Maintenance Chemotherapy in Ovarian Cancer: A Trial-Sequential Analysis

doi:10.4236/jct.2013.47145

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Journal of Cancer Therapy, 2013, 4, 1242-1243

http://dx.doi.org/10.4236/jct.2013.47145 Published Online September 2013 (http://www.scirp.org/journal/jct)

Maintenance Chemotherapy in Ovarian Cancer: A

Trial-Sequential Analysis

Andrea Messori*, Valeria Fadda, Dario Maratea, Sabrina Trippoli

HTA Unit, ESTAV Toscana Centro, Regional Health Service, Firenze, Italy.

Email: *[email protected]

Received July 26th, 2013; revised August 21st, 2013; accepted August 26th, 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

In patients with epithelian ovarian cancer who have achieved remission after initial surgery and induction chemotherapy,

the role of maintenance chemotherapy is controversial. We carried out a trial-sequential analysis that included 4 ran-

domised controlled trials. The end-point was progression at 3 years while the boundary for non-inferiority was set at

±20% in risk ratio. The results of our trial-sequential analysis indicated the futility of maintenance chemotherapy, i.e.

proof of no effectiveness. Consequently, no further trials of this type should be performed to assess the effectiveness of

this intervention in this clinical condition.

Keywords: Chemotherapy; Ovarian Cancer; Trial-Sequential Analysis; Futility

1. Introduction

In patients with epithelian ovarian cancer who have achi-

eved remission after initial surgery and induction che-

motherapy, the role of maintenance chemotherapy is con-

troversial. This pharmacological intervention is aimed at

prolonging the duration of remission and improving

overall survival; however, conflicting results have been

reported on its effectiveness in comparison with observa-

tion alone.

2. Results and Discussion

Mei and coworkers [1] have recently published a meta-

analysis on this issue based on 4 randomised controlled

trials (RCTs) that used different types of conventional

cytotoxic chemotherapy (e.g. platinum agents, doxorubi-

cin, topotecan or paclitaxel). No proof of effectiveness

was found; the pooled probability of progression-free

survival (PFS) for maintenance chemotherapy vs obser-

vation alone was 1.07 (95% confidence interval [CI]:

0.91 to 1.25), which corresponds to a relative risk of pro-

gression of 0.93 (95% CI: 0.80 to 1.10). Hence, this

meta-analysis concluded that maintenance chemotherapy

was not superior to observation alone, i.e. no proof of

effectiveness.

To better interpret the implications of this negative

finding, we applied trial-sequential analysis (TSA) [2-5]

to this data-set of survival information in order to deter-

mine whether the data available on this treatment simply

indicate no proof of effectiveness or conclusive futility

(i.e. proof of no effectiveness).

Our TSA employed the following assumptions: type 1

error, 5% (two-sided); power, 80%; event frequency for

controls, 48% (i.e. the overall event rate found in the 4

control groups). The boundaries for concluding superior-

ity or inferiority or futility were calculated according to

the O’Brien-Fleming alpha-spending function. A specific

statistical software was used (User Manual for TSA, Co-

penhagen Trial Unit 2011, see www.ctu.dk/tsa). As usual,

the main result of TSA was expressed through the graph

of cumulative z-curve. The distinction between inconclu-

siveness and futility is not assumption-free, but depends

on the choice of a specific threshold for incremental cli-

nical effectiveness. In our TSA, this threshold was set at

a relative risk reduction (RRR) of 20%; this value was

derived from the outcomes reported in the “most posi-

tive” trials evaluating remission rates and/or progression

[1].

Figure 1 shows the results of our TSA in which

“events” were cases of progression at 3 years. The raw

data from the 4 trials are presented in the supplementary

web material. According to our pre-determined assump-

tions, the TSA of these data indicated the futility of

maintenance chemotherapy, i.e. proof of no effectiveness.

Interestingly enough, although the optimal information

*Corresponding author.

Maintenance Chemotherapy in Ovarian Cancer: A Trial-Sequential Analysis 1243

Figure 1. Maintenance chemotherapy versus observation in

ovarian cancer: trial sequential analysis of 4 randomized

trials (end-point = progression). The z-curve (in blue) is

composed of consecutive segments that correspond to indi-

vidual trials; trials are plotted in chronological order (from

left to right). The x-axis indicates the cumulative number of

patients. At the cumulative number of 541 included patients,

the curve has crossed the boundaries of futility. The optimal

information size is 836 patients. Abbreviations and sym-

bols: red lines are the boundaries for superiority or inferi-

ority; green lines are the boundaries for futility. T, treat-

ment group; C, control group.

size was estimated at a cumulative number of 836 pa-

tients, the 4 trials involving a total of 514 patients were

already sufficient to prove futility.

The conclusion of our analysis depends on whether or

not the threshold of incremental effectiveness (i.e. RRR

= 20%) is agreed upon or, in other words, if this thresh-

old is assumed to reasonably reflect the criterion of cli-

nical relevance. One should keep in mind that, in disease

conditions in which life expectancy is relatively short, a

RRR of 20% generally translates into an absolute sur-

vival improvement of only a few months; hence, if one

considers that median PFS in these patients is slightly

more than 24 months [6], a relative improvement of 20%

corresponds to an absolute improvement in median PFS

of less than 5 months, which can be considered an ac-

ceptable threshold in terms of clinical relevance.

3. Conclusion

In conclusion, if our assumptions are accepted, the re-

sults of our analysis can be seen as the proof of no effec-

tiveness of maintenance chemotherapy in ovarian cancer

based on conventional cytotoxic agents. Consequently,

no further trials of this type should be performed to as-

sess the effectiveness of this intervention in this clinical

condition.

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