The present study reveals that inclusion of second primary other cancers affects the results of DFS in patients with CRC. Second primary other cancers generate a significant number of events during follow-up of patients with CRC, which causes worse DFS when the second primary other cancers are included as an event in the calculations. Almost half as many second primary other cancers were observed as endpoints as death from the same cancer or non-cancer-related deaths. The most common events to occur were distant metastases closely followed by death from CRC and non-cancer related deaths, while second primary CRC was rarely seen.
The inclusion of second primary other cancer as an event in DFS did also influence the results of multivariate Cox models, in our example causing significant changes in the HR for emergency operation. Interestingly, the inclusion of second primary other cancers had a more detrimental effect on DFS of stage II patients than stage III patients, and this effect became greater with increasing time from diagnosis. The observation of more second primary other cancers in stage II patients than other disease stages has been reported by others [16
]. The reason for this is not known. In the present study second primary other cancers were more common in those with first degree relatives with CRC, however, the proportion was similar in stages II and III, and no association was seen with adjuvant treatment. This indicates that the second other cancers are likely not therapy-induced. The reason for the greater effect of second primary other cancer on DFS survival in stage II is therefore largely explained by fewer events from other endpoints such as distant metastasis and death from CRC.
Second primary other cancers are significantly more common in patients with CRC than in the normal population [17
]. One reason for this can be related to radiation therapy for rectal cancer [19
], although this theory has been debated [20
]. Patients with family history of CRC are also more likely to develop second primary other cancers than patients without heredity [10
When studying the efficacy of adjuvant cancer treatments, the primary aim is to see whether the treatment reduces the risk of recurrence and subsequent death in the cancer of interest. In this situation TTR and CSS are the most specific endpoints because they only depend on events directly related to CRC and the effect of age is small. However, it is important to determine whether the investigated treatment is safe or whether it has serious adverse effects. Analyses that include events such as treatment-related death, non-cancer related death and second primary other cancer may then be necessary, thus OS and DFS, which include these events, serve as the primary endpoints in most randomised adjuvant trials.
Three year DFS has been suggested as a surrogate endpoint for five year OS in the setting of adjuvant treatment CRC trials [5
]. In the study second primary other cancer was not included as an endpoint in DFS [5
]. A recent publication has suggested that three year DFS is superior to five year OS and comparable with six and seven year OS, since extended survival due to more effective cancer treatments after disease recurrence is frequently seen [22
]. Unfortunately it is not possible to determine whether or not second primary other cancers are included as a DFS endpoint in these analyses. This is important as after three years second primary other cancers already generate a significant number of events that can affect the results of the DFS.
It is essential that endpoints in studies of CRC are clearly defined as this will increase the comparability of studies. The events selected should be simple to collect to minimise the risk of missing events, and the definitions should be pre-specified at the time of study design. An example of a recent study lacking definition of the endpoints is the study on the prognostic value of KRAS and BRAF [23
]. RFS and OS were analyzed according to stage in patients included in three adjuvant chemotherapy trials. The study is the largest of its type and published in a high impact journal and should therefore serve as a reliable reference for others, but it is not known if RFS refers to time to recurrence only or time to recurrence and death, nor is it clear if second primary other cancer is included as an event. This makes it difficult to interpret the results and it is impossible to compare the RFS to other studies.
A good example of endpoint definitions is found in a meta-analysis of 18 adjuvant treatment trials in colon cancer [24
]. In this study OS, DFS and TTR were clearly defined: "OS is defined as time to death from any cause. DFS is defined as the time to recurrence or death, whichever occurs first. TTR is defined as the time to disease recurrence, where deaths without recurrence were censored at the time of death. Recurrence was defined only by a reappearance of primary colon cancer; second primary colon cancers or other non-colon cancers were not classified as recurrences."
The present study is a population-based observational study, with some of the endpoints retrospectively collected. This results in an older population with a broader range of stage at diagnosis and less reliable information on disease recurrence, secondary cancers and causes of death than an adjuvant treatment trial. Yet a population-based cohort, as in the present study, has the advantage of limited patient selection, frequently being very large in clinical trials [25
]. However, our study setting represents a real life situation and a population that would be the recruitment base for clinical studies. Furthermore, the proportion of patients with second other cancers is, in CRC, largely independent of age and disease stage. Therefore we could expect an at least similar effect of second primary other cancers on DFS survival calculations in an adjuvant treatment trial compared with the present study.
It is debatable whether second primary other cancer should be regarded as a primary endpoint or as an adverse effect and therefore not included as an event in the main analysis of DFS. To increase clarity Punt [4
] recommends that if second primary other cancers are ignored as an event, the survival endpoint should be named RFS. Choice of survival endpoints is an important topic and, to the best of our knowledge, this is the first study to address the use of second primary other cancers in DFS calculations in CRC.