`
`wah
`
`Science and Treatment. Grafica, Geneva:
`449-59
`Flehinger BJ, Melamed MR (1994) Current status
`of screening for lung cancer. Chest Surg Clin
`North an 4: 1-15
`for
`hich
`1
`Ginsber;
`1991)
`Surgery
`for higherstage lun;
`cancer Chie Supe Clin ‘North An 1: 618
`8
`Ginsberg RJ, Hill LD, Eagan RT et al (1983)
`Modern thirty-day operative mortality for sur-
`gical resections in lung cancer. J Thorac
`Cardiovasc Surg 86: 654-858
`Luke WP, Pearson FG, Todd TRJ, Patterson GA,
`Cooper JD (1986) Prospective evaluation of
`mediastinoscopy for assessment of carcinoma of
`the lung. J Thorac Cardiovasc Surg 91: 53-6
`
`Lung Cancer Study Group1986) Effects of
`
`post-
`
`Screening
`Regular chest X-rays and sputumcytol--
`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 oflarge trials in the 1970s and 1980s;
`results from current screening pro-
`grammes are awaited. As with othercan-
`cers the need is for a more sensitive and
`specific tumour marker for effective
`screening (Flehinger and Melamed, 1994).
`
`Lungcancerservices
`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% improvementin
`survival would represent a saving of over
`2000lives 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.
`
`Dartevelle P, Macchiarini P, Chapelier A (1994)
`Resection for T3/4 non-small cell lung cancer.
`
`operative mediastinal radiation on completely
`resected stage II and III epidermoid carcinoma
`of the lung.
`N Engl| Med 315: 1377-81
`McCaughan BC (1994) Primary lung
`cancer
`invading the chest wall. Chest Surg Clin North
`Am 4: 17-28
`Miller JD, Gorenstein LA, Patterson GA (1992)
`Staging: the key
`to rational managementof lung
`cancer. Ann Thorac Surg 53: 170-8
`Naruke T, Goya T, Tsuchiya R, Suemasu K
`(1988) Extended radical operation for N2left
`lung cancer through median sternotomy. Lung
`Cancer 4: A89
`Rosell R, Gomez-Codina J, Camps C et al (1994)
`A randomized trial comparing preoperative
`chemotherapy plus surgery
`with
`surgery alone
`in patients with non-small cell lung cancer. N
`Engl| Med 330: 153-8
`Roth JA, Fossella F, Komaki R et al (1994) A ran-
`domized
`triaf
`comparing perioperative
`chemotherapy and surgery with surgeryalone
`in resectable stage I[LA non-small celflung can-
`cer. J] Nat Cancer Inst 86: 673-80
`Roxburgh JC, Thompson {iS Goldstraw P (1991)
`Hospital mortality and long-term survival after
`ulmonaryresection in the elderly. Ann Thorac ¢
`Sure 51: 800-3
`Shahian D, Neptune W,Ellis F (1987) Pancoast
`tumors: improved survival with preoperative
`and postoperative radiotherapy. Aun Thorac
`Surg 43: 32-8
`Tsang GMK, Watson DCT(1992) Thepractice of
`cardiothoracic surgeonsin the perioperative
`staging of non-small cell lung cancer. Thorax
`23-5
`Wermly JA, DeMeester TR (1995) Pre-operative
`assessment of patients undergoing lung
`resec-
`tion for cancer. In: Roth JA, Ruckdeschel JC,
`Weisenburger TH,eds. Thoracic Oncology. WB
`Saunders, Philadelphia: 104-23
`Whitehouse JMA (1994) Management of Lung
`Cancer.
`Standing Medical Advisory
`Committee, London
`
`In: Motta G, ed. Lung Cancer. Frontiers in
`
`
`Giuseppe Giaccone
`
`ye the last few years a number of new
`, anticancer agents which have definite
`«© activity in lung cancerand other com-
`icmon 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 Giuseppe Giaccone is Associate
`Professor of Oncology, University Hospital der
`Vrije 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 compoundsare ‘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
`
`634
`
`British Journal of Hospital Medicine, 1996, Vol 55, No 10
`
`OSI 2047
`APOTEX V. OSI
`IPR2016-01284
`
`OSI 2047
`APOTEX V. OSI
`IPR2016-01284
`
`

`

`
`
`mucositis, and a response rate in excess of
`40% was achieved (Lee etal, 1992).
`
`cured. Active drugs for SCLC arelisted
`New antimetabolites
`in Table 1.
`Gemcitabine
`Surgery is the mainstay treatment of
`Gemcitabine (2'-deoxy-2',2'-difluo-
`New microtubuline
`NSCLC; however, surgery can only cure
`rodeoxycytidine) is a novel pyrimidine
`inhibiting agents
`antimetabolite which inhibits DNA
`a minority of these patients. Chest irra-
`Vinorelbine
`diation and chemotherapy do notgreatly
`replication and repair. Its activity in
`Vinorelbine is a synthetic vinca alkaloid
`influence the survival rate of locally
`NSCLC has been reported in a recent
`antitumour agent, with minimal neuro-
`advanced or metastatic NSCLCpatients,
`study on 76 evaluable untreated patients
`toxicity, and myelotoxicity as the limit-
`although symptomatic improvement
`to whom gemcitabine was given at
`may be achieved in over 50% of the
`ing toxicity. It has been developed with
`1000-1250 mg/m?/week for 3 weeks out
`changes brought into the catharanthine
`patients treated with both modalities.
`of every 4 weeks; in this study a response
`nucleus of the vinca alkaloid chemical
`Only a small number of drugs, including
`rate of 20% was obtained (Abrattet al,
`cisplatin, ifosfamide, vinblastine, vinde-
`structure, with the aim of reducing neu-
`1994). Only very modest myelotoxicity
`rotoxicity while preserving antimitotic
`sine, mitomycin and etoposide, have
`is seen with the use of gemcitabine, caus-
`activity. This drug has shown definite
`activity in more than 15% of NSCLC
`ing mild emesis and alopecia. Another
`activity in breast cancer and NSCLC.
`patients.
`Current
`combination
`study of 79 assessable patients also
`Extensive investigations have already
`chemotherapies which are mainlycis-
`reported a 20% response rate with lower
`been performed with vinorelbine as a
`platin-based yield up to 50% response
`doses of 800-1000 mg/m? given in an
`single
`agent
`and in combination
`rates in advanced NSCLC, but the com-
`identical schedule (Andersonet al, 1994).
`Several other studies in NSCLC have
`chemotherapy.
`plete response rate is <10% and the gain
`
`in survival is marginal at the cost of sub- InaphaseII study a 33% responserate
`reported similar preliminary results, and
`was obtained in 70 evaluable untreated
`stantial toxicity, as shown bya recent
`are reviewed elsewhere (Sorenson, 1995).
`metaanalysis (Stewartet al, 1995).
`patients with NSCLC,at a weekly dose
`In 29
`assessable patients with
`of 30mg/m?
`given
`intravenously
`The most interesting new drugs with
`untreated extensive SCLC a response
`activity in lung cancer will be discussed
`(Depierre et al, 1991). Neutropenia was
`rate of 27% was obtained with gemc-
`here. Remarkably, more experience has
`severe in less than 20% of cycles and
`itabine (Cormier et al, 1994). The sched-
`neurotoxicity was observed in 36% of
`been rapidly gained in NSCLCthan in
`ule and dose used was the same reported
`SCLC,partly probably due to the more
`patients but wasof mild intensity.
`for NSCLC (Abratt etal, 1994).
`However, in a large multicentre ran-
`problematic ethical issue of testing new
`Because of the relative mild toxicity
`drugs in untreated SCLC than in
`domized trial of 612 patients comparing
`profile it will be interesting to use gemc-
`vinorelbine alone at 30 mg/m? vs cis-
`NSCLC. Because a large number of
`itabine in combination with other drugs,
`platin (120 mg/m?) and vinorelbine vs
`small phase II
`studies have been
`particularly those where myelotoxicityis
`reported, unpublished results or results
`cisplatin and vindesine, vinorelbine alone
`the majorside-effect. Reports of combi-
`not published in peer-review journals
`achieved only a 14% responserate, while
`nations of gemcitabine with cisplatin in
`the combination of vinorelbine with cis-
`will be kept to a minimumin this review.
`advanced NSCLCare extremely promis-
`platin achieved a 30% response rate (Le
`ing with over 50% response rates (Crino
`Chevalier et al, 1994). The control arm,
`et al, 1995).
`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 vs vinorelbine with cisplatin
`80 mg/m? (Depierreet al, 1991). In this
`study there was also a superior response
`rate (43% vs 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
`
` ME:\el(ome peehc) agents Namsvarrclmerci
`; Jung cancer
`
`
`
`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 wasfirst 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/m2/week for 5 weeks, myelosup-
`pression was negligible. However, two
`morerecent studies failed to demonstrate
`an activity of >15% in a total of 75
`advanced NSCLC previously untreated
`by chemotherapy (Lee et al, 1990;
`Souhamiet 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/m? to be maintained on days 1 and
`8 in this combination, without severe
`
`British Journal of Hospital Medicine, 1996, Vol 55, No 10
`
`635
`
`

`

` EES:
`
`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
`(Vokeset al, 1995).
`In a study of pretreated patients with
`SCLC,vinorelbine obtained only a 16%
`response rate (Jassem et al, 1993) in 25
`assessable ‘sensitive’ patients (see defini-
`tion below).
`
`Taxanes
`Paclitaxel and docetaxel have both been
`shownto 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 cancerpatients.
`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;
`Murphyet 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 waslife-threat-
`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 contrastto initial findingsin
`paclitaxel studies.
`Shorter infusion times and lower doses
`have also been investigated in NSCLC,
`based on the finding that shorter infusion
`times produceless 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, 1-hour infusion was given in
`1 day or over 3 days at 135 or 200 mg/m?.
`The overall response rate was 25%, butit
`was only 12% in the lower dose vs 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/m? paclitaxel
`produced only a 10% response rate
`(Milward et al, 1996), which contraindi-
`cates the use of shorter infusion times
`outside appropriateclinicaltrials.
`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/m? in a 24-hour infusion,
`together with carboplatin 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.
`
`Paclitaxel has radiosensitizing proper-
`ties, and has been investigated in combi-
`nation with chest
`radiotherapy in
`patients. with 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 60mg/m?/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 baccata, an easier drug sup-
`ply than the bark of the pacific yew
`Taxus brevifolia, from which taxolis
`extracted. The mechanism of action of
`docetaxelis 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
`andlung cancer (Table 3).
`Theresponserate in untreated NSCLC
`varied between 23% and 38% (Cerny et
`al, 1994; Fossella 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/m? every 3 weeks
`instead of 100 mg/m?) 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/m?. In another
`study, of 42 patients with advanced(stage
`IIIb or IV) NSCLC whowere 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 NSCLCpatients 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
`obtainedin 28 previously treated patients.
`
`British Journal of Hospital Medicine, 1996, Vol 55, No 10
`
`Bremscetorey eects eaeconeyc! MetinRecueome
`
`

`

`
`
`<7
`
`TopoisomeraseI inhibitors
`Three topoisomerase I inhibitors, camp-
`tothecin derivatives, are undergoing major
`clinical evaluation: irinotecan (CPT-11)
`and topotecan (which havealready shown
`evidence ofactivity in lung cancer; Table
`4), and 9-amino-camptothecin.
`
`Irinotecan
`CPT-11, or 7-ethyl-10-[4-(1-piperidino)-
`1-piperidino]carbonyoxy-camptothecin,
`was developed in Japan in the early 1980s,
`whereit first entered clinical trials. The
`drug is now being studied in Europe and
`the USA. Reports of activity of CPT-11
`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/m? weekly
`administration, a partial responserate of
`32% was obtained in 72 untreated
`NSCLCpatients (Fukuoka etal, 1992).
`Based on this, combinations of CPT-11
`with other active drugs have been studied.
`A dose-finding study in which CPT-11
`was administered weekly, in combination
`with cisplatin, to 27 untreated NSCLC
`patients achieved a 54% partial response
`rate (Masudaetal, 1992a). The recom-
`mended doses for phase IJ trials of this
`combination are CPT-11 60 mg/m? on
`days 1, 8 and 15, and cisplatin 80 mg/m?
`
`on day 1, every 4 weeks. In a further
`attempt to increase the doses of the drugs,
`20 previously untreated NSCLCpatients
`were given prophylactic G-CSF as well;
`but diarrhoea became the dose-limiting
`toxicity and preventedsignificant dose
`escalation. Safe doses of 80 mg/m? for
`both drugs were recommendedfor further
`studies in combination with G-CSF,rep-
`resenting a dose increase of 33% over the
`original regimen (Masudaet al, 1994a).
`There were 10 partial responses (50%) in
`this study, a comparable rate to the previ-
`ous study (Masudaetal, 1992a).
`A dose-finding study of combination
`irmotecan with etoposide has been under-
`taken in 25 advanced lung cancerpatients.
`CPT-11 was given at escalating doses on
`days 1, 8 and 15, in combination with
`etoposide given at a fixed dose (80 mg/m?)
`for 3 days (Masuda et al, 1994b). The
`dose-limiting toxicities were leukopenia
`and diarrhoea, the maximumtolerated
`dose being irinotecan 90 mg/m. Therec-
`ommended dosesfor previously untreated
`and pretreated patients were 80 and
`70 mg/m2, respectively, with G-CSF sup-
`port from days 4 to 21 at 2 pe/ke/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 vindesine) 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-11 was given on days 1 and
`8, together with a fixed dose of 3 mg/m?
`vindesine and either high- (100 mg/m?)
`or low- (60 mg/m?) dosecisplatin 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/m? CPT-11 in the two groups of
`patients respectively. The recommended
`doses of CPT-11 were 37.5 and
`80 mg/m?respectively. The response rate
`was in the range of that reported for
`CPT-11 combinations withcisplatin.
`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 beclassified as ‘sensitive’ (see
`below) (Masudaet al, 1992b).
`
`Topotecan
`Topotecanis 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 (Lynchet
`al, 1994), and the second obtained a 15%
`response rate in 40 assessable patients,
`with 30% 1-year survival (Perez-Soler et
`al, 1996). The main toxicity of topotecan is
`myelosuppression, with neutropenia more
`pronounced than thrombocytopenia.
`Topotecan has definite activity in
`untreated SCLCpatients and in patients
`who arestill relatively ‘sensitive’ to
`chemotherapydespite 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-
`canis 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% ina 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/m? dose and thelatter at 2 mg/m2?.
`
`Other drugsof interest
`Etoposide is a topoisomerase IT inhibitor
`for which a clear schedule dependency has
`
`637
`
`ae Peeden clonedenmaneraa
`%
`ane
`a
`
`
`
`
`
`
`
`British Journal of Hospital Medicine, 1996, Vol 55, No 10
`
`

`

`
`
`sis.]Clin Oncol 13: 1860-70
`Chang AY, Kim K, Glik J er al (1993) Phase II
`been demonstrated in SCLC patients
`study of
`taxol, merbarone and piroxantrone in
`Le Chevalier T, Brisgand D, Douillard JY et al
`(Slevin et al, 1989). Repeated administra-
`stage IV non small cell ung cancer: the Eastern
`(1994) Randomized study of vinorelbine and cis-
`Cooperative Oncology Group experience. J Natl
`platin ws vindesine and cisplatin vs vinorelbine
`tions over several days are clearly advanta-
`Cancer Inst 85: 388-94
`alone in advanced non-small-cell lung cancer:
`geous over a single administration.
`(1994) Phase I
`Choy H, Akerley W, Safran H et al
`results of a European multicentertrial including
`612 patients. J Clin Oncol 12: 360-7
`and
`concur-
`trial of outpatient weekly paclitaxel
`Recently, chronic administration of oral
`rent radiation therapy for advanced non-small-
`Lee JS, Libshitz HI, Murphy WKetal (1990) Phase
`cell lung cancer.JClin Oncol 12: 2682-6
`etoposide has produced interesting results
`If study of 10-ethyl-10-deaza-aminopterin (10-
`EDAM. CGP 30694) for stage IIIB or IV non-
`Cormier
`Y, Eisenhauer E, Muldal A et al (1994)
`in both SCLC patients (Einhorn et al,
`Gemcitabineis an active new agent in previously
`small cell lung cancer. Invest New Drugs 8:
`299-304
`1990) and in those with other malignan-
`untreated extensive small cell
`lung cancer
`(SCLC). Ann Oncol 5: 283-5
`Lee JS, Libshitz HI, Fossella FV et a! (1992)
`cies. Chronic oral etoposide administra-
`Cortes JE, Pazdur R (1995) Docetaxel. J Clin Oncol
`Improved
`therapeutic index by leucovorin of
`13; 2643-55
`tion has also shownactivity in NSCLC
`edatrexate, cyclophosphamide,and cisplatin regi-
`men for non-small cell
`lung cancer. J Natl Cancer
`Crino L, Scagliotti G, Marangolo M etal (1995)
`patients, although contradictory results
`Inst 84: 1039-40
`Cisplatin-gemcitabine combination in non-smal
`Lynch TJ, Kalish L, Strauss G et al (1994) Phase II
`have been published (Waits et al, 1992).
`cell lung cancer (NSCLC), a phaseII study. Proc
`Am Soc Clin Oncol14: 352
`.
`study of topotecan in metastatic non-small cell
`Epirubicin, another topoisomerase II
`Depierre A, Lemarie E, Dabouis G et al (1991) A
`lung'cancer. J Clin Oncol 12: 347-52
`phase II study of navelbine (Vinorelbine) in the
`inhibitor and a derivative of doxorubicin,
`Masuda N, Fukuoka M, Takada M et al (1992a)
`treatment of non-small cell lung cancer. Am J
`CPT-i1 in combination with cisplatin for
`Clin Oncol 14: 115-19
`has shownactivity in NSCLC,but only
`advanced non-small cell lung cancer. J Clin Oncol
`10: 1775-80
`Depierre A, Chastang Cl. Quiox E et al (1994)
`whengiven at high doses.
`inorelbine vs vinorelbine plus cisplatin in
`Masuda N, Fukuoka M, Kusunoki Y et al (1992b)
`advanced non-small cell lung cancer: a random-
`CPT-11: a new derivative of camptothecin for the
`ized trial. Ann Oncol 5: 37-42
`Newstrategies for drug
`treatment ofrefractory or relapsed small-cell lung
`cancer. J Clin Oncol 10: 1225-9
`Einhorn LW, Pennington K, McClean J (1990)
`developmentand conclusions
`Masuda N, Fukuoka M, KudohS etal (1994a)
`Phase II trial of daily oral VP-16 in refractory
`small cell lung cancer. A Hoosier Oncology
`Phase I study of irinotecan and cisplatin with
`A better understanding of the biology of
`Group study. Semin Oncol 17: 32-5
`ranulocyte colony-stimulating factor support
`lung cancer will offer new possibilities
`Eisenhauer
`EA,
`ten Bokkel Huinink WW,
`or advanced non-small-cell lung cancer.|Clin
`Oncol 12: 90-4
`Swenerton KD etal (1994) European-Canadian
`for drug developmentin the future. The
`Masuda N,Fukuoka M, KudohS etal (1994b) Phase
`trial of paclitaxel in relapsed ovarian cancer: high-
`challenge for new drug discovery would
`dose vs low-dose and long vs short infusion. J
`I and
`pharmacologic study of irinotecan and
`Clin Oncol 12: 2654-66
`etoposide with recombinant
`human granulocyte
`be to develop novel and selective thera-
`Ettinger DS, Finkelstein DM, Sarma RP, Johnson
`colony-stimulating factor support for advanced
`DE (1995) Phase II study of paclitaxel in patients
`pies based on the molecularalterations
`lung cancer. J Clin Oncol 12: 1833-41
`with extensive-disease small-cell lung cancer: an
`Miller VA, Rigas JR, Francis PA et al (1995) Phase II
`responsible for the malignant phenotype.
`Eastern Cooperative Oncology Group study. J
`trial of a 75 mg/m? dose of docetaxel with pred-
`Clin Oncol 13: 1430-5
`The new drugs described here clearly
`nisone premedication for patients with advanced
`Fossella FV, Lee JS, Murphy WK,et al (1994) Phase
`non-small cell lung cancer. Cancer 75: 968-72
`II study of docetaxel for recurrent or metastatic
`represent progress over older drugs, both
`Millward MJ, BishopJF, Friedlander M et al (1996)
`non-small-cell lung cancer. J Clin Oncol 12:
`in termsof increased efficacy and,at least
`Phase JItrialtrial of a 3-hourinfusion ofpaclitaxel
`1238-44
`in previously untreated patients with advanced
`for some of them, better tolerance(e.g.
`Fossella FV, Lee JS, Shin DM et al (1995) Phase II
`non-small cell
`lung cancer.J Clin Oncol 14: 142-8
`study of docetaxel for advanced or metastatic
`Murphy WK,Fossella FV, Winn RJ et al (1993)
`gemcitabine). The overall response rate
`platinum-refractory non-small-cell lung cancer. J
`Phase II study oftaxol in patients with untreated
`Clin Oncol 13: 645-51
`advanced non-small cell lung cancer. J Natl
`in NSCLC is superior to that of older
`Cancer Inst 85: 384-8
`Francis PA, Rigas
`Kris MG et al (1994) Phase II
`drugs and survival may be prolonged,
`trial of docetaxel
`in patients with stage III and IV
`Perez-Soler R, Fossella FV, Glisson BSetal (1996)
`although the complete response rate
`non-small-cell lung cancer.J Clin Oncol 12: 1232-7
`Phase II study of topotecan in patients with
`Fukuoka M, Nitani H, Susuki A et al (1992) A
`advanced non-small-cell lung cancer previously
`remains <10% in advanced disease, and
`phase II study of CPT-11, a new derivative of
`untreated by chemotherapy. J Clin Oncol14:
`503-13
`results of phase IIItrials are still awaited.
`camptothecin, for previously untreated non-small
`cell
`lung cancer. J Clin Oncol 10: 16-20
`Schiller JH, Kim K, Johnson D (1994) Phase II
`Investigation of new combinations regi-
`Gatzemeier U, Heckmayr M, Neuhauss R etal (1995)
`study of topotecan in extensive stage small cell
`mensis certainly warranted.
`ofa
`Phase II study with paclitaxel for the treatment o
`lung cancer. Proc Am Soc Clin Oncol 13: 330
`advanced inoperable non-small cell lung cancer.
`Shinkai T, Arioka H, Kunikane-Hetal (1994) Phase
`Lung Cancer 12(Suppl2): $101-6
`I clinical trial of irinotecan (cpt-11), 7-Ethyl-
`Abrate RP, Bezwoda WR, Falkson G, Goedhals L,
`Hainsworth JD, Thompson DS, Greco FA (1995)
`10-[4-{1-piperidino)-1-piperidino]carbonyloxy-
`Paclitaxel
`by 1-hour infusion: an active
`drug
`in
`Haking D, Rugg TA (1994) Efficacy and safety
`camptothecin, and cisplatin in combination with
`fixed dose of vindesine in advanced non-small
`profile of gemcitabine in non-small-cell lung can-
`metastatic non-small-cell lung cancer. J Clin
`Oncol13: 1609-14
`cer: a phaseII study. J Clin Oncol 12: 153540
`cell lung cancer. Cancer Res 54: 2636-42
`Jassem J, Karnika-Mlodkowska
`HH,
`van
`Anderson H, LundB, Bach F, Thatcher N, Walling1,
`Shum KY, Kris MG, Gralla RJ et al (1988) Phase II
`Hansen HH (1994) Single-agentactivity
`of weekly
`Pottelsberghe C et al (1993) Phase II study of
`study of 10-ethyl-10-deaza-aminopterin in
`gemcitabine in advanced non-small-cell lung can-
`vinorelbine (navelbine) in previously treated. small
`patients with stage III and IV non-small
`cell lung
`cer: a phaseII study. f Clin Oncol 12: 1821-6
`cancer. J Clin Oncol 6: 446-50
`cell lung cancer. EurJ Cancer 29A: 1720-2
`KudoS, Hino M,Fujita A et al (1994) Late phase II
`Ardizzoni A, Hansen H, DombernowskyP et al
`Slevin ML, Clark PI, Joel SP et al (1989) A random-
`ized trial to evaluate the effect of schedule on the
`(1994) Phase II study of topotecan in pretreated
`clinical study of RP 56976 (docetaxel) in patients
`small cel] lung cancer (SCL). Proc Am Soc Clin
`with non-small cell lung cancer. Jap J Cancer
`activity of etoposide in small cell lung cancer. J
`Oncol 13: 336
`Chemother 21: 2617-23
`Clin
`Oncol7: 1333-40
`:
`CernyT, Kaplan S$, Pavlidis N et al (1994) Docetaxel
`Langer CJ, Leighton JC, Comis RL eral (1995)
`SmythJF, Smith IE, Sessa C et al (1994) Activity of
`(Taxotere) is active in non-small-cell lung cancer:
`Paclitaxel and
`carboplatin in combination in the
`ocetaxel (taxotere) in small cell lung cancer. Eur
`a phase II trial of the EORTC Early Clinical
`J Cancer 30A: 1058-60
`treatmentof advanced non-small cell lung cancer:
`Trials group (ECTG). BrJ Cancer 70: 384-7
`a phase II toxicity, response, and survival analy-
`Sorenson JB (1995) Gemcitabine in non-small cell
`lung cancer. Lung Cancer 12(Suppl1): $1735
`Souhami RL, Rudd RM,Spiro SG etal (1992) Phase
`I study of edatrexate in stage III and IV non-
`small cell
`lung cancer. Cancer Chemother
`Pharmacal 30: 465-8
`Stewart LA, Pignon JP, for the Non-Small Cell
`Lung Cancer Collaborative Group (1995)
`Chemotherapy in non-small cell lung cancer: a
`meta-analysis using updated data on individual
`atients from 52 randomizedclinicaltrials. Br
`edJ 311: 899-909
`Vokes EE, Rosemberg RK, Jahanzeb M etal (1995)
`Multicenter phase II study of weekly oral
`vinorelbine for stage IV non-small-cell lung can-
`cer. J Clin Oncol 13: 637-44
`Waits TM, Johnson DH, Hainsworth JD et al
`(1992) Prolonged administration of oral etopo-
`side in non-small cell lung cancer. A phase II
`trial. J Clin Oncol 10: 292-6
`
`
`
`British Journal of Hospital Medicine, 1996, Vol 55, No 10
`
`