Núcleos

For some cancers increasing the dose and/or decreasing the interval between treatments has produced significant improvements in response rate and survival. Indeed in SCLC, treatment with etoposide as single agent therapy produced better response rates when given continuously rather than as a single shot (Clark et al., 1990). Unfortunately, despite the advent of haematopoetic growth factor support and autologous bone marrow transplantation none of the high dose chemotherapy trials have shown an improved survival in SCLC although some demonstrate improved response rates (Aridzzoni et al., 1993; Demetri, 1993; Sorensen and Hanson, 1994). This m ethodology therefore still remains investigational.

1.9.6.b ALTERNATING CHEMOTHERAPY

Resistant clones of SCLC cells, which are either present before or develop during chemotherapy are the reason for treatment failure. This provided the logical basis to use alternating chemotherapy regimens with non-cross resistant drug combinations. However, such attempts have not improved outcome.

1.9.6.0 SURGERY + ADJUVANT CHEMOTHERAPY

Surgery in the treatment of SCLC remains a subject of debate especially since this tumour métastasés early in its natural history and the detection of early métastasés is difficult. Nevertheless, a recent study has shown that in carefully selected patients surgery can produce long term survivors (Shah et al., 1992). Since SCLC is initially a chemosensitive disease the next logical step would be to examine the effect of surgery combined with adjuvant chemotherapy. A recent study has shown promising results using surgery + chemotherapy followed by cranial radiotherapy (Karrer, 1994). Proper randomised studies are urgently required.

1.9.6.d RADIOTHERAPY IN LIMITED-STAGE DISEASE

In patients with limited disease a meta-analysis including 13 trials with 2140 patients has shown that radiotherapy confers a small but significant increase in survival (5% at 3 years) when added to chemotherapy (Pignon et al., 1992). Furthermore, radiotherapy in conjunction with high dose chemotherapy and autologous marrow support may yield higher long term survival rates (Elias et al.,

1993). The timing of radiotherapy is important and should be given early rather than late in the treatment protocol to decrease the incidence of brain métastasés (Murray et al., 1993). Hyperfractionation of radiotherapy is being investigated

confers a . additional benefit in

A

patients with limited stage disease (Johnson et al., 1993).

The role of radiotherapy to prevent cerebral métastasés in patients with limited stage disease has been analysed retrospectively in a small number of patients. Among complete responders, those receiving cranial radiation had a sig nifica ntly sm aller chance of developing a brain relapse and survived significantly longer than patients who did not receive cranial radiation (Rosenstein et al., 1992). Although cerebral radiation is associated with long term morbidity including leukoencephalopathy and neuropsychological impairment, this area clearly warrants further prospective investigation.

1.9.6.e BRAIN M ETASTASES

For decades the treatment of choice in SCLC with brain métastasés has been corticosteroids and radiotherapy because of a presumed lack of penetrance of cytostatic agents through the blood/brain barrier. However, there is increasing evidence that chemotherapy is just as effective against intracerebral disease as other metastatic sites of disease (reviewed in (Kristensen et al., 1992)). This would argue against the use of elective cranial radiation in the initial treatment of patients with SCLC. Nevertheless, elective cranial radiation in patients without demonstrable cerebral involvement given together at the time of chemotherapy does reduce the risk of subsequent cranial relapse although the effect on long term survival is unclear (see 1.9.6.d. above).

1.9.6.f RELAPSE

Most patients relapse within a year of completing first line therapy and at this time subsequent treatment is usually ineffective (Andersen et al., 1990). Most of the relapses are multifocal and therefore logically require systemic treatment. Trials using agents which are non cross resistant to those used in the initial treatment of the disease produce responses in 20-25% of patients with a median survival time of 3-4 months. Patients who are fortunate enough to have a prolonged chemotherapy free interval before relapse, often are still responsive to the original drug regimen used with response rates exceeding 50%. Radiotherapy remains useful in patients who have a single site of relapse outside previously irradiated fields (Bergman et al., 1991).

1.9.7 EXPERIMENTAL THERAPIES

It is clear that new therapies are desperately needed to tackle SCLC. Some of the new approaches that have already been tried in the clinic are described below.

In te rfe ro n s -s o m e tumours have reduced levels of class I and II major histocom patibility antigens which is believed to contribute to their ability to escape from immune surveillance. In SCLC some workers have reported a decrease or absence of expression of these antigens compared to other lung cancer lines (Doyle et al., 1984; Doyle et al., 1985). However, this does not appear to be the case for all SCLC lines examined (Ball et al., 1986). Treatment with a or y - interferon has been shown to upregulate class I and II expression in SCLC cell lines. Interestingly, in some SCLC lines y-in te rfe ro n treatm ent resulted in decreased growth. This was associated with increased lysis by cytotoxic T cells but decreased sensitivity to natural killer cells in vitro. Treatment with y -in te rfe ro n has also been shown to increase the expression of intercellular adhesion molecule-

1 (ICAM-1) on SCLC cells which is important in T cell receptor binding (Azuma et al., 1992). Recently a clinical trial has shown that patients with SCLC receiving a-interferon therapy lived longer than those receiving no such therapy (Mattson et al., 1992). However, others have not been able to substantiate this result (Gilsson et al., 1993).

A n tib o d y therapy-The expression of many membrane-associated surface proteins differs significantly between normal and malignant cells. Numerous leukocyte-related surface antigens, including CD24 and CD56 (neural cell adhesion molecule), are highly expressed by most SCLC cells but not by normal tissue (Jackson et al., 1992). Therefore monoclonal antibodies directed against these antigens can be used to deliver cytotoxic agents directly to cancer cells. An anti-CD24 antibody conjugated to the potent cytotoxin ricin, inhibited SCLC growth in culture and in a xenograft model (Zangemeister-Wittke et al., 1993). Another immunotoxin, consisting of an anti-CD56 antibody conjugated to a blocked ricin molecule, showed in vitro toxicity against SCLC cells and induced a response in one of 19 patients with refractory SCLC (Lynch, 1993).

SCLC is characterized by its ability to secrete many hormones and neuropeptides including bombesin, neurotensin, cholecystokinin and vasopressin (reviewed in (Sethi et al., 1992a)). Among these, only bombesin-like peptides, which include GRP, have been shown to act as autocrine growth factors for certain SCLC cell lines (Cuttitta et al., 1985; Mahmoud et al., 1991). These lines express the bombesin receptor, secrete bombesin and show increased DNA synthesis and clonal growth in response to bombesin. Furthermore, in the presence of either anti-bombesin antibodies or a bombesin specific antagonist, the growth of certain SCLC lines in semi-solid media or as xenografts in nude mice is markedly inhibited (Cuttitta et al., 1985; Mahmoud et al., 1991). These observations led to the belief that anti-bombesin antibodies or bombesin specific antagonists could be utilized as new therapies in the treatment of SCLC. Unfortunately, in a phase I clinical study with monoclonal anti-bombesin antibodies no inhibition of tumour growth in patients with SCLC was seen (Mulshine et al., 1988). In a subsequent phase II

study of 12 SCLC patients previously treated with at least 1 cisplatinum containing

compound, 1 had a complete response to anti-bombesin monoclonal antibody

therapy lasting 5 months (Kelly et al., 1993). This responding patient had measurable GRP in the serum but no evidence of GRP receptors on tumour biopsy, and thus the mechanism of the response is unclear. Although, this result warrants further investigation, it is unlikely that a strategy based on eliminating the effects of a single growth factor will be sufficient to inhibit the growth of SCLC which is now known to be a tumour driven by multiple neuropeptide growth factors (see