Skip to main content
SpringerLink
Log in

Patterns of failure of diffuse large B‑cell lymphoma patients after involved-site radiotherapy

Rezidivmuster bei Patienten mit diffusem großzelligem B‑Zell-Lymphom nach „Involved-site“-Radiotherapie

  • Original Article
  • Published:
Strahlentherapie und Onkologie Aims and scope Submit manuscript

Abstract

Purpose

Radiotherapy (RT) in combination with chemoimmunotherapy is highly efficient in the treatment of diffuse large B‑cell lymphoma (DLBCL). This retrospective analysis evaluated the efficacy of the treatment volume and the dose concept of involved-site RT (ISRT).

Patients and methods

We identified 60 histologically confirmed stage I–IV DLBCL patients treated with multimodal cytotoxic chemoimmunotherapy and followed by consolidative ISRT from 2005–2015. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan–Meier method. Univariate analyses were performed by log-rank test and Mann–Whitney U‑test.

Results

After initial chemoimmunotherapy (mostly R‑CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), 19 (36%) patients achieved complete response (CR), 34 (64%) partial response (PR) or less. Excluded were 7 (12%) patients with progressive disease after chemoimmunotherapy. All patients underwent ISRT with a dose of 40 Gy. After a median follow-up of 44 months, 79% of the patients remained disease free, while 21% presented with failure, progressive systemic disease, or death. All patients who achieved CR after chemoimmunotherapy remained in CR. Of the patients achieving PR after chemotherapy only 2 failed at the initial site within the ISRT volume. No marginal relapse was observed. Ann Arbor clinical stage I/II showed significantly improved PFS compared to stage III/IV (93% vs 65%; p ≤ 0.021). International Prognostic Index (IPI) score of 0 or 1 compared to 2–5 has been associated with significantly increased PFS (100% vs 70%; p ≤ 0.031). Postchemoimmunotherapy status of CR compared to PR was associated with significantly increased PFS (100% vs 68%; p ≤ 0.004) and OS (100% vs 82%; p ≤ 0.026). Only 3 of 53 patients developed grade II late side effects, whereas grade III or IV side effects have not been observed.

Conclusion

These data suggest that a reduction of the RT treatment volume from involved-field (IF) to involved-site (IS) is sufficient because no marginal failures occurred. The concept of IS will likely reduce the risk for late sequelae of RT.

Zusammenfassung

Einleitung

Die konsolidierende Radiotherapie (RT) in Kombination mit einer Chemoimmuntherapie stellt eine hocheffiziente Therapiemethode in der Behandlung des diffusen großzelligen B‑Zell-Lymphoms (DLBCL) dar. Die vorliegende retrospektive Analyse evaluiert die Effektivität und Sicherheit des Volumen- und Dosiskonzepts der „Involved-site“-Radiotherapie (ISRT).

Patienten und Methoden

Wir identifizierten 60 Patienten mit histologisch gesichertem DLBCL im Stadium I–IV, die zwischen Januar 2005 und Dezember 2015 mit einer Chemoimmuntherapie und konsolidierender ISRT behandelt wurden. Progressionsfreies (PFS) und Gesamtüberleben (OS) wurden mittels Kaplan-Meier-Methode dargestellt und univariate Analysen mittels Log-rank-Test und Mann-Whitney-U-Test erhoben.

Ergebnisse

Nach einer initialen Chemoimmuntherapie (überwiegend R‑CHOP; Rituximab, Cyclophosphamid, Doxorubicin, Vincristin und Prednisolon) erzielten 19 Patienten (36 %) eine komplette (CR) und 34 (64 %) eine partielle Remission (PR) oder weniger. Ausgeschlossen wurden 7 Patienten (12 %) mit einem Progress nach Chemoimmuntherapie. Alle Patienten erhielten eine ISRT mit 40 Gy Gesamtdosis. Nach einer medianen Nachbeobachtungszeit von 44 Monaten waren 79 % der Patienten erkrankungsfrei, während 21 % ein Rezidiv oder einen systemischen Progress erlitten oder verstarben. Alle Patienten mit CR nach Chemoimmuntherapie blieben nach konsolidierender ISRT in CR. Bei 2 Patienten mit PR nach Chemoimmuntherapie trat ein Rezidiv an Stelle der initialen Läsion innerhalb des IS-Planungszielvolumens (PTV) auf. Feldrandrezidive wurden nicht beobachtet. Ein signifikant verbessertes PFS zeigten ein Ann-Arbor-Stadium I/II im Vergleich zu Stadium III/IV (93 % vs. 65 %; p ≤ 0,021) sowie ein internationaler prognostischer Index (IPI) von 0 oder 1 verglichen mit 2–5 (100 % vs. 70 %; p ≤ 0,031). Der Post-Chemoimmuntherapie-Status einer CR war verglichen mit dem einer PR mit einem signifikant erhöhten PFS (100 % vs. 68 %; p ≤ 0,004) und OS (100 % vs. 82 %; p ≤ 0,026) assoziiert. Radiogene Spätfolgen Grad 2 entwickelten 3 von 53 Patienten, Grad 3 und 4 traten nicht auf.

Schlussfolgerung

Die Daten zeigen, dass eine PTV-Reduktion von „involved-field“ (IF) zu IS suffizient ist, weil keine Feldrandrezidive beobachtet wurden. Das ISRT-Konzept reduziert darüber hinaus das Risiko radiogener Spätfolgen.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bush RS, Gospodarowicz M, Sturgeon J, Alison R (1977) Radiation therapy of localized non-Hodgkin’s lymphoma. Cancer Treat Rep 61(6):1129–1136

    CAS  PubMed  Google Scholar 

  2. Kaplan HS, Rosenberg SA (1966) The treatment of Hodgkin’s disease. Med Clin North Am 50(6):1591–1610

    Article  CAS  PubMed  Google Scholar 

  3. Lohr F, Georg D, Cozzi L et al (2014) Novel radiotherapy techniques for involved-field and involved-node treatment of mediastinal Hodgkin lymphoma: When should they be considered and which questions remain open? Strahlenther Onkol 190(10):864–866. doi:10.1007/s00066-014-0719-9 (868–871)

    Article  PubMed  Google Scholar 

  4. Kriz J, Spickermann M, Lehrich P et al (2015) Breath-hold technique in conventional APPA or intensity-modulated radiotherapy for Hodgkin’s lymphoma: comparison of ILROG IS-RT and the GHSG IF-RT. Strahlenther Onkol 191(9):717–725. doi:10.1007/s00066-015-0839-x

    Article  PubMed  Google Scholar 

  5. Girinsky T, van der Maazen R, Specht L et al (2006) Involved-node radiotherapy (INRT) in patients with early Hodgkin lymphoma: concepts and guidelines. Radiother Oncol 79(3):270–277. doi:10.1016/j.radonc.2006.05.015

    Article  PubMed  Google Scholar 

  6. Girinsky T, Ghalibafian M, Bonniaud G et al (2007) Is FDG-PET scan in patients with early stage Hodgkin lymphoma of any value in the implementation of the involved-node radiotherapy concept and dose painting? Radiother Oncol 85(2):178–186. doi:10.1016/j.radonc.2007.07.003

    Article  PubMed  Google Scholar 

  7. Girinsky T, Ghalibafian M (2007) Radiotherapy of hodgkin lymphoma: indications, new fields, and techniques. Semin Radiat Oncol 17(3):206–222. doi:10.1016/j.semradonc.2007.02.007

    Article  PubMed  Google Scholar 

  8. Girinsky T, Specht L, Ghalibafian M et al (2008) The conundrum of Hodgkin lymphoma nodes: to be or not to be included in the involved node radiation fields. The EORTC-GELA lymphoma group guidelines. Radiother Oncol 88(2):202–210. doi:10.1016/j.radonc.2008.05.012

    Article  PubMed  Google Scholar 

  9. Girinsky T, Aupérin A, Ribrag V et al (2014) Role of FDG-PET in the implementation of involved-node radiation therapy for Hodgkin lymphoma patients. Int J Radiat Oncol Biol Phys 89(5):1047–1052. doi:10.1016/j.ijrobp.2014.04.026

    Article  PubMed  Google Scholar 

  10. Illidge T, Specht L, Yahalom J et al (2014) Modern radiation therapy for nodal non-Hodgkin lymphoma-target definition and dose guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys 89(1):49–58. doi:10.1016/j.ijrobp.2014.01.006

    Article  PubMed  Google Scholar 

  11. NCCN (2017) Clinical practice guidelines in oncology. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed 25 Feb 2017

    Google Scholar 

  12. Kriz J, Baues C, Engenhart-Cabillic R et al (2017) New quality assurance program integrating “modern radiotherapy” within the German Hodgkin Study Group. Strahlenther Onkol 193(2):100–108. doi:10.1007/s00066-016-1048-y

    Article  CAS  PubMed  Google Scholar 

  13. Shi Z, Das S, Okwan-Duodu D et al (2013) Patterns of failure in advanced stage diffuse large B‑cell lymphoma patients after complete response to R‑CHOP immunochemotherapy and the emerging role of consolidative radiation therapy. Int J Radiat Oncol Biol Phys 86(3):569–577. doi:10.1016/j.ijrobp.2013.02.007

    Article  PubMed  Google Scholar 

  14. Dorth JA, Prosnitz LR, Broadwater G et al (2012) Impact of consolidation radiation therapy in stage III–IV diffuse large B‑cell lymphoma with negative post-chemotherapy radiologic imaging. Int J Radiat Oncol Biol Phys 84(3):762–767. doi:10.1016/j.ijrobp.2011.12.067

    Article  PubMed  Google Scholar 

  15. Ng AK, Dabaja BS, Hoppe RT, Illidge T, Yahalom J (2016) Re-examining the role of radiation therapy for diffuse large B‑cell lymphoma in the modern era. J Clin Oncol 34(13):1443–1447. doi:10.1200/jco.2015.64.9418

    Article  CAS  PubMed  Google Scholar 

  16. ClinicalTrials.gov (2016) Rituximab and combination chemotherapy with or without radiation therapy in treating patients with B‑cell non-Hodgkin’s Lymphoma – full text view. https://clinicaltrials.gov/ct2/show/study/NCT00278408?term=unfolder&rank=1. Accessed 28 Nov 2016

    Google Scholar 

  17. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M (1971) Report of the committee on Hodgkin’s disease staging classification. Cancer Res 31(11):1860–1861

    CAS  PubMed  Google Scholar 

  18. Cheson BD, Pfistner B, Juweid ME et al (2007) Revised response criteria for malignant lymphoma. J Clin Oncol 25(5):579–586. doi:10.1200/jco.2006.09.2403

    Article  PubMed  Google Scholar 

  19. Juweid ME, Stroobants S, Hoekstra OS et al (2007) Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 25(5):571–578. doi:10.1200/jco.2006.08.2305

    Article  PubMed  Google Scholar 

  20. CTEP (2016) Protocol development. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Accessed 25 July 2016

    Google Scholar 

  21. Horning SJ, Weller E, Kim K et al (2004) Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin’s lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol 22(15):3032–3038. doi:10.1200/jco.2004.06.088

    Article  CAS  PubMed  Google Scholar 

  22. Miller TP, Dahlberg S, Cassady JR et al (1998) Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin’s lymphoma. N Engl J Med 339(1):21–26. doi:10.1056/nejm199807023390104

    Article  CAS  PubMed  Google Scholar 

  23. Phan J, Mazloom A, Medeiros LJ et al (2010) Benefit of consolidative radiation therapy in patients with diffuse large B‑cell lymphoma treated with R‑CHOP chemotherapy. J Clin Oncol 28(27):4170–4176. doi:10.1200/jco.2009.27.3441

    Article  PubMed  Google Scholar 

  24. Marcheselli L, Marcheselli R, Bari A et al (2011) Radiation therapy improves treatment outcome in patients with diffuse large B‑cell lymphoma. Leuk Lymphoma 52(10):1867–1872. doi:10.3109/10428194.2011.585526

    Article  CAS  PubMed  Google Scholar 

  25. Hu C, Deng C, Zou W, Zhang G, Wang J (2015) The role of consolidative radiotherapy after a complete response to chemotherapy in the treatment of diffuse large B‑cell lymphoma in the rituximab era: results from a systematic review with a meta-analysis. Acta Haematol 134(2):111–118. doi:10.1159/000370096

    Article  PubMed  Google Scholar 

  26. Kaplan HS (1980) Hodgkin’s disease: unfolding concepts concerning its nature, management and prognosis. Cancer 45(10):2439–2474

    Article  CAS  PubMed  Google Scholar 

  27. Fuks Z, Kaplan HS (1973) Recurrence rates following radiation therapy of nodular and diffuse malignant lymphomas. Radiology 108(3):675–684. doi:10.1148/108.3.675

    Article  CAS  PubMed  Google Scholar 

  28. Nickson JJ (1966) Hodgkin’s disease clinical trial. Cancer Res 26(6):1279–1283

    CAS  PubMed  Google Scholar 

  29. Yahalom J, Mauch P (2002) The involved field is back: issues in delineating the radiation field in Hodgkin’s disease. Ann Oncol 1:79–83

    Article  Google Scholar 

  30. Eich HT, Müller R‑P, Engenhart-Cabillic R et al (2008) Involved-node radiotherapy in early-stage Hodgkin’s lymphoma. Definition and guidelines of the German Hodgkin Study Group (GHSG). Strahlenther Onkol 184(8):406–410

    Article  PubMed  Google Scholar 

  31. Hoskin PJ, Díez P, Williams M, Lucraft H, Bayne M (2013) Participants of the lymphoma radiotherapy group. Recommendations for the use of radiotherapy in nodal lymphoma. Clin Oncol 25(1):49–58. doi:10.1016/j.clon.2012.07.011

    Article  CAS  Google Scholar 

  32. Campbell BA, Connors JM, Gascoyne RD, Morris WJ, Pickles T, Sehn LH (2012) Limited-stage diffuse large B‑cell lymphoma treated with abbreviated systemic therapy and consolidation radiotherapy: involved-field versus involved-node radiotherapy. Cancer 118(17):4156–4165. doi:10.1002/cncr.26687

    Article  PubMed  Google Scholar 

  33. Verhappen MH, Poortmans PMP, Raaijmakers E, Raemaekers JMM (2013) Reduction of the treated volume to involved node radiation therapy as part of combined modality treatment for early stage aggressive non-Hodgkin’s lymphoma. Radiother Oncol 109(1):133–139. doi:10.1016/j.radonc.2013.07.013

    Article  PubMed  Google Scholar 

  34. Yu JI, Nam H, Ahn YC, Kim WS, Park K, Kim SJ (2010) Involved-lesion radiation therapy after chemotherapy in limited-stage head-and-neck diffuse large B cell lymphoma. Int J Radiat Oncol Biol Phys 78(2):507–512. doi:10.1016/j.ijrobp.2009.07.1706

    Article  PubMed  Google Scholar 

  35. Kwon J, Kim IH, Kim BH, Kim TM, Heo DS (2015) Additional survival benefit of involved-lesion radiation therapy after R‑CHOP chemotherapy in limited stage diffuse large B‑cell lymphoma. Int J Radiat Oncol Biol Phys 92(1):91–98. doi:10.1016/j.ijrobp.2014.12.042

    Article  CAS  PubMed  Google Scholar 

  36. Elstrom R, Guan L, Baker G et al (2003) Utility of FDG-PET scanning in lymphoma by WHO classification. Blood 101(10):3875–3876. doi:10.1182/blood-2002-09-2778

    Article  CAS  PubMed  Google Scholar 

  37. Isohashi K, Tatsumi M, Higuchi I et al (2008) 18F-FDG-PET in patients with malignant lymphoma having long-term follow-up: staging and restaging, and evaluation of treatment response and recurrence. Ann Nucl Med 22(9):795–802. doi:10.1007/s12149-008-0186-4

    Article  PubMed  Google Scholar 

  38. Lowry L, Smith P, Qian W et al (2011) Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial. Radiother Oncol 100(1):86–92. doi:10.1016/j.radonc.2011.05.013

    Article  PubMed  Google Scholar 

  39. Avilés A, Delgado S, Nambo MJ, Alatriste S, Díaz-Maqueo JC (1994) Adjuvant radiotherapy to sites of previous bulky disease in patients stage IV diffuse large cell lymphoma. Int J Radiat Oncol Biol Phys 30(4):799–803

    Article  PubMed  Google Scholar 

  40. Pfreundschuh M, Schubert J, Ziepert M et al (2008) Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B‑cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 9(2):105–116. doi:10.1016/s1470-2045(08)70002-0

    Article  CAS  PubMed  Google Scholar 

  41. Song M‑K, Chung J‑S, Sung-Yong O et al (2010) Clinical impact of bulky mass in the patient with primary extranodal diffuse large B cell lymphoma treated with R‑CHOP therapy. Ann Hematol 89(10):985–991. doi:10.1007/s00277-010-0964-7

    Article  CAS  PubMed  Google Scholar 

  42. Held G, Murawski N, Ziepert M et al (2014) Role of radiotherapy to bulky disease in elderly patients with aggressive B‑cell lymphoma. J Clin Oncol 32(11):1112–1118. doi:10.1200/jco.2013.51.4505

    Article  PubMed  Google Scholar 

  43. Jegadeesh N, Rajpara R, Esiashvili N et al (2015) Predictors of local recurrence after rituximab-based chemotherapy alone in stage III and IV diffuse large B‑cell lymphoma: guiding decisions for consolidative radiation. Int J Radiat Oncol Biol Phys 92(1):107–112. doi:10.1016/j.ijrobp.2015.01.025

    Article  PubMed  PubMed Central  Google Scholar 

  44. Wilder RB, Tucker SL, Ha CS et al (2001) Dose-response analysis for radiotherapy delivered to patients with intermediate-grade and large-cell immunoblastic lymphomas that have completely responded to CHOP-based induction chemotherapy. Int J Radiat Oncol Biol Phys 49(1):17–22

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Oncology and Radiotherapy, University Medical Center Mainz, Langenbeckstraße 1, 55131, Mainz, Germany

    Eva Holzhäuser M.D., Maximilian Berlin, Thomas Bezold, Arnulf Mayer & Heinz Schmidberger

  2. Institute for Medical Biostatistics, Epidemiology and Informatics, University Medical Center Mainz, Obere Zahlbacher Str. 69, 55131, Mainz, Germany

    Daniel Wollschläger

  3. Department of Internal Medicine, University Medical Center Mainz, Langenbeckstraße 1, 55131, Mainz, Germany

    Georg Heß

Authors
  1. Eva Holzhäuser M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maximilian Berlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel Wollschläger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas Bezold
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arnulf Mayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Georg Heß
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Heinz Schmidberger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eva Holzhäuser M.D..

Ethics declarations

Conflict of interest

E. Holzhäuser, M. Berlin, D. Wollschläger, T. Bezold, A. Mayer, G. Heß and H. Schmidberger declare that they have no competing interests.

Ethical standards

This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Holzhäuser, E., Berlin, M., Wollschläger, D. et al. Patterns of failure of diffuse large B‑cell lymphoma patients after involved-site radiotherapy. Strahlenther Onkol 193, 1014–1023 (2017). https://doi.org/10.1007/s00066-017-1186-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00066-017-1186-x

Schlüsselwörter

Keywords

Search

Navigation