Chemotherapy for Advanced NSCLC

Chemotherapy for Advanced NSCLC* Will Meta-analysis Provide the Answer? Thierry le Chevalier, MD

Meta-analyses of pub lished data show a modest b ut significant survival or response rate benefit for chemotherapy plus supp ortive ca re over b est supportive ca re alone in non-small cell lung cancer (NSCLC), but these findings may b e bi ased in favo r of positive results b ec ause they are lit e rature b ased. A meta-analysis of individual p atient data from 11 publish ed and unpublish ed randomized studies shows a significant benefit for cispl atin-based chemo therapy ove r supportive ca re , a small (not significant) b enefit for vinca alkalo ids and etop oside, and no benefit for alkylating agents. The b enefi t is independent of age, sex, stage, hi stologic type, or p e rformance status. Single large trials wo uld avoid the pitfalls of meta-analyses, but these have so far proved diffi cult to organize . Physicians need to b e co nvince d that even a small increase in median survival in NSCLC as a result of ch emotherapy may represent a co nsiderable in crease in life expectancy for individual patients. (CH EST 1996; 109:107S-109S)

A II

the trials so far und ert aken comparing cherno~herapy with best supportive care in non-small cell lung cancer (NSCLC) are small, and this present s probl ems in detecting any significant differences between therapeutic approaches. One way of circumventing this problem is to assemble all the trials and to und ertake meta-analysis, which allows a sufficient number of patients to be pooled so that the significance of any differences found can be assessed. This article summarizes the findings of the met a-analysis of published studies and also describes a meta-analysis based on individual data from published and unpublish ed trials. Finally, it discusses the shortcomings of metaanalyses. M ETA-ANALYSES OF P UBLISHED T RIALS

To our knowledge , only eight trials comp aring chemotherapy with best sUPf-0rtive care in NSCLC have been pub lished to date. -8 Surprisin gly, thr ee metaanalyses based on various selections of these same eight trials have been published in the last 2 years.9-11 Th e first of these, performed by Souquet et al,9 included seven of the trials,I-, six of which showed a small but significant survival advantage for chemotherapy compared with best supportive care, with p values for the differences in median survival ranging from 0.15 to 0.005. Althou gh the trial of Kaasa et ai' included in this meta-analysis did not show a significant advantage for chemotherapy, the overall odds ratio for survival at 3 months was about 0.6 in favor of chemotherapy, which was significant. "Fro m the Institut Gustave Roussy, Villejuif, France. Reprint requests: Dr. Ie Chevalier, lnstitut Gustave Roussy , m e Camille Desmoulins, 94805 Villeju if Cedex, France

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- - - Chemotherapy ................ Supportive care

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Relative risk

3

12

9

6 Time (months)

0.63

0.66

1.25

0.86

95% CI (0.51-0.80) (0.52-0.87) (0.90-1.73) (0.59-1.26)

FIGURE 1. Patterns of survival for che mothe rapy and best suppo rtive care in NSC LC with the corresponding relative risk values estimated for each 3-month period (meta-analysis of six trials). From Grilli et al.lO

Grilli et ap oanalyzed onlysixofthe trials 1-5,7 in terms of relative risk. In this type of analysis, a relative risk value greater than 1 indicates that chemotherapy is harmful , and a value less than 1 indicates that it is effective. All of the studies, except that of Kaasa et aI,' showed a small relative risk advantage for chemotherapy over best supportive care, and again the metaCHEST / 109 / 5 / MAY, 1996 / Supplement

1078

Chemotherapy better

Again, there was a small but clear overall advant age for chem oth erapy over best supportive care .

Best supportive care better

Cormier' -4."--

•

M ETA-ANALYSIS OF I NDI VIDUAL DATA

Buccheri" Woods4 Oellerino"

Kaasa" Pooled

-.I

o

1

I

I

2

3

F I GUHE 2. Individual and poole d odds ratios and corresponding 95% CIs for chemo therapy and best suppo rt ive care in N SC LC (meta -analysis of seven trials). From Marino et al.' !

analysis revealed a small but significant overall advantage for che mothe rapy compared with best supportive care. Th e overall relative risk for any che mothe rapy vs best supportive care was 0.76 (95% confid ence inte rval [eIl, 0.66 to 0.87), but this increased to 0.79 (95% CI , 0.67 to 0.93) if only those regimens containing cisplatin were considered. Thi s relative risk advantage transl ated into a survival advantage for chemothe rapy, which is significant at 6 months but not at 12 months, as seen in Figure 1. Th e last of th e three meta- analyses performed by Marino et al11 included all eight published trials (Table 1)1-8 and det ermined the ind ividual and pool ed odds ratios and corresponding 95% CIs (Fig 2).11

In an attempt to avoid the bias of a literature-bas ed meta-analysis (see later ), data from all 11 randomized studi es so far conducted , and offering acceptable methods and available follow-up , were pooled, including a total of 1,190 patients.I -8,12 Th e treatment regimen s were different, but fell into th ree groups: long-term alkylating agents, vinca alkaloids and etoposid e, and cisplatin-based regimens. Thi s meta-analysis was thus based on the individual dat a with follow-up of 1,190pati ents enrolled in these trials, and the method is probably the only one that can provide a real result. Th e met a-analysis showed that although there was an overall significant advantage for chemotherapy over best supportive care, this was dep endent on th e che motherapy regime n used. Thus, long-term alkylating agents (cyclophospha mide , given for at least 1 year) actually had a negative effect compared with best supportive care . Vinca alkaloids or etoposide, however, conferred a small but nonsignificant benefit , while the ben efit of cisplatin-based regim ens was mor e clearly significant. Th ere was no confounding overlap of the trials giving long-term alkylating agen ts and those giving cisplatin-bas ed regimens, becau se the Conner was abandoned when the latter were introduced . Th e absolute ben efit of th e different regimens is shown in Table 2; in this context, it must be remem bered that a small increase in median survival, of perhaps 1 to 2 months, may represent up to 6 months' increase in survival for 20 to 30% of patients. As yet, however , th e patients who would benefit most cannot be identified.

Table I-Characteristics of the Eight Published NSCLC Trials Considered for Meta-analysill* Chemotherapy

Best Suppo rtive Care I

C hem otherapy Regimen Meth otrexate, doxornbi cin , cyclophosphamide, Iomustine I C isplatin, vtndcs me Cis platiu, vinblastin e" Methotrexate, doxorubicin , cycloph osphamide, lomustine'' Cisplatin, vindesine" Cyclophospha mide , epiru bicin , cisplatin/m ctho trc xatc , e toposide, lomustine'' Cisplatin, vindesi ne'' Cisplatin, etoposide 7

%

I Median Survival, mo

p Valne

17

24

2.0

·<0,001

50 32

27

3.9 3.1

0.01

17

3fi

49

6.9

0.09 04 8

91 61

40 41

3.9 4.9

0 .33 0.15

2.4 3.8

<0.001

%

Med ian Survival, mo

No. or Patients

20

75

7.0

44 31 38

5R

7.5

31

71

4.7 10.8

52 .'56

7.9

No. of Patient s

97

62

6·m o Survival,

6.2

6·IIIo Survival.

24

70

6.5

22

12

44

32

5.0

43

32

0.50

~ Fro m Marino c t al.!'

1088

NSCLC: Planning for the Future

Table 2-Absolute Suroival Benefit for Patients With NSCLC Receiving Diffe rent Chemotherapy Regimens or Best Supportive Care * % Absolute Survival Benefit

I

,

Chemoth erap y Regimen

Hazard Ratio

95% CI

x-

p Value

Long-tenn alky latiug agents Vinca alkaloid, etoposide Cisplatin based

1.26 0.87 0.73

0.96-1.66 0.64-l.20 0.63-0.8.5

2.79 0.70 15.92

0.09.5 0.403 <0.000 1

*Adapted

At 1 yr (Baseline » 15%)

Median Survival (Baseline e-l mo)

-6 4

-1 0.5 1.5

10

from reference 12.

Prognostic Factors Although several parti cipants expressed the view that women have a better prognosis than men with chemotherapy, and that the outcome of treatm ent is dependent on performance status and stage of disease, this was not borne out by the subgroup analysis. Th e ben efits of chemotherapy in terms of hazard ratios compa red with best supportive care were similar in all th e subgroups analyzed (by age, sex, stage of disease, histologic type, and performance status), thou gh of course by splitting th e patient popul ation into subgroups, the numbers were considerably reduced . P ROB LE~I S

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M ETA-A1'.'ALYSIS

Each of the types of meta-analysis described above suffers from particular problems of interpretation. Th e major shortcoming of literature-b ased meta-analysis is the tendency of researchers to submit, and journals to accept, th ose articles showing a positive result of active treatment ; this not only means that negative results often do not appear in the literature, but also that investigators may publi sh positive interim results even when the longer-term results may ultimately be equivocal or negative. This inevitably produces bias in any met a-analysis based solely on publi shed data. Th e pooling of results from all known trials, published and unpublished, is often seen as a way round this difficulty . Th ere is always a risk that some trials will be missed and th e method of meta-analysis only allows researchers to draw hypotheses for new trials. There is therefore a need to conduct single large trials th at recruit sufficient numbers of patients to identify any treatm ent advantages. Th e necessary size of such trials can be dedu ced from th e hazard ratios for adjuvant chemotherapy in various settings (surgery , surgery plus radiotherapy, radical radiotherapy, best support ive care ). For example, the hazard ratio for adjuvant chemothe rapy compared with no adjuvant chemo therapy after surgery is abou t 0.9 and so at least 3,000 patients must be enrolled for any differen ces to

be conclusive. To undertake such a large trial , lung physicians and surge ons must be convinced to propose patients for chemotherapy, as well as the patients themselves. R EFER ENCES

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Cormier Y, Bergeron Rj, La Fo rge J, et al. Ben efits of polyche motherapy in advanced non- small cell broncho geni c ca rcinoma. Cancer 1982; 50:845-49 Rapp E , Pater JL , Willan A, et al. C hemotherapy can prol on g survival in patient s with advanced non-small cell cancer: rep ort of a Canadian multi cent er rand omized trial. J C lin Oncol 1988; 6:633-41 Ga nz PA, Filgin RH , H askell C M, et al. Suppo rtive care ve rsus supportive ca re and com bination chemo the rapy in met astatic no n-small cell lung cance r. Cancer 1989; 63:1271-78 Wood s RL, Williams CJ, Le vi J, et al. A randomized trial of cisplatin and vi ndesine vs suppo rtive care on ly in advance d non small cell lung cancer. Br J Canc er 1990; 61:608-11 Cellerino R, T umm arello D , C uidi F, et ai. A rando mized trial of alternating che moth erapy versus best suppo rtive care in advanced non-small cell lung cancer. J C lin On col 1991 ; 9:1453-61 Quoix E , D eitemann A, Charbonnea u J, et ai. La chimiotherapie eompo rtan t du cisplatin est-elle utile dans la cance r bron chique non microc ellulaire au stade IV?: resultats d 'un e etude randomi see. Bull Can cer 1991; 78:341-46 Kaasa S, Lu nd E, Th orud E , et al. Sym ptomatic treatm ent vs co mbination che mothe rapy for pati ents with extensive non- small cell lun g cance r. Ca nce r 1991; 67:244:3-47 Buccheri GF , F errigno D , C urcio A, et al. Co ntinuation of chemotherapy vs suppo rtive care alone in patients with inoperable non- small cell lung can cer and stable disease after two or three cycles of MACC . Cance r 1989; 63:428-32 Souq uet PJ, C hauvin F , Boissel [P , et al. Polychemotherapy in advanced non-small cell lung cancer: a meta-analysis. Lancet 199:3; 342:19-21 C rill! R, Oxma n AD, Julian JA. Che mothe rapy for advanced non- small cell lung cance r: how much be nefit is enough? J C lin On co l 1993; 11:1866-72 Marino P, PampaIlona S, Preatoni A, et al. C he motherapy vs suppo rtive care in advanced non- small ce ll lung cancer: results of a met a-analysis of the literatu re. C hest 1994; 106:861-65 No n-small Cell Ca ncer Collaborative Gro up. C hemothe rapy in non -small cell lung cancer: a meta-analysis using up dated data on individual pati ents from 52 rando mised clinical trials. BMJ 199.5; 3 11:899-909

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