`
`”$53M
`
`Screening
`Regular chest X—rays and sputum cytol- v
`ogy have been proposed for screening
`populations at high risk of lung cancer in
`the hope of detecting early stage disease
`curable by surgery. There was conflicting
`evidence for survival benefit from a num—
`ber of large trials in the 19703 and 19805;
`results from current screening pro-
`grammes are awaited. As with other can-
`cers the need is for a more sensitive and
`
`specific tumour marker for effective
`screening (Flehinger and Melamed, 1994).
`
`Lung cancer services
`in the UK
`The UK has one of the highest rates of
`lung cancer in the world. The trend in
`UK males has decreased slightly but in
`females it continues to rise. The 5-year
`survival rate for all patients with lung
`cancer is 7% in the UK compared with
`
`14% in the USA. The majority of these
`survivors have undergone surgery. The
`resection rate for lung cancer, barely 10%
`in the UK, is over 20% in the USA.
`There are dangers in comparing crude
`statistics from different countries, but it
`is difficult to avoid the conclusion that
`
`surgical stage lung cancer is undertreated
`in the UK, where a 7% improvement in
`survival would represent a saving of over
`2000 lives per annum (Whitehouse, 1994).
`The recent Calman report recom—
`mended a major reorganizatiOn of cancer
`services in the UK. With lung cancer,
`emphasis must be on a multidisciplinary
`team approach in which the surgeon’s
`main role is to ensure that all patients
`with operable disease are identified and
`offered surgery.
`mi
`Dartevelle P, Macchiarini P, Chapelier A (1994)
`Resection for T3/4 non—small cell lung cancer.
`In: Motta G, ed. Lung Cancer. Frontiers in
`
`Compiéiefiuréi'Ca eicision offersthebeSt ch
`.u
`can
`
`Science and Treatment. Grafica, Geneva:
`449—59
`Flehinger B], Melamed MR (1994) Current status
`of screening for lung cancer. Chest Surg Clin
`Gins er
`1991 Sur e
`or ii
`er sta e um
`Nogth ARI} 4:1—15
`f
`1
`h
`l
`g
`cancerg. Cbe(st Sugg Clign feiort}; Ag; 1: 61—%
`Ginsberg R], Hill LD, Eagan RT et al (1983)
`Modern thirty—day operative mortality for sur—
`gical resections in lung cancer. ] Theme
`Cardiovasc Surg 86: 654-858
`Luke WP, Pearson FG, Todd TR], Patterson GA,
`Cooper JD (1986) Prospective evaluation of
`mediastinoscopy for assessment of carcinoma of
`the lung. ] Thorac Cardiovasc SW 91: 53—6
`Lung Cancer Study Group((1986) Eifects of ost-
`operative mediastinal ra iation on comp etely
`rcsected sta e II and III epidermoicl carcmoma
`of the lung.
`’ Engl] Med 315: 1377—81
`McCaughan BC (1994) Primary lun cancer
`invading the chest wal . Chest Sing C in North
`Am 4: 17—28
`Miller JD, Gorenstein LA, Patterson GA (1992)
`Staging: the kc
`to rational management of lung
`cancer.Arm T ornc Surg 53: 170—8
`Naruke T, Gova T, Tsuchiya R, Suemasu K
`(1988) Extended radical operation for N2 left
`lung cancer through median sternotomy. Lung
`Cancer 4: A89
`Rosell R, Gomez-Codina J, Camps C et al (1994)
`A randomized trial comparin preoperative
`chemotherapy lus surge Wi
`surgery alone
`in patients witii non-smal cell lung cancer. N
`En If Med 330: 153—8
`RothfiA, Fossclla F, Komaki R et al (1994) A ran-
`domized
`trial
`comparing perioperative
`chemotherapy and surgery with sur ery alone
`in resectable stage IIIA non—small celilung can—
`cer.]Nat Cancer Inst 86: 673—80
`Roxburgh C, Thompson )C, Goldsrraw P (1991)
`Hospit mortalitv and ong—term surviva after
`ulmonary resection in the elderly. Ann Thorac '
`gurg 51: 800—3
`Shahian D, Neptune W, Ellis F (1987) Pancoast
`tumors: improved survival with preoperative
`and postoperative radiotherapy. Ann Tborac
`Surg 43: 32—8
`Tsang GMK, \Vatson DCT (1992) The practice of
`cardiothoracic sur eons in the penoperative
`: —o
`:gtggng of non-smal cell lung cancer. Thorax
`Wermly JA, DeMeester TR (1995) Pre-operative
`assessment of patients un ergoin lun resec-
`tion for cancer. In: Roth JA, Ruc desc iel JC,
`Weisenburwer TH, eds. Thoracic Oncology. \VB
`Saunders, Philadelphia: 104—23
`Whitehouse JMA 1994) Management 0 Lung
`Cancer.
`Stan ing Medical
`A visory
`Committee, London
`
`i ervices based/on multid'scipi'
`
`
`go lung cancer is, ndertre 1'
`g
`,
`
`
`Giuseppe Giaccone
`
`“gig/n the last few years a number of new
`$9: anticancer agents Which have definite
`té activity in lung cancer and other com-
`;fiamon malignant diseases have been
`developed. Interestingly, some of these
`new agents have activity not only in small
`cell lung cancer (SCLC), which is gener—
`
`Professor Giuse pe Giaccone is Associate
`Professor of Onco ogy, Umversrty Hospital der
`Vl‘lje UniverSiteit, Amsterdam, The Netherlands
`
`ally sensitive to chemotherapy, but also in
`non-small cell lung cancer (NSCLC), a far
`less sensitive tumour. Among the new
`active compounds are’the taxanes, pacli—
`taxel and docetaxel, and the topoisomerase
`I inhibitors, irinotecan and topotecan,
`which are drugs with novel mechanisms of
`action. The new antimetabolites, such as
`gemcitabine, and the new vinca alkaloid
`vinorelbine have also been shown to have
`
`substantial activity.
`
`The mainstay treatment for SCLC is
`combination chemotherapy, which
`achieves approximately 80% or higher
`response rate; common regimens for
`the treatment of this disease include
`
`cyclophosphamide and doxorubicin in
`combination with vincristine or etopo~
`side, or cisplatin and etoposide. Despite
`the high response rate, the vast major—
`ity of patients relapse within 2 years,
`and less than 5% can eventually be
`
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`British Journal of Hospital Medicine, 1996, Vol 55, No 10
`
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`
`

`

`
`
`cured. Active drugs for SCLC are listed
`in Table 1.
`
`New antimetabolites
`Gemcitabine
`
`mucositis, and a response rate in excess of
`40% was achieved (Lee et al, 1992).
`
`Surgery is the mainstay treatment of
`NSCLC; however, surgery can only cure
`a minority of these patients. Chest irra—
`diation and chemotherapy do not greatly
`influence the survival rate of locally
`advanced or metastatic NSCLC patients,
`although symptomatic improvement
`may be achieved in over 50% of the
`patients treated with both modalities.
`Only a small number of drugs, including
`cisplatin, ifosfamide, vinblastine, vinde-
`sine, mitomycin and etoposide, have
`activity in more than 15% of NSCLC
`patients.
`Current
`combination
`chemotherapies which are mainly cis-
`platin—based yield up to 50% response
`rates in advanced NSCLC, but the com—
`plete response rate is <10% and the gain
`in survival is marginal at the cost of sub—
`stantial toxicity, as shown by a recent
`metaanalysis (Stewart et a1, 1995).
`The most interesting new drugs with
`activity in lung cancer will be discussed
`here. Remarkably, more experience has
`been rapidly gained in NSCLC than in
`SCLC, partly probably due to the more
`problematic ethical issue of testing new
`drugs in untreated SCLC than in
`NSCLC. Because a largernumber of
`small phase II
`studies have been
`reported, unpublished results or results
`not published in peer-review journals
`will be kept to a minimum in this review.
`
` Table 1. Active agents in small cell
`
`' lung cancer
`
`
`
`Gemcitabine (2'-deoxy-2',2'-difluo-
`rodeoxycytidine) is a novel pyrimidine
`antimetabolite which inhibits DNA
`
`replication and repair. Its activity in
`NSCLC has been reported in a recent
`study on 76 evaluable untreated patients
`to whom gemcitabine was given at
`1000—1250 mg/mZ/week for 3 weeks out
`of every 4 weeks; in this study a response
`rate of 20% was obtained (Abratt et al,
`1994). Only very modest myelotoxicity
`is seen with the use of gemcitabine, caus-
`ing mild emesis and alopecia. Another
`study of 79 assessable patients also
`reported a 20% response rate with lower
`doses of 800—1000 mg/rn2 given in an
`identical schedule (Anderson et al, 1994).
`Several other studies in NSCLC have
`
`reported similar preliminary results, and
`are reviewed elsewhere (Sorenson, 1995).
`In 29
`assessable patients with
`untreated extensive SCLC a response
`rate of 27% was obtained with gemc—
`itabine (Cormier et al, 1994). The sched-
`ule and dose used was the same reported
`for NSCLC (Abratt et al, 1994).
`Because of the relative mild toxicity
`profile it will be interesting to use gemc—
`itabine in combination with other drugs,
`particularly those where myelotoxicity' is
`the major side-effect. Reports of combi—
`nations of gemcitabine with cisplatin in
`advanced NSCLC are extremely promis-
`ing with over 50% response rates (Crino
`et al, 1995).
`
`Edatrexate
`
`Edatrexate-(10-ethyl—10-deaza—amino-
`pterin) is a derivative of methotrexate,
`with superior in—vitro potency compared
`with the parent compound. Its activity in
`NSCLC was first demonstrated in 1988
`
`(Shum et al, 1988), with a 32% response
`rate in 19 assessable NSCLC patients
`previously untreated by chemotherapy.
`Major toxicity was mucositis and in this
`study, where edatrexate was given at
`80 mg/mz/week for 5 weeks, myelosup-
`pression was negligible. However, two
`more recent studies failed to demonstrate
`
`an activity of >15% in a total of 75
`advanced NSCLC previously untreated
`by chemotherapy (Lee et al, 1990;
`Souhami et al, 1992). Edatrexate has been
`recently investigated in combination
`chemotherapy with cisplatin
`and
`cyclophosphamide. The addition of leu-
`covorin rescue allowed a dose of
`
`80 mg/m2 to be maintained on days 1 and
`8 in this combination, without severe
`
`New microtubuline
`inhibiting agents
`Vinorelbine
`
`Vinorelbine is a synthetic vinca alkaloid
`antitumour agent, with minimal neuro-
`toxicity, and myelotoxicity as the limit-
`ing toxicity. It has been developed with
`changes brought into the catharanthine
`nucleus of the vinca alkaloid chemical
`
`structure, with the aim of reducing neu~
`rotoxicity while preserving antimitotic
`activity. This drug has shown definite
`activity in breast cancer and NSCLC.
`Extensive investigations have already
`been performed with Vinorelbine as a
`single
`agent
`and in combination
`chemotherapy.
`In a phase II study a 33% response rate
`was obtained in 70 evaluable untreated
`
`patients with NSCLC, at a weekly dose
`of
`30 mg/m2
`given
`intravenously
`(Depierre et al, 1991). Neutropenia was
`severe in less than 20% of cycles and
`neurotoxicity was observed in 36% of
`patients but was of mild intensity.
`However, in a large multicentre ran—
`domized trial of 612 patients comparing
`Vinorelbine alone at 30 mg/m2 m cis-
`platin (120 mg/mz) and Vinorelbine vs
`cisplatin and vindesine, Vinorelbine alone
`achieved only a 14% response rate, while
`the combination of Vinorelbine with cis-
`
`platin achieved a 30% response rate (Le
`Chevalier et al, 1994). The control arm,
`cisplatin and vindesine, yielded a 19%
`response rate. The median survival time
`of the cisplatin and Vinorelbine arm
`(40 weeks) was significantly better than
`those of the other two arms (31 and
`32 weeks for the Vinorelbine alone and
`
`the control arm respectively). This study
`confirms the necessity of reassessing the
`results obtained in single institution
`studies, and raises concern about the
`level of activity of this drug in NSCLC
`as a single agent. Similar results were
`obtained in another large randomized
`study (231 eligible patients) comparing
`Vinorelbine w Vinorelbine with cisplatin
`80 mg/m2 (Depierre et al, 1991). In this
`study there was also a superior response
`rate (43% v5 16%) and longer progres—
`sion-free interval in the combined arm
`
`than in the single agent arm, although
`survival was similar.
`
`Interestingly, Vinorelbine is also
`absorbed by the oral route, and a large
`phase II study in 162 stage IV NSCLC
`patients achieved a response rate of
`
`British Journal of Hospital Medicine, 1996,V0155, No 10
`
`635
`
`

`

`
`
`Paclitaxel has radiosensitizing proper—
`ties, and has been investigated in combi—
`nation with chest
`radiotherapy in
`patientswith locally advanced NSCLC.
`Oesophagitis was the dose—limiting toxi—
`city in a weekly administration of 3-hour
`infusion of paclitaxel, at the maximum
`tolerated dose of 6Omg/m2/week (Choy
`et al, 1994).
`Activity of paclitaxel has been demon—
`strated in 34% of 32 assessable SCLC
`
`patients who had extensive disease which
`had not been pretreated by chemother-
`apy (Ettinger et al, 1995).
`Docetaxel: Docetaxel is a semisynthetic
`taxane extracted from a quickly renew-
`able source, the needles of the European
`plant Taxus bacmm, an easier drug sup-
`ply than the bark of the pacific yew
`Taxm brevifolia, from which taxol is
`extracted. The mechanism of action of
`
`docetaxel is identical to that of paclitaxel.
`The toxicity profile of docetaxel is simi—
`lar to that of paclitaxel, although the
`development of peripheral oedema and
`effusions have been reported only in
`patients treated with docetaxel for pro—
`longed periods of time. Docetaxel is
`active in ovarian cancer, breast cancer
`and lung cancer (Table 3).
`The response rate in untreated NSCLC
`varied between 23% and 38% (Cerny et
`al, 1994; Fossclla et al, 1994; Francis et al,
`1994). A study tried to reduce infusional
`reactions and rash by giving a lower dose
`of docetaxel (75 mg/m2 every 3 weeks
`instead of 100 mg/mz) in combination
`with premedication with prednisone, to
`20 previously untreated NSCLC patients
`(Miller et al, 1995). The response rate was
`25%, with a
`reduction of allergic
`episodes and skin toxicity, but a similar
`level of neutropenia. The authors sug—
`gested that premedication be used with
`the higher dose of 100 mg/mz. In another
`study, of 42 patients with advanced (stage
`IIIb or IV) NSCLC who were refractory
`to prior cisplatin-based chemotherapy, a
`21% response rate was obtained (Fossella
`et al, 1995).
`Activity of docetaxel in several malig—
`nancies has recently been reviewed
`(Cortes and Pazdur, 1995): in a total of
`262 NSCLC patients reported in 9 stud—
`ies, cumulative response rates of 31.3%
`in chemotherapy—naive patients and of
`19.4% in platinum—pretreated patients
`were observed.
`
`So far only one study of SCLC has
`been published (Smyth et al, 1994), in
`which a partial response rate of 25% was
`obtained in 28 previously treated patients.
`
`14.5%, following administration of
`40 mg of the drug every week. Given the
`palliative intent of chemotherapy in stage
`IV NSCLC, further investigation of this
`route is warranted, although the
`bioavailability is only around 20% and
`nausea and vomiting are more frequent
`than with the intravenous administration
`(Vokes et al, 1995).
`In a study of pretreated patients with
`SCLC, vinorelbine obtained only a 16%
`response rate (Jassein et al, 1993) in 25
`assessable ‘sensitive’ patients (see defini—
`tion below).
`
`Taxanes
`Paclitaxel and docetaxel have both been
`
`shown to have significant activity in lung
`cancer. The taxanes are a new class of
`
`anticancer agents which stimulate the
`polymerization of microtubules and
`inhibit their depolymerization. The latter
`action distinguishes the taxanes from
`vinca alkaloids, which are pure spindle
`poisons; Both taxanes show significant
`activity in ovarian cancer patients and
`breast cancer patients.
`Paclitaxel: Several studies have demon-
`
`strated significant activity of paclitaxel in
`advanced untreated NSCLC (Table 2).
`The first two studies employed paclitaxel
`with 24-hour infusion. In these initial
`
`studies a response rate of 21—24% was
`reported with relatively high doses given
`every 3 weeks (Chang et al, 1993;
`Murphy et al, 1993). Interestingly, in
`both reports, the 1—year survival was
`somewhat longer than expected in this
`patient population (42% and 30%
`respectively). The, major toxicity was
`granulocytopenia, which was life—threav
`ening in 16 patients in the study per—
`formed with the higher dose, and one
`patients died of sepsis. The prophylactic
`use of colony—stimulating factor at this
`dose level is indicated. As both studies
`
`employed premedication with dexam—
`ethasone, diphenhydramine and cimeti—
`
`dine, allergic reactions were only a minor
`problem, in contrast to initial findings in
`paclitaxel studies.
`Shorter infusion times and lower doses
`
`have also been investigated in NSCLC,
`based on the finding that shorter infusion
`times produce less haematological toxicity
`than longer infusions, without substan—
`tially reducing the activity (Eisenhauer et
`al, 1994). On the other hand, dose might
`influence response rate and progression-
`free survival. Interestingly, in a study of
`53 patients with assessable metastatic
`NSCLC, l-hour infusion was given in
`1 day or over 3 days at 135 or 200 ing/m2.
`The overall response rate was 25%, but it
`was only 12% in the lower dose '05 31%
`in the higher dose (Hainsworth et al,
`1995). Toxicity was mild in this study,
`with only 12% of the courses given at the
`higher dose producing grade 3—4 leukope—
`nia. There was no difference in response
`rate between the 1—day or the 3—day frac—
`tionated doses. However, in one study, a
`3—hour infusion of 175 mg/m2 paclitaxel
`produced only a 10% response rate
`(Millward et al, 1996), which contraindi—
`cates the use of shorter infusion times
`
`outside appropriate clinical trials.
`Several combinations of paclitaxel
`with other drugs have been tested; very
`promising results of combinations with
`cisplatin or carboplatin have been
`reported. In a combination of paclitaxel
`135 mg/m2 in a 24—hour infusion,
`together with carboplarin given at 7.5
`AUC (area under the concentration x
`titre curve; using the Calvert formula),
`followed by granulocyte-colony stimu—
`lating factor (G—CSF), a response rate
`of 62% with 9% complete responses
`were obtained in 54 treated patients
`with advanced NSCLC (Langer et al,
`1995). Interestingly, the 1—year survival
`was 54%. Similar results were obtained
`in other reported studies, also employ—
`ing shorter infusion times (3—hour) of
`paclitaxel.
`
`7' T bleZ Results of phaseziistudies etioadl'taixei in Itingicl'aneer: ’1 i
`
`i
`
`British Journal of Hospital Medicine, 1996, Vol 55, No 10
`
`

`

`
`
`(.7
`
`TopoisOmerase I inhibitors
`Three topoisomerase I inhibitors, camp-
`tothecin derivatives, are undergoing major
`clinical evaluation: irinotecan (CPT~11)
`and topotccan (which have already shown
`evidence of activity in lung cancer; Table
`4), and 9—amino—camptothecin.
`
`Irinotecan
`
`CPT—l 1, or 7—ethyl-10-[4—(1-piperidino)-
`1—piperidino]carbonyoxy—camptothecin,
`was developed in Japan in the early 19805,
`where it first entered clinical trials. The
`
`drug is now being studied in Europe and
`the USA. Reports of activity of CPT-ll
`have been published for lung cancer, col—
`orectal cancer,
`leukaemias and lym—
`phomas,
`and
`other malignancies.
`Granulocytopenia and diarrhoea are the
`limiting toxicities reported. In a large
`phase II trial with 100 mg/m2 weekly
`administration, a partial response rate of
`32% was obtained in 72 untreated
`NSCLC patients (Fukuoka et al, 1992).
`Based on this, combinations of CPT—11
`with other active drugs have been studied.
`A dose—finding study in which CPT—ll
`was administered weekly, in combination
`with cisplatin, to 27 untreated NSCLC
`patients achieved a 54% partial response
`rate (Masuda et al, 1992a). The recom—
`mended doses for phase II trials of this
`combination are CPT—l’l 60 mg/m2 on
`days 1, 8 and 15, and cisplatin 80 mg/m2
`
`on day 1, every 4 Weeks. In a further
`attempt to increase the doses of the drugs,
`20 previously untreated NSCLC patients
`were given prophylactic G-CSF as well;
`but diarrhoea became the dose-limiting
`toxicity and prevented significant dose
`escalation. Safe doses of 80 mg/m2 for
`both drugs were recommended for further
`studies in combination with G-CSF, rep—
`resenting a dose increase of 33% over the
`original regimen (Masuda et al, 1994a).
`There were 10 partial responses (50%) in
`this study, a comparable rate to the previ-
`ous study (Masuda et al, 1992a).
`A dose—finding study of combination
`irinotecan with etoposide has been under-
`taken in 25 advanced lung cancer patients.
`CPT—ll was given at escalating doses on
`days 1, 8 and 15, in combination with
`etoposide given at a fixed dose (80 mg/mz)
`for 3 days (Masuda et al, 1994b). The
`dose—limiting toxicities were leukopenia
`and diarrhoea, the maximum tolerated
`dose being irinotecan 90 mg/m2. The rec-
`ommended doses for previously untreated
`and pretreated patients were 80 and
`70 mg/m2, respectively, with G—CSF sup—
`port from days 4 to 21 at Zpg/kg/day.
`Response rates of 58% and 22% were
`observed in 12 SCLC and 9 NSCLC
`
`patients respectively. Most SCLC patients
`were pretreated by chemotherapy.
`A three-drug combination (irinotecan,
`cisplatin and v'indesine) has been investi—
`
`gated in a dose—finding study, under—
`taken in patients with advanced NSCLC
`(Shinkai et al, 1994). In two cohorts of
`patients CPT—l] was given on days 1 and
`8, together with a fixed dose of 3 rug/m2
`vindesine and either high— (100 mg/mz)
`or low— (60 mg/mz) dose cisplatin on day
`1. Colony-stimulating factor support
`was not allowed in this study. Grade 4
`granulocytopenia associated with grade 3
`diarrhoea was dose-limiting at 50 and
`100 mg/m2 CPT—ll in the two groups of
`patients respectively. The recommended
`doses of CPT—11 were 37.5 and
`
`80 mg/m2 respectively. The response rate
`was in the range of that reported for
`CPT—11 combinations with cisplatin.
`A small study in 15 evaluable SCLC
`patients treated with the weekly schedule
`of irinotecan obtained a 47% response
`rate. All patients
`received prior
`chemotherapy, but all patients except
`one could be classified as ‘sensitive’ (see
`below) (Masuda et al, 1992b).
`
`Topotecan
`Topotecan is another water—soluble camp-
`tothecin analogue synthesized in Europe.
`Two studies have been published in
`untreated advanced NSCLC with modest
`
`results: the first obtained no responses in
`20 previously untreated patients (Lynch et
`al, 1994), and the second obtained a 15%
`response rate in 40 assessable patients,
`with 30% 1—year survival (Perez—Soler et
`a1, 1996). The main toxicity of topotecan is
`myelosuppression, with neutropenia more
`pronounced than thrombocytopenia.
`Topotecan has definite activity in
`untreated SCLC patients and in patients
`who are still relatively ‘sensitive’ to
`chemotherapy despite prior treatment (i.e.
`patients who responded to prior chemo—
`therapy and had an off—chemotherapy
`time >3 months, after only one regimen).
`The response rate was 39% and 7% in the
`44 ‘sensitive’ and 43 ‘refractory’ patients
`respectively, indicating clearly that topote—
`can is largely cross—resistant to previously
`administered chemotherapy agents, which
`mostly included topoisomerase
`II
`inhibitors (Ardizzoni et al, 1994; and per-
`sonal communication). The response rate
`in untreated patients was 37% in a prelim—
`inary analysis of another study (Schiller et
`al, 1994). Both studies used 30 minutes
`infusion for 5 days, the former at a daily
`1.5 mg/m2 dose and the latter at 2 mg/mz.
`
`Other drugs of interest
`Etoposide is a topoisomerase II inhibitor
`for which a clear schedule dependency has
`
`
`
`
`
`
`
`
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`British Journal of Hospital Medicine, 1996, Vol 55, No 10
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`

`
`
`been demonstrated in SCLC patients
`(Slevin et a1, 1989). Repeated administra-
`tions over several days are clearly advanta—
`geous _over a single administration.
`Recently, chronic administration of oral
`etoposide has produced interesting results
`in both SCLC patients (Einhorn et al,
`1990) and in those with other malignan-
`cies. Chronic oral etoposide administra—
`tion has also shown activity in NSCLC
`patients, although contradictory results
`have been published (Waits et al, 1992).
`Epirubicin, another topoisomerase II
`inhibitor and a derivative of doxorubicin,
`has shown activity in NSCLC, but only
`when given at high doses.
`
`New strategies for drug
`development and concluSions
`A better understanding of the biology of
`lung cancer will offer new possibilities
`for drug development in the future. The
`challenge for new drug discovery would
`be to develop novel and selective thera—
`pies based on the molecular alterations
`responsible for the malignant phenotype.
`The new drugs described here clearly
`represent progress over older drugs, both
`in terms of increased efficacy and, at least
`for some of them, better tolerance (e.g.
`gemcitabine). The overall response rate
`in NSCLC is superior to that of older
`drugs and survival may be prolonged,
`although the complete response rate
`remains <10% in advanced disease, and
`results of phase III trials are still awaited.
`Investigation of new combinations regi—
`mens is certainly warranted. W
`Abratt RP, Bezwoda WR, Falkson G, Goedhals L,
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