Management depends on stage and the presence of CD20 antigen. Survival can be estimated by the International Prognostic Index (IPI); since the advent of rituximab the revised IPI is used (R-IPI).
Early Disease
The standard approach for stage I-II, non bulky DLBCL is sequential chemotherapy and radiotherapy, usually:
- 3 cycles R-CHOP, followed by
- Involved field radiotherapy (30-45 Gy)
- The lower dose of radiotherapy is supported by the Lowry trial (2011) where patients were randomised to 30 Gy vs 45 Gy. No difference in survival was seen; about 82% of included patients had DLBCL and about 84% of these were treated with first line radiotherapy rather than for relapse. Higher doses may be suggested in patients who have a partial response to systemic therapy (ie. PET positivity after completion of chemotherapy).
5 year survival approaches 95% with the above regimen for patients with low risk disease. Controversy exists over whether chemotherapy alone should be the preferred method of treatment - there have been numerous trials done before the introduction of rituximab with mixed results between chemotherapy alone and combined treatments. Examples include the SWOG 8736 trial (chemo-RT better short term but worse long term for high risk patients); the GELA 93-1 trial (CHOP + RT worse than ACVBP); and the ECOG study (8 cycles CHOP +/- RT; RT arm had better disease free survival but no difference in overall survival). Non randomised studies performed since the introduction of rituximab have not shown that radiotherapy can be safely omitted.
Therefore, standard of care remains 3 cycles R-CHOP + involved field radiotherapy to 30-45 Gy. In patients unable to receive or who have relative contraindications for radiotherapy, equivalent outcomes may be expected with 6 cycles of R-CHOP but this would be associated with increased toxicity during treatment. Patients with a high IPI score may benefit from 6 cycles of R-CHOP followed by involved field radiotherapy (similar to protocol for bulky disease below).
Importantly, the Mabthera International Trial (MInT) which established the role for rituximab in low risk disease compared 6 cycles of CHOP to 6 cycles of R-CHOP; 3 out of 4 patients had early stage disease. Those with bulky disease (> 7.5 cm) or extranodal disease received additional radiotherapy (30-36 Gy). This is cited as the reason to use 6 cycles of R-CHOP for all stages of disease; however given the good results seen with 3 cycles of CHOP + RT it seems a bit excessive.
Bulky Disease
Patients with bulky disease are at high risk of disease recurrence. More intensive chemotherapy is usually recommended, typically 6 cycles of R-CHOP followed by involved field radiotherapy (30-45 Gy). Even with more intensive treatment survival is worse than stage I-II non-bulky disease.
Refractory Disease
Patients should be restaged with PET scan at the completion of systemic therapy, although the optimal timing is not clear.
- Patients with complete response should proceed to involved field radiotherapy (30-45 Gy)
- Patients with partial response form an interesting group. Partial response may be due to slower response to systemic therapy; higher doses may be required to ensure local control is achieved. Some advocate proceeding to second line therapy with autologous stem cell transplant immediately for the partial response group but this is not a standard practice for low risk disease.
- Patients with stable or progressive disease (refractory) should proceed to either high dose systemic therapy with plan for autologous stem cell transplant, or be treated palliatively
Advanced Disease
About 70% of patients with DLBCL will have disease that is not encompassable within a radiotherapy field. These patients are treated with CHOP; rituximab is added if CD20 positivity is confirmed.
Maintenance
There is no evidence for ongoing benefit for rituximab if it was used in the initial treatment of a DLBCL.
Choice of Chemotherapy Regimen
R-CHOP was proven in a number of randomised studies to be superior to CHOP alone and is now the standard of care.
Frequency of dosing has been studied but there is no randomised evidence that more frequent dosing (eg. R-CHOP 14) is any better than standard R-CHOP 21. The number of cycles has only been evaluated with R-CHOP 14, which demonstrated no difference in outcomes between 6 and 8 cycles. Most randomised trials have used six doses of R-CHOP 21 rather than basing the number of cycles on disease response.
Many other regimens were evaluated before the development of rituximab but none have shown superiorty to CHOP. R-ACVBP (doxorubicin, cyclophosphamide, videsine, bleomycin, prednisolone) has been shown recently to have improved disease outcomes but at the expense of haematological and non-haematological toxicities;
Specific Extranodal Primary Sites
Testicular Lymphoma
Lymphoma of the testis is a poor prognosis disease which has specific issues in its management:
- Testicular DLBCL is a high risk local disease and should therefore receive an extended course of systemic therapy (R-CHOP 6 cycles) consistent with bulky disease
- The contralateral testis is a common site of relapse after systemically treated testicular lymphoma. Radiotherapy to the uninvolved contralateral testis is routinely given (typically 30 Gy / 15 #); typically involved field radiotherapy would be given (to the scrotum +/- other adjacent regional nodal sites) to a similar dose.
- The CNS is another common site of relapse. There is debate regarding appropriate prophylaxis (intrathecal versus high dose systemic therapy); either may be considered appropriate but adding intravenous methotrexate with leucovorin rescue during the systemic portion of treatment seems appropriate.
Treatment Technique
Scrotal irradiation is uncommonly used outside of lymphoma treatment and this technique has been described on line (not available in any of the usual textbooks!)
- The patient is simulated in the frog leg position with a vacuum bag. The arms are elevated above the head on a wing board
- The scrotum is supported on a bench and the penis is retracted out of the field.
- The scrotum is wrapped in 1 cm bolus to facilitate even dose distribution and to increase dose to the scrotal skin
- The scrotum can be treated with a direct electron technique or with AP/PA photons depending on the thickness of the scrotum.
- Typical dose varies for prophylactic treatment (25/15 to 30/15)
Patients with stage II disease should have the contralateral scrotum and other involved nodal regions (eg. para-aortic or inguinal) treated also.
Early effects include radiation dermatitis, diarrhoea and fatigue. Late effects include permanent sterility, decreased testosterone function over years, cosmetic skin changes, erectile dysfunction and second malignancies.
Other High Risk Primary Sites
DLBCL of the orbit, paranasal sinuses, ovary or dura are also 'high risk' sites that necessitate treatment with 6 cycles of R-CHOP and CNS prophylaxis.
CNS Prophylaxis
Prophylaxis of the CNS outside of the specific high risk sites above is more problematic. The overall risk for CNS involvement by DLBCL is about 5%; this increases with advanced stage disease (III/IV), high IPI score, or advancing age; typically prophylaxis would be considered for patients with high-intermediate or high risk IPI scores.
CNS Lymphoma
Important studies to acquire - TROG study (high RT bad), German study (RT good), American study (RT bad), 2007 MSKCC study (Low dose RT good)
CNS lymphoma has a very poor prognosis, and is usually (90%) diffuse large B cell lymphoma. The management of CNS lymphoma is highly controversial given poor outcomes and significant toxicities associated with the available treatments.
Aside from obtaining tissue biopsy, surgery has no role to play in the management of CNS lymphoma.
Steroids are very effective but can cause the lesion to involute rapidly, making biopsy difficult. Steriods should be delayed if possible until after surgical biopsy; once this is done they are very effective at controlling symptoms.
Classical treatment was whole brain radiotherapy to a dose of 50.4 Gy in 28 fractions, and this is still used for patients unable to receive chemotherapy. Most patients had a complete response but rapid recurrence was common and median survival was 12 months.
A series of non-randomised trials identified improved outcomes with methotrexate therapy compared to historical outcomes with radiotherapy and therefore methotrexate has become the cornerstone of management of primary CNS lymphoma. Unfortunately, the combination of methotrexate and radiotherapy has not been proven to improve outcomes but does result in severe neurotoxicity (25% of patients developing rapidly progressive dementia, particularly older patients > 60). Intravenous methotrexate is equivalent to intrathecal methotrexate due to good penetration of the blood brain barrier.
Aside from initial treatment with methotrexate, recommendations vary considerably:
- Combination of methotrexate with other cytotoxics is usually recommended for patients with a good performance status. The most common combination is cytrabine, but rituximab has also been used.
- The use of whole brain radiotherapy following systemic treatment is very country and centre specific.
- Some advocate avoiding radiotherapy in all patients who obtain a complete response to chemotherapy, and reserving radiotherapy for recurrence if it occurs. This has the potential to avoid neurotoxicity in cured patients, but may risk the potential of cure in other patients.
- Some advocate the regular use of radiotherapy in patients under 60 who have a lower risk of neurotoxicity
- Radiotherapy is generally recommended if patients only have a partial response to systemic therapies
- The dose of radiotherapy varies from 24-36 (complete response) Gy to 45 Gy (partial response) to 50.4 Gy (radiotherapy alone)
My Recommendation
It seems I can say whatever I want here!
I believe that all patients should discuss their options with a radiation oncologist. I would recommend chemotherapy using a methotrexate based regimen for all patients unless they were unable to tolerate treatment (eg. renal dysfunction, ECOG 3-4 despite steroids). I would offer radiotherapy to all patients but would only recommend it in young patients to give them the best chance at long term survival; I would counsel older patients that they would be at high risk of dementia if both treatments were offered.
I would give the whole brain a dose of 36 Gy for a complete response or 45 Gy for a partial response to systemic therapy.
