Treatment of Hodgkin lymphoma and lymphosarcoma in Germany

Once the diagnosis has been made, the stage of the disease must be determined in order to choose the treatment strategy. The generally accepted staging system for Hodgkin lymphoma and non-Hodgkin lymphoma in the Cotswolds modification, known as "Ann Arbor staging", takes the following into account:

• physical examination findings;
• imaging findings (chest X-ray, CT of the chest, abdomen and pelvis, and PET);
• less often – a unilateral bone marrow biopsy.
• assessment of cardiac and pulmonary function to identify contraindications to particular drugs;

Laparotomy is not required to establish the diagnosis. The Ann Arbor staging system in the Cotswolds modification also takes into account the presence of bulky disease and the sites of tumour involvement.

The letter A at any stage means the absence of B symptoms. The letter B means the presence of at least one B symptom. The presence of B symptoms indicates a poorer response to treatment.

• Stage I: involvement of only 1 lymph node region;
• Stage II: involvement of ≥ 2 lymph node regions on the same side of the diaphragm;
• Stage III: involvement of lymph nodes, the spleen, or both, on both sides of the diaphragm;
• Stage IV: extranodal involvement (for example, bone marrow, lungs, liver)

• chemotherapy;
• radiotherapy;
• surgery;
• in selected cases – haematopoietic stem cell transplantation.

The choice of treatment is complex and depends on precise staging of the disease. Before treatment begins, men of reproductive age should be offered sperm banking and women hormonal protection of the ovaries.

Patients with stage IA, IIA, IB or IIB disease usually receive the ABVD combination chemotherapy regimen, which comprises:

• doxorubicin (adriamycin);
• bleomycin;
• vinblastine;
• dacarbazine

in combination with radiotherapy, or a prolonged course of chemotherapy without radiotherapy. This treatment option cures up to 80% of patients. In patients with bulky mediastinal disease a larger number of treatment cycles or a more aggressive combination chemotherapy regimen is required, and radiotherapy is usually given as well.

In patients with stage IIIA and IIIB disease, ABVD combination chemotherapy without radiotherapy is usually used. The cure rate is 75–80% in patients with stage IIIA disease and 70–80% in patients with stage IIIB disease.

The ABVD regimen in patients with stage IVA and IVB disease produces complete remission in 70–80% of cases, and 5-year relapse-free survival exceeds 50%. In advanced stages, drugs such as nitrosourea derivatives, ifosfamide, procarbazine, cisplatin or carboplatin, and etoposide are also effective. Combination chemotherapy regimens that are also used in advanced Hodgkin lymphoma include bleomycin, etoposide, doxorubicin (adriamycin), cyclophosphamide, vincristine (oncovin), procarbazine and prednisolone (the BEACOPP regimen), or mechlorethamine (not registered in Russia), doxorubicin, vinblastine, vincristine, etoposide, bleomycin and prednisolone (the Stanford V regimen). The Stanford V regimen also includes radiotherapy to the initially involved sites as consolidation of remission.

Autologous haematopoietic stem cell transplantation should be considered as a treatment option in all medically fit patients with relapsed or refractory Hodgkin lymphoma who have responded to second-line therapy.

In Germany, patients with Hodgkin lymphoma are treated under programmes known as therapy optimisation studies; at present these are the HD16, HD17 and HD18 programmes. These are standardised clinical trials. Their aim is to treat patients according to modern protocols and at the same time to improve the effectiveness of treatment. Within these protocols the prognostic value of PET-2 is being investigated in patients in the low- and intermediate-risk groups, in order to decide whether additional radiotherapy is indicated when no active lymph nodes are seen on the scans.

The HD16 GHSG protocol. The HD16 therapy optimisation study of first-line treatment of Hodgkin lymphoma for early stages with a favourable prognosis. This protocol investigates the prognostic value of PET-2 negativity (no active lymph nodes seen on the scans) in patients in the low- and intermediate-risk groups, in order to decide whether additional radiotherapy is indicated.

Protocol HD17 GHSG. The HD17 therapy optimisation study of first-line treatment of Hodgkin lymphoma for intermediate stages is designed to test the non-inferiority of the experimental arm compared with the standard treatment arm in terms of progression-free survival.

Protocol HD18 GHSG. The HD18 therapy optimisation study of first-line treatment of Hodgkin lymphoma for advanced stages of Hodgkin lymphoma is designed to answer the following questions: in PET-negative patients after 2 cycles of BEACOPPesc chemotherapy, can the number of cycles be reduced without compromising progression-free survival (2 additional cycles versus 6 cycles) for patients with a positive PET after 2 cycles; and does intensification of BEACOPPesc chemotherapy by adding rituximab improve progression-free survival.

In classical Hodgkin lymphoma, the absence of any sign of disease for 5 years after the completion of treatment is regarded as a cure. Relapse after 5 years is very rare. With chemotherapy, with or without radiotherapy, a cure is achieved in 70–80% of patients. Factors associated with a high risk of relapse include male sex, age > 45 years, multiple extranodal sites and the presence of B symptoms at diagnosis. Patients who do not achieve complete remission, or who relapse within the first 12 months after the completion of treatment, have an unfavourable prognosis.

Chemotherapy, particularly with drugs such as mechlorethamine (not registered in Russia), vincristine, procarbazine and prednisolone, increases the risk of leukaemia, which usually develops 3 or more years after chemotherapy. Both chemotherapy and radiotherapy increase the risk of solid malignancies (including tumours of the breast, gastrointestinal tract, lungs and soft tissues). Irradiation of the mediastinum increases the risk of coronary atherosclerosis. The risk of breast cancer rises in women 7 years after the completion of radiotherapy to the adjacent lymph node regions. Follow-up after the completion of treatment

Standard investigations are carried out to detect relapse of the disease. After completing a course of treatment, patients undergo regular systematic follow-up

• rapid arrangement of an appointment with leading German haemato-oncologists;
• therapy in Germany in specialised clinics and departments and in comprehensive cancer centres;
• the world's highest 5-year survival rates;
• treatment that starts without delay;
• accurate pathological diagnosis in certified institutes of pathology;
• appropriate therapy (as gentle as possible) that takes the patient's age and psychological characteristics into account and matches the extent and aggressiveness of the disease;
• interdisciplinary collaboration between haemato-oncologists, surgeons, radiologists, chemotherapists, nuclear medicine and radiotherapy specialists and psycho-oncologists;
• multimodal therapy;
• implantation of a port system for chemotherapy to avoid damage to the peripheral veins;
• treatment with genuine, latest-generation cytostatic drugs;
• successful autologous and allogeneic (donor) haematopoietic stem cell transplantation;
• allogeneic transplantation of stem cells from peripheral blood or bone marrow from a related or unrelated donor;
• high-dose combination chemotherapy followed by autologous stem cell transplantation in advanced forms of the disease;
• strict adherence to international protocols for allogeneic blood and bone marrow stem cell transplantation;
• unique programmes for preventing severe graft-versus-host reactions using antisera and gene therapy protocols;
• protocols for the use of donor lymphocytes (adoptive immunotherapy) to prevent and treat relapse of the disease;
• post-transplant vaccination strategies for the treatment of minimal residual disease;
• an individually tailored radiotherapy plan;
• radiotherapy that spares healthy organs and tissues as far as possible (dose-volume histogram);
• comprehensive topometry of patients using biometric, radiological, isotope, ultrasound and MRI methods for the clinical and dosimetric planning of the course of radiotherapy.

Innovative methods of treating lymphomas include:

• biological therapy for lymphoma in Germany;
• treatment with monoclonal antibodies;
• targeted therapy for lymphoma;
• radioimmunotherapy for lymphosarcoma.