British Journal of Cancer (2002) 87, 825 – 833
`ª 2002 Cancer Research UK All rights reserved 0007 – 0920/02 $25.00
`www.bjcancer.com
`
`Review
`Platinum drugs in the treatment of non-small-cell lung cancer
`
`J Cosaert1 and E Quoix*,2
`1AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK; 2Service de Pneumologie Lyautey, Hoˆpitaux Universitaires, 1, Place de l’Hoˆpital,
`67091 Strasbourg, France
`
`lung cancer that
`The use of chemotherapy is considered standard therapy in patients with locally advanced non-small-cell
`cannot be treated with radiotherapy and in those with metastatic non-small-cell
`lung cancer and good performance status.
`This approach is also accepted in patients with earlier stage disease, when combined with radiotherapy in those with non-
`resectable locally advanced disease, or in the preoperative setting. Randomised clinical studies and meta-analyses of the
`literature have confirmed the beneficial survival effect of platinum-based chemotherapy. Cisplatin and carboplatin have been
`successfully used with other drugs in a wide variety of well-established two-drug combinations while three-drug combinations
`are still under investigation. Cisplatin and carboplatin use is limited by toxicity and inherent resistance. These considerations
`have prompted research into new platinum agents, such as the trinuclear platinum agent BBR3464, the platinum complex
`ZD0473 and oxaliplatin. These compounds could be developed in combination with agents such as paclitaxel, gemcitabine or
`vinorelbine in patients with advanced and/or refractory solid tumours.
`British Journal of Cancer (2002) 87, 825 – 833. doi:10.1038/sj.bjc.6600540 www.bjcancer.com
`ª 2002 Cancer Research UK
`
`Keywords: cisplatin; carboplatin; ZD0473; BBR3464; oxaliplatin; non-small-cell lung cancer
`
`Lung cancer has the highest mortality rate of any major malig-
`nancy in the developed world, causing an estimated 1 million
`deaths worldwide annually (Abratt, 1995). In the United States
`alone it has been estimated that 157 400 deaths from lung cancer
`will occur in 2001 (American Cancer Society (http://www.cancer.
`org/ (accessed 18 September 2001)). Mortality due to lung cancer
`exceeds that related to breast, prostate, colorectal and ovarian
`cancers combined (American Cancer Society, 2001). Approximately
`85 – 90% of cases of lung cancer are attributable to smoking (Bunn
`et al, 1998).
`lung cancer (NSCLC) represents approximately
`Non-small-cell
`75 – 80% of all lung cancer (Abratt, 1995; Bunn et al, 1998; Natale,
`1998). Fewer than 25% of patients have resectable disease, due to
`locally advanced or metastatic disease, which does not allow surgery
`despite improvements in diagnosis and peri- and postoperative care
`(Bulzebruck et al, 1992). Also, comorbidities, mostly linked to
`tobacco, may prevent patients with potentially resectable disease
`from receiving surgery. Overall 5-year survival is between 5 and
`13%, and varies with the different stages of the disease (Johnson,
`1995; Mountain, 1997; Natale, 1998; Breathnach et al, 2001).
`This review outlines current treatment options for patients with
`NSCLC with emphasis on the use of platinum-containing regi-
`mens. This disease is inherently resistant to chemotherapy and is
`associated with lower response rates than many other malignancies
`(Bunn et al, 1998; Natale, 1998) and the optimal treatment is yet to
`be determined (Breathnach et al, 2001).
`
`MANAGEMENT OF NSCLC
`
`Surgery or radiotherapy is the standard option for patients with
`early stages of NSCLC. Chemotherapy has shown benefit when
`
`*Correspondence: E Quoix; E-mail: elisabeth.quoix@chru-strasbourg.fr
`Received 8 February 2002; revised 4 July 2002; accepted 23 July 2002
`
`used alone in patients with stage IV disease, in combination with
`radiotherapy in patients with locally advanced disease and in the
`preoperative setting in those with early stages of NSCLC.
`
`Surgery and primary radiotherapy
`
`Surgery provides the best chance for cure of localised disease. It is
`therefore the treatment of choice in stages 0, I and II NSCLC
`(Deslauriers and Gregoire, 2000). With very careful patient selec-
`tion, surgery may also be used as part of combined modality
`treatment in stages IIIA and IIIB (T4) disease (Rosell et al, 1994;
`Roth et al, 1994; CancerLinksUSA, http://www.cancer101.net
`(accessed May 26, 2001)) or stage IV disease to remove single
`metastatic lesions. However, even if surgery is the best treatment
`possible, the results are still unsatisfactory with a 5-year survival
`of less than 35%. These results have led clinicians to evaluate
`combined modalities of treatment including chemotherapy.
`Primary radiotherapy (with curative intent) can be considered in
`patients with inoperable stages I or II of the disease and sufficient
`pulmonary reserve. Analysis of one randomised and 26 nonrando-
`mised studies
`in more than 2000 patients
`receiving radical
`radiotherapy for stage I or II disease found that 5-year survival
`rates ranged from 0 to 42% (Rowell and Williams, 2001). Primary
`radiotherapy used to be the ‘gold standard’ treatment in locally
`advanced NSCLC.
`
`Chemotherapy
`
`The poor efficacy and considerable toxicity of chemotherapy
`caused great pessimism for many years regarding this approach,
`as only a small impact on survival was observed.
`During the 1980s, cisplatin and carboplatin were studied exten-
`sively in NCSLC (Bunn, 1989a,b). Randomised trials as well as
`meta-analyses provided scientific evidence that platinum-based
`therapy prolonged survival of patients with advanced NSCLC
`
`OSI EXHIBIT 2001
`APOTEX V. OSI
`IPR2016-01284
`
`

`

`826
`
`Platinum drugs in NSCLC
`J Cosaert and E Quoix
`
`(stage IIIB with pleural effusions and stage IV) and advanced regio-
`nal NSCLC (non resectable stages IIIA and IIIB disease) (Non-
`Small Cell Lung Cancer Collaborative Group, 1995). Experience
`over the past two decades has shown improvements in survival,
`symptom control and quality of life in patients with NSCLC who
`receive
`chemotherapy instead of best
`supportive
`care,
`and
`chemotherapy is now considered standard treatment in individuals
`with advanced NSCLC (Splinter, 1990; Non-Small Cell Lung
`Cancer Collaborative Group, 1995; Bunn and Kelly, 1998; Johnson,
`2000; Bahl and Falk, 2001). More
`recently, platinum-based
`chemotherapy has shown to be of
`interest in the neoadjuvant
`setting, before surgery in patients with resectable stage IIIA (Rosell
`et al, 1994; Roth et al, 1998) and stages I to II disease (Depierre et
`al, 2002). Combined therapy with a platinum and taxane before
`surgery has also shown notable results, with a 1-year survival rate
`of 85% in patients with stages I to IIIa NCSLC reported after treat-
`ment with paclitaxel and carboplatin (Pisters et al, 2000). Another
`large randomised Intergroup trial is ongoing in the United States
`that is evaluating the efficacy of paclitaxel plus carboplatin in
`patients with early stage NSCLC.
`The first generation agents in NSCLC (cisplatin, mitomycin-C,
`iphosphamide/cyclophosphamide, vindesine, vinblastine and etopo-
`side) produced response rates ranging from 15 to 25% when used
`as monotherapy (Bakowski and Crouch, 1983; Grant and Kris,
`1995) but, with the exception of cisplatin, had an unclear effect
`on survival. Second generation agents (gemcitabine, paclitaxel,
`docetaxel, vinorelbine, irinotecan and topotecan) showed response
`rates of 20 – 25% (Bunn et al, 1998). Moreover, randomised studies
`comparing monochemotherapy with paclitaxel, gemcitabine or
`docetaxel versus best supportive care showed a survival benefit in
`the chemotherapy arm, (Anderson et al, 2000; Ranson et al,
`2000; Roszkowski et al, 2000) emphasising the results of
`the
`meta-analysis of the NSCLCCOG (Non-Small Cell Lung Cancer
`Collaborative Group, 1995). Additional reports of large randomised
`trials (one a pooled analysis of two trials), each conducted in more
`than 700 patients, have confirmed the survival benefit of cisplatin-
`based combined two- or three-agent chemotherapy versus best
`supportive care (Cullen et al, 1999; Stephens et al, 2002).
`
`Cisplatin and carboplatin
`
`Platinum agents have currently shown the greatest promise in
`patients with NSCLC. These agents induce their cytotoxic effects
`by targeting cellular DNA and are active against a number of
`tumour types (Go and Adjei, 1999). Cisplatin is thought to act
`by activating apoptosis and altering a number of other cellular
`parameters. It forms adducts with all DNA bases but preferentially
`binds to the N7 positions of guanine and adenine in intact DNA.
`The main DNA lesions produced by both cisplatin and carboplatin,
`accounting for a total of 95% of platinum-DNA adducts, are at the
`G-G, A-G and G-X-G intrastrand crosslinks (Fink and Howell,
`2000).
`The dosages at which these agents are given varies according to
`the agent(s) with which they are being combined and the status of
`the patient. However, cisplatin is usually given at a dosage of 50 –
`72 per cycle, whereas the dose of carboplatin is usually
`120 mg m
`customised for each patient using the area under the concentra-
`tion-time curve (AUC) and renal function of the patient (Calvert
`et al, 1989; Chatelut et al, 1995), because this drug undergoes
`extensive renal excretion. An AUC of 4 – 6 per cycle, which is
`approximately
`equivalent
`to a dose
`in the
`range
`200 –
`72 per cycle, is usual. Both platinum agents are usually
`350 mg m
`given every 3 – 4 weeks, according to the haematological status of
`the patient, for 3 – 6 cycles.
`Analysis of the Southwest Oncology Group (SWOG) database of
`2531 patients with extensive NSCLC (1974 – 1988) showed the use
`of cisplatin to be an independent predictor of improved outcome
`
`(Albain et al, 1991). Thus, most clinical studies of chemotherapy
`in advanced or locoregionally advanced NSCLC in recent years
`have incorporated cisplatin. However, because of the toxicity of
`cisplatin (see below),
`less toxic platinum alternatives have been
`developed. The most extensively evaluated has been carboplatin
`(Bunn, 1989b), with studies demonstrating the efficacy of carbopla-
`tin, alone (Bonomi et al, 1989; Bunn, 1989a,b; Gatzemeier et al,
`1990a; Kreisman et al, 1990) or in combination (Gatzemeier et
`al, 1990b). The available data suggest that carboplatin can substi-
`tute cisplatin in patients with stage IIIB/IV NSCLC (Lokich and
`Anderson, 1998; Go and Adjei, 1999; Zatloukal et al, 2001).
`However, direct comparisons between cisplatin- and carboplatin-
`based chemotherapy have been very rare (Klastersky et al, 1990;
`Gatzemeier et al, 1999). Rodriguez et al (2001) presented the
`results of a randomised study comparing docetaxel plus cisplatin
`or carboplatin versus vinorelbine plus cisplatin at the 2001 meeting
`of the American Society of Clinical Oncology. Although the study
`was not designed to compare carboplatin with cisplatin, results in
`the carboplatin arm were inferior.
`Two drug combinations Two types of trials have been conducted
`to compare monochemotherapy with cisplatin-containing two agent
`chemotherapy:
`comparisons with cisplatin monotherapy and
`comparisons using monotherapy with the non-platinum agent.
`The relative benefits of combination therapy over monotherapy,
`shown in many publications, resulted in combination therapy
`becoming recognised standard practice (Splinter, 1990; Marino et
`al, 1995; Lilenbaum et al, 1998) and a number of phase III studies
`are currently underway or completed that investigate the relative
`efficacies of several new platinum-containing two-agent combina-
`tion regimens (Table 1) (Kelly et al, 2001; Rodriguez et al, 2001;
`Scagliotti et al, 2001; van Meerbeeck et al, 2001; Schiller et al, 2002).
`Of note, Schiller et al (2002) compared cisplatin plus paclitaxel
`(the ECOG standard of care) with the new combination regimens
`of cisplatin plus gemcitabine or docetaxel and paclitaxel plus
`carboplatin (four-arm study). No major differences were observed
`in terms of efficacy (objective response rate and survival) or toxi-
`city. Similar findings were reported in a trial comparing paclitaxel
`plus carboplatin with vinorelbine plus cisplatin (Kelly et al, 2001).
`
`Comparisons between cisplatin containing double therapy and
`monotherapy with the non-platinum agent Results of trials
`comparing monotherapy with vindesine (Elliott
`et al, 1984;
`Einhorn et al, 1986), etoposide (Rosso et al, 1990), teniposide
`(Splinter et al, 1996), and vinorelbine (Depierre et al, 1994; Le
`Chevalier et al, 1994) with the respective agent combined with
`cisplatin showed consistently higher response rates in the combina-
`tion therapy arm, but only about half showed a survival benefit for
`the combination (Table 2). Similarly, preliminary analysis of a
`multicenter phase III trial comparing docetaxel vs docetaxel plus
`cisplatin in patients with inoperable advanced and metastatic
`NSCLC showed no survival advantage but a significant improve-
`ment
`in objective
`response
`rate with combination therapy
`(Georgoulias et al, 2002; Table 2).
`
`Comparisons between cisplatin containing double therapy and
`cisplatin monotherapy Comparisons of cisplatin monotherapy
`and combination therapy with cisplatin plus vindesine (Kawahara
`et al, 1991), etoposide (Klastersky et al, 1989; Crino et al, 1990),
`vinorelbine (Wozniak et al, 1998), paclitaxel (Gatzemeier et al,
`2000), gemcitabine (Sandler et al, 2000) and tirapazamine (von
`Pawel et al, 2000) consistently showed a higher response rate in
`the combination therapy arm, but again only half of the trials showed
`a survival benefit for the combination therapy arm (Table 3).
`
`Comparisons between carboplatin containing double therapy
`and monotherapy with the non-platinum agent A comparison
`between monotherapy with paclitaxel and paclitaxel plus carbopla-
`
`British Journal of Cancer (2002) 87(8), 825 – 833
`
`ª 2002 Cancer Research UK
`
`

`

`Table 1 Recent phase III studies comparing platinum-based two agent combination therapies for patients with stage IIIb or IV NSCLC
`
`Platinum drugs in NSCLC
`J Cosaert and E Quoix
`
`Trial
`
`Schiller et al (2000)
`
`Kelly et al (2001)
`
`Rodriguez et al (2001)
`
`Scagliotti et al (2001)
`
`Van Meerbeeck et al (2001)
`
`Platinum
`
`Additional agent
`
`72 d2
`Cisplatin 75 mg m
`72 d1
`Cisplatin 100 mg m
`72 d1
`Cisplatin 75 mg m
`Carboplatin AUC 6 d1
`72 d2
`Cisplatin 100 mg m
`Carboplatin AUC 6 d1
`72 d1
`Cisplatin 75 mg m
`Carboplatin AUC 6 d1
`72 d1
`Cisplatin 100 mg m
`72 d2
`Cisplatin 75 mg m
`Carboplatin AUC 6 d1
`72 d1
`Cisplatin 100 mg m
`72 d1
`Cisplatin 80 mg m
`72 d1
`Cisplatin 80 mg m
`
`71
`
`72 d1
`Paclitaxel 135 mg m
`72 d1, d8, d15
`Gemcitabine 1000 mg m
`72 d1
`Docetaxel 75 mg m
`72 d1
`Paclitaxel 225 mg m
`
`Vinorelbine 25 mg m72 week
`72 d1
`Paclitaxel 225 mg m
`72 d1
`Docetaxel 75 mg m
`72 d1
`Docetaxel 75 mg m
`
`Vinorelbine 25 mg m72 d1, d7, d14, d21
`72 d1, d8
`Gemcitabine 1250 mg m
`72 d1
`Paclitaxel 225 mg m
`
`Vinorelbine 25 mg m72 d1, d7, d14, d2162 then d1, d14
`72 d1
`Paclitaxel 175 mg m
`72 d1, d8
`Gemcitabine 1250 mg m
`72 d1+gemcitabine 1250 mg m
`Paclitaxel 175 mg m
`
`72 d1, d8
`
`827
`
`Frequency
`
`Every 21 days
`Every 28 days
`Every 21 days
`Every 21 days
`Every 28 days
`Every 21 days
`Every 21 days
`Every 21 days
`Every 28 days
`Every 21 days
`Every 21 days
`Every 28 days
`Every 21 days
`Every 21 days
`Every 21 days
`
`Table 2 Comparisons between cisplatin containing double therapy and monotherapy with the second agent in patients with advanced NSCLC
`
`Study
`
`Patients enrolled
`
`Drugs
`
`Overall response rate (%)
`
`Median survival
`
`Georgoulias et al (2002)
`
`279
`
`Splinter et al (1996)
`
`225
`
`Depierre et al (1994)
`
`231
`
`Le Chevalier et al (1994)
`
`612
`
`Rosso et al (1990)
`
`Einhorn et al (1986)
`
`216
`
`124
`
`Elliott et al (1984)
`
`105
`
`72 d1, d3, d5 or 360 mg m72 d1
`
`72 d163 weeks
`Docetaxel 100 mg m
`72 d2+docetaxel
`Cisplatin 80 mg m
`72 d163 weeks
`100 mg m
`72 d1, d3, d5
`Teniposide 120 mg m
`72 d1
`or 360 mg m
`72 d1+teniposide
`Cisplatin 80 mg m
`
`120 mg m
`71
`72 week
`Vinorelbine 30 mg m
`7263 weeks+
`Cisplatin 80 mg m
`71
`72 week
`vinorelbine 30 mg m
`72 week
`71
`Vinorelbine 30 mg m
`72 d1 and 29, then
`Cisplatin 120 mg m
`72 week
`every 6 weeks+vinorelbine 30 mg m
`72 d1 and d29, then
`Cisplatin 120 mg m
`every 6 weeks+vindesine
`72 week
`7166 weeks then every other week
`3 mg m
`72 d1 – 3
`Etoposide 120 mg m
`72 d1 – 2+etopside
`Cisplatinm 60 mg m
`72 d1 – 3
`20 mg m
`Vindesine
`72+vindesine
`Cisplatin 120 mg m
`72+vindesine+
`Cisplatin 60 mg m
`mitomycin C
`Vindesine
`Cisplatin+vindesine
`
`71
`
`18
`35a
`
`6
`
`22a
`
`16
`43a
`
`14
`30
`
`19
`
`7
`25.8a
`
`14
`27
`20
`
`7
`33
`
`10 months
`13 months
`
`5.9 months
`
`7.2 months
`
`32 weeks
`33 weeks
`
`31 weeks
`40 weeks
`
`32 weeks
`
`6 months
`8 months
`
`18 weeks
`26 weeks
`17 weeks
`
`4 months
`11 monthsa
`
`aStatistically significant difference relative to monotherapy.
`
`tin in 584 patients with advanced NSCLC showed a significant
`advantage in terms of objective response rate (16 vs 30%,
`P50.0001)
`and survival distribution (6.5
`vs
`8.5 months,
`P=0.023) in favour of combination therapy but no significant
`difference between treatments in 1-year survival rate (31 vs 36%)
`(Lilenbaum et al, 2002). Similarly, a comparison of gemcitabine
`with gemcitabine plus carboplatin in 275 patients with advanced
`NSCLC showed higher objective response rates (12 vs 30%) and
`a significantly longer
`time to progression (4 vs 6 months,
`P=0.001) with combination therapy; the median survival was 9
`months for the whole study population (Sederholm, 2002).
`
`Conclusions The survival results reported to date suggest that
`the importance of inclusion of a platinum agent in the combina-
`tion therapy setting is still at least open for discussion, although
`it appears to be accepted that two-agent combination therapy is
`better than monotherapy.
`
`Three drug combinations No statistically significant survival
`difference has been observed between regimens containing cisplatin
`in combination with doxorubicin and cyclophosphamide (CAP),
`doxorubicin and 5-fluorouracil
`(AFP), cyclophosphamide and
`bleomycin (CBP), vindesine (VP), etoposide (EP), or vindesine
`and mitomycin-C (MVP). Median survival ranged from 21.6 to
`26.6 weeks. The MVP regimen showed a trend towards a higher
`response rate than the other regimens in certain trials with no
`benefit on survival (Ruckdeschel et al, 1985). MVP showed super-
`iority to EP in another trial (Ginopoulos et al, 1997). A recent trial
`that compared triple therapy with cisplatin plus ifosfamide plus
`mitomycin (MIP) with gemcitabine plus cisplatin showed a higher
`response rate in the ‘modern’ double therapy regimen and no
`difference in survival between the two arms (Crino et al, 1999).
`Other comparisons between double and triple therapy with
`modern drugs did not show any advantage for triple therapy over
`double therapy (Alberola et al, 2001; Souquet et al, 2001).
`
`ª 2002 Cancer Research UK
`
`British Journal of Cancer (2002) 87(8), 825 – 833
`
`

`

`828
`
`Platinum drugs in NSCLC
`J Cosaert and E Quoix
`
`Table 3 Comparisons between cisplatin containing double therapy and cisplatin monotherapy in patients with advanced NSCLC
`
`Study
`
`Patients enrolled
`
`Drugs
`
`Overall response rate (%)
`
`Median survival
`
`Gatzemeier et al (2000)
`
`414
`
`Sandler et al (2000)
`
`522
`
`von Pawel et al (2000)
`
`437
`
`Wozniak et al (1998)
`
`415
`
`Kawahara et al (1991)
`
`160
`
`Crino et al (1990)
`
`156
`
`Klastersky et al (1989)
`
`162
`
`7263 weeks
`Cisplatin 100 mg m
`7263 weeks+
`Cisplatin 80 mg m
`7263 weeks
`paclitaxel 175 mg m
`72 d164 weeks
`Cisplatin 100 mg m
`72 d164 weeks+
`Cisplatin 100 mg m
`72 d1, d8 and d1564 weeks
`gemcitabine 1000 mg m
`7263 weeks
`Cisplatin 75 mg m
`726+tirapazamine
`Cisplatin 75 mg m
`7263 weeks
`390 mg m
`7264 weeks
`Cisplatin 100 mg m
`7264 weeks
`Cisplatin 100 mg m
`
`71
`vinorelbine 25 mg m72 week
`72 d1
`Cisplatin 80 mg m
`72 d1+vindesine
`Cisplatin 80 mg m
`72 d1, d8, d15
`3 mg m
`7263 weeks
`Cisplatin 120 mg m
`72+etoposide
`Cisplatin 120 mg m
`72 d1 – 363 weeks
`100 mg m
`72+etopside
`Cisplatin 120 mg m
`72 d1 – 363 weeks+
`100 mg m
`72 d1, d21, d42, then 6-weekly
`mitomycin-C 10 mg m
`72 d1
`Cisplatin 120 mg m
`72 d1+etoposide
`Cisplatin 120 mg m
`72 d1 – 3
`100 mg m
`
`17
`26a
`
`11
`30a
`
`14
`28a
`
`12
`26a
`
`12
`29a
`
`4
`30
`
`26
`
`19
`26
`
`8.6 months
`8.1 months
`
`7.6 months
`9.1 monthsa
`
`27.7 weeks
`34.6 weeksa
`
`6 months
`8 monthsa
`
`39 months
`45 weeks
`
`18 weeks
`35 weeksa
`
`37 weeksa
`
`26 weeks
`22 weeks
`
`aStatistically significant difference relative to monotherapy.
`
`Regimens containing oxaliplatin
`
`Three small studies are underway to assess combinations of oxali-
`platin and gemcitabine (Franciosi et al, 2001), paclitaxel (Hoffman
`et al, 2001) or vinorelbine (Monnet et al, 2002) in patients with
`advanced NSCLC. Early results in 24 previously untreated (Hoff-
`man et al, 2001), 28 previously untreated (Monnet et al, 2002)
`and 10 previously treated (Franciosi et al, 2001) patients show
`response rates of 25, 35 and 30%, respectively. Oxaliplatin mono-
`therapy has also demonstrated activity in a small study of 33
`patients with poor-prognosis NSCLC (Monnet et al, 1998).
`
`Other chemotherapy options
`
`In addition, combinations of paclitaxel or docetaxel with nonplati-
`num agents such as gemcitabine have shown promising results
`(Douillard et al, 2001b; Georgoulias et al, 2001). Indeed, such
`combinations may be an option for patients unable to tolerate
`platinum agents or those with compromised performance status.
`In addition, patients with a performance status of 2 do not benefit
`from platinum-based chemotherapy (Soria et al, 2001). In general,
`studies comparing non-platinum regimens with platinum-based
`regimens are still ongoing. In one that is published (Georgoulias
`et al, 2001), no significant difference was seen between gemcitabine
`plus docetaxel and cisplatin plus docetaxel. The results of such
`trials need to be confirmed.
`Several of the newer agents have been studied as second line
`chemotherapy in patients with NSCLC and have shown some effi-
`cacy (Socinski and Langer, 1999; Huisman et al, 2000; Miller and
`Kris, 2000), especially docetaxel
`for which there has been two
`randomised studies (Fossella, 1999a,b; Shepherd et al, 2000).
`
`Combined modality and adjuvant therapy
`
`The use of platinum-based chemotherapy in conjunction with
`radiotherapy
`in patients with locally
`advanced unresectable
`NSCLC has become standard since the studies of Le Chevalier
`et al (1991) and Dillman et al (1990). The NSCLCCG meta-analy-
`
`sis confirmed the survival benefit provided by giving cisplatin-
`based chemotherapy before radiotherapy over radiotherapy alone
`(Non-Small Cell Lung Cancer Collaborative Group, 1995).
`Although it is standard to use induction chemotherapy followed
`by radiotherapy, there are some arguments favouring concurrent
`chemoradiation using chemotherapy at systemic dosages (Eber-
`hardt et al, 1998;
`Jeremic et al, 1999) or at radiosensitising
`dosages (Trovo et al, 1992; Schaake-Koning et al, 1994; Bardet
`et al, 1997; Clamon et al, 1999). These two different treatment
`modalities have been studied in a number of promising phase II
`trials but there are very limited data from positive randomised
`phase III trials (Schaake-Koning et al, 1994; Furuse et al, 1999).
`Results of these phase III studies support the use of concurrent
`chemotherapy and radiotherapy in preference to radiotherapy
`alone (Schaake-Koning et al, 1994) or sequential chemotherapy
`then radiotherapy (Furuse et al, 1999).
`
`Problems with currently used platinum drugs
`
`Toxicity
`Severe adverse effects limit the use of cisplatin (McKe-
`age, 1995). Nephrotoxicity may be reduced but not suppressed by
`hyper-hydration (Hamilton et al, 1989; Bissett et al, 1990).
`However, this hyper-hydration is not possible in patients with
`congestive heart failure, a condition that is not rare in patients
`with NSCLC. Cisplatin is also one of the most emetogenic drugs
`used, with considerable variability between individuals. Systematic
`use of serotonin antagonists has improved control of acute emesis
`but not delayed emesis (Fauser et al, 1999; Gralla et al, 1999).
`Anemia can also occur during treatment with cisplatin. This can
`be due to several mechanisms,
`including depletion of
`intrinsic
`erythropoietin production (caused by peritubular renal cell deple-
`tion), reduced bone marrow stem cell activity and the absence of
`the stem cell reaction of administered erythropoietin (Dufour et
`al, 1990; Canpolat et al, 1994; Wood and Hrushesky, 1995).
`Nephrotoxicity
`and neurotoxicity have been considerably
`reduced by replacing cisplatin with carboplatin, which shows
`nephrotoxicity only when used in high dosages. Carboplatin,
`however, causes dose-limiting myelosuppression (McKeage, 1995;
`
`British Journal of Cancer (2002) 87(8), 825 – 833
`
`ª 2002 Cancer Research UK
`
`

`

`Platinum drugs in NSCLC
`J Cosaert and E Quoix
`
`829
`
`Bunn, 1989b; ; Judson and Kelland, 2000). Transient rises in bilir-
`ubin levels have also been observed (Fields et al, 1995).
`
`Resistance Kelland (2000)
`reviewed
`(2000)
`and Giaccone
`recently in detail the inherent resistance of NSCLC to current plati-
`nums. NCSLC is inherently resistant to treatment with cisplatin
`(Giaccone, 2000), so an understanding of the mechanisms behind
`this could help to improve the prognosis of many patients with
`the cancer. Thus, resistance to cisplatin has been studied exten-
`sively in vitro. A number of resistance mechanisms have been
`identified including: (a) increased repair of platinum-induced
`DNA damage (increased nucleotide excision repair or loss of
`DNA mismatch repair); (b) glutathione or metallothionein drug
`deactivation; (c) reduced cellular uptake of
`the platinum; (d)
`altered apoptosis (Kelland, 2000).
`The clinical relevance of these mechanisms is currently not
`entirely clear; however, tumour cell overexpression of metallothio-
`nein has been shown to correlate with chemo-resistance and
`prognosis in patients with oesophageal and urothelial cancer (Go
`and Adjei, 1999). Similarly, clinical trials have shown that prog-
`nosis is related to lung resistance-related protein abnormalities,
`which may alter transport of cisplatin; increased repair of cispla-
`tin-DNA adducts; and loss of mismatch repair (Fink and Howell,
`2000; Giaccone, 2000). Nucleotide excision repair appears to be
`the most important pathway for cisplatin-DNA damage, and the
`critical gene appears to be excision repair cross-complementing
`(ERCC1) (Giaccone, 2000). A number of studies have shown that
`high levels of the ERCC1 relative messenger RNA are associated
`with response and survival after cisplatin treatment (Giaccone,
`2000; Rosell and Felip, 2001). Another genetic abnormality though
`to be related to cisplatin resistance affects the apoptosis gene p53;
`60% of NSCLC patients have p53 mutations (Giaccone, 2000).
`Resistance to carboplatin is less well studied, but it is assumed that
`similar mechanisms are involved (Go and Adjei, 1999). The phar-
`macogenomics of these agents is therefore being intensively studied
`and may dictate therapy choices in the future.
`
`New platinum agents
`
`The problems associated with the use of current platinum agents,
`and the need to improve response and survival in patients with
`NSCLC (and other cancers), have prompted research into new
`platinum agents that have improved toxicity profiles, may circum-
`vent resistance mechanisms, and have administration schedules
`that are acceptable to physicians and patients.
`New agents include nedaplatin, a cisplatin-like compound regis-
`tered in Japan and active in NSCLC (Judson et al, 1997), and
`satraplatin, an orally available drug with dose-limiting toxicity
`
`similar to that of carboplatin currently being explored in prostate
`cancer. Two other novel agents, BBR3464 and ZD0473, have shown
`good results in preclinical and in vitro studies, and have potential
`in the treatment of solid tumours (Judson and Kelland, 2000).
`
`BBR3464 BBR3464 is a trinuclear platinum complex that binds
`to DNA more rapidly than cisplatin and forms long-range inter-
`strand and intrastrand crosslinks. Phase I studies show diarrhoea
`and neutropenia to be dose-limiting toxicities, without significant
`nephro-, neuro- or pulmonary toxicity (Calvert et al, 1999; Sessa
`et al, 2000). Antitumour activity was observed in colorectal and
`pancreatic
`cancer
`patients
`after
`a
`one-hour
`infusion of
`72 every 28 days (Calvert et al, 1999). A second study
`1.1 mg m
`72
`(Sessa et al, 2000) showed similar toxicity (0.03 – 0.17 mg m
`71 for 5 days, repeated every 28 days), in patients with solid
`day
`tumours unresponsive to previous antitumour treatment. Phase
`II trials are currently underway.
`
`ZD0473 ZD0473 is a new-generation platinum agent designed to
`deliver an extended spectrum of antitumour activity and overcome
`platinum resistance mechanisms. A common mechanism of resis-
`tance is
`the replacement of
`the platinum centre by a thiol
`moiety. This substitution is hindered by increasing the steric bulk
`of the molecule, and ZD0473, with its methyl-substituted pyridine
`side chain, was designed with this property in mind (Holford et al,
`1998b).
`Biochemical studies show that ZD0473 at least partially over-
`comes mechanisms of inherent or acquired resistance (Holford et
`al, 1998a), and preclinical work indicates activity against cell lines
`resistant to older platinum agents (Raynaud et al, 1997). In man,
`dose-limiting toxicity is myelosuppression, particularly in patients
`previously treated with carboplatin (Trigo et al, 1999; Hoctin-Boes
`et al, 2001); without evidence of clinically relevant neurotoxicity,
`nephrotoxicity or ototoxicity when given at doses of 120 or
`72 (Hoctin-Boes et al, 2001).
`150 mg m
`Of the newer platinum agents, the new-generation agent ZD0473
`could be of interest in NSCLC, with good tolerability having been
`reported in phase I trials in which the drug has been given in combi-
`nation with paclitaxel, gemcitabine or vinorelbine in patients with
`advanced and/or refractory solid tumours (Table 4). These trials
`are ongoing, as are phase II monotherapy studies of first- and
`second-line treatment in patients with NSCLC in which ZD0473
`72 every 3 weeks.
`is being given at a dosage of 120 – 150 mg m
`
`CONCLUSIONS
`
`Chemotherapy is now broadly accepted in stage IIIB/IV NSCLC,
`and there is growing interest in its use in earlier disease when
`
`Table 4 Phase I studies of ZD0473 in combination with paclitaxel, gemcitabine or vinorelbine in patients with advanced solid tumours
`
`Study
`
`Regimens
`
`Patients
`
`Results reported to date
`
`Douillard et al (2001a)
`
`Gatzemeier et al (2001)
`
`O’Dwyer et al (2001)
`
`72 1 – 2 h
`ZD0473 60 – 120 mg m
`infusion d1+vinorelbine
`72 6 – 10 min
`15 – 30 mg m
`infusion d1 and 8 every 3 weeks
`ZD047360, 90 or
`72 1 h infusion+
`120 mg m
`72 3 h
`paclitaxel 135 mg m
`infusion every 3 weeks
`72 1 h
`ZD0473 60 – 120 mg m
`infusion d1+gemcitabine
`72 d1 and 8 every 3 weeks
`600 – 750 mg m
`
`Patients with advanced solid
`tumours
`
`No DLT reported for doses up to
`72 ZD0473/vinorelbine
`90/15 mg m
`
`7 NSCLC; 2 mesothelioma
`1 SCLC (all refractory
`malignancies)
`
`26 with various advanced
`solid tumours
`
`Grade 3 – 4 leucopenia in four patients. No
`DLT. SD in five out of seven evaluable patients
`(including two NSCLC with 25%
`reduction in tumour size)
`Grade 3 – 4 thrombocytopenia or grade 4
`neutropenia in seven patients. Two MR, both in
`patients with gemcitabine- and cisplatin-pretreated
`NSCLC; 10 SD. No clinically
`relevant nephro- or neurotoxicity
`
`DLT=dose-limiting toxicity; MR=minor response; SD=stable disease; SCLC=small cell lung cancer.
`
`ª 2002 Cancer Research UK
`
`British Journal of Cancer (2002) 87(8), 825 – 833
`
`

`

`830
`
`Platinum drugs in NSCLC
`J Cosaert and E Quoix
`
`combined with other (local) therapy. Platinum drugs are still
`considered of crucial
`interest based on clinical studies and the
`results of meta-analyses, with the inconvenience of the observed
`toxicity and the inherent
`resistance. These observations have
`
`second generation drugs and
`prompted the development of
`newer platinums (oxaliplatin, BBR3464, ZD0473) and any relative
`benefits for these approaches will be investigated in the ongoing
`trials.
`
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