SCLCchemotherapy

Introduction

SCLC accounts for 16-20% of all lung cancers and its incidence is rising in the developed world, particularly in women. It is a rapidly growing tumour that is now recognized as a systemic disease making surgery inappropriate for the vast majority of patients.

Prior to the introduction of systemic treatment with chemotherapy in the 1970s, the outlook for patients diagnosed with this disease was dreadful, with a median survival of six weeks for patients with extensive disease and three months for those with limited disease. Combination chemotherapy is now the standard treatment for both categories of disease.

Overall survival has been extended significantly in recent years— 5-10% of selected patients with limited disease can survive long term. Unfortunately, the vast majority of patients die of their disease, and patients with extensive disease only have a median survival of 7-11 months.

Staging and prognostic factors

A much simplified staging system is used for SCLC as the vast majority of patients are initially treated with chemotherapy irrespective of disease extent. A two-stage system was drawn up by the Veterans Administration Lung Group:

♦ Limited-stage disease: tumour confined to one hemithorax and regional nodes that may be encompassed within tolerable radiation therapy fields.

♦ Extensive-stage disease: disease beyond these bounds.

Within these broad categories, subgroups may be defined according to one or more of the following prognostic factors:

♦ Performance status

♦ Alkaline phosphatase

♦ Hyponatraemia

A number of drugs have been found to have activity as single agents and a variety of combination regimens have been developed (see Table). CAV and EP have similar efficacy. EP causes more nausea and vomiting but less myelosuppression, neurotoxicity, and cardiac toxicity. The substitution of ifosfamide for EP has shown a modest improvement in survival in extensive disease.

Table 16.5 Commonly used combination regimens in SCLC

EP

Etoposide

115 mg/m2 i.v. days 3-5 q. 3 weeks

Cisplatin

60-80 mg/m2 i.v. day 1 q.3 weeks

CAE

Etoposide

50 mg/m2 i.v. days 1-5 q. 3 weeks

Doxorubicin

45 mg/m2 i.v. day 1 q.3 weeks

Cyclophosphamide

1000 mg/m2 i.v. day 1 q.3 weeks

CAV

Cyclophosphamide

1000 mg/m2 i.v. day 1 q.3 weeks

Doxorubicin

50 mg/m2 i.v. day 1 q. 3 weeks

Vincristine

2 mg/m2 i.v. day 1 q.3 weeks

These combination regimens produce response rates of over 80%, with complete responses in 30-40% of patients with limited disease and 10-20% with extensive disease. Many patients with SCLC are elderly, with co-morbid conditions, and it was hoped that single-agent oral etoposide would be effective and better tolerated by this group. However, in two randomized trials oral etoposide was found to be detrimental to quality of life and less effective than the standard regimens.

Chemotherapy alone is not entirely responsible for improvement in survival, with developments in thoracic and cranial irradiation taking place in tandem. The wide range in survival rates between different clinical trials can be explained in part by differences in selection criteria. Intrinsic and emergent drug resistance are thought to underlie ultimate treatment failure in SCLC and a number of strategies have been investigated in an attempt to overcome this.

Alternating chemotherapy regimens

Goldie et al.2 proposed a hypothesis, based on a mathematical model, that drug resistance could be overcome by using alternating regimens, provided that each regimen was capable of producing high rates of complete remission and that the two regimens were not cross-reactive. However, several trials have failed to show clinically significant improvement in survival with this approach.

Dose intensification

This can be achieved by decreasing the interval between treatments or by increasing the dose at each treatment. Modest increases in the doses of CAV and EP regimens have been achieved but failed because of increasing haematological toxicity. An improvement in median survival was found in patients with limited stage disease when a combination of ifosfamide, carboplatin, etpoposide, and vincristine was given in a three-weekly compared to a four-weekly schedule.

If there is a role for dose intensification it is likely to be in patients with limited disease. Failure to achieve planned dose intensification as a result of toxicity may actually result in shorter survival for patients in the intensified arm.

The addition of colony-stimulating factors to facilitate dose escalation has been shown to decrease haematological toxicity in some trials but not to affect survival. Their routine use is not therefore currently recommended. High-dose therapy with autologous haemopoietic cell support has again failed to show an increase in survival and currently is not recommended for use outwith a clinical trial.

Maintenance chemotherapy

It was postulated that extending the period of chemotherapy might delay relapse. Several trials have assessed the benefit of following standard induction treatment with maintenance chemotherapy. Overall, though they have shown longer times to progression with maintenance treatment, there has been little impact on survival.

Biological therapies are always more likely to be effective in cancer patients with a low tumour burden, and for this reason their use has been explored in patients with SCLC in complete remission following standard treatment. However, trials of maintenance interferon in such patients have failed to show any survival advantage.

New drug development

The demonstration of activity with novel chemotherapeutic drugs in SCLC is difficult since most patients with the disease will have received first-line chemotherapy, and there is a danger that active agents may be dismissed because they fail to show activity as second-line agents. However, it has been observed that patients relapsing longer than three months from the completion of chemotherapy have a much greater chance of responding to the same treatment, suggesting continued drug sensitivity. Patients in this clinical situation are appropriate candidates to receive investigational combinations. Similarly, patients who relapse within three months, and who are, therefore, thought to have disease refractory to conventional therapy, test non-cross-resistant drugs with novel modes of action.

Docetaxel, paclitaxel, topotecan, irinotecan, and gemcitabine have all been found to be active in SCLC. Whether they are incorporated into standard regimens will depend on a number of factors including toxicity, cost-effectiveness, and the demonstration of non-cross-resistance with current standard drug. Other novel treatments under development include:

♦ Drugs interfering with autocrine growth-factor loops

♦ Matrix metalloproteinase inhibitors

♦ Anti-angiogenic factors

♦ Gene transfection approaches

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