Introduction

The last 30 years have seen significant developments in the treatment of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). These advances have come in the areas of chemotherapy, radiotherapy and treatment with monoclonal antibodies and supportive care. As a result, many patients with lymphoma can expect to be cured of their disease with modern combined therapies. However, it is an unfortunate fact that some patients either do not respond to their initial therapy or relapse after an initial remission. Until recently, the outlook for these people was bleak and few could expect to be cured with subsequent treatment. The last decade has seen a dramatic improvement in the prognosis for this group of patients. The main improvement has been in the area of high dose therapy, a general term which describes the combination of an increased dose of anti-cancer treatment given with state of the art supportive care (modern antibiotics and anti-emetics, growth factors, nutritional support, blood products, stem cells etc). High dose therapy has resulted in 200-400% improvements in survival over conventional treatment for certain patients.

Background

Experimental models and clinical trials have shown that there is a dose response relationship for many anti-cancer treatments i.e. the more treatment given, the more cancer cells killed. However, anti-cancer treatments are unlike most other standard medical therapies in that, when used at an effective dose, they are associated with significant side effects. The main dose-limiting toxicity (i.e. the side effect which prevents administration of greater doses of treatment) for most chemotherapy drugs is bone marrow toxicity. The bone marrow is exquisitely sensitive to the effects of chemotherapy and increasing doses can result in irreversible damage.

Within the bone marrow are a group of cells called 'stem cells'; these are immature cells that either replicate to provide an identical copy of themselves, or grow and differentiate into the three main types of cells found in blood; red cells, white cells and platelets.

In the 1970's and 1980's, pioneering work was carried out on the removal and freezing of bone marrow stem cells. Patients were subsequently given large doses of anti-cancer treatments that potentially eradicated all the underlying tumour cells but caused irreversible damage to the bone marrow. The bone marrow cells that had been stored were then re-infused to replace the damaged marrow, there was a delay of 14-21 days from return of the marrow cells to recovery of the blood count whilst the marrow re-acclimatised and started to work. This procedure is known as a bone marrow transplant and remains an important treatment for many patients.

The last ten years have seen significant technological improvements, resulting in our ability to stimulate the bone marrow to release stem cells into the blood. The circulating stem cells are called 'peripheral blood stem cells' (PBSC) and can be collected using a cell separator, which is similar to a dialysis machine. The two main advantages of opting to use PBSC over bone marrow stem cells are:

• they are easier to collect and
• work more quickly when they are given back to the patient, resulting in more rapid recovery of the blood count after high dose therapy. Consequently patients are in hospital for a significantly shorter period of time and have fewer serious complications.

This whole procedure goes by a number of different names including high dose therapy, stem cell transplant, stem cell rescue etc.

The type of high dose therapy given e.g. chemotherapy, radiotherapy etc, and the source of the stem cells, i.e. patient's own, sibling, unrelated donor, varies from patient to patient. The majority of patients receive their own stem cells, in part because most patients do not have a suitable donor.

As high dose therapy became safer, it was only natural that it would be evaluated in an increasing number of situations. The results of rigorous clinical trials have allowed us to define more accurately who is most likely to benefit from this treatment. However, our understanding is by no means complete, further trials are ongoing and important developments are occurring on a regular basis.

Clinical trials have shown that the lymphoma patients most likely to benefit from high dose therapy and PBSC rescue are those aged 60 or under who have relapsed after initial treatment for high grade NHL or HL. It is likely that, with further developments, other patient groups will be shown to benefit from this approach.

Patient pathway (figure 1)

The initial phase of treatment usually includes further chemotherapy. This serves a number of functions (figure 2) including getting the patient back into remission. At the same time a number of investigations will be carried out to ensure that the patient is fit for high dose therapy. These may include lung function tests, echocardiogram and a number of blood tests. High dose therapy is a complex treatment and poses significant logistic challenges. A proposed plan for treatment will be drawn up at an early stage and the patient will have significant input into this.

A few weeks after the successful stem cell harvest the patient will be admitted for high dose therapy. This involves giving mega doses of chemotherapy with or without radiotherapy over 4-5 days. This is usually followed by a rest period of 1-2 days (to allow the chemotherapy to be cleared from the body) and the PBSC are then thawed and re-infused. This 'PBSC transplant' is often an anticlimax as the PBSC are returned like a simple blood transfusion. The PBSC are frozen in a mixture of plasma and a chemical called DMSO. This prevents crystal formation in the frozen mixture which would destroy the cells. It has been variably described as smelling of ripe beetroot, corn and rotten fish!

While the PBSC are acclimatising the blood count is very low. The patient is susceptible to infection and will undoubtedly require blood and platelet transfusions and antibiotics. The majority of patients will feel very run down and tired, they may have a sore mouth and feel nauseated. However, many of these side effects causing discomfort can now be successfully controlled. As the blood count begins to recover around day 11, the patient's general condition improves and they are discharged when counts are adequate.Thereafter they will require regular follow up to ensure that their treatment has worked and to deal with any side effects of therapy.

New developments

Notwithstanding the very real benefits of HDT, it remains a blunt tool with significant room for improvement. A list of some of the ongoing developments is given in figure 3.

As we have become more expert in the safe administration of high dose therapy, it has been evaluated in a number of new clinical situations. It is showing significant promise in low grade lymphoma but the results of ongoing trials are awaited. Trials of high dose therapy as first line therapy for patients with high grade NHL at high risk of recurrence are also ongoing.

The identification of novel agents and treatment approaches that act in a different way to conventional chemotherapy is progressing apace. These would include vaccine treatments and other biological approaches. One of the most exciting new drugs is rituximab, an antibody that acts against lymphoma cells. Its role in high dose therapy is under evaluation but it is hoped that it will complement conventional drugs.

Allogeneic transplants (using donor cells) are appropriate for many patients. The main difference between an autologous and allogeneic transplant is that the donor cells will not be completely identical to the patient's cells. They may react against the patient's lymphoma (this is beneficial) or against the patient's normal healthy tissue (this can be a significant problem). A new form of allogeneic transplant, a 'mini-transplant' is being evaluated in an attempt to maximize the benefits and minimize the side effects. These have shown great promise but remain developmental.

Innovative ways to avoid the other unwanted acute and long term side effects of high dose therapy on normal healthy tissues are also being studied. These include attempts to preserve fertility in women by removing part of the normal ovary before treatment, to be transplanted back after treatment.

For the future

There is no doubt that developments in high dose therapy over the last decade have resulted in many more patients being cured of their illness than ten years ago. However, further improvements are urgently required. These will only come from a co-operation between scientists, clinicians and patients. Clinical trials, based on scientific principles and cutting edge research, adequately funded and rigorously carried out, are the only way by which further improvements will be achieved.

Revised June 2004

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