Cancer Letters

Cancer Letters

Volume 262, Issue 1, 8 April 2008, Pages 48-53
Cancer Letters

The relationship between progression-free and post-progression survival in treating four types of metastatic cancer

https://doi.org/10.1016/j.canlet.2007.11.032Get rights and content

Abstract

Context

A number of authors have found that there exists a positive relationship between progression-free survival and overall survival in clinical trials of cancer treatments for particular types of metastatic cancer. However, such an outcome is consistent with an increase in progression-free survival generally leading to an increase, a decrease or no change in survival following disease progression (post-progression survival) and which of these theories is valid has yet to be thoroughly investigated.

Objective

To test theories of this nature in relation to the use of chemotherapy in treating four different types of metastatic cancer by performing a systematic search of published clinical trials. The four types of metastatic cancer are metastatic breast cancer, colorectal cancer, hormone-refractory prostate cancer and non-small-cell lung cancer.

Methods

The data sources were systematic reviews of randomized controlled trials (RCTs) published between January 1990 and June 2007 that appear in Medline or the Cochrane Database of Systematic Reviews and the abstracts of articles referenced in such reviews. For an RCT to be included in the study, chemotherapy had to be administered to both the treatment and control groups and the chemical composition of the chemotherapy had to be different between the two groups. The median time to disease progression and the median overall survival time had to be reported in the data sources.

Results

The trial data found through the systematic search shows much greater support for the theory that, for all four types of metastatic cancer being considered, changes in post-progression survival are uncorrelated with changes in time to disease progression than for the theory that gains in post-progression survival are proportional to gains in time to progression.

Conclusion

The theories about the relationship between progression-free and post-progression survival in cancer treatment that have been examined in this study are worthy of further investigation.

Introduction

Trying to predict overall survival on the basis of either disease-free or progression-free survival in cancer studies is important because, for a new type of cancer treatment, data for disease-free or progression-free survival will often become available far sooner that data for overall survival. For this reason, the relationship between progression-free or disease-free survival and overall survival in clinical trials of cancer treatments has been studied by a number of researchers. Sargent et al. [1] studied the relationship between disease-free and overall survival for the adjuvant treatment of colon cancer. For the general treatment of metastatic colon cancer, the relationship between progression-free and overall survival was studied by Louvet et al. [2], for both metastatic colon and non-small-cell lung cancer this relationship was studied by Johnson et al. [3] and for metastatic breast cancer this relationship was studied by Sherrill et al. [4]. All of these studies found a positive correlation between either disease-free or progression-free survival and overall survival.

This study will analyse the relationship between progression-free and overall survival for cancer treatments in a way that is not explored in the above studies by attempting to answer the following question in relation to four different types of metastatic cancer:

Does an increase in progression-free survival generally lead to an increase, a decrease or no change in the time between disease progression and death, i.e. the post-progression survival time?

By attempting to answer this question, it is hoped that a clearer understanding will be obtained about the extent to which increases in progression-free survival that appear to be caused by new types of cancer treatment will be generally reflected in increases in overall survival.

The four types of metastatic cancer that will be studied are metastatic breast cancer, colorectal cancer, hormone-refractory prostate cancer and non-small-cell lung cancer. The four general cancer types of breast, colorectal, prostate and lung cancer were selected because within the UK, apart from non-melanoma skin cancer, they are by far the most common types of cancer in terms of incidence and on the basis of the most recent data (Cancer Research UK 2005 Data) they are the four most common causes of death from cancer within the UK.

Similar to the study design used by Johnson et al. [3] but unlike the other studies mentioned above, the effect on overall survival of differences in progression-free survival between treatment and control groups will be examined rather than progression-free survival being simply compared with overall survival for each individual treatment arm. In particular, we will analyse results from randomized controlled trials (RCTs) where one type of chemotherapy has been compared to another type of chemotherapy. This restriction on the type of cancer treatment considered, although not imposed by Johnson et al. [3], was put in place as an attempt to reduce potential biases caused by heterogeneity between studies.

Note that Edwards et al. [5] studied the relationship between the time to relapse and the time from relapse to death for individual patients pooled from five trials of adjuvant therapy for early stage breast cancer. However, comparing progression-free survival with post-progression survival for individual trial subjects rather than comparing mean or median differences between treatment arms would not be very useful in attempting to answer the question of interest outlined above. Moreover, the existence of a positive relationship at the patient level between these two types of survival time could simply be due to differences in the resistance to the spread of the cancer for the patients concerned.

Section snippets

Materials and methods

The literature search was conducted for any systematic reviews of randomized controlled trials (RCTs) that study the effectiveness of chemotherapy in treating either metastatic breast cancer, hormone-refractory prostate cancer, colorectal cancer or non-small-cell lung cancer. The search was conducted over Medline and the Cochrane Database of Systematic Reviews using the date range of January 1990 to June 2007. The reviews had to be written in English. The search strings used can be found in

Results

For metastatic breast, colorectal, hormone-refractory prostate and non-small-cell lung cancer, the number of systematic reviews that were found by the literature search was 42, 30, 13 and 31, respectively, and from amongst these reviews, the number of treatment comparisons that were found that satisfied the given inclusion criteria was 34, 42, 25 and 17, respectively, which were contained within, respectively, 33, 38, 23 and 13 RCTs. For the analysis of these RCT results that will now be

Discussion

On the basis of Fig. 1, Fig. 3, Fig. 4, it is important to note that for breast, hormone-refractory prostate and non-small-cell lung cancer, most of the changes in post-progression survival are negative rather than positive. In particular, for hormone-refractory prostate and non-small-cell lung cancer, the outcome of a sign test for the direction of changes in post-progression survival is significant at the 5% and 1% levels of significance, respectively. This suggests that for

Acknowledgement

This work was supported by the Engineering and Physical Sciences Research Council of the UK through the MATCH Programme (Grant GR/S29874/01).

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