Treatment

Revised 1 June 2013

Treatment of malignant lymphoma is based on histologic subtype, extent of disease, and age of the patient as is shown in the following table. In the case of discordant (two separate sites of disease with differing types of lymphoma), composite (one site of disease with two discrete types of lymphoma at that site) or transformed (a second lymphoma developing out of a background of previously known lymphoma) lymphoma, treatment must be directed at the most aggressive phase of the disease.

See Table 3.1 for specific subtypes of lymphoma. Note that the approaches outlined in this table are generally applicable to both B-cell and T-cell lymphomas, however, special approaches to gastric low grade MALT, mycoses fungoides, HTLV-1 lymphoma and lymphomas presenting at special sites or in association with immunodeficiency are outlined in the Special Problems section. In addition, the use of rituximab is only appropriate for B cell lymphomas.

Type	Stage	Treatment (see Chemotherapy Protocols)
Indolent*	Limited	INRT (Campbell 2008)
	Advanced asymptomatic	Close follow-up under continued observation is appropriate for patients without requirement for systemic treatment. Patients with asymptomatic advanced stage follicular lymphoma within 6 months of diagnosis without requirement for systemic therapy are eligible to receive rituximab monotherapy (LYRITUX) which has been shown to delay the need for cytotoxic therapy.(Ardeshna, ASH annual meeting abstracts, Nov 2010;116,6 and Kahl, ASH annual meeting abstracts, Nov 2011;118,LBA6)
	Symptomatic	LYBENDR(Rummel, Lancet 2013:381:1184) followed by maintenance rituximab (LYRMTN)if the BEND-R results in at least a partial response*. Note: CAP approval is required for LYBENDR and also for LYRMTN Localized irradiation can be useful for local symptoms
Follicular, grade 3 B Diffuse large cell⁺ B cell, unclassifiable, with features intermediate between DLBCL and Burkitt B cell, unclassifiable, with features intermediate between DLBCL and Hodgkin lymphoma	Limited	LYCHOPR* x 3& (see Chemotherapy Protocols) After completion of above chemotherapy: If PET positive or indeterminate -> INRT (Campbell 2012); If PET negative -> 1 more cycle of LYCHOPR* Exceptions: (1) Limited stage composite indolent and aggressive lymphoma treat with LYCHOPR x 3 then IFRT; (2) Limited stage aggressive T-cell lymphoma treat with LYCHOP x 3 then IFRT.
	Advanced	LYCHOPR*** (Coiffier, N Engl J Med, 2002;346:235-42) x 6 then CT scan and biopsies or other assessment as needed if originally positive. After completion of above chemotherapy: If CR, no further treatment; if otherwise in CR but residual mass > 2 cm do PET scan; if PET neg, no further treatment; if PET pos and encompassable in a reasonable radiation volume-> residual disease radiotherapy; if PET pos and not encompassable in a reasonable radiation volume-> close observation or biopsy to direct further treatment on proof of persistent lymphoma.
Primary mediastinal large B cell	All stages	LYCHOPR*** (Coiffier, N Engl J Med, 2002;346:235-42) x 6 then CT scan and biopsies or other assessment as needed if originally positive After completion of above chemotherapy: If CR, no further treatment; if otherwise in CR but residual mass >2 cm do PET scan; if PET neg, no further treatment; if PET pos and encompassable in a reasonable radiation volume-> residual disease radiotherapy; if PET pos and not encompassable in a reasonable radiation volume-> close observation or biopsy to direct further treatment on proof of persistent lymphoma
Mantle cell	Limited	LYCHOPR x 3 then INRT
Mantle cell	Advanced	LYBENDR x 6 cycles (Rummel, Lancet 2013:381:1184) followed by 2 years of maintenance rituximab (ULYRMTN). (Kluin-Nelemans JC, Blood, ASH Annual meeting abstracts, Nov 2011; 118:439) Note: CAP approval is required for LYBENDR and also for LYRMTN Exception: Patients with mantle cell lymphoma who are ≤65 years of age should receive 6 cycles of LYBENDR followed by autologous stem cell transplantation and 2 cycles of consolidation rituximab (administered as LYRITUX at 8 and 24 weeks following ASCT).
Special	All	These diagnoses constitute an emergency. They may require intensive high dose chemotherapy with central nervous system prophylaxis. Treatment with cyclophosphamide or multi-agent chemotherapy as needed should begin within 48 hours whether staging is complete or not. The patients should be managed at a major referral Center. They often require high dose chemo/radiotherapy and hematopoietic stem cell transplantation as part of their management.

*Note: small lymphocytic lymphoma is managed similarly to chronic lymphocytic leukemia, not as an indolent lymphoma, and, follicular grade 3B lymphoma is managed similarly to diffuse large B cell lymphoma, not as an indolent lymphoma

**Central Nervous System Prophylaxis. Patients with initial involvement of paranasal sinuses with diffuse large B-cell or peripheral T-cell lymphoma (all subtypes) may require prophylactic intrathecal chemotherapy as outlined in the Special Problems section. The specific dose and schedule are shown in the Central Nervous System (CNS) Lymphoma section.

*** Rituximab should only be included if the lymphoma is documented to express CD20 (note: some B-cell lymphomas often do not express CD20 (for example, plasmablastic))

Involved Node Radiotherapy (INRT)

- Adopted mainly from Campbell’s papers on “INRT<5cm” = pre- and post-chemo involved lymph nodes (within post-chemo anatomical limits) + 1.5-5cm to field edge[1] or to PTV[2], [3]

CTV = pre- and post-chemo involved lymph node(s), restricted by post-chemo anatomic limits, + 1cm axially and 1-4cm craniocaudally along lymphatic pathways
- o craniocaudal margin adjusted based on level of uncertainty in localization of PET-avid abnormality (allows for positional and anatomical changes from pre-chemo PET to RT)[2], [3]
PTV = CTV + ~1cm, depending on set-up variation and physiological intra-fraction and inter-fraction movement[4]
Mediastinal Area[4], [5]
- Length of CTV = length of mediastinal mass or LN(s) before chemo
- Width of CTV = width of mediastinal mass or LN(s) after chemo
- The normal mediastinum is contoured and the CTV should not exceed the lateral mediastinal boundaries, except where LN remnants persist

Residual Disease Radiotherapy (RDRT)

CTV = pre- and post-chemo involved lymph node(s), restricted by post-chemo anatomic limits, + 1cm axially and 1-4cm craniocaudally along lymphatic pathways
- craniocaudal margin adjusted based on level of uncertainty in localization of PET-avid abnormality (allows for positional and anatomical changes from pre-chemo PET to RT)[2], [3]
- Do not include any pre-chemo involved LN region that is far away from the residual disease
PTV = CTV + ~1cm, depending on set-up variation and physiological intra-fraction and inter-fraction movement[4]
Mediastinal Area[4], [5]
- Length of CTV = length of mediastinal mass or LN(s) before chemo
- Width of CTV = width of mediastinal mass or LN(s) after chemo
- The normal mediastinum is contoured and the CTV should not exceed the lateral mediastinal boundaries, except where LN remnants persist

References

[1] B. A. Campbell et al., “Involved-Nodal Radiation Therapy As a Component of Combination Therapy for Limited-Stage Hodgkin's Lymphoma: A Question of Field Size, ”Journal of Clinical Oncology, vol. 26, no. 32, pp. 5170–5174, Oct. 2008.

[2] B. A. Campbell et al., “Long-term outcomes for patients with limited stage follicular lymphoma,”Cancer, vol. 116, no. 16, pp. 3797–3806, May. 2010.

[3] B. A. Campbell, J. M. Connors, R. D. Gascoyne, W. J. Morris, T. Pickles, and L. H. Sehn, “Limited-stage diffuse large B-cell lymphoma treated with abbreviated systemic therapy and consolidation radiotherapy,” Cancer, vol. 118, no. 17, pp. 4156–4165, Jan. 2012.

[4] T. Girinsky, “Radiotherapy Recommendations for Patients with Early Stage Hodgkin's Lymphoma: Involved Node Radiation Therapy (INRT),” pp. 1–9, Mar. 2008.

[5] T. Girinsky et al., “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,” Radiotherapy and Oncology, vol. 88, no. 2, pp. 202–210, Aug. 2008.

[6] P. J. Hoskin, P. Díez, M. Williams, H. Lucraft, and M. Bayne, “Recommendations for the Use of Radiotherapy in Nodal Lymphoma,” Clinical Oncology, vol. 25, no. 1, pp. 49–58, Jan. 2013.

[7] Rummel MJ, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 2013:381:1184