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188 Thorax 1992;47:188-194

Newperspectives in lung cancer 5S Series editor: S G Spiro Thorax: first published as 10.1136/thx.47.3.188 on 1 March 1992. Downloaded from New drugs in lung cancer

D C Talbot, I E Smith

The best hope for improved treatment of lung receptors for autocrine and paracrine growth cancer lies in the development of effective new factors for small cell lung cancer and of the drugs. Lung cancer is the main cause of events occurring after activation of the cancer related death in Britain, accounting for receptors. Other possible drug targets include 17% of all new registered cases of cancer and the DNA replicative machinery, the genes for 25% of cancer deaths.' Over 90% of patients tumour promoters and suppressors and the with lung cancer die of their disease. Despite tumour regulatory genes, and the dramatic developments with cytotoxic transcripts and products of these genes. for some malignancies over the last four decades, very little impact has been Small cell lung cancer made on cure rate for patients with lung WHEN TO ASSESS NEW DRUGS cancer. This is brought into perspective by Small cell lung cancer is one of the most comparing the change in five year survival chemosensitive ofthe solid tumours, and many rates of lung cancer and childhood acute drugs have activity against this form of lung lymphoblastic leukaemia over the last two cancer.4 Much clinical research effort has gone decades. The five year survival rate for acute into investigating combination chemotherapy, lymphoblastic leukaemia has increased from alternating chemotherapy and high dose 8% to 70% as a result of improved treatment chemotherapy with autologous bone marrow with cytotoxic drugs, whereas the five year rescue, yet the median survival has been survival rate for lung cancer for all ages prolonged by only a few months. The rapid remains unchanged at 8%, with over 40 000 recurrence seen in most patients after initial deaths each year in the United Kingdom tumour regression indicates that the key http://thorax.bmj.com/ alone. problem is multidrug resistance, either innate Prospects are bleak for all histological or acquired. This points to an important subtypes. Small cell lung cancer is very question in the development of drugs: when chemosensitive in its initial clinical stages; should new drugs be assessed? The conven- treatment with appropriate chemotherapy tional approach has been to test new drugs only does improve survival, but only to around after conventional chemotherapy has failed. 10-15 months for patients with limited disease Not unexpectedly, in this multidrug resistant

and to 7-11 months for those with extensive environment results are much worse than when on October 4, 2021 by guest. Protected copyright. disease. Deaths from small cell lung cancer the same agent is tested in previously untreated continue to occur beyond two years from patients. when given as a single diagnosis and a recent report gave a dismal five agent had a response rate of 80% in untreated year survival rate of only 2.5%.2 For patients patients5 but only 10% in patients previously with non-small cell lung cancer surgery offers treated with cytotoxic drugs.6 Similarly, ten- the best chance of cure, but by the time the iposide had a reported 90% response rate in diagnosis is made most patients have inoper- untreated patients,7 compared with 6% in able disease. The role of chemotherapy in the previously treated patients.8 In our initial management of advanced non-small cell lung studies with at the Royal Marsden cancer is controversial. Modest response rates Hospital we found response rates of 60% for of 25-50% are achieved with combination untreated patients, compared with 19% for chemotherapy containing , but the treated patients.9 response usually lasts only a few months and Testing new drugs in previously untreated the survival benefit is marginal at most.3 patients clearly minimises the risk ofrejecting a Most drugs in use today have been clinically useful drug because it lacks efficacy in developed by empirical means with extensive patients with resistant disease. On the other screening processes. Many of the biochemical hand, this approach is not straightforward and pharmacological properties of a new drug because the survival and quality of life of the are not determined until some time after the patient may be put in jeopardy if an inactive Lung Unit, Royal Marsden drug has achieved wide clinical application. drug is tested in untreated patients. In a phase Hospital, Sutton, Technological advances and a fuller under- II trial of oral in 21 untreated Surrey SM2 5PT standing of the biology of cancer may allow us patients with extensive disease a response rate D C Talbot I E Smith to identify specific molecular targets for which of only 14% was observed. Despite a policy of Reprint requests to: to design new drugs. An encouraging develop- switching promptly to , vin- Dr Talbot ment is the characterisation of many of the cristine, and etoposide, only 14 patients were New drugs in lung cancer 189

well enough to do this and the response rate was small cell lung cancer, Cohen concluded that it low at 19%, with a short median survival of six was not essential to study previously untreated months.'0 The outcome was the same in two patients to assess activity with a new drug.'4 other trials of similar design in patients with A third technique would be to randomise extensive disease: median survival times of previously untreated patients to receive Thorax: first published as 10.1136/thx.47.3.188 on 1 March 1992. Downloaded from only seven weeks were achieved with standard first line induction drugs or the phase triglycidylurazole" and eight weeks with II drug. Patients with stable or progressive mitoxantrone2-similar to the survival expec- disease after one or two cycles or progressive ted for untreated patients with extensive small disease after an initial response would receive cell lung cancer. If the agent under investiga- conventional salvage chemotherapy. This tion has low activity then the patient is method was used in the Eastern Cooperative effectively receiving no treatment, and the Oncology Group phase II study of menogaril. chance for useful palliation with conventional The standard induction drugs were cyclo- chemotherapy is lost. phosphamide, (Adriamycin), and What therefore is the best way to evaluate , with etoposide and cisplatin as new drugs in small cell lung cancer? An salvage chemotherapy. Menogaril was found to important prerequisite is for patients receiving be inactive in terms ofthe response criteria; the a trial drug to have a good performance status estimated median survival times were 42 weeks without metastatic disease that is currently life for patients receiving cyclophosphamide, threatening. Several methods are then possible. doxorubicin, and vincristine and 38 weeks for The first is to add the drug under investiga- those having menogaril, but the differences tion to an otherwise standard combination and were not significant.'5 compare this regimen with the standard com- We are currently investigating a variant bination alone. When this method was used to of this approach, in which patients are evaluate cisplatin, 100 patients with extensive randomised to receive standard induction small cell lung cancer were randomised to treatment or the study drug for a maximum of receive etoposide, cyclophosphamide, doxo- two cycles only. Patients with progressive rubicin, and vincristine with or without cis- disease after one cycle of the study drug platin. The objective response rate was 48% in are immediately switched to the standard the four drug combination and 83% in the five combination and all other patients on the new drug combination containing cisplatin.'3 This drugs are automatically switched to standard method overcomes the problem of testing drugs after two cycles irrespective of response. drugs with low activity but has a number of This enables the response to be appropriately disadvantages. Because most combinations evaluated without, we hope, jeopardising the now give high response rates, large numbers of chance of long term survival with conventional patients need to be randomised in this kind of chemotherapy; the randomised nature of the study if an increase in response resulting from trial allows us to confirm whether this is indeed http://thorax.bmj.com/ the new agent is to be seen. Furthermore, the the case. activity of the drug as a single agent cannot be determined by this means. NEW DRUGS A second approach would be to lower the The phase II studies of single agents in the last threshold for determining activity to below three years are shown in table 1; about half were 10% when a new drug is assessed in previously performed on previously untreated patients. treated patients. This would necessarily One of the most active agents developed

increase the number of patients required for recently is the water soluble semisynthetic on October 4, 2021 by guest. Protected copyright. accrual to maintain satisfactory confidence analogue CPT1 1. Camptothecin limits. After reviewing 97 phase II studies in is a plant alkaloid isolated from the Asian tree

Table 1 Clinical trials of new drugs (single agents) for small cell lung cancer Median Not Total duration of previously Previously No Response survival Drug Dose and schedule treated treated evaluable CR PR (0) (w) Reference Amonafide 300 mg/m2IV d 1-5 q 21 d 13 0 12 0 0 0 31 Evans54 120 mg/m2 IV q 21 d 80 0 71 4 30 48 30 Eckhardt2' Methylglyoxal 500 mg/m2 IV q 7 d x 4w 0 24 24 0 1 4 - Simon55 bisgluanglhydrazone then q 14 d Sulofenur 800 mg/m2PO d 1-5 9 0 9 0 0 0 - Shepherd56 x 3wq28d Interleukin-2 4-5 x 106MU/m2/d 0 67 10 2 1 30 - Clamon'0 IVfor96hq7d x 4* Spirogermanium 125-200mg/m2IVtiw x 2w 15 0 15 0 0 0 - Lad57 reducing to once weekly 800 mg/m2 IV daily x 5 q 28 d 0 14 14 0 0 0 - Holoye58 120-140 mg/M2 12 36 44 4 11 34 34 Giaccone59 IV d 1,3,5 q 21 d Iproplatin 300 mg/m2 IV q 28 d 0 16 16 0 0 0 - Kramer' Menogaril 200mg/m2 IV q 28 d 40 0 40 0 2 5 38 Ettinger"' Mitozolomide 70-90 mg/M2 PO q 42 d 11 9 18 0 5 28 - Harding62 CPT-11 100 mg/m2 IV q 7 d 8 33 35 2 7 37 - Negoro'8 5 g/m2 IV q 21 d 0 14 14 0 6 43 - Cantwell26 *All patients given induction chemotherapy followed by interleukin-2 for patients with assessable disease. IV-intravenously; d-day; q-every; w-week; PO-orally; tiw-three times a week; CR-complete response; PR-partial response. 190 Talbot, Smith

Camptotheca acuminata and, although it is phase specific drugs acting in the G2 phase of active against experimental tumours, its the cell cycle. Their efficacy depends on the clinical use is limited by severe haemorrhagic schedule of administration. The response and cystitis and low respone rates.'6 CPT11 survival of patients with small cell lung cancer is a potent inhibitor of topoisomerase I, is better when etoposide is given as repeated Thorax: first published as 10.1136/thx.47.3.188 on 1 March 1992. Downloaded from has encouraging preclinical and antitumour daily infusions of 100 mg/M2 for five days than activity, and in man is better tolerated than the as a single infusion of 500 mg/M2.2' The parent compound. Phase I studies with single bioavailability of etoposide after oral adminis- doses have shown that it has a maximum tration is about 50%, which makes it a good tolerated dose of 250 mg/m2, the dose candidate for repeated low dose oral adminis- limiting toxicity being myelosuppression. tration. This has the potential advantages of Other adverse reactions include alopecia and easy administration and acceptable toxicity.24 gastrointestinal toxicity but not haemorrhagic Ifosfamide also appears to be well suited to cystitis.'7 The results ofthe first phase II study combination chemotherapy in the treatment of of CPT1 1 in small cell lung cancer are small cell lung cancer as it is less myelo- encouraging. The 41 patients received CPT1 1 suppressive than its parent compound, cyclo- 100 mg/m' by intravenous infusion over 90 phosphamide and is not cross resistant with minutes every week with dose reduction for standard alkylating agents, and its dose limiting neutropenia. Two of 27 previously treated toxicity, haemorrhagic cystitis, can be evaluable patients had a complete response and abrogated by Mesna without loss ofefficacy.25 It seven had a partial response (objective response has activity as a single agent in patients 33%). Of eight evaluable previously untreated previously treated with etoposide, vincristine, patients four had a partial response. The and doxorubicin,26 though response rates median duration of response was 50 days.'8 appear to be reduced ifprior treatment includes Pharmacokinetic studies of CPT1 1 and its cyclophosphamide.27 We reported a study at active metabolic SN38 showed that elimination the Royal Marsden Hospital using ifosfamide is triphasic, with a long terminal half life of 18 in combination with carboplatin and etoposide, hours, which is clearly an advantage for a drug with a high response rate of 94% and a median active in S phase.'9 Other camptothecin survival of 19 months.28 analogues are being evaluated, including Drugs containing platinum, and in particular (SKF104864), which is currently carboplatin, continue to play a prominent part undergoing phase I clinical trials. in the management of small cell lung cancer.29 Much of the effort put into development of The major dose limiting toxicity ofcarboplatin drugs for small cell lung cancer has focused on is myelosuppression, and it is therefore a good the assessment of analogues of existing active candidate for dose escalation studies in groups ofdrugs, notably the and combination with haematopoietic growth epipodophyllotoxins. Epirubicin (4-epidoxo- factors, including interleukin-3. Several http://thorax.bmj.com/ rubicin) has been in clinical use for some years promising new platinum analogues are being but interest recently has been focused on dose developed, but their clinical efficacy in small escalation studies in patients with solid cell lung cancer has still to be assessed. tumours. The clinical trials group of the Biological responsemodifiers representanew National Cancer Institute of Canada gave modality in cancer treatment. Preliminary epirubicin 100-120 mg/m2 intravenously every results are becoming available from studies in three weeks to patients with extensive disease. small cell lung cancer. A phase II trial of

An objective response rate of 50% was interleukin-2 in extensive disease is currently in on October 4, 2021 by guest. Protected copyright. achieved, with a median survival of 35 weeks.20 progress.0 Previously untreated patients were Adverseeffects included, predictably, moderate initially given four cycles of doxorubicin, myelosuppression, alopecia, nausea, and cyclophosphamide, etoposide, and platinum. vomiting but not cardiotoxicity. A similar Four weeks later all patients not achieving a response rate was reported by Eckhardt in 80 complete response received a continuous previously untreated patients receiving 120 infusion of interleukin-2 (4-5 x 106 mU/M2 a mg/m2 every three weeks. In this series one day) for four days repeated weekly for four patient developed congestive cardiac failure, weeks. Of the 67 patients, only 10 were treated which was fatal.2' with interleukin-2; three had an objective res- Despite the synthesis of many new deriva- ponse, including two with complete remis- tives of the epipodophyllotoxins, etoposide and sions. Toxicity was severe enough to require teniposide remain the most effective members of discontinuation of treatment in at least 10% of this class of cytotoxic agent. Epipodo- patients. Dose limiting toxicity included phyllotoxins in combination with other drugs, hypotension, haemolysis, renal failure, hepatic notably compounds containing platinum, are dysfunction, and allergy. The long term role, if currently one of the most active combinations any, for interleukin-2 in the treatment of small for treatment of small cell lung cancer. We now cell lung cancer remains to be determined. The know more about their mechanism of action, role of interferon-y as maintenance treatment is which is thought to be interaction with being evaluated in an EORTC trial in patients topoisomerase II and DNA, causing formation achieving a complete response to conventional of stable DNA-enzyme complexes. With the chemotherapy. help of computer assisted molecular modelling it may be possible to design new analogues with greater specificity for binding to topoisomerase Non-small cell lung cancer II and to DNA.22 The epipodophyllotoxins are Non-small cell lung cancer is considerably New drugs in lung cancer 191

more chemoresistant than small cell lung schedule was not optimal, as was the case for cancer and the role of chemotherapy in its ifosfamide.3 Several studies have been reported management remains controversial. Only a few in the last three years, carried out in both cytotoxic drugs have even modest single agent previously treated and "chemotherapy naive" activity in non-small cell lung cancer. The patients. Thorax: first published as 10.1136/thx.47.3.188 on 1 March 1992. Downloaded from most active include ifosfamide, , Camptothecin analogues show considerable , mitomycin C, and cisplatin, all activity in early clinical trials. A Japanese study with average response rates of around 20%.3 has had a response rate of 41 % in previously Combination chemotherapy regimens contain- untreated patients, but this was based on data ing cisplatin achieve response rates of 30-50%, from only 22 evaluable patients out of the 41 but the response is of short duration and real who entered the study.3' Leucopenia, nausea clinical benefit is uncertain. Consequently there and vomiting, and diarrhoea occurred in about is less of a problem in the timing of treatment half the patients. This group of drugs clearly with new drugs for patients with non-small cell warrants further clinical evaluation. lung cancer than with small cell lung cancer. It Navelbine is a semisynthetic vinca alkaloid is our view that results with conventional drugs that acts by inhibition of tubulin polymerisa- are not sufficiently good to justify their use as tion. It has a long terminal half life by orthodox treatment and our practice is comparison with the other vinca alkaloids and a therefore to offer new drugs as first line treat- large volume of distribution, suggesting high ment in patients who are both fit enough to tissue uptake, which is most striking in the receive this and who are anxious to have such lung. A 33 % objective response rate was seen in treatment on an experimental basis. 69 previously untreated patients evaluable for Table 2 shows several new agents that have response, out of the original 78; and similar recently been tested in patients with non-small response rates were seen for squamous cell cell lung cancer. False positive results of phase carcinoma and adenocarcinoma.32 Of particular II studies are often due to bias from low accrual importance, the incidence of neuropathy (7%) rates, high exclusion rates for evaluation of was lower than with vincristine or vindesine. response, and premature publication. On the The dose limiting toxicity was granulo- other hand, drugs may be wrongly rejected on cytopenia, but recovery time was short. These the grounds of low activity because the results are encouraging and warrant further

Table 2 Clinical trials of new drugs (single agents) for non-small cell lung cancer Median Not Total duration of previously Previously No Response survival Drug Dose and schedule treated treated evaluable CR PR (%) (w) Reference http://thorax.bmj.com/ 70 mg/m2 IV q 21 d 47 0 45 0 6 13 19 Drings"3 4'-Deoxydoxorubicin 30-40 mg/m2 IV q d 11 0 35 0 4 11 - Rose'M Tauromustine 130 mg/M2 PO q 35 d 25 0 22 0 0 0 21 Gatzemeier65 450-900 mg/d PO q 21 d 69 0 69 0 7 10 33 KokronTM Interleukin-2 + 1 x 106 cetus U/M2/24h 16 0 12 0 4 33 - Yang42 tumour necrosis IV inf q 21 d factor a 25-100 ug/m2/d d 1-5 q 21 d Sulofenur 800 mg/m2 PO 26 0 24 0 0 0 Munshi6' Mon-Fri x 3 w q 28 d Chloroquinoxaline 18-3385 mg/m2 IV q 28 d 33 40 73 0 1 2 - RigasTM sulphonamide on October 4, 2021 by guest. Protected copyright. 800mg/m2 IV q 7 d x 3 36 0 29 0 7 24 - Anderson's 100 mg/m2 IV q 21 d 8 24 29 0 6 21 - Monnier" 10-EDAM 80 mg/m2 IV q 7 d 50 0 47 0 5 11 - Souhami35 Navelbine 30 mg/m2 IV q 7 d 0 78 69 0 23 33 48 Depierre32 Zeniplatin 145 mg/m2 IV q 21 d 24 0 18 1 5 33 - Jones33 CPT-11 100 mg/m2 IV q 7 d 41 0 22 0 9 41 - Fukuoka3 Epirubicin 150-165 mg/m2 IV q 21 d 63 0 63 0 12 19 22 Feld69 Interferon-# 30 x 106U IV 38 0 25 0 0 0 - Chachouas" + interferon 2mg IV tiw x 4 Trimetrexate 8mg/M2 IVdaily x 5q21-28d 52 18 59 0 11 19 26 Maroun37 Ifosfamide 500mg PO twice daily x 51 0 51 0 10 20 - Manegold" 5 d q 28 d 500 mg PO twice daily x 14dq28d Interleukin-2 30 x 106 lU/M2 IV 78 0 73 1 2 4 36 Krigel' + interferon f 6 x 106 U/m2IVq21 d Iproplatin 300 mg/m2 IV q 28 d 17 0 17 0 1 6 - Kramer60 Teniposide 120-180mg/M2 IV d 1, 3, 5, 34 8 42 0 7 17 - Giaccone"2 q21 d (Glycolate-0,0') 100 mg/M2 IV q 28 d 38 30 68 0 10 15 - Fukuda73 diammine- platinum (II) Carboplatin 130 mg/m2 IV q 28 d 51 0 51 0 10 20 19 Gatzemeier74 TCNU 40 mg/m2 PO daily d 1-3 q 28 d 38 0 37 0 5 14 22 Sorensen40 N-methylformamide 2 g/m2 IV d 1, 8, 15 q 42 d 10 44 54 0 0 0 - Ettinger" Spirogermanium 200 mg/M2 IV d 1, 4 q 7 d 9 39 48 0 1 2 Ettinger" 4-Demethoxy- 35-45 mg/M2 q 21 d 22 20 42 0 1 2 Ettinger"

*All patients given induction chemotherapy followed by interleukin-2 for patients with assessable disease. TCNU-(1-(2-chloroethyl)-3-2(dimethylaminosulfonyl)-ethyl-1-). IV-intravenously; q-every; P0-orally; tiw-three times a week; CR-complete response; PR-partial response. 192 Talbot, Smith

evaluation of navelbine in combination with receive interleukin-2 (30 x 106 IU/m2) or other drugs. interleukin-2 plus interferon-fl (6 x 106 U/M2) Zeniplatin is a water soluble, third generation intravenously three times a week. There was no platinum analogue active against murine significant difference between the two groups, Thorax: first published as 10.1136/thx.47.3.188 on 1 March 1992. Downloaded from tumour models and in human tumour xeno- though the overall median survival of 35-6 grafts. In preclinical studies it had a superior weeks was longer than that seen in historical therapeutic dose ratio to that of cisplatin. We controls.4" In a small trial of 12 evaluable have given this drug to 29 previously untreated patients a 33% response rate was achieved with patients with advanced non-small cell lung the combination of interleukin-2 and tumour cancer, six of whom achieved an objective necrosis factor a.42 response. In general, zeniplatin was well tolerated, apart from neutropenia, but one New targets and future directions for the patient developed renal failure thought to be treatment of lung cancer due to the drug.33 New targets for treatment will, it is hoped, At least three new have come from an increased understanding of the activity as single agents in non-small cell lung biology of tumour growth control. Several cancer. 10-EDAM (10-ethyl-5-deaza-amino- approaches are possible. pterin) is a analogue that has a modification at the N-10 position and is a potent ONCOGENES AND ANTI-ONCOGENES inhibitor of dihydrofolate reductase. It has The proliferation rate of human lung cancer better cellular uptake and polyglutamation and cell lines may be increased through overexpres- greater preclinical antitumour activity than sion of the myc family of proto-oncogenes.43 methotrexate. Early- phase II trials had a Any stage in proto-oncogene expression could promising response rate of 32% in 20 ultimately be a target for therapeutic interven- previously treated patients' but, as so often tion. The phorbol esters are agents that induce happens, the response rate has fallen as larger monocyte differentiation but they also decrease trials have been performed.35 Trimetrexate is a c-myc transcription, which results in slower new lipophilic that differs from growth rates in leukaemic cell lines. Possibly a classical in that it is not similar approach could inhibit the growth of polyglutamated but enters cells by a different lung cancer in vitro and perhaps eventually in mechanism and accumulates to give higher the clinic. intracellular concentrations. The maximum A fundamental and probably early event in tolerated dose varies widely among patients, most types of lung cancer is a deletion in depending on several factors, including serum chromosome 3, principally in the 3p 14-23 albumin concentration; schedule, and presence region.' This may represent a loss of a or absence of hepatic metastases.? As a single suppressor gene, resulting in the permissive http://thorax.bmj.com/ agent it has only modest activity in non-small expression of the malignant phenotype. The cell lung cancer.37 Preclinical studies, however, molecular biology ofthe 3p deletion has not yet suggest that it may act synergistically with been fully worked out, but an enzyme encoded 5- and this combination may be by the 3p 14-23 region, aminoacyclase I, is worth evaluating. underexpressed in lung cancer and particularly The pyrimindine gemcitabine in small cell lung cancer.45 Further studies (difluorodeoxycytidine) is an analogue of should determine the function of this enzyme, cytosine arabinoside (Ara-c) and has preclinical which may represent a target for therapeutic activity in several murine and human tumour manipulation. on October 4, 2021 by guest. Protected copyright. cell lines (including those resistant to Ara-c) and in lung xenografts. The side effects are "ANTISENSE" TREATMENT schedule dependent fever and hypotension. It Much "venture" capital is currently being has moderate activity in non-small cell lung invested in the development of antisense cancer, with a 24% partial response rate in 29 oligonucleotides. These are short, synthetic, evaluable patients who had not previously had single strand nucleotides containing sequences any treatment.8 complementary to target messenger RNA or Ofthree new alkylating agents that have been DNA. By virtue ofthehighly specific sequences assessed, two have modest activity. Fotemustine of antisense oligonucleotides they can be used is a chloronitrosourea that alkylates and to block expression of defined oncogenes or carbamoylates DNA. An overall response rate oncogene products. Successful inhibition of of 21% was found in 29 evaluable patients, 24 c-myc expression with inhibition of cell of whom had had previous treatment.39 proliferation has already been achieved in vitro TCNU-(1-(2-chloroethyl)-3-2 (dimethylamino- in this way.' There are many practical difficul- sulfonyl)-ethyl- -nitrosourea)-is a water ties to be overcome with this approach in vivo; soluble nitrosourea, which given orally is these include nuclease degradation of synthetic reported to have a 14% response rate as a single oligonucleotides and difficulties of cellular agent in previously untreated patients.' Phase access. The possibilities of specifically targeted II studies .of some- other agents with rather oligonucleotide drugs against oncogene expres- lower response rates areshown in table 2. sion in lung cancer are, however, exciting. Studies on biologicat response modifiers are disappointing in non-small cell lung cancer. An AUTOCRINE GROWTH CONTROL objective response rate Qf 4% was achieved in Lung cancer, and in particular small cell lung 73 evaluablepatients with metastatic non-small cancer, is associated with the production of a cell lung cancer who had been randomised to series ofautocrine growth factors that stimulate New drugs in lung cancer 193

malignant cell proliferation. These include centration than the placebo group. The median bombesin like peptides, such as the mammalian duration of survival was 292 days in the group homologue of bombesin, gastrin releasing pep- having sulphate compared with 187 tide, insulin like growth factor I and transferrin days in the placebo group but this difference Thorax: first published as 10.1136/thx.47.3.188 on 1 March 1992. Downloaded from (see second article in this series, December was not statistically significant." 1991, p924). Our group, for example, has shown that insulin like growth factor I is an autocrine growth factor in human small cell Conclusion lung cancer and that in vitro tumour cell Prospects for conventional treatment of lung growth can be inhibited by monoclonal anti- cancer remain poor. Developments in biology, bodies against insulin like growth factor I and however, suggest new targets for treatment. its major receptor.47 This raises the possibility Current research must be designed in such a of antibody or oligopeptide analogue drugs way as to allow useful drugs to be identified and directed against the receptor. Gastrin releasing ineffective drugs to be excluded in well designed peptide has also been shown to be an important clinical trials. The trials must allow new drugs growth factor for human small cell lung can- to be tested as quickly as possible, early in the cer.' We are currently investigating a group of natural history of the disease, but at the same 11-amino acid oligopeptide analogues of sub- time they must give the patient the best chance stance P, a sensory neurotransmitter, and look- of a good quality of life and the possibility of ing at the effect of one on the growth of human prolonged survival. small cell lung cancer xenografts. Some ofthese analogues are powerful inhibitors of human 1 Office of Population Census and Surveys. Cancer Statistics: Registrations, England & Wales 1983. London: HMSO, lung cancer growth in vitro and they are 1986. thought to act at least in part through inhibition 2 Souhami R, Law K. Longevity in small cell lung cancer. A report to the Lung Cancer Subcommittee of the United of gastrin releasing peptide. Preliminary Kingdom Coordinating Committee for Cancer Research. studies also show activity in xenografts. One Br J Cancer 1990;61:584-9. agent might be subjected to clinical trial within 3 Splinter TAW. Chemotherapy in advanced non-small cell lung cancer. Eur J Cancer 1990;26:1093-9. the next two years. 4 Joss RA, Cavalli F, Goldhirsch A, et al. New drugs in small cell lung. Cancer Treat Rev 1986;13:157-76. HAEMATOPOIETIC GROWTH FACTORS 5 Clark P, Talbot D, Price C, et al. Single agent etoposide in untreated extensive small cell lung cancer [abstract]. Lung Several haematopoietic growth factors are now Cancer 1988;4:108. being used in the management of lung cancer 6 Issell BF, Einhorn LH, Comis RL, et al. Multicenter phase II trial of etoposide in refractory small cell lung cancer. and other malignancies to increase the rate of Cancer Treat Rev 1985;69:127-8. recovery from drug induced myelosuppression 7 Bork E, Hansen M, Dombernowsky P, et al. Teniposide (VM-26), an overlooked highly active agent in SCLC: (see previous article in this series, p119). They results ofa phase II trial in untreated patients.J Clin Oncol should reduce treatment related toxicity and 1986;4:524-7. may enable larger doses ofcytotoxic drugs to be 8 Creech RH, Tritcher D, Ettinger DS, et al. Phase II study of http://thorax.bmj.com/ PALA, , teniposide and zinostatin in small cell given.' Neutrophil recovery can be accelerated lung cancer (EDT 2579). Cancer Treat Rep 1984;68: in a dose and schedule dependent manner with 1183-4. 9 Smith IE, Harland SJ, Robinson BD, et al. Carboplatin: a granulocyte colony stimulating factor or very active new cisplatin analogue of small cell lung granulocyte macrophage colony stimulating cancer. Cancer Treat Rep 1985;69:43-6. factor.'o Thrombocytopenia, however, is not 10 Cullen MH, Smith SR, Benfield GFA, Woodruffe CM. Testing new drugs in untreated small cell lung cancer may affected by these agents. Newer haematopoietic prejudice the results of standard practice: a phase II study growth factors, including interleukin-3, of oral idarubicin in extensive disease. Cancer Treat Rep factor, 1987;71: 1227-30. on October 4, 2021 by guest. Protected copyright. interleukin-1, and colony stimulating 11 Lund B, Hansen F, Hansen M, et al. Phase II study of 1,2,4- have the potential for stimulating throm- triglycidylurazol (TGU) in previously untreated and bopoiesis as well as granulopoiesis and may treated patients with small lung cancer. Eur J Cancer Clin Oncol 1987;23:1031-3. have a part to play in very high dose chemo- 12 Malik STA, Rayner H, Fletcher J, et al. Phase II trial of therapy. as first-line chemotherapy for extensive small cell lung cancer. Cancer Treat Rep 1987;71:1291-2. 13 Jackson D, Cruz J, White D, et al. Cisplatin in extensive IMPROVING QUALITY OF LIFE small cell lung cancer: a randomised trial by the Piedmont Despite its limited impact on survival, Oncology Association [abstract]. Proc Am Soc Clin Oncol 1989;8:222. cytotoxic chemotherapy has a useful role in 14 Cohen EA, Gralla RJ, Kris MG, et al. Phase II studies in symptom relief.5' Efforts in this direction must small cell lung cancer: an analysis of 97 trials [abstract]. Proc Am Soc Clin Oncol 1985;4:1190. be encouraged. 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Proc Am Soc Clin Oncol 1991;10:241. binding prealbumin and retinol binding 19 ChabotGG, BarileroI, Armand JP, et al. Pharmacokinetics of the camptothecin analogue CPT-l 1 and its active protein. The improvement was seen in patients metaboliteSN38 in cancer patients [abstract]. Proc Am with small cell lung cancer and in patients with Assoc Cancer Res 1991;32:175. 20 Blackstein M, Eisenhauer EA, Wierzbicki R, Yoshida S. other malignancies.52 In a similarly designed Epirubicin in extensive small cell lung cancer: a phase II trial patients with unresectable non-small cell study in previously untreated patients: a National Cancer lung cancer receiving hydrazine sulphate had a Institute of Canada Clinical Trials Group Study.J Clin Oncol 1990;8:385-9. higher energy intake and serum albumin con- 21 EckhardtS, Kolaric K, Vukas D, et al. Phase Ii study of 4'- 194 Talbot, Smith

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