Lymphomas

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51 Lymphomas

Key points

Lymphoma is cancer of the lymphatic system and accounts for approximately 3% of new cases of cancer reported in the UK each year. The primary cancerous cell of origin is the lymphocyte; as a result, there is often considerable overlap between lymphomas and lymphoid leukaemias. Lymphomas are subdivided into two main categories: Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). Both HL and NHL can be further classified based on histology.

The site of malignancy is usually a lymph node. Extranodal disease, most frequently of the stomach, skin, oral cavity and pharynx, small intestine and CNS, can occur and is more common in NHL than HL.

Hodgkin’s lymphoma

Hodgkin’s disease, now known as HL, was first described by Thomas Hodgkin in 1832. HL accounts for 30% of all lymphomas and has an incidence in the UK of 2.2 per 100,000 for women and 3.3 per 100,000 for men. It is predominantly a disease of young adults, having a peak incidence between the ages of 15 and 35 years.

Investigations and staging

Once the diagnosis has been made on biopsy, further investigations are needed to assess disease activity and the extent of its spread through the lymphoid system or other body sites. This is called staging and is essential for assessing prognosis, with cure rates for localised tumours (stage I or II) being much higher than those for widespread disease (stage IV). The staging of HL is assessed by the Cotswolds modification of the Ann Arbor classification system (Box 51.1). Information about prognostic factors such as mediastinal mass and bulky disease is included in the classification system. The tests required to establish the stage include a complete history, physical examination, FBC, urea and electrolytes (U and Es), chest X-ray and computed tomography (CT). Other useful tests include erythrocyte sedimentation rate (ESR), serum LDH and liver function tests (LFTs). Positron emission tomography (PET) can be used to detect active residual disease.

Box 51.1 Cotswolds modification of the Ann Arbor classification system for Hodgkin’s lymphoma

Clinical stage Defining features
I Involvement of a single lymph node region or lymphoid structure
II Involvement of two or more lymph node regions on the same side of the diaphragm
III Involvement of lymph node regions or structures on both sides of the diaphragm:

IV Involvement of extranodal site(s) beyond that designated E Modifying characteristics   A: no symptoms
B: fever, drenching sweats, weight loss
X: bulky disease
>one-third width of the mediastinum
>10 cm maximal dimension of nodal mass
E: involvement of a single extranodal site, contiguous or proximal to known nodal site
CS: clinical stage
PS: pathological stage

Management

HL is potentially curable and, in general, sensitive to both chemotherapy and radiotherapy; therefore, the two main goals of treatment are to maximise the likelihood of cure whilst minimising the risk of late toxicity such as infertility. Stage of disease is the biggest factor in treatment choice and outcome. The management of classic HL is determined by the stage of the disease, and this is summarised in Fig. 51.1. Localised NLPHL frequently involves one isolated lymph node and tends to be indolent (slow growing). If there are no risk factors, it can be treated with IFRT alone (30 Gy); all other types are treated as advanced (stage III or IV) classic HL.

In Europe, the treatment of classic HL is determined by whether the disease is staged as early favourable disease, early unfavourable disease, advanced disease or relapsed (see Box 51.2).

Advanced disease

Patients with advanced disease (stages III and IV) are treated with combination chemotherapy. The first widely used combination chemotherapy regimen was MOPP (mechlorethamine, vincristine (Oncovin), procarbazine and prednisolone) which produced a response rate of 80% and long-term disease-free survival of approximately 50%. ABVD has replaced MOPP chemotherapy as the regimen of choice as it is as effective but less toxic in terms of fertility, haematological toxicity, and the development of acute leukaemia and myelodysplasia. Six to eight cycles of ABVD is considered the current standard treatment for advanced disease.

Despite advances in HL, 30–40% of patients progress or relapse and respond poorly to salvage chemotherapy. A number of regimens have been investigated to both increase dose intensity and density of treatment, for example, BEACOPP (bleomycin, etoposide, Adriamycin (doxorubicin), cyclophosphamide, vincristine, procarbazine, prednisolone) and escalated BEACOPP (Table 51.1). In a trial comparing escalated BEACOPP, standard BEACOPP and COPP-ABVD, escalated BEACOPP demonstrated increased overall survival compared with the other two treatment arms but at the cost of significant toxicity (Engert et al., 2009). First-line escalated BEACOPP can only be recommended currently as part of a clinical trial. A study to investigate the role of BEACOPP and PET imaging in patients with advanced HL is under way and will close in 2012 (UK Clinical Research Network Study Portfolio, 2010).

Table 51.1 Combination chemotherapy regimens effective in the treatment of Hodgkin’s lymphoma

Regimen Dose and route Frequency
ABVD (28-day cycle)
Doxorubicin 25 mg/m2 i.v. Days 1 and 15
Bleomycin 10,000 iu/m2 i.v. Days 1 and 15
Vinblastine 6 mg/m2 i.v. Days 1 and 15
Dacarbazine 375 mg/m2 i.v. Days 1 and 15
BEACOPP escalated (21-day cycle)a
Bleomycin 10,000 iu/m2 i.v. Day 8
Etoposide 200 mg/m2 i.v. Days 1–3
Adriamycin (doxorubicin) 35 mg/m2 i.v. Day 1
Cyclophosphamide 1250 mg/m2 i.v. Day 1
Vincristine 1.4 mg/m2 i.v. (max. 2 mg) Day 8
Procarbazine 100 mg/m2 orally Days 1–7
Prednisolone 40 mg/m2 orally Days 1–14
BEACOPP standard dose (21-day cycle)a
Bleomycin 10,000 iu/m2 i.v. Day 8
Etoposide 100 mg/m2 i.v. Days 1–3
Adriamycin (doxorubicin) 25 mg/m2 i.v. Day 1
Cyclophosphamide 650 mg/m2 i.v. Day 1
Vincristine 1.4 mg/m2 i.v. (max. 2 mg) Day 8
Procarbazine 100 mg/m2 orally Days 1–7
Prednisolone 40 mg/m2 orally Days 1–14
ChlVPP
Chlorambucil 6 mg/m2 orally Days 1–14
Vinblastine 6 mg/m2 i.v. Days 1 and 8
Procarbazine 100 mg/m2 orally Days 1–14
Prednisolone 40 mg/m2 orally (max 60 mg) Days 1–14

a Escalated BEACOPP and standard BEACOPP have shown activity in Hodgkin’s lymphoma, but their usage is not standard in the UK.

Other options for patients unlikely to tolerate ABVD include ChlVPP (chlorambucil, vinblastine, procarbazine, prednisolone) and CHOP (cyclophosphamide, doxorubicin (hydroxydaonorubicin), vincristine (Oncovin), prednisolone, rituximab.

Salvage therapy for relapsed disease

Relapsed disease refers to disease progression after completion of primary treatment which resulted in a complete remission. Depending on previous treatment, options include salvage radiotherapy, salvage chemotherapy or high-dose chemotherapy with autologous stem cell support. In this procedure, stem cells are collected from the patient and returned following high-dose chemotherapy. Patients who relapse after initial radiotherapy alone have a good chance of cure with combination chemotherapy, at least equal to that of patients initially treated with chemotherapy for advanced disease. Occasionally, radiotherapy is used if the disease is localised and previously non-irradiated. Those who relapse after combination chemotherapy have a worse prognosis, although durable remissions can be obtained with further conventional therapy.

Length of remission following first-line chemotherapy influences the success of subsequent salvage therapy and so failure of chemotherapy can be used to classify disease and determine appropriate therapy. If the duration of remission was greater than 12 months (late relapse), then the patient can be re-treated with their initial chemotherapy, salvage regimen or considered for high-dose chemotherapy with autologous transplantation.

Commonly used chemotherapy salvage regimens are listed in Table 51.2. If relapse occurs less than a year after treatment (early relapse), then high-dose chemotherapy with autologous stem cell support should be considered. A patient who has never achieved complete remission (primary refractory disease) should receive high-dose chemotherapy with autologous stem cell support.

Table 51.2 Salvage chemotherapy regimens effective in the treatment of lymphoma

Regimen Dose and route Frequency
DHAP
Cisplatin 100 mg/m2 i.v. Days 1
Cytarabine 2000 mg/m2 i.v. 12 hourly Day 2
Dexamethasone 40 mg orally Days 1–4
ESHAP
Etoposide 40 mg/m2 i.v. Days 1–4
Methylprednisolone 500 mg/m2 i.v. Days 1–5
Cytarabine 2000 mg/m2 i.v. Day 1
Cisplatin 25 mg/m2 i.v. Days 1–4
ICE
Ifosfamide 5000 mg/m2 i.v. Day 2
Carboplatina AUC 5 i.v. Day 2
Etoposide 100 mg/m2 i.v. Days 1–3
IVE
Epirubicin 50 mg/m2 i.v. Days 1
Etoposide 200 mg/m2 i.v. Days 1–3
Ifosfamide 3000 mg/m2 i.v. Days 1–3

AUC, area under the curve; GFR, glomerular filtration rate.

a Carboplatin dose (mg) = target AUC (mg/mL × min) × (GFR (mL/min) + 25).

High-dose chemotherapy plus autologous stem cell support is associated with a 40–50% 5-year survival rate. However, the significant toxicity of autologous stem cell transplantation means that it should be reserved for patients in whom there is a clear increase in chance of cure. Allogeneic transplant is an option in patients relapsing after autologous transplant (Brusamolino et al., 2009).