Disease management: a systems approach to improving patient outcomes

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abdominal diseasewhich is present in a substantial proportion of such cases (Castellino et al., 1983). Techniques such as flow cytometry for kappa/lambda ratios (Smith et al., 1984) or the polymerase chain reaction (Stetler-Stevenson et al., 1988), have recently been used to demonstrate more widespread clinically inapparent disease. However, the clinical significance of such findings is at present uncertain.
Once staging is complete, approximately 5-10% of patients will be found to have stage I and 10-15% stage II disease. Low grade lymphoma is very sensitive to radiotherapy and local control using this treatment modality occurs in the vast majority of cases (Fuks et al., 1973). How extensive should treatment fields be? Most clinicians use involved field treatment. Although there has been a suggestion that wide fields should be used, as relapse commonly occurs within lymph nodes and relapse-free survival is improved (Paryani et al., 1983;Lawrence et al., 1988), the limited available data show that survival is not affected. The low grade lymphomas are generally incurable by chemotherapy and no evidence exists to support the addition of chemotherapy to radiotherapy for these tumours (Monfardini et al., 1980). What determines outlook? Age is a predominant factoryounger patients fare significantly better than their older counterparts (Paryani et al., 1983). Stage is also important: stage I was clearly separable from stage II in a recent update of a multicentre study, but this study failed to demonstrate a significant difference between stages II, III and IV (Simon et al., 1988). In addition, tumour bulk has been found to be important in some series (Gospodarowicz et al., 1984), though not in others (Paryani et al., 1983).
Most series report approximately 50% of early stage patients relapse-free at 5 years after radiotherapy, with a far higher percentage alive and well. Prolonged follow-up of these patients is necessary as relapse may occur after many years. Rebiopsy at relapse is valuable, as a proportion of cases will prove to have intermediate grade lymphoma (Paryani et al., 1983;Lawrence et al., 1988).

Intermediate grade non-Hodgkin's lymphoma
The intermediate grade lymphomas (follicular large cell, diffuse small cleaved, diffuse mixed, diffuse large cell and immunoblastic) are found to be localised more commonlyapproximately 40-45% will be found to be stage I or II, comprising 10-20% stage I and 20-30% stage II (Anderson et al., 1982;Simon et al., 1989). Comparable staging procedures to those used for low grade lymphomas are indicatedthe yield of staging laparotomy is low and this investigation is not recommended (Goffinet et al., 1977).
The range of reported treatments for these patients is wider than for the low grade lymphomas. Radiotherapy or chemotherapy alone, or in a variety of combinations, are recommended by various groups.
These lymphomas are less predictably radiosensitive than their low grade counterparts (Fuks et al., 1973). A number of series have, however, reported good treatment results in patients with low volume stage I disease or stage II disease in a limited number of sites (Levitt et al., 1985;Vokes et al., 1985;Kaminski et al., 1986;Horwich et al., 1988). It should be noted that many of these patients underwent staging laporatomy and that in some cases the radiation fields used were extensive. It should also be noted that some series have reported poor salvage results when chemotherapy has been given after relapse from radiotherapy (Kaminski et al., 1986;Armitage & Wen, 1987). In Southampton we have adopted a pragmatic policy of treating patients with low volume (less than 5 cm) stage I intermediate grade lymphoma with involved field radiotherapy. Staging laparotomy has not been used. All our patients achieved a complete remission and 12 (44%) have since relapsed. Ten of these 12 have been rendered disease-free with salvage CHOP (McKelvey et al., 1976) chemotherapy. The advent of effective doxorubicin containing combination chemotherapy for the advanced stage of these diseases has led to the use of chemotherapy alone for patients with stages I and II disease -most commonly using the CHOP regime. Treatment results have been impressive, particularly in younger patients (Miller & Jones, 1983;Cabanillas, 1985;Mauch et al., 1985) and those with stage I disease (Cabanillas, 1985), but it was recognised early on that in patients with bulky stage II (greater than 10 cm) disease or disease involving the gastrointestinal tract, the results were less good. Such patients have commonly been treated with more intensive regimens, although without a proven increase in survival.
Combined radiotherapy and chemotherapy have been used in either sequence by a number of centre. Early studies compared irradiation alone to irradiation plus chemotherapy (e.g. Glatstein et al., 1977;Monfardini et al., 1980). These studies were small, gave conflicting results and used sub-optimal chemotherapy. More recently, Stanford published their experience of combined irradiation and chemotherapy and found that the results were an improvement on their previous experience with irradiation alone (Prestidge et al., 1988). Initial combination chemotherapy followed by irradiation to sites of tumour bulk has also been evaluated, although again their is a dearth of clinical trials (Connors et al., 1987;O'Connell et al., 1988). The approach used by Connors et al. is attractive as the chemotherapy is of limited duration (three cycles of CHOP) and the overall results are excellent.
In general, treatment results for limited stage intermediate grade lymphoma are very good, and the majority should be cured. Prognostic factors have varied between studies but in most series younger age, stage I disease, low tumour bulk and a limited number of sites have all proved favourable (Kaminski et al., 1986;Mackintosh et al., 1988). A number of late relapses have been recorded in these patients. Rebiopsy is recommended as some of these have been shown to be due to a recurrence of low grade lymphoma (Cabanillas, 1985), which has important consequences for future management.
What management approach should be used in patients with stage I and II intermediate grade lymphoma? For patients with stage I disease of low bulk, treatment with either radiotherapy or chemotherapy is likely to be highly effective. Treatment choices may be determined in these cases by the anticipated toxicity of either modality, taking account of disease site. For patients with more extensive disease within stage I and II, doxorubicin containing chemotherapy should almost certainly be the initial treatment of choice. The number of cycles of chemotherapy and the exact role of radiotherapy to previously involved sites are uncertain and are suitable subjects for clinical trials.
In conclusion, early stage non-Hodgkin's lymphoma is a heterogeneous condition. Although useful additions to the literature have been made recently, much of it still comprises either small randomised trials or retrospective reviews. Any centre in the United Kingdom will see only a limited number of such cases. Co-operative studies are needed in the future to answer some of the pressing clinical questions relating to these disorders.