Limited-stage diffuse large B-cell lymphoma (DLBCL) treated with abbreviated systemic therapy and consolidation radiotherapy: Involved field radiotherapy (IFRT) versus involved nodal radiotherapy (INRT≤5cm)

Reporter: Arpi Thukral, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 5 de junio del 2010

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Presenter: B. A. Campbell
Affiliation: British Columbia Cancer Agency and the University of British Columbia, Vancouver, Canada

Background

  • Diffuse large B-cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma (NHL), and accounts for approximately 30-35% of patients with NHL.
    • Limited stage DLBCL is defined as Ann Arbor Stage I-II (£3 adjacent LN regions), no B symptoms, & non-bulky (<10 cm)
  • Optimal management of limited-stage DLBCL is still evolving. Although radiation alone was considered standard of care in the 1980s, current strategies include a combined modality approach with a combination of chemotherapy, biologic agents and consolidative radiation therapy.
  • The current standard of care for treatment includes 3 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy and Rituxan, followed by consolidative involved-field radiation therapy (IFRT), as demonstrated by the SWOG 8736 trial (Miller, et. al., NEJM).
    • After chemotherapy alone, 40% of patients relapse locally. The aim of radiation therapy in the latter treatment regimen is to improve local control.
    • However, the use of radiation has been questioned due to late complications, which are dependent on the irradiated volume and radiation dose delivered.
  • The efficacy of radiation doses below the conventional 36– 40 Gy has been demonstrated for lymphoma in various previous trials. A decline in late complications is expected with lower radiation doses. Smaller radiation fields should also lead to a decrease in late complications as the amount of irradiated normal tissue is reduced via this approach.
  • A novel concept, first introduced in Hodgkin’s disease, is to decrease radiation volumes to include only the pre-chemotherapy involved nodes (INRT) as opposed to including entire nodal chains (IFRT).
  • The purpose of this study was to assess the influence of RT field size on patterns of failure in patients with limited-stage DLBCL: Namely, are smaller field sizes associated with increased marginal recurrence?

Methods

  • This study is a retrospective review of the British Columbia Cancer Agency Lymphoid Cancer database in which patients with a diagnosis of limited stage DLBCL were enrolled between 1/1/81 and 12/31/07.
  • Inclusion criteria:
    • Ann Arbor Stage IA or IIA
    • Bulk < 10 cm
    • Centrally-reviewed pathology
  • Exclusion criteria:
    • stage III/IV
    • bulk ? 10cm
    • B symptoms
    • Testicular primary tumor site
  • Systemic Therapy:
    • Systemic therapy involved 3 cycles of CHOP / CHOP-like chemotherapy; rituximab was added beyond 2003.
  • Radiation Therapy:
    • Era-specific guidelines for RT were:
      • IFRT: 1981 to 1996. IFRT was defined as pre-chemotherapy involved nodal group.
      • INRT?5cm: 1996 - 2007. INRT?5cm was defined as RT to the pre-chemotherapy involved nodes with margins ? 5cm to account for movement and set-up variation.
    • PET was not used for staging or radiation treatment planning.
    • Median RT dose was 35 Gy (range 30-45 Gy). Dose was chosen at discretion of the treating radiation oncologist.
    • CT simulation and 3D conformal RT were not mandatory (due to early treatment era).
  • The endpoints of the study were patterns of failure, time to progression (TTP), progression-free survival (PFS), overall survival (OS), and prognostic factors.

Results

  • 288 patients were eligible: 61% male; 56% aged > 60 years; 34% stage IIA; 55% extranodal disease; 19% elevated LDH; 45% ECOG ? 1; 74% stage-adjusted IPI ? 1.
  • 15% received rituximab.
  • RT groups were: IFRT 138 (48%), INRT?5cm 150 (52%).
  • Median follow-up of living patients was 96 months.
    • 9.8 years for IFRT group and 7.4 years for INRT group
  • Patients were well-balanced in the two groups. 56% of patients were over 60 years old and 34% of patients were Stage IIA.
  • 64 patients relapsed: IFRT 32 (23%), INRT?5cm 32 (21%).
  • The most common site of failure was outside the RT field: IFRT 24 (17%), INRT?5cm 26 (17%).
  • Marginal relapse was defined as relapse beyond the INRT?5cm field but within a conventional IFRT field.
    • After INRT?5cm, marginal relapse occurred in only 3 (2%) patients.
  • OS at 10 years was 65%. At 5 years, time to progression (TTP) was 84%, progression-free survival (PFS) 75% and overall survival (OS) 82%; with no significant difference between the two RT groups.
  • No difference in outcome was seen for TTP between pre- and post-Rituxan eras.
  • Long term follow-up showed a late plateau in TTP: only 2 relapses occurred after 13 years. Age (less than 60 years versus greater than 60 years) was the only significant predictive factor for TTP (p = 0.009) and OS (p < 0.001).
  • Prognostic factors for PFS were age (p < 0.001) and performance status (p = 0.050). RT field size was not a significant predictor for TTP, PFS or OS.

Author’s Conclusions

  • For limited-stage DLBCL patients treated with combination therapy, INRT as performed in this study, appears to be safe and has no adverse impact on TTP, PFS, or OS.
  • Distant relapse was the most common type of failure, with a clinically significant late relapse rate to 13 years.
  • Smaller RT fields are likely to reduce risks of RT induced toxicities and may improve the therapeutic ratio for these patients.

Clinical Implications

  • Radiation therapy for Hodgkin’s Disease (HD) has evolved from extended-field radiation therapy (EFRT) to involved-field radiation therapy (IFRT), reducing toxicity while maintaining high cure rates. A recent trial by the author of this study, Campbell, et. al, in JCO 2008 showed that reduction in field size appears to be safe in HD, and is not associated with an increased risk of LRR.
  • Although radiation therapy for limited-stage diffuse large B cell lymphoma is necessary for local control, its use is often discouraged due to the risk of long-term toxicity secondary to radiation. Therefore, it is important to continue to study how to reduce volume of RT or dose of RT, or both in order to improve therapeutic ratio for patients.
  • Studies examining the role of INRT have been previously performed in both Hodgkin’s Disease (German-EORTC trial) and follicular lymphoma (Campbell, et al.) patients with promising results.
  • This study demonstrated similar results with IFRT and INRT. It provides valuable information about INRT and supports the hypothesis that INRT does not result in an increased marginal recurrence rate.
  • Limitations of the study:
    • The study is retrospective and an inherent selection bias/physician bias is present in who received IFRT vs. INRT. It can be assumed that patients with more aggressive/ worse disease were more likely to have IFRT and do better than those who would have received INRT.
  • The authors of this study have conducted a thorough study to address the issue of INRT vs. IFRT in limited-stage DLBCL patients.
  • Given that this is a retrospective study, these data can only be hypothesis generating. To determine the clinical relevance of this study, this hypothesis should be tested in future prospective trials.
  • One important question to be considered when designing the future phase III trial will be patient selection. Certain patient populations may be better candidates for INRT given factors such as bulk of disease, age of patient, and stage, and it will be important to determine how to select the patient population for the next trial.
  • Furthermore, guidelines to determine who should receive IFRT vs. INRT need to be established and adherence to these to be monitored.
  • In addition, overall survival data with longer follow up will be necessary to determine the clinical relevance of this treatment regimen and potentially change standard of care.
  • It will also be useful to examine differences between Stage I and Stage II patients and older and younger populations in future studies.
  • The ability to improve therapeutic ratio by reducing RT volume and dose is an exciting area of research for lymphoma patients and warrants further investigation.

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