By SURENDER SINGH

Hodgkins lymphoma

Hodgkins lymphoma was first described in 1832, but the nature of the pathognomic Reed-Sternberg cell, on which diagnosis of the disease is based, has only been elucidated in the past few years. Radiotherapy has been used to treat localised disease since the 1940s, and in the 1960s, effective combination chemotherapy regimens were introduced for anatomically advanced disease. The past three decades have witnessed continued improvement in outcome to such an extent that Hodgkins lymphoma is now one of the most curable of all non-cutaneous malignancies. With improved survival and extended follow-up, relevance of treatment-induced late effects has become apparent, and modern therapeutic strategies must fully account for these effects. We review the pathology of Hodgkins lymphoma, and its clinical presentation, investigation, present management, and natural history, including late effects of treatment. Hodgkins lymphoma is a rare malignancy, with an incidence of about 24 per 100 000 per year.1 Prevalence in women peaks in the third decade and then falls, but in men it remains fairly constant after this time.1 Diagnosis of Hodgkins lymphoma is based on the finding of Hodgkin/Reed-Sternberg cells in an appropriate cellular background of reactive leucocytes and, in some cases, fibrosis. The disorder is classified into two distinct entities: nodular lymphocyte-predominant Hodgkins lymphoma; and classical Hodgkins lymphoma.2 Nodular lymphocyte-predominant Hodgkins lymphoma represents about 5% of all cases of the disease. It is most common in males, and typically presents with limited nodal disease of the neck without constitutional symptoms.3 Classical Hodgkins lymphoma is divided into four subtypes (panel 1). In the developed world, nodular sclerosing classical Hodgkins lymphoma accounts for over two-thirds of all cases. Lymphocyte-rich classical Hodgkins lymphoma is a newly defined entity, and is closely similar to the disorder previously classified as diffuse lymphocyte-predominant Hodgkins disease. Lymphocyte-depleted Hodgkins lymphoma is now rarely diagnosed; most patients diagnosed with this entity would now be classified as having nodular sclerosing disease or anaplastic large-cell lymphomas. All subtypes of classical Hodgkins lymphoma are at present treated in the same way.

Panel 1: WHO classification of Hodgkins lymphoma

Nodular lymphocyte-predominant Hodgkins lymphoma Classical Hodgkins lymphoma Nodular sclerosis classical Hodgkins lymphoma Mixed cellularity classical Hodgkins lymphoma Lymphocyte-rich classical Hodgkins lymphoma Lymphocyte-depleted classical Hodgkins lymphoma

Pathogenesis

In nodular and classical lymphocyte-predominant subtypes of Hodgkins lymphoma, the malignant cell is derived from a B lymphocyte, with clonal immunoglobulin gene rearrangements in most patients.46 Malignant cells in nodular lymphocyte-predominant Hodgkins lymphoma have the immunophenotype and

genotype of post-germinal-centre B cells, whereas in classical Hodgkins lymphoma, mature B-cell antigen expression can be low or absent, and no immunoglobulin is produced despite immunoglobulin gene rearrangements and subsequent somatic mutations (panel 2). In some cases of the disease, absence of immunoglobulin production is attributable to mutations in the immunoglobulin gene (eg, creation of stop codons),7,8 but in others, dysregulation of transcriptional machinery entailed in immunoglobulin gene expression takes place.8 The immunoglobulin receptor complex provides important survival signals to developing B cells, and absence of immunoglobulin expression could put Hodgkin/Reed-Sternberg cells at a survival disadvantage unless other antiapoptotic events had happened. Epstein-Barr virus infection is one such possible event.911 Nuclear proteins of this virus, such as EBNA and LMP1 (latent membrane protein 1), have been detected in about 40% of cases of classical Hodgkins lymphoma, with the highest frequency in mixed cellularity disease.12 LMP1 is known to have oncogenic potential by triggering BCL2 expression and acting via the CD40 cell-signalling pathway, allowing cells to evade cellular apoptotic mechanisms.13 Association with Epstein-Barr virus varies with age; childhood Hodgkins lymphoma is almost invariably associated, as are most cases in elderly people. The lowest rates of Epstein-Barr virus-associated Hodgkins lymphoma are reported in young adults (age

Search strategy and selection criteria

We systematically searched Medline with terminology relating to the aspects of Hodgkins lymphoma discussed in this Seminar. Articles were retrieved up to October, 2002, and studies reported in full and abstract form have been included.

Panel 2: Comparison of phenotypes of classical and lymphocyte-predominant Hodgkins lymphoma

Antigen Classical Hodgkins lymphoma (Reed-Sternberg cells) Occasionally positive Usually negative Nodular lymphocytepredominant Hodgkins lymphoma (L&H cells) Usually positive Usually positive Negative Negative Present

Panel 3: Ann Arbor staging system with Cotswold modifications for Hodgkins lymphoma
Stage 1 Involvement of one lymph-node region or lymphoid structure (eg, spleen, thymus, Waldeyers ring) 2 Two or more lymph-node regions on the same side of the diaphragm 3 Lymph nodes on both sides of the diaphragm 31: with splenic hilar, coeliac, or portal nodes 32: with para-aortic, iliac, or mesenteric nodes 4 Involvement of extranodal site(s) beyond that designated E Modifying features A No symptoms B Fever, drenching night sweats, weight loss greater than 10% in 6 months X Bulky disease: greater than a third widening of mediastinum greater than 10 cm maximum diameter of nodal mass E Involvement of single, contiguous, or proximal extranodal site CS Clinical stage PS Pathological stage

CD20 Other B-cell antigens CD30 Positive CD15 Usually positive Immunoglobulin Absent expression

L&H=atypical and lymphocytic and histiocytic.

1534 years),9 raising the possibility that alternative lymphotropic viruses are implicated in the pathogenesis of cases negative for Epstein-Barr virus.13 Hodgkins lymphoma associated with immunosuppressed states such as HIV-1 infection, post-solid organ and bone-marrow transplantation, and congenital immunodeficiency states is also usually associated with this virus.14 A further mechanism by which Hodgkin/ReedSternberg cells might escape apoptosis is via the NF B pathway (figure 1).1518 NF B belongs to a family of transcription factors implicated in regulation of many processes, including apoptosis and oncogenesis. It is upregulated in Reed-Sternberg cells in most patients with classical Hodgkins lymphoma, and is regulated by several upstream elements, including CD40 ligand and tumour necrosis factor-receptor-associated factors, though the exact mechanism is still unclear.17 NF B is present in the cytosol of the resting cell attached to its inhibitor I B. Activation of the cell by various routes, such as via CD40 ligand or LMP1, leads to activation of I kinase (IKK) and phosphorylation of I B and subsequent ubiquitination with degradation by the 26S proteasome.16 Liberated NF B is then able to move into the nucleus in which it activates transcription of several target genes implicated in prevention of apoptosis. Furthermore, the C-FLIP protein, which inhibits apoptosis and has been implicated in germinal-centre cell survival, was expressed in malignant cells of 18 of 19 patients with Hodgkins lymphoma.19

Clinical presentation

The presenting features of Hodgkins lymphoma are many. Most patients present with an enlarged but otherwise asymptomatic lump, typically in the lower neck or supraclavicular region. Mediastinal masses are frequent and are sometimes discovered after routine chest radiography. Patients might complain of chest discomfort with a cough or dyspnoea. About 25% of patients will have systemic symptoms at presentation, typically fatigue, fever, weight loss, and night sweats. Pruritus and intermittent fevers usually associated with night sweats are classic symptoms of Hodgkins lymphoma.

Staging

The Ann Arbor staging system was developed more than 30 years ago to define patients who could be treated by radiotherapy, and it is still valuable in defining treatment even though radiation alone is not generally used. The system was modified in 1989 (Cotswold modifications; panel 3),20 taking into account the importance of bulky disease and the fact that laparotomy and splenectomy were no longer recommended as staging procedures, because they have no effect on overall survival and are

LMP P I B P

Cytokines, eg, TNF I kinase

CD40

Panel 4: EORTC risk factors in localised disease25

Favourable Patients must have all features: Clinical stage 1 and 2 Maximum of three nodal areas involved Age younger than 50 years Erythrocyte sedimentation rate (ESR) less than 50 mm/h without B symptoms or ESR less than 30 mm/h with B symptoms Mediastinal/thoracic ratio less than 035 Unfavourable Patients have any features: Clinical stage 2 with involvement of at least four nodal areas Age older than 50 years ESR greater than 50 mm/h if asymptomatic or ESR greater than 30 mm/h if B symptoms Mediastinal/thoracic ratio greater than 035

I B P I B p50 p65 p65 Target gene transcription p50 p65

Proteasomal degradation

p50

Figure 1: NF B activation
TNF=tumour necrosis factor; P=phosphate. p50 and p65 are heterodimers of NF B.

Cumulative proportion surviving (%)

Panel 5: Hasenclever index26

1 2 3 4 5 6 7 Age older than 45 years Male sex Serum albumin less than 40 g/L Haemoglobin concentration less than 105 g/dL Stage 4 disease Leucocytosis (white-cell count greater than or equal to 15 109/L Lymphopenia (less than 06 109/L or less than 8% of the total white-cell count)

100 80 60 40 20 0 0 5 10 15 20 Time (years) 25 30 35

p<0001 1980s (n=1755) 1990s (n=1177)

1970s (n=1540)

associated with significant morbidity and occasionally mortality.21 Lymphangiography is also now rarely done, and CT is the major means of staging intrathoracic and intraabdominal disease. MRI is largely restricted to assessment of specific situations such as bony involvement and spinal-cord compression. Fluorodeoxyglucose-positron emission tomography (FDG-PET), relying on the uptake of 2-fluoro-2-deoxy-D-glucose by metabolically active tissues, might provide more accurate staging information than CT,2224 but is not yet standard practice.

Figure 2: Survival in Hodgkins lymphoma

Data of 4472 patients recorded on the BNLI (British National Lymphoma Investigation) database with all stages of Hodgkins lymphoma treated with radiotherapy, chemotherapy, or combined therapy.

Prognostic factors

The British National Lymphoma Investigation (BNLI) published a prognostic index in localised Hodgkins lymphoma in 1985 based on analysis of more than 2000 patients.21 This index was complex and not widely adopted, though the principle of determining treatment on the basis of risk factors has become well established. The EORTC (European Organisation for the Research and Treatment of Cancer) have identified several features indicative of a worse prognosis in stage 1 and 2 disease and have used them to stratify treatment (panel 4).25 In advanced disease, the international prognostic score (or Hasenclever index) was developed (panel 5)26 on the basis of analysis of 5141 patients treated initially with an anthracycline-containing chemotherapy regimen. Seven factors were identified, which individually reduced predicted 5-year freedom from progression rate by around 8%.

On the basis of clinical findings and results of PET, patients can be closely monitored with repeat PET if necessary, or might be offered further treatment. However, PET cannot reliably assess extranodal or inflammatory disease well,32 and at present, biopsy of unusual lesions is recommended.

Treatment

Both localised and advanced Hodgkins lymphoma can be cured in most patients, and outcome has improved over the past three decades (figure 2). Unlike many other forms of cancer, it is often possible to cure Hodgkins lymphoma even if first-line treatment fails. This fact creates the dilemma of whether it is better to use a more extensive treatment initially, to cure as many individuals as possible, or whether a less intensive treatment should be used first, followed by aggressive salvage therapy in more patients. Nodular lymphocyte-predominant Hodgkins lymphoma No prospective randomised trials have been undertaken specifically in patients with nodular lymphocytepredominant Hodgkins lymphoma. Disease is usually localised, and is often treated with surgical excision and involved-field radiotherapy, though if excision is complete then radiotherapy might be unnecessary. The European Task Force on Lymphoma reported a 96% complete response rate to primary treatment, with a 99% and 94% 8-year disease-specific survival for stage 1 and 2 disease, respectively.3 Patients with advanced-stage or relapsed disease are generally treated in the same way as patients with classical Hodgkins lymphoma (see below). Researchers from Germany and Stanford, USA, have reported use of the CD20 monoclonal antibody rituximab in patients with nodular lymphocytepredominant Hodgkins lymphoma. Treatment is welltolerated, and results have been encouraging, with a very high response rate.33,34 These data are preliminary, and need longer follow-up, but rituximab should certainly be considered in patients failing combination chemotherapy. Classical Hodgkins lymphoma All forms of classical Hodgkins lymphoma are usually treated in the same way, although in some centres specific histological subtypes are used as prognostic factors, and could therefore modify the risk group and treatment prescribed. Therapy is mainly based on anatomical stage.

Response assessment

Residual masses after treatment are very frequent in Hodgkins lymphoma, creating problems in establishing which patients have had a complete response. The entity of unconfirmed or uncertain complete response has been introduced,27 which refers to patients in whom there is uncertainty about remission status because of persistent radiological abnormalities, especially in the mediastinum. Planar and single-photon emission CT (SPECT) gallium scanning have been used to assess residual masses.28 Gallium is predominantly excreted via the gastrointestinal tract, which could limit its use in assessment of abdominal disease.29 Comparative studies between gallium scanning and PET are underway.30 PET scanning is likely to have an important role in clarification of remission status in patients with an uncertain or unconfirmed complete response since 2-fluoro-2-deoxyglucose is taken up by residual metabolically active tumour cells and not fibrotic tissue.31 FDG-PET has been shown to have significantly higher sensitivity, specificity, and positive and negative predictive values for disease-free survival than CT.31,32 Our practice is to do PET no earlier than 3 weeks after completion of treatment in patients who have suspicious symptoms or a residual mass on end-of-treatment CT.

Localised disease Many trials have been done in localised Hodgkins lymphoma, but to directly compare results from different trials is difficult. Entry criteria vary, and some groups stratify localised disease into several different risk groups. The EORTC, for instance, has divided localised disease into two risk groups (panel 4). In the UK, usual practice has been to have only one category of localised disease, and patients with stage 2B or 3A disease are automatically regarded as advanced disease. Traditionally, treatment for localised disease was radiotherapy alone. Complete remission rates were very high, but relapse was frequent. The more extensive the radiation fields, the lower the relapse rate, and in a randomised trial done by the BNLI, mantle or inverted-Y fields resulted in a roughly 11% higher time-to-treatmentfailure value than involved-field radiotherapy.35 In Europe, even more extended radiation fields have been used routinely, but even so, 2030% of patients still relapse. More extensive radiation fields have not translated into improved survival, attesting to the success of chemotherapy in radiation failures.36 Nonetheless, such high relapse rates are now deemed unacceptable. Relapse risk can be reduced by use of combined treatment with chemotherapy and radiotherapy. Little evidence exists that this combined modality treatment improves survival;36 however, with this therapy, shorter courses of chemotherapy than are used in advanced disease and more restricted radiation fields can be used. In the EORTC H7 combined modality treatment trial for unfavourable-risk disease, four cycles of chemotherapy were as effective as six, and involved-field radiation was as effective as subtotal nodal irradiation.37 Even in this poorrisk group of patients, failure-free survival and overall survival at 6 years were 89% and 90%, respectively. By contrast, in patients with better-risk disease, shorter courses of chemotherapy are adequate. For example, in the EORTC/GELA H8 trial for favourable-risk disease, three cycles of a MOPP (chlormethine, vincristine, procarbazine, and prednisolone)/ABV (doxorubicin, bleomycin, and vinblastine) hybrid regimen plus involvedfield radiotherapy were more effective than subtotal nodal irradiation, and gave a 4-year event-free survival of 99%.38 Three cycles of combination chemotherapy (usually ABVD [doxorubicin, bleomycin, vinblastine, and dacarbazine]) plus involved-field radiotherapy should thus be judged the standard for treatment in favourable-risk localised disease. Various even shorter chemotherapy regimens have been combined with involved-field radiotherapy,39 and although they might be less efficacious than three cycles of ABVD or equivalent, they probably have fewer short-term and long-term toxic effects. As well as reducing the amount of chemotherapy, it might also be possible to reduce the radiation field and dose in combined modality treatment. In the German HD8 trial, patients with stage 1 or 2 disease and at least one risk factor were treated with four courses of alternating COPP (cyclophosphamide, vincristine, procarbazine, and prednisone) and ABVD. Rates of survival or freedom from treatment failure did not differ between patients receiving consolidation involved-field radiotherapy and those receiving extended-field radiation.40 The present HD10 trial is designed to investigate use of reduced doses of radiation and restricted fields.41 Concern over radiation-induced second malignancies has raised the issue of whether localised disease should be treated with chemotherapy alone, and this issue is the subject of ongoing trials.

Trial name CALGB48

Disease stage 3, 4

Number of patients 361

Treatment

FFS (%)

OS (%) 66 75 76 74 72

Time (years) 5 10

INT Milan49 1A4

427 (415 evaluable)

NCIC50

3B4 or after wide field radiotherapy

301

CALGB 895251

34 or after 856 radiotherapy failure

MOPP 50* MOPP/ABVD 65* ABVD 61* MOPP/ABVD 67 alternating MOPP/ABV 69 hybrid (radiotherapy to initial bulk in both arms) MOPP/ABV 71 hybrid MOPP/ABVD 67 alternating MOPP/ABV 67 ABVD 65

81 83 85 87

5 3

CALGB=Cancer and Leukaemia Group B; NCIC=National Cancer Institute of Canada; FFS=failure-free survival; OS=overall survival. *p<005. This trial was closed early due to an excess of treatment-related deaths and second malignancies in the hybrid arm.

Selected randomised trials of chemotherapy alone or with radiotherapy in advanced disease

Advanced disease Introduction of the MOPP chemotherapy regimen in the 1960s was a major landmark in treatment of advanced Hodgkins lymphoma.42 Over the next few years, several modifications to this regimen were made, which maintained efficacy but reduced associated toxic effects.4346 The ABVD regimen was introduced in the 1970s as non-crossresistant salvage for patients failing MOPP,4347 and was later used as first-line treatment, particularly because the drugs in ABVD were far less likely to induce infertility and secondary leukaemia than were those in MOPP. ABVD was also combined with MOPP or MOPP-like therapy in either an alternating or hybrid regimen to introduce many drugs over a short period in the hope of reducing development of tumour resistance. A series of randomised trials4851 subsequently established ABVD as the gold standard (table) on the basis of its efficacy and reduced long-term toxic effects. Encouraging results have been reported with some alternative regimens. The Stanford V regimen is a 12-week course of seven active drugs with radiotherapy to sites of initial bulk disease. Data for 142 patients showed a 5-year failure-free survival of 89% and a 5-year overall survival of 96%.52 A small randomised Italian study, however, noted the Stanford V regimen to be inferior to ABVD;53 randomised trials of Stanford V versus ABVD are continuing in several countries. The German Hodgkin Study Group54 compared their standard alternating regimen (COPP and ABVD) with a hybrid regimen (BEACOPP [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone]) and a dose-intensified version of this regimen (escalated BEACOPP). Escalated BEACOPP needs routine administration of granulocyte-colony stimulating factor. Results of the final analysis showed significant improvement in freedom from treatment failure at 5 years in the BEACOPP arm compared with the COPP and ABVD arm (76% vs 69%); a further substantial improvement was seen in the escalated BEACOPP arm, in which freedom from treatment failure at 5 years was 87%.54 Both BEACOPP arms showed an advantage in overall survival at 5 years over the standard COPP and

ABVD arm; however, no significant difference between baseline BEACOPP and escalated BEACOPP was noted. Nine cases of acute myeloid leukaemia/myelodysplastic syndrome were reported in the escalated dose arm compared with four in the baseline BEACOPP arm and one in the COPP and ABVD arm.54 This finding emphasises the fact that longer follow-up will be needed before final conclusions can be drawn. Furthermore, patients have considerably more chance of infertility with a procarbazine-containing regimen than with ABVD.55 At the very least, results of this study show there is a clear dose-response relation within the dose range possible without haemopoietic stem-cell support. A further issue is whether intensive regimens, such as escalated BEACOPP, should be reserved for high-risk patients. In the UK, the ChlVPP alternating with PABLOE regimen56 has been widely used, and analysis of 326 patients showed not only a reduced failure-free survival in poor-risk patients (IPS 47) but also a reduced salvage rate with alternative therapies.57 Thus, regimens such as escalated BEACOPP might be most beneficial in high-risk patients. Researchers have suggested that highrisk patients might benefit from high-dose therapy and stem-cell transplantation in first remission,58 but results of a randomised trial did not substantiate this.59 It is noteworthy in this trial that patients receiving continued conventional dose therapy had good 5-year failure-free survival of 83%, showing the difficulty in defining a poorprognosis group once a good response to initial therapy has been obtained. Radiotherapy in advanced Hodgkins lymphoma Consolidation radiotherapy has frequently been used in patients with advanced Hodgkins lymphoma, especially in patients achieving an unconfirmed or uncertain complete response or in those with bulky disease at presentation. Evidence for this practice is not strong. The Groupe dEtude des Lymphomes de LAdulte H89 trial indicated no benefit to radiotherapy consolidation compared with two extra cycles of a doxorubicin-containing regimen.60 Results of the EORTC 20884 trial similarly showed no advantage of consolidation radiotherapy in remission after MOPP/ABV hybrid therapy.61 Furthermore, a metaanalysis comparing chemotherapy with combined modality therapy suggested that the addition of radiotherapy might be associated with a reduced survival attributable to longterm effects of treatment.62 Despite these negative conclusions about consolidation radiotherapy, two regimens with good results both use radiotherapy consolidation in most patients. In Stanford V,52 85% of patients received radiotherapy, and in escalated BEACOPP,54 radiotherapy was given to most patients. Treatment of childhood Hodgkins lymphoma Hodgkins lymphoma in children and adolescents is curable in over 90% of cases.63 Several specific childhood treatment regimens have been developed, which encompass the same general principles, namely, avoidance of laparotomy staging, risk-adjusted therapy, combined modality treatment at all stages of disease, avoidance of procarbazine in boys to protect future fertility, and keeping radiation dose and field and anthracycline dose to a minimum.64 Many of these same principles are now being applied in adults with Hodgkins lymphoma. Relapsed disease Some patients receiving chemotherapyeither de novo or after radiation failurewill have refractory disease or will relapse. Occasionally, patients can be cured by

radiotherapy if persistent or relapsed disease is localised, but most patients will need systemic treatment. Many patients with long first remissions can be cured by further standard dose chemotherapy, but results of such approaches are poor if remission has been short or disease was refractory to initial chemotherapy.65,66 High-dose chemotherapy and autologous stem-cell transplantation was pioneered in patients with relapsed Hodgkins lymphoma more than 40 years ago, but it has only become an established modality of treatment in the past two decades.67 Procedure-related mortality has fallen over recent years because of better selection of patients and improved supportive care68 and more rapid engraftment associated with peripheral-blood stem cells, which have now largely replaced bone marrow as the source of haemopoietic stem cells.69 In large single-centre series,68 and in Registry reviews,70 about 4050% of transplanted patients with relapsed or resistant disease are alive after 5 years. Several different conditioning regimens have been used, and high-dose chemotherapy is generally preferred to total-body irradiation. This preference is because chemotherapy is logistically easier to administer, is as effective as total body irradiation, and might be associated with less pneumonitis, although high-dose chemotherapy is undoubtedly also associated with pneumonitis, especially in patients who have received mediastinal radiation in the preceding year.71,72 After highdose therapy, irradiation of persistent masses or sites of previous large volume disease is common practice, although no trial data to substantiate this practice are available. Before high-dose therapy, standard-dose chemotherapy is usually given to reduce disease bulk and determine chemosensitivity. In patients who have disease that progresses through standard-dose salvage therapy, or have persistent B symptoms or a raised concentration of lactate dehydrogenase, results of high-dose therapy are probably too poor to justify proceeding to this course of action. However, in some cases, a mass will not immediately reduce in size, and failure to achieve a formal response (complete or partial remission) should not exclude a patient from receiving an autograft. The BNLI did a small randomised trial of BEAM (carmustine, etoposide, cytarabine, and melphalan) followed by autologous stem-cell transplantation or miniBEAM (the same drugs at reduced doses) in patients with refractory or relapsed disease. A highly significant progression-free survival advantage was noted in the highdose treatment arm,73 and similar results have subsequently been reported from a larger German study.74 Neither study showed an overall survival benefit, which might, in part, be attributable to the small size of these trials, or might be because some patients failing standarddose salvage therapy can still be rescued by high-dose therapy at a later time. When therefore is the optimum time to consider an autograft procedure? This procedure is widely recommended for all patients younger than age 65 years who fail first-line chemotherapy, although this treatment might not be appropriate if first complete remission lasted more than 3 years. The value of allogeneic transplantation in patients with Hodgkins lymphoma is unclear. In large published series, high rates of transplant-related mortality have been reported.7578 Nonetheless, patients surviving an allogeneic transplant may have a reduced relapse rate,7779 suggesting a graft-versus-lymphoma effect. There is interest in use of less toxic non-myeloablative allogeneic transplants in Hodgkins lymphoma, especially in patients who have failed a previous autograft. In a UK study of 24 patients

SEMINAR

Panel 6: Late effects of Hodgkins lymphoma and its treatment

Second malignancies Cardiac disease Endocrine dysfunction Psychological trauma Lung damage (usually subclinical) Hyposplenism (after splenectomy or splenic irradiation) Dental caries

with relapsed or refractory disease, only two procedurerelated deaths were reported. Several patients who subsequently relapsed responded to donor lymphocyte infusions. Further follow-up and larger trials will be needed to ascertain the role of this modality of treatment.80

Because the cure rate for Hodgkins lymphoma has risen, and longer-term follow-up data have become available, the importance of late effects of treatment have become more apparent (panel 6). In a study of young adult patients aged younger than 29 years at diagnosis, who achieved continuing complete remission after first-line or second-line treatment, actuarial overall survival at 20 years was 93% and 85%, respectively, compared wth 985% in the age-matched general population.81 Further review of patients treated for favourable-risk disease indicated that treatment-related mortality exceeded that from Hodgkins lymphoma by 1215 years after initial therapy.82 The two most frequent causes of excess deaths are second malignancies and ischaemic heart disease. The most common second malignancy in patients with Hodgkins lymphoma is lung cancer. This disease is mainly attributable to radiotherapy, although chemotherapy also contributes to the risk.83,84 It is imperative that all patients who have had thoracic radiation are strongly encouraged never to smoke. Risk of developing secondary myeloid leukaemia is related to the cumulative dose of alkylating agents received, and therefore, arises predominantly in patients who have had remitting and relapsing disease. Secondary breast cancer mainly occurs after irradiation to the mediastinum or axillae, especially when given to adolescent females or young women. A dose-response relation exists, which underscores use of the minimum radiation dose needed for tumour control.85 Risk in such patients of ever developing breast cancer is about 2050%,86 and patients at such high risk need to be aware of this fact and offered a screening programme. Other malignancies that arise in excess in patients treated for Hodgkins lymphoma include non-Hodgkin lymphomas, head and neck tumours, cancers of the colon, stomach, and thyroid, and malignant melanoma.84,86,87 Patients should be advised to consult their doctor if they have any suspicious symptoms, and they should be strongly advised to use effective measures to avoid sunburn. The Stanford group reported about a three-fold increase in relative risk of cardiac death in patients who did not die from Hodgkins lymphoma,88 which is a major risk because prevalence of cardiac disease in the general population is so high. The major contributing factor is mediastinal irradiation when a dose in excess of 30 Gy is used.88 Whether or not the increasing use of anthracyclines will have a long-term effect on cardiac disease is not yet clear.

Late effects of Hodgkins lymphoma and its treatment

The most common endocrine disorders are hypothyroidism after radiation to the lower neck and infertility. Around 50% of patients receiving neck irradiation will develop hypothyroidism, and these individuals should have their thyroid function assessed every year.89 Recipients of neck irradiation are also at higher risk of development of dental caries and other oral diseases.90 The importance of regular dental attention should be emphasised to patients. Infertility arises after irradiation of the gonads and after use of drugs such as procarbazine and alkylating agents. Repeated use is most damaging, and young female patients receiving an autologous transplant will often remain fertile if they are still menstruating before receiving high-dose therapy.68 Sperm cryopreservation before chemotherapy is standard practice for men who have not completed their families. Artificial insemination has a low success rate per cycle; however, intracytoplasmic sperm injection may improve the success rate.91 Hodgkins lymphoma can typically be slow-growing, which might permit harvesting of eggs, in-vitro fertilisation, and embryo storage in those young women who have an established partner.92 Oocyte cryopreservation and ovarian tissue banking are presently in development.93 Psychological trauma associated with contracting a malignant disease, receiving radiotherapy and chemotherapy, and coping with risk or eventuality of relapse is great. In one survey,94 many patients reported a lower perceived level of overall health and dissatisfaction in their personal relationships as a result of disease, its treatment, or both. Many also had difficulties in obtaining life assurance and financial loans. Present treatment strategies must therefore aim to give minimum therapy without jeopardising the high rates of cure that are now possible with front-line therapy. Cytotoxic drugs Gemcitabine, an analogue of cytarabine, has antitumour activity in Hodgkins lymphoma.95 It is well tolerated with a favourable toxicity profile, and given at a dose of 1250 mg/m2, it has been reported to have a response rate in excess of 35% in heavily pretreated patients.96 In view of the fact that NF B is frequently activated in Hodgkin/Reed-Sternberg cells, this pathway is an important target for new drug development. Particular attention is focused on proteasome inhibitors, which prevent degradation of I B and thus keep the liberation of active NF B to a minimum.17,97 Immunotherapy Ex-vivo generation of Epstein-Barr virus-specific cytotoxic T lymphocytes for reinfusion into patients with Hodgkins lymphoma has had limited success.98 However, strategies aimed at generation of LMP-selective cytotoxic T lymphocytes with autologous dendritic cells could prove more efficacious.99 One of the most promising antigens for targeted immunotherapy is the CD30 antigen, which is highly expressed on Hodgkin/Reed-Sternberg cells. Several groups of researchers have shown that antiCD30 monoclonal antibodies chemically linked to active toxins have antitumour activity in Hodgkin cell lines and also in SCID mice inoculated with tumour.100103 Studies investigating radioimmunotherapy with 131I-labelled antiCD30 are also underway.104 Internalisation of an antibody-conjugated toxin can be amplified by use of antibodies with specificity for both a tumour-associated antigen and a cell-surface antigen,

Novel treatments

which facilitates internalisation of the formed complex. CD25 is the interleukin 2 receptor. An antiCD30 and CD25 immunotoxin was tested in SCID mice inoculated with Hodgkins lymphoma and achieved a substantially higher cure rate than that achieved with single agent alone.105 Phase 1 and 2 trials have been done in patients with refractory disease, and moderate responses have been reported.106 An alternative use of bispecific antibodies is to augment cell-mediated tumour killing by target-killer cell interaction. Bispecific antibodies recognising CD30 and CD3 or CD28 on T cells have been developed and are active in animals.107,108 Bispecific antibodies recognising CD30 and either CD16, which is expressed on natural killer cells, granulocytes, and macrophages, or CD64, which is expressed on monocytes, macrophages, and activated neutrophils, have also been developed.109,110

Conclusion

The nature of the malignant cell in Hodgkins lymphoma is now understood, but the mechanism of tumorigenesis has not been fully elucidated. Results of treatment continue to improve, and with such high cure rates, late effects become more important. In many situations, the same ultimate survival can be achieved with different therapeutic approaches. Less intensive initial therapy cures fewer patients, but many failures can be rescued by subsequent more intensive treatment. Choice of approach is thus dependent on an appreciation of short-term and long-term side-effects, and increasingly the patient must be involved in an informed decision-making process.
Conflict of interest statement
None declared.

Acknowledgments

LY is funded by the Lymphoma Research Trust and DL receives funding from the Medical Research Council, Cancer Research UK, the Leukaemia Research Fund, and the Lymphoma Research Trust. DL sits on the Roche Oncology Advisory Board. The funding sources had no role in the writing of this Seminar.

References
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