The management of follicular lymphoma

Annals of Oncology, Supplement 2 to Volume 2: 131-135, 1991. © 1991 Kluwer Academic Publishers. Printed in the Netherlands.

Original article The management of follicular lymphoma T. A. Lister Department of Medical Oncology, St. Bartholomew's Hospital, London, United Kingdom

Introduction

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Fig. 1. Survival of 147 previously untreated adults with follicular lymphoma.

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Patterns of survival at St. Bartholomew's Hospital All patients One hundred forty-seven previously untreated adults, presenting to St. Bartholomew's Hospital between 1972 and 1983, with follicular lymphoma diagnosed by Dr. A. G. Stansfeld, form the basis of the most recent analysis. Clinical stage was determined by conventional methods, and treatment recommended according to the protocols of the day, as previously described. Fiftythree patients are still alive, with 94 having died, only 18 of causes unrelated to lymphoma. The overall survival cure is shown in Figure 1, with a minimum followup of seven years. Survival according to initial stage is shown in Figure 2, deaths due to other causes (n =• 18) having been excluded. A significant difference in survival pattern between 'early' and 'late' stage is demonstrated. This difference is not apparent, or significant, if all causes of death are included.

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Fig. 2. Correlation between survival and stage (censored for 18 'other' causes of death).

Stage III + IV only (i) Patients and therapy. One hundred ten patients (75%) had stage HI or IV disease, for which chemotherapy was the treatment of choice; the remainder of the analysis including the figures, refers only to them. There were three 'eras' of therapy. During the first, chlorambucil was compred with cyclical combination chemotherapy using cyclophosphamide, vincristine,

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Fifty years ago, when irradiation was the only treatment available, Symmers recorded that giant follicular lymphadenopathy (Brill-Symmers Disease) could be manifest in four ways [1]. It could follow a relatively benign remitting-recurring course, without change in histology; a leukaemic picture could develop; or evolution into a sarcomatous form, or even Hodgkin's disease, could occur. Shortly thereafter, Gall and Mallory showed the median survival to be five years [2]. It is clear today, that despite the introduction of an array of cytotoxic chemicals into the therapeutic armamentarium, the two main patterns of persistent follicular lymphoma and blastic transformation still dominate the clinical course of the disease. Few patients have been cured, even though the median survival has been extended to nine years [3] with the approaches adopted during the last two decades. The experience at a single centre over this period is presented below, to provide the background against which to evaluate the most recent trials and reflect upon their chances of success.

132 on neither occasion was there any difference between survival of patients for whom complete remission (CR) or good partial remission (GPR) was achieved. fiv) Survival from, first and subsequent relapse, pro-

vided that the histological pattern remained follicular, is shown in Figure 5. This pattern of survival may be contrasted with that following transformation at any time (Figure 6); survival from remission (after initial therapy or subsequent therapy at relapse) is shown in Figure 7. 100

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Fig. 3. Duration of first and subsequent remissions (CR and GPR).

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and prednisone (CVP); during the second, chlorambucil was allocated according to risk factors determined previously, and during the third chlorambucil was the treatment for all but a few patients who received experimental treatment before chlorambucil. All treatment was short term and the survival for the patients treated during these eras was the same. They have accordingly been presented as a single group. A management policy of short-term therapy followed by observation with rebiopsy and restaging at relapse to determine further therapy was pursued throughout. Response to therapy was defined as previously described [3]. (ii) Response to therapy and duration of response. It was possible to induce repeated remission with a high frequency [3]. The duration of first and subsequent remission is shown in Figure 3. This confirms the remitting and recurring patterns of the disease, provided that the histology is unchanged, with the results only deteriorating significantly after three remissions. It is important to note, however, that a small proportion remain in continuous remission, even with the relatively modest treatment prescribed.

133 Based on data suggestive of synergy between interferon and cytotoxic chemotherapy for treatment of murine leukaemia and lymphoma, as well as human cancer in nude mice [17-21], and given the possibility of extrapolation to lymphoma in humans, a phase II trial was conducted at St. Bartholowmew's Hospital to test the feasibility of administering the combination of IFNa and chlorambucil [22]. The result was considered promising enought to warrant the initiation of a randomized trial in which chlorambucil is compared with chlorambucil and IFNa as initial therapy for stage HI and IV follicular lymphoma, with a further randomisation to IFNa or no further therapy for those patients for whom remission is achieved. Interim results from this collaborative trial between St. Bartholomew's Hospital, the Christie Hospital and the Queen Elizabeth Hospital, Birmingham, into which 120 patients have been entered, indicate that the response rates are the same but that there is a significant advantage in terms of remission duration for patients receiving maintenance IFNa. No survival advantage has yet emerged [23]. (ii) Bone marrow ablative therapy. It may be postulated that the administration of very high doses of treatment known to cause regression of lymphoma, and theoretically highly active against resting cells, might be the best way to consolidate remission and possibly cure patients whose remission and subsequent survival would otherwise be brief. Since cyclophosphamide and total body irradiation are a well-tried combination, and autologous bone marrow transplantation has been shown to be able to rescue patients from such therapy, it was selected as the treatment of choice. Since in vitro treatment of bone marrow with antibody and complement directed against potential residual lymphomatous infiltration had been shown to be safe [24] and since it confers an obvious potential advantage, it was incorporated into the treatment programme, regardless of the fact that its efficacy would be hard to prove. It was elected to test the treatment, not in first remission (at which point the median survival was 12 years) but at second, or subsequent remission. Thirty-eight patients have been treated to date, in complete remission or in a maximum response, minimal disease state. Recurrence has occurred in 8 so far, with a median follow-up of two years, and a treatment-related mortality of 5-10% [25].

All these results argue strongly in favour of the Svatch and wait' policy emanating from Stanford, whereby treatment is only instituted if there is a strong clinical indication [11]. Since cure is the primary objective and since obvious regressions are achieved relatively easily for the majority of patients, it is tempting to ask whether the patients predicted to do best (who are not treated de horo) might be the group to treat most intensively. The trial testing this hypothesis is in progress at the National Cancer Institute, Bethesda and compares a watch-and-wait policy with intensive chemotherapy using prednisone, methotrexate, Adriamycin, cyclophosphamide, and etoposide (VP-16) plus nitrogen mustard, vincristine, procarbazine, and prednisone (ProMACE-MOPP) at initial presentation [12]. The preliminary analysis revealed an advantage in terms of freedom from recurrence for those treated intensively at presentation. There was no overall survival advantage, but accrual to the study and follow-up continue. The result will obviously be of great imporMuch longer follow-up is required to determine tance. whether either of these approaches will result in a change in the overall survival pattern of patients with follicular lymphoma, by their incorporation into its management either early or late in the course of the Alternatives disease. Other treatments are being tested in patients with ft) Interferon, interferon and chlorambucil. AlphaInterferon (IFNa) has been shown to cause regression refractory disease to determine whether they have of lymphadenopathy with minimal toxicity in patients enough 'activity1 to warrant further study. Perhaps the with follicular lymphoma when given over a prolonged most promising new chemotherapy agent is fludaraperiod in low doses. The response rate (CR plus PR) is bine, known to cause complete remission of chronic approximately 40%, being highest for previously un- lymphatic leukaemia. Several studies [26-28] have shown remissions to be induced in approximately 40% treated patients [13-16].

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These results suggest strongly that the effect of the treatments was relatively modest and that for most patients the natural history of the disease was changed only marginally. This does not of course mean that the treatment was not to the benefit of the patients, but indicates that better could be done. Studies conducted elsewhere tend to confirm this interpretation. A randomized trial conducted at Stanford [4] yielded higher remission rates with longer administration of singleagent chemotherapy (cyclophosphamide) or CVP, but no statistical difference between the two treatments. The survival curves were identical to those shown above, and similar results have been achieved by others [5]. Prolonged administration of chlorambucil as 'maintenance' of remission achieved with CVP increased remission duration, but had no influence on survival in a trial conducted at the Christie Hospital, Manchester [6]. The introduction of anthracycline antibiotics into combination chemotherapy did not yield significantly higher CR rates (77%) [7] than reported for others treated with CVP. More important, the survival patterns, overall, are no better following cyclophosphamide, Adriamycin, vincristine, and prednisone (CHOP) as initial therapy than for any less intensive treatment except possibly for the small group of patients whose lymphomas contain a relatively high proportion of blast cells [8,9,10].

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of patients with follicular lymphoma, the treatment being well tolerated. Antibody therapy alone or conjugated to radioisotope or immunotoxins is being evaluated in phase I and II trials, and benefit has been reported for selected patients [29-32]. a-Calcidol has been shown to induce remissions and is being tested as maintenance therapy [33]. It may not be possible to demonstrate a potential major role for such new treatments without their being tested at specific points in the course of the disease, prior to the developments of resistance to conventional therapy.

options at the different points of the natural history of the disease and the potential benefits must also be evaluated fully to enable the physician to select the best therapy for any given patient. Acknowledgements I am grateful to Jackie Lim for providing the data and Sian Evans for typing the manuscript. References

New studies

Table 1. More is better (and needs to be). 1. CVP 2. CHOP

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The rationale and the justification for these trials may be debated. They must be seen as applying to selected patients by virtue of their toxicities and within the context of other studies in progress and their differing relevance to those at the extremes of the age range of the population at risk. They will be judged on their design and perceived chances of providing an unequivocal answer, and finally whether or not they result in a change in the clinical course of the disease described by Symmers [1]. All treatment, however, is not administered with curative intent. The palliative role of all therapeutic

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The major trials recently conceived to test new ways of influencing the survival pattern of patients with follicular lymphoma by modifying the nature of their initial treatment are shown in Tables 1, 2, and 3. They reveal a polarisation of interest from very intensive therapy on the one extreme to a biological approach on the other. Studies addressing the management of initial (refractory) or later (recurrent) disease are not easy to identify.

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33.

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Correspondence to: T. A. Lister Dept. of Medical Oncology SL Bartholomew's Hospital London, United Kingdom

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