

41

66.1

4

21

33.9

Response to first-line chemotherapy

Complete response

15

24.2

Partial response

42

67.7

Unidentified

5

8.1

First-line consolidative RT technique

Mantle and/or inverted-Y

2

3.2

Involved-field RT

10

16.1

Involved-site RT

14

22.6

Bulky disease or PR site only

36

58.1

Second-line

Second-line chemotherapy

Cytarabine-based

48

77.4

Others

14

22.6

Second-line RT

Yes

15

24.2

Yes, as consolidative treatment

5

-

Yes, and as re-irradiation to primary site

6

-

No

47

75.8

Second-line RT dose [Gy]

30

8

53.3

> 30

7

46.7

ASCT as consolidation for second-line chemotherapy

Yes

4

6.5

No

58

93.5

Table 3. Demographic description and treatment protocol according to delivery or not of second-line radiotherapy (RT) (p-values stand for the correlation between each variable and the use of RT)

Patients characteristics

Second-line RT

p

No

N = 47 (75.8%)

Yes

N = 15

(24.2%)

Age

< 60 years

> 60 years

25 (53.2%)

22 (46.8%)

11 (73.3%)

4 (26.7%)

0.169

ECOG

01

2 or more

38 (80.9%)

9 (19.1%)

13 (86.7%)

2 (13.3%)

0.608

R-IPI

Very good

Good

Poor

2 (4.3%)

15 (31.9%)

30 (63.8%)

0

7 (46.7%)

8 (53.3%)

0.080

Bulky disease

Absent

Present

12 (25.5%)

35 (74.5%)

2 (13.3%)

13 (86.7%)

0.325

Extranodal disease

Absent

Present

8 (17.0%)

39 (83.0%)

2 (13.3%)

13 (86.7%)

0.735

B symptoms

Absent

8 (17.0%)

5 (33.3%)

0.177

Present

39 (83.0%)

10 (66.7%)

HIV

Negative

Positive

42 (89.4%)

5 (10.6%)

14 (93.3%)

1 (6.7%)

0.651

First-line chemotherapy regimen

R-CHOP

Other

41 (87.2%)

6 (12.8%)

9 (60.0%)

6 (40.0%)

0.020

Second-line chemotherapy regimen

Cytarabine-based

24 (51.1%)

8 (53.3%)

0.878

Other

23 (48.9%)

7 (46.7%)

With a mean follow-up of 32.8 months, median overall survival was 18.6 months (1.3 – 121.0). There were 47 (75.8%) deaths reported. The mean first progression-free survival (PFS) was 16.4 for the sample that did progress, but it was 48.5 months for the first initial 359 patients. Median PFS2 was 7.7 months (0.2–88.6) with 19 (30.6%) second recurrences in the period (Fig. 1 and 2). None of the studied variables correlated with OS or PFS2 in the univariate analysis (Tab. 4, Fig. 3 and 4).

Mauro-1.png
Figure 1. Overall survival (OS, median 18.6 months)
Mauro-2.png
Figure 2. Survival free from second progression (PFS2, median 7.7 months)
Table 4. Univariate analysis of variables related to overall survival (OS) and second progression-free survival (PFS2)

Variable

Categories

Univariate analysis (OS)

Univariate analysis (PFS2)

n (events)

p

n (events)

p

Age

< 60 years

> 60 years

27

20

0.99

13

6

0.37

ECOG

01

24

39
8

0.57

17

2

0.34

R-IPI

Very good

Good

Poor

1

16

30

0.57

2

5

12

0.08

Bulky disease

Present

Absent

35

12

0.58

15

4

0.89

Extranodal disease

Present

Absent

39

8

0.44

19

0

0.03

B symptoms

Present

Absent

36

11

0.96

6

13

0.06

HIV

Negative

Positive

42

5

0.70

15

4

0.08

First-line chemotherapy

R-CHOP

Other

9

38

0.76

7

12

0.41

Second-line chemotherapy

Cytarabine-based

Other

25

22

0.70

8

11

0.74

Second-line RT

No
Yes

34

13

0.30

13

6

0.08

Mauro-3.jpg
Figure 3. Overall durvival by second-line radiotherapy (median value was 23.9 months for the non-second-line radiotherapy (RT) group and 16.8 months for the second-line RT group, p = 0.30)
Mauro-4.jpg
Figure 4. Second progression-free survival by second-line radiotherapy (median value was 18.3 months for the non-second-line radiotherapy (RT) group and 4.7 months for the second-line RT group, p = 0.08

Discussion

Recently, the International Lymphoma Radiation Oncology Group (ILROG) [8] addressed the need for a review and consensus on the use of radiation for relapsed and refractory non-Hodgkin lymphomas. Even though we observe a consistent decrease in the use of radiotherapy for lymphomas [9], patients have been referred to radiation oncology departments particularly after treatment regimens without radiation have failed. In our sample, patients that were not treated with the standard R-CHOP regimen at first, were most suitable to need radiotherapy as part of the salvage treatment (p = 0.02). Our results show a trend to use radiotherapy when usual protocols were not applied.

It is important to stress that radiotherapy has already been compared to regimens containing ASCT in the PARMA trial. Without new evidence for the use of radiation instead of other consolidation regimens it cannot be favored. Nevertheless, this study shows data that raise two important questions. First, the investigation arm for this trial used radiotherapy, even in larger fields, with less technology and lower dose (26 Gy) than is currently used. Second, even amongst highly selected patients for a randomized trial, a fraction of patients received ASCT.

We compared the use of radiotherapy in this setting with other published data. In our sample, 24.2% of relapsed patients did receive radiotherapy. The decrease in the use of radiotherapy is consistent with global trends. It is important to stress that technology has evolved, and patients would have been treated differently from those in the PARMA trial, with smaller volumes and more technology invested into radiation delivery quality assessment [10].

Not every patient that relapses receives ASCT. In the PARMA trial, 41.9% of patients did not respond after high-dose chemotherapy and in the investigation arm, 11% of patients randomized to receive ASCT did not. Our numbers are consistent with this setting, since only four patients did receive ASCT. Even though guidelines stress the importance of ASCT in the relapsed setting, patients usually don’t reach that far. New prospective trials should be designed to investigate the use of radiation as a consolidative treatment after second-line chemotherapy in the setting where ASCT is not possible or feasible.

There is a growing body of evidence in the treatment of recurrent DLBCL with CAR-t cells. This cellular immunotherapy could have a synergy with radiotherapy [11]. As it has been investigated for ASCT, with CAR-T cell treatments the correct order to offer radiotherapy has also been under investigation [12]. This is, nevertheless, a growing application for radiotherapy [13] and new, prospective data is needed.

Radiotherapy for DLBCL has been correlated with toxicities. Even though acute and long-term toxicities are rare [10], particularly with advanced technology, secondary neoplasms are always possible. In the setting of relapsed disease, nevertheless, this is a minor issue compared to the chance of death from the relapsed lymphoma. In special settings, such as patients living with HIV for whom ASCT is not always possible [14], radiotherapy should be more largely used, even with the risk of increased toxicities [15].

Re-irradiation is possible. This study was designed to assess whether patients that receive radiotherapy in the first line regimen would be exposed to radiation again. The chances of in-field relapse for patients treated with radiotherapy in the first line are very small, less than 2% [16]. In our sample, six (9.7%) patients had in-field relapses and were treated with re-irradiation to a dose of 30 Gy, in 2 Gy fractions. No outstanding toxicities were found. Data on re-irradiation for these patients are scarce and our experience may represent a modest but interesting highlight of our study.

Furthermore, there is a paucity of data for patients that have partial response or progress to second-line regimens. Radiotherapy has been investigated before and after ASCT transplantation, with better results when patients receive ASCT with as little residual disease as possible [5]. There is also a place for radiotherapy in the palliative setting. Nevertheless, all those situations haven’t been investigated in prospective trials.

Conclusion

Radiotherapy can be an important tool in the treatment of relapsed DLBCL patients, but its underused. Since the preferred regimen of ASCT regimen is not always feasible, irradiation should be considered mostly in patients that will not undergo ASCT. New trials should be designed to address the role of radiotherapy in the relapse setting as it deserves further studies, mainly in prospective trials.

Ethics approval and consent to participate

Ethics committee authorization was obtained in the local ethics committee according to Brazilian law and the Declaration of Helsinki. All patients have given written consent to participate.

Consent for publication

The author grants the publisher the sole and exclusive license of the full copyright. The authors guarantee that this manuscript has not been previously published elsewhere. The authors declare that any person named as co-author of the contribution is aware of the fact and has agreed to being so named.

Availability of supporting data

data on this research is available on request to the corresponding author

Competing interests

The authors do not have any conflict of interest to declare.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors contributions

G.M. was responsible for study design. G.M. was responsible for ethics committee approval. G.M. was responsible for data collection. G.M. and M.N. have written project’s final draft. G.M. was responsible for statistical analysis. H.C. was responsible for overall orientation and manuscript review.

Acknowledgement

We thank Dr. Antonio Brandão, hematologist, for his efforts and help.

References

  1. Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015; 125(1): 22–32, doi: 10.1182/blood-2014-05-577189, indexed in Pubmed: 25499448.
  2. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med. 1993; 328(14): 1002–1006, doi: 10.1056/NEJM199304083281404, indexed in Pubmed: 7680764.
  3. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med. 1995; 333(23): 1540–1545, doi: 10.1056/NEJM199512073332305, indexed in Pubmed: 7477169.
  4. Wirth A, Prince HM, Roos D, et al. A Prospective, Multicenter Study of Involved-Field Radiation Therapy With Autologous Stem Cell Transplantation for Patients With Hodgkin Lymphoma and Aggressive Non-Hodgkin Lymphoma (ALLG HDNHL04/TROG 03.03). Int J Radiat Oncol Biol Phys. 2019; 103(5): 1158–1166, doi: 10.1016/j.ijrobp.2018.12.006, indexed in Pubmed: 30553941.
  5. Oehler-Jänne C, Taverna C, Stanek N, et al. Consolidative involved field radiotherapy after high dose chemotherapy and autologous stem cell transplantation for non-Hodgkin’s lymphoma: a case-control study. Hematol Oncol. 2008; 26(2): 82–90, doi: 10.1002/hon.839, indexed in Pubmed: 18085574.
  6. Biswas T, Dhakal S, Chen R, et al. Involved field radiation after autologous stem cell transplant for diffuse large B-cell lymphoma in the rituximab era. Int J Radiat Oncol Biol Phys. 2010; 77(1): 79–85, doi: 10.1016/j.ijrobp.2009.04.036, indexed in Pubmed: 19647953.
  7. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010; 28(27): 4184–4190, doi: 10.1200/JCO.2010.28.1618, indexed in Pubmed: 20660832.
  8. Ng AK, Yahalom J, Goda JS, et al. Role of Radiation Therapy in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys. 2018; 100(3): 652–669, doi: 10.1016/j.ijrobp.2017.12.005, indexed in Pubmed: 29413279.
  9. Yeboa D, Aneja S, Montana G, et al. Historical trends of radiotherapy use in prevalent malignancies over 38 years in SEER. J Radiat Oncol. 2015; 4(1): 11–17, doi: 10.1007/s13566-015-0182-y.
  10. Yahalom J. Transformation in the use of radiation therapy of Hodgkin lymphoma: new concepts and indications lead to modern field design and are assisted by PET imaging and intensity modulated radiation therapy (IMRT). Eur J Haematol Suppl. 2005(66): 90–97, doi: 10.1111/j.1600-0609.2005.00461.x, indexed in Pubmed: 16007875.
  11. Fan J, Adams A, Sieg N, et al. Potential synergy between radiotherapy and CAR T-cells - a multicentric analysis of the role of radiotherapy in the combination of CAR T cell therapy. Radiother Oncol. 2023; 183: 109580, doi: 10.1016/j.radonc.2023.109580, indexed in Pubmed: 36842663.
  12. Figura NB, Sim AJ, Jain MD, et al. Radiation therapy prior to CAR T-cell therapy in lymphoma: impact on patient outcomes. Expert Rev Hematol. 2022; 15(12): 1023–1030, doi: 10.1080/17474086.2022.2147919, indexed in Pubmed: 36369950.
  13. Jones G, Plastaras JP, Ng AK, et al. The Evolving Role of Radiation Therapy in DLBCL: From Early-Stage to Refractory Disease. Oncology (Williston Park). 2022; 36(12): 718–727, doi: 10.46883/2022.25920980, indexed in Pubmed: 36548096.
  14. Krishnan A, Molina A, Zaia J, et al. Durable remissions with autologous stem cell transplantation for high-risk HIV-associated lymphomas. Blood. 2005; 105(2): 874–878, doi: 10.1182/blood-2004-04-1532, indexed in Pubmed: 15388574.
  15. Medici CT, Mauro GP, Casimiro LC, et al. Impact of HIV infection on consolidative radiotherapy for non-Hodgkin diffuse large B-cell lymphoma. Radiat Oncol. 2020; 15(1): 153, doi: 10.1186/s13014-020-01589-1, indexed in Pubmed: 32539797.
  16. Persky DO, Unger JM, Spier CM, et al. Southwest Oncology Group. Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. J Clin Oncol. 2008; 26(14): 2258–2263, doi: 10.1200/JCO.2007.13.6929, indexed in Pubmed: 18413640.



Reports of Practical Oncology and Radiotherapy