The objective of this study was to find out if the shared risk factor tobacco smoking leads to a significantly increased risk of TRSPC among persons with TRFPC compared to the general population. Furthermore, we tried to gain new insights into the possible etiology of the evaluated cancer types.
Comparisons between our own results and results from other research groups can be difficult because of different employed classifications of diagnosis groups. Hence, a one-to-one comparison is not always possible. All studies discussed in this section were registry-based and gave risk estimates for all subsequent cancers.
The SEER Program (Surveillance, Epidemiology and End Results Program) is the only available study that has analysed the risk of subsequent cancer in more than 50 cancer types in adults, that is based on a long observation period (1973–2000), and on a large population of more than 2 million cancer survivors
]. With regard to tobacco-related malignancies, the results of SEER
] are summarized in Figure
by identifying groups with mutually and significantly increased risk of TRSPC on the one hand, and by comparison with our own results on the other hand.
Figure 1 Comparison between own results and SEER results. Groups of tobacco-related malignancies with mutually and significantly increased risk of subsequent malignancy according to sex. Significant associations found both by SEER and in Bavaria are highlighted (more ...)
In contrast to our study, colon and rectum cancer were separately evaluated, and lip cancer was excluded from the evaluation of first primary cancers in the oral cavity/pharynx, respectively, in the SEER study. However, in subsequent malignancies, the SEER study provided results on cancer of the oral cavity/pharynx including lip cancer (as was done in our study). Consequently, with respect to corresponding results, we can only perform a crude comparison in the aforementioned two cancer sites.
In contrast to our results, based on the SEER results, a group of malignancies can be identified in both genders consisting of the oral cavity/pharynx, oesophagus, lung/bronchus, and larynx. In addition to tobacco smoking, low fruit and vegetable intake is considered to be a shared risk factor for these cancer types (Table
Tobacco smoking accounts for about 60% of all lung/bronchus cancer cases in women and for 90% of all lung/bronchus cancer cases in men
]. The relative risk of lung/bronchus cancer among current smokers is 33 among men and 20 among women compared with lifelong non-smokers
]. In our study, the diagnosis group of lung/bronchus showed a mutually significantly increased risk with almost every other diagnosis group. Therefore, with the exception of pancreatic cancer, stomach cancer, colorectal cancer, and leukemia, tobacco smoking can be confirmed as a shared risk factor in all tobacco-related cancer types considered in this study. The lack of mutually significantly increased relative risks between cancer in the oesophagus, larynx and lung/bronchus among women in our study might be due to insufficient sample size.
In both sexes, the group of urinary bladder, kidney and lung/bronchus was only found based on our own results, because in the SEER study, no mutually and significantly increased risk of SPC between the kidneys and the lung/bronchus was identified. However, tobacco smoking is the only known shared risk factor of these cancer types (Table
). According to SEER, tobacco smoking accounts for about 50-65% of cases of urinary bladder cancer among men and for 20-30% of cases among women, respectively
]. Furthermore, the hazard ratio of developing bladder cancer is 3.9 (95% CI, 3.5-4.4) among current male smokers and 4.7 (95% CI, 3.7-5.8) among current female smokers compared to never smokers
The lack of a mutually significantly elevated risk of SPC between the urinary tract and bladder in men with regard to our own results may possibly be explained by the fact that in former decades, the misuse of phenacetin-containing analgesics (Table
), a known risk factor for urinary cancer, was more common in European women than in men
]. This fact might also explain the larger SIR with respect to these cancer sites in women compared to men (Table
According to both the results of SEER and of the Bavarian Cancer Registry, the colon was a member of a group with increased risk of TRSPC in men but not in women. With regard to the results of SEER, the colon was a member of a dyad with the urinary tract, whereas in our study the colon/rectum formed a dyad with the oral cavity/pharynx. Based on the results shown in Figure
, smoking does not appear to be a major risk factor in colorectal cancer. According to published reports, the multivariate-adjusted rate ratio of colorectal cancer mortality for current compared with never smokers is 1.3 (95% CI, 1.2-1.5) among men and 1.4 (95% CI, 1.3-1.6) among women
]. Cigarette smoking accounts for only about 12% of colorectal cancer deaths
]. Moreover, it is surprising that the dyad colon and oral cavity/pharynx was not found in the SEER study because of the additional shared risk factor low fruit and vegetable intake (Table
) which may hint to differences between both countries with respect to the extent of this issue
]. However, in our study, but not in the SEER study, the rectum was an additional member of this diagnosis group which somewhat limits the interpretation of this comparison.
Among both men and women, an isolated dyad was identified consisting of primary cancers in the stomach and pancreas which was found only in Bavaria. A mutually significantly increased risk of subsequent maligancy between these two cancer types was found in our study. However, neither in our own study nor in the SEER study was any of these two cancer types included in any other significant association. Furthermore, tobacco smoking is not considered to be a strong risk factor for stomach cancer. Therefore, tobacco smoking was not confirmed as a main risk factor in stomach and pancreas cancer. This finding, however, does not rule out a possible weaker etiological association of these two cancer types with tobacco smoking. The second known shared risk factor obesity (Table
) may possibly help to explain this significant association. This dyad, however, was not observed in the SEER study although obesity appears to be a larger problem in the United States than in Europe
]. Furthermore, it should be noted that pancreatic cancer has a very unfavourable prognosis which in turn leads to small absolute numbers of subsequent cancers. Among persons with pancreatic cancer, the relative 5-year survival rate in Germany is only 5-7% among men and 3-8% among women
]. Consequently, the precision of the respective risk estimates was very limited.
Based on Figure
, the diagnosis group of leukemia is the only cancer type which was not included in any group of mutually increased risk of TRSPC. In line with this finding, only a weak etiologic association with tobacco smoking has been reported for this malignancy
In contrast to our results, SEER identified several significantly reduced risks of TRSPC. According to SEER, a significantly decreased risk of SPC in the lung/bronchus and in the urinary bladder after pancreatic cancer was identified in men. The explanation used by SEER is that pancreatic cancer has a very poor prognosis which in turn prevents the development of larger numbers of TRSPC. However, we neither found significantly decreased nor increased risks with regard to the aforementioned tumour sequences in our results, although tobacco smoking is a confirmed risk factor for all three cancer types.
The most surprising SEER result, however, was a significantly reduced risk of SPC in the oral cavity/pharynx and in the lung/bronchus, respectively, after kidney cancer in men. This is surprising because tobacco smoking is assumed to be a shared risk factor of these three cancer types. By contrast, our results showed a slightly increased risk of SPC in the oral cavity/pharynx in men, and a significantly increased risk (men: SIR, 1.51; women: SIR, 2.06) of subsequent lung cancer, respectively, after kidney cancer.
Furthermore, in contrast to our results, significantly decreased risks of SPC in the stomach (SIR, 0.8; 95% CI[SIR], 0.7-1.0) and colorectum (SIR, 0.7; 95% CI[SIR], 0.6-0.9) were identified in men with lung cancer in Finland during the period 1953–1995
]. In women, the respective risks were also (but not significantly) decreased (stomach cancer: SIR, 0.7; 95% CI[SIR] 0.3-1.4); colorectal cancer: SIR, 0.9; 95% CI[SIR], 0.5-1.6). In Finland, lung cancer has typically been a cancer type of the lower social classes in men whereas it was more frequent in the higher social classes in women at least until the mid-1980s
]. Moreover, in Finland, the highest incidence of stomach cancer has been found in the poorer social strata, whereas colorectal cancer has typically been a cancer of the affluent classes
]. These findings might possibly explain the observed significantly reduced risk of colorectal cancer among male patients, the decreased risk of stomach cancer among female patients, and the slightly decreased risk of colorectal cancer among female patients. An additional explanation of decreased risks might be the unfavourable prognosis of lung cancer (similar to pancreatic cancer) which in turn prevents the development of larger numbers of TRSPC in diseased persons.
Radiotherapy was administered in at least 42% of persons with FPC in the mouth/pharynx (Table
). Furthermore, a considerable proportion of patients with cancer in the oesophagus (at least 24%), larynx (at least 29%), and lung/bronchus (at least 25%) was also treated with radiotherapy. Therefore, radiotherapy might have contributed to the significantly increased risk of TRSPC in these patients.
Since chemotherapy was applied in a relatively high proportion of persons with FPC in the mouth/pharynx (at least 23%), oesophagus (at least 29%), stomach (at least 18%), colon/rectum (at least 24%), pancreas (at least 39%), lung/bronchus (at least 39%), and leukemia (at least 41%), it might also have contributed to the significantly increased risk of TRSPC.
In comparison with our results, surgery was generally administered in a higher proportion of persons according to published German studies
). These discrepancies may be due to the different observation periods. During the last decade, there seems to have been a tendency to conduct more clinical studies compared to former decades. This may have lead to a decreased proportion of exclusive surgical treatment and to an increased proportion of other treatments, which in turn may help to explain the observed differences with respect to treatment of cancer in the stomach, colon/rectum, pancreas, and urinary bladder.
Table 5 Cancer treatment according to site of first primary cancer in Germany (Munich Cancer Registry [1977–1993] unless mentioned otherwise; data sources,[32,33])
Moreover, kidney cancer was most frequently treated with surgery alone, and leukemia was predominantly treated with chemotherapy (Table
). Consequently, adherence to the recommendations of the Deutsche Krebsgesellschaft can be concluded with respect to the aforementioned two cancer types
In summary, despite some differences, the main results of our study are confirmed by published international studies. With the exception of pancreatic cancer, stomach cancer, colorectal cancer, and leukemia, we were able to confirm the hypothesis of a significantly increased risk of TRSPC among persons with TRFPC compared to the general population. Hence, the aforementioned finding was most prominent in cancer types which are known to be strongly related to tobacco smoking.
The smoking prevalence of adults aged between 25 and 69 years in Germany has decreased in men and increased in women since 1986, but in the year 2006, the proportion of smokers among men (36%) was still higher than among women (28%)
]. Due to the comparison with the general population in which the proportion of female smokers, and thus the risk of developing a tobacco-related cancer, is smaller compared to the study population, the relative risk of TRSPC among women with TRFPC compared to the female general population may be higher than that among men. Therefore, the aforementioned sex difference with respect to smoking prevalence might be the cause of higher SIR`s among women than among men in several tobacco-related cancer sites. However, there are known sex differences with regard to the attributable fractions of tobacco smoking in tobacco-related cancers. Therefore, this explanation is difficult to verify without knowledge of the individual smoking status in our study population.
The importance of smoking cessation programs for cancer patients with a TRFPC is underlined by results of a study of the National Cancer Institute (NCI) in Maryland revealing that 12 out of 55 (22%) lung cancer patients continued to smoke for at least six months after the diagnosis of lung cancer
]. In view of the long-term reduction of tobacco-related cancer incidence, a rigid tobacco control policy should be advanced in Germany to further reduce the smoking rate
]. The efficacy of a rigid tobacco control policy has previously been confirmed in all age groups
]. Furthermore, lung cancer patients who stop smoking after the diagnosis of cancer show a steadily decreasing risk of TRSPC over time
]. Since the relative 5-year survival rate of patients with cancer of the oesophagus, pancreas, and lung is below 23% in Germany
], the efficacy of a rigid tobbacco control policy especially with regard to these cancer types would be considerable. By contrast, primary cancers in the kidney, urinary tract, and urinary bladder have a better prognosis with 5-year survival rates above 64%.
Limitations of our study
Despite the large underlying data base obtained from a population-based cancer registry with an extensive catchment area, a number of limitations apply.
Firstly, no data on tobacco smoking among cancer patients was available. Consequently, an unknown degree of confounding can be assumed with regard to the obtained risk estimates which should be expected to differ considerably between smokers and non-smokers.
Secondly, only crude data about the applied therapies was available. For this reason and because the numbers of cases in each treatment stratum were too small to permit the calculation of meaningful results, we did not evaluate the risk of SPC stratified by treatment in order to evaluate possible risk differences. Likewise, calculation of the risk of SPC according to different histological tumour types was not possible due to insufficient numbers of events. Therefore, future studies should evaluate the risk of TRSPC according to different treatments and histological tumour types, respectively.
Thirdly, registration completeness of tobacco-related cancer cases was intermittingly below 90% in some parts of Bavaria during the observation period. In the year 2002, for example, the registration completeness among different diagnosis groups ranged between 67 and 99%. In general, a registration completeness of at least 90% is required to obtain valid results from population-based cancer registries
]. This deficiency, however, was compensated in part by the employed standardisation of risk estimates based on the Bavarian general population, thus limiting the extent of severe risk underestimation. Therefore, the degree of confounding caused by this deficiency appears to be acceptable.
Fourthly, the overall duration of the present study was only seven years. However, Bavaria is the federal state (Bundesland) with the second largest population in Germany. Therefore, we consider the overall study population of 197,517 cancer patients and 331,759 person-years at risk to be sufficient for valid analyses. Furthermore, tobacco-related carcinogens can be assumed to have acted for several decades in many smokers prior to the diagnosis of TRFPC
]. Therefore, in many smokers, TRSPC can be expected to develop within a relatively short time span (less than 10 years) after TRFPC. Consequently, we were able to evaluate the short-term risk of tobacco-related SPC according to 11 sites of first primary cancer.