Hodgkins disease

Epidemiology and aetiology

Hodgkin's disease (HD) is a rare malignancy, with an annual UK incidence of 1000-1500 new cases. The age distribution is bimodal, with a large peak in the 20-30 year age group, and a smaller peak at 50-60 years. The cause is unknown, and may differ between the various histological subtypes. An association between infection with Epstein-Barr virus and HD is well documented, although its precise aetiological role is unclear.

Pathology

The characteristic diagnostic feature is the binucleate Reed-Sternberg (RS) cell, seen in an appropriate cellular background of small lymphocytes, eosinophils, neutrophils, histiocytes, and plasma cells. The RS cell is the malignant cell in HD, and recent molecular studies have confirmed its B-cell lineage. The major subtypes are:

♦ Lymphocyte/histiocyte predominant (LP, HP) (~10%) Lymphocyte-depleted HD is very rare—studies have showed that cases previously diagnosed as lymphocyte-depleted HD were mostly B-cell non-Hodgkin's lymphoma (NHL). Lymphocyte/histiocyte-predominant HD is a distinct entity, characterized by 'L&H Hodgkin's cells' which are of B-cell lineage. A small proportion develop into diffuse, large, B-cell NHL. This subtype has a favourable prognosis, as does a recently described similar entity—lymphocyte-rich classical HD. Some subtypes of NHL, particularly anaplastic large-cell lymphoma, can be confused with HD. Expert review of the pathology is an essential component of management.

Presentation

♦ Painless lymphadenopathy (cervical nodes especially)

♦ May be generalized lymphadenopathy

♦ Later spread to liver, lungs, marrow

—alcohol-induced pain in nodes

Table 27.3 Ann Arbor staging system

Stage

Feature

I Disease in a single lymph node region

II

Disease in two or more regions on the same side of the

diaphragm

III

Disease in two or more regions on both sides of the diaphragm

IV

Diffuse or disseminated disease in extra lymphatic sites

including liver and bone marrow

Various suffixes are added to each anatomical stage:

A No systemic symptoms

B Systemic symptoms present

E Extranodal disease

E Extranodal disease

Staging

Spread of HD is typically to contiguous lymph node groups. As a result, anatomical staging using the Ann Arbor system has been the basis of treatment decisions in HD. However, the identification of other prognostic factors has refined treatment decisions, which are now rarely made on the basis of anatomical stage only.

Prognostic factors

Recent studies have identified various presenting factors that may influence outcome in HD. For patients with early stage (I and IIA) disease, several studies have identified prognostic groups based on histological subtype, age, sex, symptom status, number ofnodal regions involved, and the presence ofbulky mediastinal disease.

For patients with advanced (Stage IIB to IVB) disease, various prognostic factors have been identified in an analysis of over 5000 patients. The adverse factors are as follows:

Table 27.4 EORTC prognostic groups in early-stage HD

Group

Prognostic factors

Very favourable

Stage I and age <40 or 'A'+ ESR <50 or female and

MT ratio* <0.35

Favourable

All other patients

Unfavourable

Age >40, or 'A'and ESR >50,or 'B'and ESR >30,or

Stage 114/5, or MT ratio >0.35

* MT ratio = size of mediastinal mass compared with transverse diameter of the chest on chest X-ray.

* MT ratio = size of mediastinal mass compared with transverse diameter of the chest on chest X-ray.

♦ Leukocytosis 15 x 109/1

In the absence of any adverse factors, the five-year failure-free survival (FFS) rate is 84%. The presence of each of these factors reduces the expected five-year FFS by about 8%.

Treatment

Since HD predominantly affects young adults, potential long-term toxicities of therapy are of major importance. The recognition of the long-term toxicities of radiation therapy, particularly to the mediastinum (second malignancies, including lung and breast cancer; pulmonary fibrosis; coronary artery disease) and alkylating agent-based chemotherapy (secondary leukaemia and NHL; infertility; early ovarian failure) has had a major impact on therapy.

Early stage

The majority of patients with early-stage HD present with supra-diaphragmatic disease. For these patients, treatment should be determined by prognostic factors that predict the likelihood of occult subdiaphragmatic disease not detected by routine clinical staging techniques.

Standard therapy for these patients comprises nodal irradiation with the classic mantle field (occipital, cervical, supraclavicular, axillary, mediastinal, and hilar nodes). In the US this is commonly extended to the upper abdomen to incorporate the coeliac nodes, splenic hilar nodes, and spleen (subtotal nodal irradiation—STNI). 70-80% of patients achieve long-term Disease Free Survival (DFS) with this approach. Although relapse occurs in up to 30% of patients, subsequent salvage with chemotherapy is very successful, in around 80-90% of patients.

In view of the long-term toxicity of extended field radiotherapy, the role of chemotherapy combined with limited (involved field) radiotherapy has been explored in many centres, and is currently being assessed in randomized clinical trials. Regimens such as VBM (vinblastine, bleomycin, methotrexate) and ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) combined with involved field radiotherapy can produce long-term DFS equivalent to STNI, with fewer relapses after initial therapy and less long-term toxicity.

Patients with very favourable prognostic features (e.g. female patients with LP or NS histology, low ESR, and presentation with high cervical nodes) are at very low risk of subdiaphragmatic relapse and are treated in some centres with involved field radiotherapy alone.

Advanced stage

MOPP (mustine, vincristine, procarbazine, and prednisone) and its variants have been considered standard chemotherapy for advanced HD until recently. However, doxorubicin-based chemotherapy, particularly ABVD, has now become widely accepted as standard therapy following the completion of a major trial by the CALGB.1 This study compared MOPP, MOPP alternating with ABVD, and ABVD alone. The respective five-year failure-free survival (FFS) rates were 50%, 65%, and 61%, demonstrating that ABVD and MOPP/ABVD were equivalent, and both superior to MOPP alone.

More recently, brief-duration regimens such as Stanford V (mustine, doxorubicin, vinblastine, prednisone, vincristine, bleomycin, etoposide) and BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) have been introduced, on the basis of increased dose intensity but reduced total doses of therapy, with a lower potential for long-term toxicity. These regimens are combined with limited field radiotherapy to sites of disease bulk. Initial reports have shown high response and FFS rates. For example, Stanford V produced a three-year actuarial overall survival (OS) and FFS of 96% and 87% respectively in patients with advanced HD. Similar results have been reported for BEACOPP. These regimens are now being compared with standard regimens such as ABVD in randomized trials.

Salvage therapy

Patients with early-stage HD who relapse after radiotherapy have high response rates to subsequent chemotherapy, with most (80-90%) achieving long-term DFS. For patients who relapse after first-line chemotherapy, high response rates are seen with second-line conventional dose regimens, especially if the initial remission duration is greater than 12 months. However, only 20-25% of patients achieve long-term DFS with conventional-dose salvage therapy.

High-dose therapy and autologous stem cell transplantation (ASCT) can produce superior long-term DFS compared with conventional-dose salvage and are now generally regarded as standard salvage therapy in HD, producing long-term DFS in 40-50% of patients. Primary refractory HD is rare, and the role of high-dose therapy and ASCT in this setting is unknown.

Future directions

If adverse prognostic features, consider:

♦ High-dose therapy and ASCT as first-line

♦ Antibodies against CD30 antigen on R-S cell; some responses in Phase II trials

Reference

1. Canellos, G.P., et al. (1992) Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. NEJM 327: 1478-84.

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