The three significant guidelines for the surveillance of RCC patients following surgery (National Comprehensive Cancer Network [NCCN], European Association of Urology [EAU], and American Urological Association [AUA]) differ in terms of their recommendations for imaging modalities and frequencies [12]. Although there is no consensus with regards to an optimal surveillance strategy for patients after RCC treatment, it is often recommended that patients are followed-up closely for 3–5 years after surgery since relapse is most commonly seen within the first 5 years of surgery. Another common recommendation is to select different examination modalities based on individual risk stratification. The number of follow-up assessments can be reduced after the first 3 years but should continue for at least 5 years [13, 14]. In our study, it suggested that it’s important that long-term follow-up should not be stopped; rather, the surveillance modality and frequency should be adjusted based on individual risk.
Interestingly, the contralateral kidney showed the highest SIR (54.6) and accounted for the largest proportion of SPM cases (11.8%) in survivors of primary RCC. This indicates that it is crucial to perform lifelong follow-up assessments for RCC survivors, and that we pay particular attention to contralateral kidney carcinoma. Furthermore, it is important to routinely screen general patients or RCC survivors for malignancies associated with the prostate, breast, lung, bladder, colon/rectum, and thyroid [1]; these types of tumors accounted for most of the SPM cases seen in our current study. Although our results indicated that the early occurrence of SPM can exert impact on the OS, it was evident that survival can be prolonged if new cases of SPM are detected and treated early. Moreover, we found that if SPM cases were detected later, or involved a higher stage of solid SPM, then curative surgical treatment would be difficult and threaten long-term OS. The early detection of a small local SPM in the contralateral kidney would benefit from PN, particularly in patients who experienced RN for their primary RCC. Conversely, considering the risk of contralateral kidney cancer following surgery for primary RCC, it is recommended that we perform PN for the first kidney surgery in order to retain renal function, even if a contralateral SPM occurs. The early detection of a local small RCC is critical and could benefit from PN, and this technique may protect the normal renal parenchyma [15–18].
With regards to the design of individual surveillance plans, the selection of patients at risk could help to balance follow-up benefits and save costs, thus allowing the close monitoring of high-risk patients while reducing the over-medical treatment of low-risk patients. In the present study, we identified a series of independent high-risk predictors for the occurrence of SPM: increased age at the primary RCC diagnosis, black race, male gender, patients with high family income, papillary types of cancer, small tumors, the absence of lymph node invasion, a lower T stage, and a lower AJCC TNM stage. Our results further suggest that although some patients, such as those with a low TNM stage of RCC, may represent a low-risk group for recurrence after RCC [19], further follow-up is still necessary because this group is at high risk of developing SPM. Furthermore, the emergence of SPM is related to gender and the pathological type of RCC, thus indicating that SPM may be related to certain genes or other exposure environmental. Interestingly, SPM is known to be related to economic factors, and may be more prevalent in patients with a certain financial status; some patients may pay more attention to their follow-up and general health status and also have the financial means to afford the costs associated with follow-up.
Age is an independent risk factor for the occurrence of SPM. Interestingly, when predicting non-RCC SPM, the risk of SPM increases with age. However, when considering contralateral kidney tumors, it is evident that the elderly patients do not have an increased risk. Our univariate analysis found that the risk of patients over 60 years-of-age was lower for contralateral kidney SPM than that of patients under 44 years-of-age; this was consistent with previous literature [20, 21]. Age itself is an independent risk factor for cancer [22], and because the risk of developing tumors increases with age. As long as patients survive long enough, they are likely to develop more than two types of malignant tumors in their lives. It has been reported that 33% of cancer survivors over the age of 60 will be diagnosed with another type of cancer [23]. For some patients, RCC is only one of the earliest malignant tumors that could develop; however, with improvements in the prognosis and survival of RCC patients, it is now possible to detect SPM during the follow-up period. In elderly patients with RCC as their first cancer, SPM may be recorded shortly after RCC diagnosis. In contrast, younger patients may need a longer follow-up time for SPM to be detected, perhaps because the follow-up time required is relatively longer (in other words, the patients need to reach a certain age for successful detection). It is therefore possible that SPM was not detected by the end of the follow-up period in this study, or that the occurrence of a variety of competitive events prevented the occurrence of SPM.
The increased risk of secondary SPM in RCC patients still needs further verification and in-depth research in order to identify the precise connection between these two conditions. Possible mechanisms include renal insufficiency, and even renal failure after RCC, thus leading to long-term metabolic disorders and an increased risk of cancer in patients surviving from RCC. Furthermore, RCC patients may have experienced frequent episodes of computer tomography to monitor the disease, thus causing increased levels of exposure to radiation, or changes in the complex immune microenvironment. The biological characteristics of RCC confer all patients with kidney cancer with a higher risk of SPM. Renal cell carcinoma is also related to smoking [24]; however, smoking does not just affect the kidney. There may be a higher risk of cancer in patients with RCC who did not give up smoking after treatment, or in patients who smoked frequently over a long period prior to RCC diagnosis. However, these are hypotheses that have yet to be confirmed.
Furthermore, we analyzed the survival function for patients with SPM. We found that the occurrence of SPM, and an early time interval to SPM, could significantly shorten the OS when compared with patients who did not have SPM. However, the same site of SPM was not significantly associated with outcomes; for example, SPM of thyroid cancer, ipsilateral RCC, and prostate cancer, all showed an excellent 5-year OS after the diagnosis of SPM was made. After adjusting for other risk factors, we also found that SPM of contralateral RCC, cecum/small intestine, female breast, thyroid, and prostate cancer, had a similar or significantly better OS when compared with ipsilateral RCC. A worse OS was associated with SPM of the brain, liver, gallbladder/bile duct, lungs/bronchi, pancreas, and esophagus/stomach; furthermore, these sites of SPM also had a higher SIR compared with the general population. Another interesting finding was that the stage of SPM was also significantly associated with OS following the diagnosis of SPM; an SPM of a local disease had a better OS than regional and distant SPM. In addition, patients with SPM also could benefit from surgical treatment. These results clearly suggested that SPM can influence the OS. However, early detection and surgical intervention for solid SPM tumors is of great significance and can influence outcomes; this emphasizes the need to establish lifelong follow-up strategies rather than performing surveillance over the short-term.
This study had same limitations that need to be considered. First, all analyses were carried out using a registry-based dataset with inherent limitations. For example, we did not have access to any detailed clinical information such as patient comorbidities or a poor performance that lead to mortality within a period of follow-up time. This represents a vital competing risk for the occurrence of SPM and could not be adjusted in our multivariate analysis for SPM prediction. In addition, when analyzing the prediction of SPM for ipsilateral and contralateral kidney cancer, we had no access to information relating to hereditary RCC, such as von Hippel Lindau (VHL), hereditary papillary renal carcinoma, Birt Hogg Dube´ syndrome, and hereditary leiomyomatosis RCC [25]; these factors have all been identified previously as significant predictors for the metachronous de novo development of RCC over a long-term follow-up period. We did not have access to information relating to environment exposure, lifestyle, family history, and genetic mutation, all of which are known to act as risk factors for SPM. Second, patients with primary RCC or other diseases would generally pay more attention to routine cancer screening or surveillance than the general population, thus increasing the chances of identifying the occurrence of SPM in RCC survivors. Therefore, it is possible that surveillance bias may exist in our study. Third, after the first primary diagnosis of RCC, it is possible that the preexisting or concomitant malignancy, metastasis diseases, or relapse in the patients with RCC, may have confounded the subsequent detection of SPM. To control for confounding factors, we only included patients with SPM that had been diagnosed at least 6 months after the first primary RCC diagnosis as our study cohort. When using the SEER dataset, we maintained quality assurance by performing systematic and standardized data collection procedures. Finally, due to a lack of information relating to local recurrence, we included patients with ipsilateral kidney cancer; these cases may have just been recurrences rather than SPM. However, more than 90% of ipsilateral kidney tumors were diagnosed more than 3 years after RCC diagnosis; 50% were diagnosed after more than 5 years. Furthermore, 35.6% of patients with RCC showed histological changes between the first and second occurrence of ipsilateral kidney cancer.