Cytotoxic dose-response relationships in small cell lung cancer

Cancer

Treatmenr

Reviews

(1997)

23, 191-207

Cytotoxic dose-response lung cancer A. L. Thomas

relations

and P. J. Wall

CRC Department of Clinical Oncology, Nottingham NG5 IPB, U.K.

City Hospital,

Hucknall

Road,

Introduction There is accumulating evidence in a variety of tumours that cytotoxic dose intensity is an important determinant of treatment outcome. In both in vitro systems and experimentally induced tumours in vivo, there is a relationship between cytotoxic dose and tumour cell kill. The gradient of the dose-response curve is related to the sensitivity of the tumour to a given drug, with tumours such as leukaemias, lymphomas, germ cell tumours and small cell lung cancers having very steep gradients. In addition, experiments have shown that even in tumours which are relatively insensitive to chemotherapy, such as osteogenic sarcomas, increasing dose intensity can lead to higher cell kill rates (1). These findings raised the concern that conservative dosing could compromise tumour cure rates, and therefore full dose treatment, preferably over a short duration, should be attempted. Animal studies have suggested that dose ascalation is an effective strategy to overcome drug resistance. Small cell lung cancer is initially chemo-sensitive, but the majority of patients eventually die from chemo-resistant disease. As neither prolonged primary treatment nor maintenance treatment improve outcome, there has been considerable interest in methods of increasing the dose intensity of treatment in an attempt to improve survival (2, 3). This review will summarize strategies that have been employed to achieve this, examine some of their problems, and discuss novel methods under evaluation which are trying to improve the outcome in this difficult and often tantalising tumour.

Staging

and prognostic

factors

in small cell lung cancer

Without treatment, the median survival is 6 weeks for extensive stage small cell lung cancer and 12 weeks for limited stage small cell lung cancer. Chemoradiotherapy at conventional doses has resulted in high response rates 0305-7372/97/040191+

0 1997

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Saunders

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but rarely in cure. In extensive disease, the 2-year survival rate is less than 5%. Intensive treatment of selected patients with limited stage disease has extended their median survival to 18 months with up to 30% surviving for 2 years. Although the long term survivors from small cell lung cancer are few (3-8%) it remains important to identify factors that predict better survival since they can be used to tailor the treatment to the patient. The simple staging system for small cell lung cancer of ‘limited’ and ‘extensive’ is generally applied in clinical practice (4). Limited disease is confined to one hemithorax with or without ipsilateral or contralateral mediastinal or supraclavicular lymph node metastasis, with or without ipsilateral pleural effusions. Extensive disease is any disease at sites beyond this. In addition to anatomical staging, performance status and biochemical parameters have been used to stratify patients into different prognostic subgroups (5, 6). Multivariate analysis on large sets of prospective data have demonstrated the usefulness of measuring albumin, alkaline phosphotase (ALP) and lactate dehydrogenase (LDH) as prognostic tools. Other variables have been shown to offer prognostic importance with performance status, serum ALP, aspartate aminotransferase (AST), LDH and sodium being the most important (7).

Cytotoxic Retrospective

studies:

dose intensity planned

in small cell lung cancer

vs achieved

dose intensity

The first studies to draw attention to the potential importance of cytotoxic dose intensity were reviews by Hryniuk of data from earlier publications (8,9). These milestone studies generated interest and enthusiasm for studying dose intensity further, but had a number of serious limitations. Firstly, none of the trials included had been designed with cytotoxic dose intensity as an endpoint. In particular, none compared two similar treatments given at different dose intensities. Any conclusions drawn must therefore be tentative. Secondly, the estimates of dose intensity used were based on the planned dose regimen, not on the received dose intensity. Patients can receive dose intensities very different from those proposed, and until recently, dose reduction or delays were commonly employed to reduce treatment toxicities. Thirdly, values for dose intensity were assigned by the authors for different drugs and schedules to allow comparisons, introducing the possibility of systematic bias. More recent studies have retrospectively compared outcomes in patients who received different cytotoxic dose intensities, although they were all planned to receive the same treatment (IO). The finding in such studies that reduced dose intensity is related to worse survival is unsurprising; the use of arbitrary dose categories merely emphasizes that poorly patients tolerate treatment less well and have shorter survival. In order to test the hypothesis that ‘more is better’, prospective randomized studies of cytotoxic dose intensity are required. The

CYTOTOXIC

DOSE-RESPONSE

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193

mathematical models on which the calculation of dose intensity is based are reviewed extensively by Wampler (11) and Gurney (12, 13) and will not be discussed further here. The first study to apply Hryniuk’s methodology to small cell lung cancer was performed by Klasa er al. (14). In this meta-analysis, they found a positive correlation between response and median survival with planned cytotoxic dose intensity, both with combination therapies and treatment with single-agent etoposide in extensive stage small cell lung cancer. No such correlation was found for limited stage disease. This study can be criticized since of the 60 studies analysed, barely half (33) were randomized. None was designed to address the question of dose intensity and they disregarded the fact that some patients had radiotherapywhich could have influenced outcome. It did, however, serve to identify the difficulty with retrospective studies of this nature, in that the actual delivered dose to any patient is often not recorded and therefore the analysis is based on intended dose which may be inaccurate. Although there is now clear evidence in some tumours that ‘less is worse’, there remains the need for prospective studies designed specifically to address the question ‘is more better?’ (15) To date, such prospective studies have only been carried out in a limited number of tumour types and have given conflicting results (16, 17). Even with true randomized studies, problems are encountered when analysing the results. Some studies use dosing schedules which have no relevance to current oncological prescribing. Scheduled or planned dose intensity is rarely the same as received or delivered dose intensity. In reports of clinical trials, the intended dose and duration of treatment are described, but the actual dose and the period of time over which it was administered are rarely recorded. This leads to difficulty when interpreting dose intensity in clinical studies. Until recently, oncologists often reduced the dose of chemotherapy in standard regimens to avoid toxicity. The impact of this practice on patients with extensive stage small cell lung cancer was investigated in a study comparing 85 historical controls, who received low dose intensity cyclophosphamide, adriamycin and vincristine, and a contemporary group of 37 patients receiving higher dose intensity CAE chemotherapy and CAV/EP. Both complete response rates and overall survival rates were significantly better in the higher dose intensity treatment groups. This work, therefore, supported the notion that survival advantage in extensive stage small cell lung cancer can be achieved by giving full dose planned treatment (18).

Prospective

studies

with different

cytotoxic

dose intensities

One of the first prospective randomized studies looking at dose escalation in small cell lung cancer was performed by Cohen et al. (19). They found that by increasing the dose of cyclophosphamide, methotrexate and lomustine, they obtained a higher complete response rate and more long-term survivors compared with patients receiving standard therapy. Attempts to repeat this have not all been in agreement. The Southeastern Cancer Group randomized 298 patients with extensive small cell lung cancer to standard or high dose cyclophosphamide, doxorubicin and vincristine. Although patients in the dose

194

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intensive arm were more likely to achieve a complete response, they experienced worse toxicity and no significant difference was obtained in overall response rate or survival (20). Taking this further, Ihde’s group performed a randomized prospective comparison of high- and standard-dose etoposide and cisplatin in extensive stage small cell lung cancer (21). Ninety patients were randomized to receive either standard-dose treatment with etoposide 80 mg/m’ on Days l-3, and cisplatin 80 mg/m’ on Day 1 of a 3-weekly cycle, or high-dose treatment with etoposide 80 mg/m* and cisplatin 27 mg/m’ on Days l-5 of a 3-weekly cycle. After two treatment cycles, all the patients were treated with the standard schedule for a further two cycles. The increase in dose intensity achieved was 46%, and no difference in survival was seen. The authors concluded that there was no therapeutic advantage in increasing the planned dose in extensive small cell lung cancer. However, the protocol for chemotherapy following the first four cycles was complicated and may affect the interpretation of this study. In tumours such as small cell lung cancer which are initially very chemosensitive, it seems logical that treating with maximal chemotherapy at first would be advantageous. Retrospective analysis of received dose intensity in 131 patients with limited stage small cell lung cancer enrolled on two consecutive phase II studies, showed that survival was better in those who received higher doses of cyclophosphamide and cisplatin (22). These studies provided the basis for a randomized study of initial dose intensity performed in France. One hundred and five patients with limited stage small cell lung cancer were enrolled (23). They were randomized to receive either higher or lower doses of cisplatin (100 or 80mg/m* and cyclophosphamide (300 or 225 mg/m’) in the first treatment cycle only; all patients received the same doses of etoposide and doxorubicin. After the first cycle of chemotherapy, the patients went on to receive a further five cycles of chemotherapy at the lower dose and three courses of radiotherapy. Although there was more granulocytopenia after Cycle 1 in the higher dose treatment group, this problem did not continue at cycle 2. The median follow-up was 33 months. The 2-year survival for the 55 patients in the higher dose group was 43% compared with 26% for the 50 patients in the lower dose group (p=O.O2). This astonishingly large difference was quite unexpected and has not yet been confirmed by other investigators.

Weekly alternating

chemotherapy

The majority of patients with small cell lung cancer relapse with chemo-resistant disease. One potential way to overcome this problem is to give rapid treatment on a weekly basis, alternating non cross-resistant drugs. This type of scheduling found favour in the 198Os, especially for non-Hodgkin’s lymphoma, but has not been demonstrated to be superior to conventional chemotherapy (24,251. There was initial enthusiasm for this method in small cell lung cancer after some non-randomized studies were published (26-28). However, randomized studies have been less encouraging.

CYTOTOXIC

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The strategy of alternating two non-cross resistant chemotherapy regimens was popular in the 1980s following the work of Goldie and Coldman (29). In a Canadian trial in 288 patients with extensive stage small cell lung cancer, an improved median survival was reported for the CAV/PE treatment (30). However, this study compared CAV/PE with PE alone; therefore, the advantage of alternating the two regimens was not truly tested. A Japanese group who designed a three-arm study comparing alternating CAV/PE with CAV and PE alone addressed this criticism (31). Here no differences in median survival were demonstrated in 142 patients with limited stage and 137 patients with extensive stage small cell lung cancer. A larger virtually identical study by the Southeastern Cancer Study Group demonstrated similar results with no survival advantage in the alternating arm (32). These trials comparing alternating regimens have been reviewed recently (33). In a randomized trial of the London Lung Cancer Group, 438 patients with good prognosis small cell lung cancer were treated with either a weekly alternating schedule of ifosfamide/doxorubicin and cisplatin/etoposide, or 3weekly alternating cyclophosphamide/doxorubicin/vincristine and cisplatin/ etoposide. The overall response rates were the same in both arms. Received dose intensity was 73.9% for the weekly group and 92.7% for the 3-weekly group, reflecting the high incidence of dose reductions and delays due to myelotoxicity in the weekly group (34). An interesting subset study to this work was a quality-of-life assessment in a cohort of 75 patients (35). Daily diary cards were used to score different parameters of well being. Worse scores were obtained in the weekly group implying that the patients preferred the 3-weekly arm. The authors discuss the problems of such quality-of-life studies and suggest that quality of life is a particularly important issue in small cell lung cancer where, for the most part, treatment is palliative. To try and overcome the difficulties with haematological toxicity in the weekly arm, a small further study was performed to assess the potential advantage of using granulocyte colony-stimulating factor (G-CSF). In this trial, 40 patients with small cell lung cancer and good prognostic features receiving weekly cisplatin 50 mg/m*, etoposide 75 mg/m* alternating with weekly ifosfamide 2g/m* and doxorubicin 25 mg/m* were randomized to chemotherapy with or without G-CSF. The incidence of leukopenia was certainly higher in the control arm but the numbers of cycles delayed due to leukopenia were similar in both treatment arms. The authors concluded that G-CSF alone was not sufficient to dose intensify as dose intensity was only increased by 10% (36). One caution when interpreting these studies is that different chemotherapy regimens have often been used in the two arms making direct comparisons difficult; also, a meta-analysis of all randomized trials has yet to be done. Even so, there seems little to be gained from giving chemotherapy on a weekly basis, and other methods of dose intensification should be investigated. It may be that the Goldie-Coldman hypothesis has not been borne out because truly non-cross resistant regimens have not been used. There is evidence that there is partial synergy between CAV and PE. Certainly when alternating CAV/PE was compared with CAV and etoposide, there was no survival advantage (37). For the Goldie hypothesis to be fully tested, randomized trials comparing alternating regimens of truly non-cross-resistant drugs need to be established.

196

Haemopoietic

A. L. THOMAS

growth

factors

AND

P. J. WOLL

to support

planned

cytotoxic

dose intensity

Haemopoietic growth factors are a family of glycoproteins that regulate proliferation, activation and differentiation of blood cell precursors. Recent studies in small cell lung cancer have demonstrated that both granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) are able to reduce the depth and duration of neutropenia and its complications, as well as accelerating haemopoietic recovery after chemotherapy (38-42). In the American licensing study for filgrastim, 211 patients with small cell lung cancer receiving six cycles of cyclophosphamide, doxorubicin and etoposide (CDE) chemotherapy were randomly assigned to treatment with placebo or G-CSF (filgrastim) on Days 4-17 of a 21-day cycle. In the placebo group, 57% of patients experienced neutropenic fever during the first treatment cycle compared with 28% in the G-CSF group (p
CYTOTOXIC

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197

that GM-CSF should not be used in this setting but investigated further in chemotherapy trials (42). There is concern that the haemopoietic growth factors could stimulate tumour growth. Various solid tumours and cell lines have receptors for G-CSF and GMCSF, but their significance is uncertain. Some lung tumours appear to secrete G-CSF, but it does not seem to function as an autocrine growth factor (43). Although G-CSF and GM-CSF have been shown to enhance the clonal growth of a few lung cancer cell lines, growth inhibition and differentiation have also been described. The most comprehensive studies, including panels of 10 and 11 lung cancer cell lines, found no evidence of growth effects with G- or GMCSF (44, 45). It seems unlikely that these haemopoietic growth factors will have any important clinical effect on lung tumour growth, but it is essential that long-term-follow up is maintained in randomized clinical trials in order to determine whether relapse or second malignancy rates differ in patients receiving them.

Erythropoietin

and thrombopoietins

to support

planned

dose intensity

The aetiology of anaemia in patients with malignancy is multifactorial. Cytotoxic chemotherapy and platinum analogues, in particular, blunt the response to erythropoietin. Recombinant human erythropoietin (r-Hu-EPO) has been used to alleviate the anaemia of cancer patients. In a study by deCampos et al., rHu-EPO was given in a randomized three-arm study to 36 patients receiving vincristine, etoposide, carboplatin and ifosfamide (VICE) chemotherapy for small cell lung cancer (46). They found a statistically significant reduction in blood transfusions in patients either receiving 150 or 3OOlU/kg r-Hu-EPO compared to controls. There also was a trend towards fewer platelet transfusions in the r-Hu-EPO treated arms. Similar studies have demonstrated improvements in the performance status and quality of life of patients receiving erythropoietin (47). Although anaemia is rarely dose limiting in the treatment of small cell lung cancer, thrombocytopenia commonly limits cytotoxic dose intensity. Further studies with erythropoietin and the thrombopoietins are currently in progress.

Haemopoietic

growth factors shortening

to support increased the interval between

cytotoxic cycles

dose intensity:

The importance of achieving planned dose intensity has already been discussed. As most chemotherapy is dose limited by myelosuppression, haemopoietic growth factors held out the promise of increasing cytotoxic dose intensity without incurring the costs and toxicities of high-dose therapy and autologous bone marrow transplantation (ABMT). A number of small phase II studies in small cell lung cancer have been reported addressing this issue. Ardizzoni assessed the feasibility of using GM-CSF to allow standard CDE chemotherapy to be administered at 2 rather than the usual 3-weekly intervals (48). Of the 15 patients (four with extensive and 11 with limited stage), only nine were able to

198

A. L. THOMAS

AND

P. J. WOLL

receive all six planned cycles. The relative dose intensity achieved was 1.44. The rate-limiting factors were thrombocytopenia and anaemia that worsened particularly after Cycle 4. They concluded that GM-CSF could allow an increase in the dose intensity but would only be feasible for a limited number of courses. This in itself should not be seen as unacceptable since it is known from randomized studies that most benefit from combination chemotherapy in small cell lung cancer is with the first four cycles (49,501. In a randomized placebo-controlled study with 330 patients with limited stage small cell lung cancer, GM-CSF was used to dose intensify treatment with adriamycin, ifosfamide and vincristine alternating with cisplatin and etoposide. Here treatment was given every 15 days providing that the leucocytes were >3.5 x IO’ cells/l and platelets >I00 x 10gcells/l. If the counts were not adequate, treatment was delayed for 1 week. After five cycles of chemotherapy, the patients went on to receive thoracic irradiation. There was a significant reduction in the treatment duration in the GM-CSF group (12 vs 13 weeks, p
CYTOTOXIC Table

1.

Dose

intensity

in G-CSF

and

DOSE-RESPONSE GM-CSF

randomized

IN SCLC

199

studies

Reference

Patient number

Stage

Treatment

Dose intensification

P

Miles

et al. (26) et a/. (42)

GP GP LD

RDI 82% RDI 84% None

108 65 64 34 78

LD GP GP GP GP

PEIA+ G-CSF PElAfcontrol PE + GMCSF + DXT PE fcontrol + DXT CDE + G-CSF CDE fcontrol VlCaE + G-CSF VlCaE + GM-CSF VlCaE + control

NS

Bunn

23 17 107

Trend to increased DI RDI=1.34 Median DI 33%

NS

81

GP

Trillet-Lenoir

et al. (40)

*Wall et a/. (46) *Steward et al. (57)

LD, Limited disease; intensity; RDI, relative C, cyclophosphamide; randomized.

NS

=O.OOl NS

GP, good prognosis disease, i.e. could be limited or extensive disease; DI, dose dose intensity; P, cisplatin; E, etoposide; I, ifosfamide, D or A, doxorubicin; V, vincristine; Ca, carboplatin; NS, not significant. *Trials which were

in full (56). Sixty-five patients with good prognosis small cell lung cancer receiving VICE chemotherapy (vincristine, ifosfamide, carboplatin and etoposide) were randomized to receive G-CSF or no additional treatment. Both groups were subjected to the same dose intensification strategy; there was no fixed dose interval and patients were eligible for re-treatment when the white blood cell count was above 3 x IO’/1 and the platelet count above 100 x log/l. No dose reductions were permitted. G-CSF patients received Cycle 2 1 day earlier than the control group, but there was no significant difference in time to treatment in the other cycles. Standard VICE is given at 4-week intervals (relative dose intensity=l). Both groups achieved dose intensification, with the G-CSF group receiving a significantly higher dose intensity than the control group, with the greatest difference in the first three cycles (RDI 1.34 vs 1.17, p=O.OOl). The 2-year survival was also better in the intensive treatment group at 32% compared with 15% in the control group. A further prospective study of dose intensity in patients with good-prognosis small cell lung cancer has been published in abstract form (57). Over 300 patients were randomized in a 2 x 2 study to receive either 3- or 4-weekly VICE chemotherapy with or without GM-CSF. Interim analysis from the first 154 patients showed that 3-weekly treatment was feasible in most patients, with a median of 33% greater dose intensity in the intensive arm. More episodes of neutropenic fever occurred in the intensive arm although the number of deaths was the same in both arms. At the time of reporting, more complete response rates (53.5% vs 38.5%) had been seen in the intensive arm, but the final analysis is awaited (Table I). Haemopoietic

growth

factors

to support increased dose escalation

cytotoxic

dose

intensity:

Several groups have used haemopoietic growth factors to support the use of higher chemotherapy doses rather than shorter intervals between cycles. In a

200

A. L. THOMAS

AND

P. J. WOLL

Japanese study, 46 patients with small cell lung cancer were treated with combination chemotherapy in which the dose of VM-26 was escalated from 60 to 120 mg/m’, supported by G-CSF. Overall response rates were 100% in limited disease and 83% in extensive stage disease. A 1.6-fold dose escalation of VM26 was achieved (58). Another Japanese group used G-CSF to support escalating doses of carboplatin in combination with fixed dose etoposide. Seventy-five patients with limited and extensive stage small cell lung cancer were enrolled; of note, 14 were over 70 years of age (59). The major limiting toxicity was thrombocytopenia and as a result of the protocol dose reductions the planned dose intensity could not be reached. In a retrospective comparison with regimens giving standard treatment there was no therapeutic advantage with the dose intensity achieved. GM-CSF has also been used to successfully dose escalate etoposide, cisplatin and epirubicin chemotherapy in small cell lung cancer (60). Forty-one consecutive patients with either limited (23 patients) or extensive (18 patients) disease were recruited in a phase l/II dose escalation study. The administration of GM-CSF allowed the delivered dose intensity of cisplatin and etoposide to increase by approximately 30% and that of epirubicin by 60%. To date, no randomized studies have been reported comparing dose-escalated therapy with standard treatment for small cell lung cancer.

High-dose

therapy

with

bone marrow

transplantation

There have been a number of small non-randomized studies, often from single centres, investigating the role of high-dose chemotherapy followed by autologous bone marrow transplantation (ABMT) in small cell lung cancer. The high-dose treatment has either been given ‘up front’ or as late intensification. The rationale for late-intensification chemotherapy is in part based on the ‘Norton Simon’ hypothesis. Essentially, this proposes that the growth fraction of a tumour increases as the tumour responds to treatment, so the intensity of chemotherapy that induces tumour regression may not be enough to maintain a continued tumour response. There have been few prospective studies in small cell lung cancer set up to address this issue. Spitzer et al. gave ‘conventional’ chemotherapy to 32 patients with limited stage small cell lung cancer followed by two courses of high-dose cyclophosphamide and etoposide with or without vincristine and/or methotrexate. Autologous bone marrow transplantation was used to restore haematological function. Although after late intensification the complete response rate improved, the overall response duration of 14 months was not significantly different from that seen using standard protocols (61). Smith et al. treated 36 patients with high-dose cyclophosphamide 7g/m* and 17 went on to receive ABMT. Despite this aggressive approach, the median response duration was only 10 months (62). The only randomized study comparing high-dose therapy with autologous bone marrow transplantation against standard therapy in small cell lung cancer was performed by Humblet et al. (63). After induction chemotherapy, patients with limited stage disease who achieved any response and those with extensive disease achieving a complete response were randomized to receive further

CYTOTOXIC Table

2.

Randomized

Reference Johnson lhde

et al. (20) et al. (21)

Arriagada Humblet

er al. (23) et al. (63)

studies

DOSE-RESPONSE

of different

dose

IN SCLC

201

intensities

Patients

Treatment

Response

Survival

P

101 146 28 33

HD-CAV CD-CAV HD-PE CD-PE

63% 53% 23% 22%

OR OR CR CR

NS

HD-CPDE CD-CPDE HD-BCNUE +ABMT CD-BCNUE

67% 54% 79%

CR CR CR

29.3weeks 34.7weeks 11.4 months 10.7 months (median) 2YS 43% 2YS 26% RFS 28 weeks

39%

CR

RFS

55 50 23 22

NS

= 0.02 = 0.002

10 weeks

HD, high dose; CD, conventional dose; C, cyclophosphamide; A or D, doxorubicin; P, cisplatin; E, etoposide; OR, overall response rate; CR, complete response; 2YS, RFS, relapse-free survival; NS, not significant.

V, vincristine; 2-year survival;

conventional chemotherapy or intensive chemotherapy with cyclophosphamide, etoposide and carmustine with ABMT. Of the 101 patients registered, 45 reached randomization and of these 23 received high-dose therapy. Although relapse-free survival was extended from 10 to 28 weeks (pcO.001) in the late intensification group, there was no statistically significant difference in overall survival in the two groups (68 and 55 weeks, respectively). The results of these studies were disappointing to those who had hoped that high dose therapy would dramatically improve survival in small cell lung cancer. In the Humblet study, it is notable that 15 of 16 patients with limited disease receiving late intensification relapsed locally in the thorax. Elias et a/. used a similar approach but added radiotherapy to control intrathoracic disease (64). They took 19 patients with limited small cell lung cancer who had achieved a response to conventional chemotherapy and treated them with high-dose cyclophosphamide, cisplatin, carmustine and ABMT. After recovery, the patients went on to receive thoracic radiotherapy (50-60 Gy in 25-30 fractions over 5-6 weeks) and cranial radiotherapy (30 Gy in 15 fractions during 3 weeks). The disease free survival was 53% at 2 years with one patient dying from sepsis and the other patients having relatively low morbidity. The patients for this study were a highly selected group; therefore, to confirm the observation, a prospective randomized trial using this combined modality approach is underway (Table 2). Farha et al. treated 14 patients with small cell lung cancer with two courses of cyclophosphamide 1.5-4.5mg/m2, etoposide 200-600 mg/m*, vincristine 3 mg/m2 and doxorubicin 80 mg/m*, followed by ABMT (65). The patients then went on to receive prophylactic cranial irradiation, four courses of the same drugs at conventional doses before thoracic irradiation. Despite this combined modality approach, the median survival was only 10 months. This may reflect the fact that nine of the patients had extensive disease at presentation and only seven of the 13 evaluable patients had a complete response, implying that their tumour burden was too great for even the most intensive treatment. Souhami’s group has reported 75 patients who have received high-dose therapy with ABMT either as first line or late intensification treatment. These patients

202

A. L. THOMAS

AND

P. J. WOLL

were treated in four consecutive studies (66). Despite very intensive treatment, there was no improvement in the number of complete responders or overall survival compared with conventional chemotherapy. High-dose therapy with bone marrow transplantation is a high-risk procedure which carries a significant morbidity and mortality in addition to the economic costs. It cannot be recommended in small cell lung cancer outside carefully controlled clinical studies.

High-dose

therapy

with blood

progenitor

cell transplantation

The discovery that cytotoxics and cytokines can mobilize blood progenitor cells (BPC) into the circulation, and that re-infused BPCs lead to earlier haemopoietic engraftment than autologous bone marrow, has made high-dose therapy cheaper and safer. Several methods for mobilizing BPC exist. Chemotherapy with G-CSF is currently the most popular method although other cytokines such as GM-CSF and interleukin-3 have also been used (67). The first study of high-dose etoposide, ifosfamide, carboplatin and epirubicin with BPC transplantation in small cell lung cancer was reported by Brugger et a/. (68). In a phase l/II study in patients with limited stage disease, high dose chemotherapy with BPC transplantation was used as part of an intensification strategy following two cycles of induction chemotherapy. Eighteen patients were treated with induction chemotherapy and G-CSF prior to leukapheresis of BPC. Responders were then given high-dose treatment with the above agents followed by autologous BPC transplantation. All patients then received thoracic irradiation, and those in complete remission received prophylactic cranial irradiation. Thirteen patients received this intensive treatment and at median follow-up of 14 months, 11 patients were alive and well with nine in complete remission. Toxicities were ‘acceptable’ with severe oral mucositis being the most frequently observed adverse effect. Prospective randomized trials using this approach are needed. One potential problem in the use of BPC transplantation is the possibility of malignant contamination of the graft. This is of particular concern in patients with small cell lung cancer because bone marrow involvement is common at presentation. Furthermore, in patients with extensive stage disease, BPC mobilizing regimens have been shown to release tumour cells into the circulation (69). Therefore, a risk remains that when PBPC are re-infused after the high dose treatment, they may be contaminated with tumour cells. Sensitive methods of detecting minimal residual disease are needed.

Multicyclic

chemotherapy

and blood progenitor

cell transplantation

High cytotoxic dose intensity can be achieved with a single high dose treatment followed by ABMT or BPC transplantation, but single high dose treatments do not seem to be adequate to control the tumour burden in small cell lung cancer. Studies have shown that multicyclic dose-intensive treatment maximizes dose intensity in solid tumours (70,711. This approach risks re-infusing at each

CYTOTOXIC

DOSE-RESPONSE

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203

treatment cycle contaminated BPC collected at presentation. To minimize this risk, the authors developed a technique of sequential re-infusion, in which BPC are collected and re-infused at each treatment cycle, to take advantage of in vivo purging (72). In Manchester, it was found that the administration of G-CSF following ICE chemotherapy leads to the release of large numbers of PBPC into the circulation. Further work established that BPC remain viable in whole blood at 4” for a few days (73). A pilot study was performed that demonstrated that it was possible to shorten the interval of ICE chemotherapy from 4 to 2 weeks using BPC collected in whole blood at Day 15 of each cycle and re-infused 48 h later, after administering the next cycle of chemotherapy. This marks a substantial increase in cytotoxic dose intensity that could not be achieved with G-CSF alone(72). Following this, in a phase II study, 50 patients with small cell lung cancer of favourable prognosis were randomized to receive either standard 4-weekly ICE chemotherapy or intensive 2-weekly ICE with re-infusion of haemopoietic progenitors in whole blood as support. The relative dose intensity of ICE chemotherapy was increased from 0.99 in the first three treatment cycles in the standard arm to 1.80 in the patients having the whole blood re-infusion (p=O.OOOl). Moreover, unexpectedly less toxicity was seen in the patients receiving the higher dose chemotherapy. Eighty percent of patients on the standard arm experienced neutropenic sepsis, whereas only 52% of patients on the intensive arm did (74). This approach is now the subject of a multicentre phase III study designed to determine whether this increase in cytotoxic dose intensity impacts upon survival.

Radiotherapy Advances have been made in the treatment of small cell lung cancer using a combination of chemotherapy and radiotherapy. Meta-analysis has been used to clarify the role of thoracic radiotherapy with combination chemotherapy in patients with limited stage small cell lung cancer. Data from 2140 patients has shown a significant advantage using combined modality treatment with overall 3-year survival improved from 8.9% in the chemotherapy alone group compared to 14.3% with chemoradiotherapy. Sub group analysis confirmed that this was particularly apparent for the younger patients (75). Radiotherapy confers no survival benefit to patients with extensive stage small cell lung cancer, although it has a useful role in palliation. Intercalating platinum containing regimens with concurrent radiotherapy have been used with improved survival rates; however, this advantage has been of fset with worse toxicities (42, 76). More recent work has looked at the role of both thoracic and prophylactic cranial irradiation in combination with chemotherapy, and the results are encouraging (77). Other novel treatment options with radiotherapy include the use of hyperfractionated regimens (78). Debate still exists regarding the optimal timing of radiotherapy, but there is probably an advantage to using it early in the treatment schedule (33). If doseintensive treatments are to be given, the radiotherapy regimen must be planned with this objective in view.

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A. L. THOMAS

AND

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Conclusions A clearly defined dose-response has not been demonstrated in clinical studies in small cell lung cancer. Although the concept of dose intensification in small cell lung cancer remains interesting, it is as yet unproven. Prolonged primary treatment and maintenance chemotherapy have been shown to be of little value and therefore it is imperative that cytotoxic dose intensity is optimized in order to improve patient outcomes. Many of the trials reviewed here are compromised by small numbers, small differences in dose intensity, and failure to randomize. Cytotoxic dose intensity can be increased by reducing the intervals between cycles of chemotherapy or by increasing the drug doses, but the toxicity is increased. It is important to assess the acceptability of such approaches and the effects on quality of life, so that patients can make an informed decision on the price they might pay for a small chance of long-term survival. The use of high-dose therapy remains controversial, but the use of BPC to support multicyclic treatment is an exciting development now being subjected to randomized trial. New agents, including cytotoxic drugs, biological response modifiers and thrombopoietins, are currently under evaluation. In addition, knowledge about the biology of small cell lung cancer is improving the understanding of this frustrating tumour. These offer the hope that real improvements may be offered to future patients with small cell lung cancer.

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