Example of an IPD metaanalysis Postoperative radiotherapy in nonsmallcell lung cancer

Introduction Worldwide, over half a million new cases of lung cancer are diagnosed each year [58] and it is the leading cause of cancer deaths. Surgery is the treatment of choice for non-small-cell lung cancer (NSCLC), and around one fifth of tumours are suitable for potentially curative resection [59]. However, even for patients with apparently completely resected disease, survival rates are disappointing - around 40 per cent at two years. In an effort to improve both local control and survival, the use of adjuvant post-operative radiotherapy (PORT) has been explored.

Despite the conduct of a number of randomized trials, which had recruited a total of over 2000 patients, the role of PORT in the treatment of NSCLC remained unclear. Owing to their small size, individual trials did not have sufficient statistical power to detect moderate survival differences and had shown inconclusive and conflicting results. An international systematic review and meta-analysis was therefore initiated by the British Medical Research Council Cancer Trials Office and conducted on behalf of the PORT Meta-analysis Trialists' Group. It is important to note that the PORT meta-analysis was of individual patient data. This involved the central collection, validation and analysis of the updated original data from individual eligible trials and did not rely on data extracted from published papers.

Methods The main methods underlying the meta-analysis, which were all pre-specified in a formal protocol, are presented in more detail elsewhere [60]. In brief, all eligible randomized trials were included irrespective of publication status. To be eligible for inclusion, trials had to have used adequate methods of randomization, accrued between January 1965 and December 1995 and should not have used orthovoltage radiotherapy. They should have aimed to randomize NSCLC patients who had undergone a potentially curative resection. Analyses were done on an intention-to-treat basis using the log rank test stratified by trial. Expected numbers of events and variance for individual trials were combined according to a fixed effect model. In this way individual patient survival times were used to calculate hazard ratios giving the overall chance of dying on PORT at any time compared to surgery alone. This is a relative difference and so absolute effects at various points were also calculated by applying the HR to the survival rate on the surgery arm (see Section 11.5.7).

Data Data were available from all nine eligible trials and 2128 patients representing 99 per cent of patients from all known eligible randomized trials. Table 11.8 shows the main trial characteristics. Further details of the radiotherapy techniques used can be found elsewhere [60]. Total radiotherapy doses ranged from 30 to 60 Gy, given in between 10 and 30 fractions and there was considerable diversity in other aspects of radiotherapy planning. Patients were mostly male and had stage II or III tumours with squamous cell histology and good performance status. Updated follow up was obtained for most trials such that the overall median was around four years, with a range of 2-10 years in individual trials.

Survival Survival data were available for all trials and included information from 2128 patients and 1368 deaths. Results are shown in Fig. 11.15 where trials are ordered from earliest to most recent and Fig. 11.6 shows the corresponding survival curves for all patients. Although the confidence intervals (CI) for individual trial results are wide, there is a clear pattern of results in favour of surgery alone and there is no clear evidence of statistical heterogeneity (p = 0.11) between trials. The combined results show a significant adverse effect of PORT on survival (p = 0.001). The hazard ratio of 1.21 indicates a 21 per cent greater chance of death on PORT than on surgery alone (95 per cent CI 1.08-1.34). This is equivalent to an absolute detriment of 7 per cent at two years (95 per cent CI 3-10 per cent) reducing overall survival from 55 per cent to 48 per cent.

Table 11.8 Characteristics of trials included in the PORT meta-analysis.

Trial Recruitment Patients Disease stage Radiotherapy dose

Total (Gy) Fractions Weeks

Table 11.8 Characteristics of trials included in the PORT meta-analysis.

Total (Gy) Fractions Weeks

Belgium

1966-

77

202

I,II,III

60

30

6

LCSG 773

1978-

85

230

M.III

50

25

27.5

5-5.5

CAMS

1981 -

95

31 7

II,III

60

30

6

Lille

1985-

91

163

I

45-60

22

5-30

6

EORTC 08861

1986-

90

106

II,III

56

28

5.5

MRC LU11

1986-

93

308

II,III

40

15

3

GETCB 04CB86

1986-

94

189

I,II,III

60

24

30

6

Slovenia

1988-

-92

74

III

30

10

12

2

GETCB 05CB88

1988-

94

539

I,II,III

60

24

30

6

LCSG = Lung Cancer Study Group, CAMS = Chinese Academy of Medical Sciences, EORTC = European Organization for Research and Treatment of Cancer, MRC = Medical Research Council, GETCB = Groupe d'Etude et de Traitement des Cancers Bronchiques Twenty small-cell patients excluded.

(no. events/no. entered)

PORT

No PORT

O-E

Variance

Belgium

88/98

80/104

16.04

40.67

LCSG 773

84/110

81/120

4.77

41.02

CAM

83/153

100/164

1.07

44.88

Lille

59/81

45/82

10.87

25.66

EORTC 08861

26/52

20/54

5.53

11.20 h

MRC LU11

116/154

123/154

-2.48

59.39

GETCB 04CB86

69/99

59/90

4.95

31.59

Slovenia

30/35

33/39

-2.56

15.63

GETCB 05CB88

152/274

120/2 65

25.13

67.08

Total

707/1056

661/1072

63.32

PORT better

PORT better

No PORT better

Fig. 11.15 Hazard ratio plot for survival in the PORT meta-analysis. Reproduced with permission from [42].

Hazard ratio

Fig. 11.15 Hazard ratio plot for survival in the PORT meta-analysis. Reproduced with permission from [42].

Beta Blockers And

PORT 1056 743 493 340 242 160

No PORT 1072 802 541 396 295 224

PORT 1056 743 493 340 242 160

No PORT 1072 802 541 396 295 224

Fig. 11.16 Kaplan-Meier curve for survival in the PORT meta-analysis. Reproduced with permission from [42].

The cause of this detriment was not apparent from these analyses, although the limited cause-of-death information available suggested that the excess mortality on PORT might be the result of causes of death other than cancer. The addition of radiation treatment post-operatively may exert a deleterious effect by virtue of acute or delayed radiation effects, such as radiation pneumonitis or cardiotoxicity, on lungs likely to be already damaged by surgery and perhaps smoking.

Additional outcomes For recurrence-free survival, that is the time from randomization to the first event - local recurrence, distant recurrence or death - a total of 1447 events were observed. Of these, 402 first events were deaths, 252 were local recurrences and 793 were distant recurrences. The overall pattern of results is similar to survival and there is no evidence of gross statistical heterogeneity between trials (p = 0.21). The HR of 1.13 indicates a 13 per cent relative detriment of PORT equivalent to an absolute detriment of 4 per cent at two years, reducing the recurrence-free survival rate from

Hazard ratio

Stage

Nodal status 0

PORT better

No PORT better

Fig. 11.17 Survival by stage and nodal status. Reproduced with permission from [42].

50 to 46 per cent. Analyses of local and distant recurrence-free survival also indicated an adverse effect of PORT with HRs of 1.16 (95 per cent CI 1.05-1.29) and 1.16 (95 per cent CI 1.04-1.29), respectively. As the observed detriment was somewhat less for these outcomes, this perhaps suggests that there may be anti-tumour activity attributable to radiotherapy and that the increased risk of death from PORT may be attributable to other mechanisms. Taken as a whole, the results suggest that although PORT may be beneficial in terms of preventing local recurrence, the effect is likely to be small and outweighed by the deleterious effect on survival.

Subgroups Analyses were also performed to determine whether there was evidence of a differential effect of PORT in pre-defined subgroups of patients. For survival there was no evidence to suggest that PORT was differentially effective in any group of patients defined by age, sex or histology.

However, as shown in Fig. 11.17, there was some evidence that the effects of PORT were more detrimental in patients with stage I than in those with stage II disease. Considering the results for stage III patients alone, there was no clear evidence of a detriment. Similarly, there was a trend that PORT was increasingly detrimental with lower nodal status. However, the confidence intervals are wide indicating that there is no clear evidence of a difference between treatments for stage III or N2 patients.

PORT conclusions This meta-analysis has demonstrated an adverse effect of PORT on survival for NSCLC patients with completely resected tumours. The 21 per cent relative increase in the risk of death associated with PORT represents a considerable hazard. Although exploratory analyses by stage and by nodal status suggested that this effect was most pronounced for earlier stage patients and those with lower nodal status, it is important to note that no patient group showed evidence of a clear benefit from PORT.

Although based on data from trials that used different radiotherapy doses and schedules, there was no indication from the meta-analysis that any of these individual schedules were less detrimental than others. There could still be scope for investigating more modern techniques, such as conformal or hyper-fractionated radiotherapy. However, there would need to be a clear expectation that these newer techniques would not produce similar adverse effects.

As for any such study, this meta-analysis can only provide average estimates of the effect of PORT. Nevertheless, it is probably the best available evidence on which to base future treatment policy. The results indicate that PORT should not be used routinely to treat patients with early stage, completely resected NSCLC.

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