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SN Comprehensive Clinical Medicine

, Volume 1, Issue 11, pp 900–904 | Cite as

Prognosis of the Metachronous and Synchronous Bilateral Renal Cancer and Second Primary Cancer After the Bilateral Renal Cancer: a Population-Based Analysis

  • Mierxiati Abudurexiti
  • Jun Wang
  • Ning Shao
  • Fang-Ning Wan
  • Wen-Kai Zhu
  • Bo Dai
  • Yao ZhuEmail author
  • Ding-Wei YeEmail author
Medicine
  • 92 Downloads
Part of the following topical collections:
  1. Topical Collection on Medicine

Abstract

It is essential to summarize independent prognostic factors of bilateral kidney cancer and to clarify how the second primary cancer develops under these prognostic factors. Patients first diagnosed with bilateral renal cancer between 1973 and 2015 were abstracted from the SEER database. The Kaplan-Meier survival curves were conducted to depict survival difference and the log-rank tests were used to determine statistical significance. Multivariate Cox proportion hazard regression analyses were established to evaluate statistical significance for survival probability of each substage. The data of the second primary cancer after bilateral renal cancer were collected by MP-SIR session. There were 847 cases of synchronous bilateral renal cancer and 1218 cases of metachronous bilateral renal cancer. The 5-year cancer-specific survival (CSS) rate of the synchronous bilateral renal cancer is 51.5% and it is 93.6% in the metachronous group. In the synchronous group, there exists a CSS difference among the age subgroups (p < 0.001), the behavior subgroups (p < 0.001), the tumor size subgroups (p = 0.044), and the stage subgroups (p < 0.001). And in the metachronous group, there was a statistical significance among the age subgroups (p < 0.001), the tumor size subgroups (p = 0.015), and the stage subgroups (p < 0.001). Only 5 cases were observed in the synchronous group as the second primary cancer, while 268 cases were discovered in the metachronous group. Compared with synchronous bilateral renal cancer, metachronous bilateral renal cancer had a better CSS. And the incidence of second primary cancer is higher in the metachronous group than in the synchronous group. Further studies should be conducted.

Keywords

Renal cancer Bilateral Metachronous Synchronous Second primary cancer 

Introduction

The incidence of kidney cancer is growing with the highest incidence rate in developed countries. And the incidence of second primary cancer, a late effect after kidney cancer, is also increasing. Previous studies already reported the risk of second primary cancer after kidney cancer and the risk of subsequent primary kidney cancer after another malignancy [1, 2]. Nevertheless, little is known about the incidence of second primary cancer after the synchronous or metachronous bilateral cancer in paired organs, such as breasts, eyes, and kidneys.

Although, the risk of bilateral kidney cancer was reported in a previous study [3], it is still essential to summarize independent prognostic factors of the bilateral kidney cancer and to clarify how the second primary cancer develops under these prognostic factors. Indeed, it is necessary to make intensive follow-up for patients with high risk of developing second primary cancer. To this end, we used the Surveillance, Epidemiology and End Results (SEER) registry database, which encompasses approximately 28% of the American population, to examine the prognostic factors of bilateral kidney cancer and the total amount of second primary cancers after bilateral kidney cancer. As the incidence of the kidney pelvis cancer is lower than the renal cancer, we focused on the latter entity in our study.

Patients and Methods

Data Acquisition

The data used for analyses in our study were obtained from the SEER database by the SEER-stat software (SEER* 8.3.5). The data were collected from the case listing session and the multiple primary-standardized incidence ratios (MP-SIR) session.

Study Population

This study included patients who were first diagnosed with bilateral renal cancer between 1973 and 2015. To identify synchronous and metachronous bilateral renal cancer, the “Bilateral” code was chosen as the synchronous renal cancer in the SEER-stat software. For the metachronous, we chose the right side of renal cancer first and we can get the data of the left side cancer from the MP-SIR and vice versa. Finally, we combined these data together in order to calculate the total number of metachronous bilateral renal cancers. We excluded cases without data about survival months and cancer-specific survival status. Cases diagnosed at autopsy and those lost to follow-up were also excluded. The patients were followed up from the date of diagnosis to the date of last known vital status, death, or the last point of data collection. Second primary cancer was defined as the cancer which happened 1 month later than the first malignancy. The numbers of the second primary cancer after the synchronous bilateral renal cancer were collected by MP-SIR session; however, the total numbers of the second primary cancer after the metachronous bilateral renal cancer were calculated after the collection of each patient’s data according to their patient ID.

Statistical Analysis

The Kaplan-Meier survival curves were conducted to depict survival difference and the log-rank tests were used to determine statistical significance. To further compensate for potential baseline bias, 1:1 propensity score matching (PSM) was performed by R package. Multivariate Cox proportion hazard regression analyses were established to evaluate statistical significance for survival probability of each substage (Table 1). Overall survival and cancer-specific survival (CSS) were used as the endpoint and the statistically significant p value was set at p ≤ 0.05. Conditional survival (CS), which was defined as the probability of surviving for an additional year with this condition, was analyzed by Kaplan-Meier method. The standard incidence was calculated by dividing the observed incidence by the expected incidence of second primary cancer in the general population. The data of standard incidence after the synchronous bilateral renal cancer were obtained from MP-SIR session. However, this information was not available in the metachronous group as the number of the patients was calculated one by one according to the patients’ ID. For this reason, the expected cases in the metachronous group were calculated by applying a ratio within the number of group incidence, which was the ratio, inherited from the synchronous group, that is, the rate of the expected cases in group incidence. All statistical analyses were performed based on the statistical package for social science (SPSS version 22; SPSS Inc., IL, USA).
Table 1

Multivariate analysis of factors that influence cancer-specific survival in patients with simultaneity bilateral renal cancer between 1973 and 2015

  

Synchronous

Metachronous

Variable

Categories

N

H.R.

95% CI

p value

N

H.R.

95% CI

p value

Age

> 45 years

553

1.00

0.395–0.797

0.001

646

1.00

0.293–0.618

< 0.001

≤ 45 years

294

0.561

201

0.425

Race

Others

174

1.00

0.853–1.374

0.515

205

1.00

0.602–1.172

0.305

White

673

1.082

642

0.840

Gender

Female

337

1.00

0.868–1.313

0.536

336

1.00

0.679–1.212

0.510

Male

510

1.067

882

0.907

Behavior

Papillary

30

1.00

 

< 0.001

87

1.00

 

0.662

Renal cell

338

1.166

0.635–2.143

352

1.210

0.514–2.847

Nephroblastoma

220

0.206

0.096–0.443

2

0.001

0.000–6.506E33

Clear cell

99

0.975

0.514–1.848

333

1.218

0.512–2.899

Others

160

1.049

0.557–1.974

73

1.575

0.621–3.997

Tumor size

Blank + NA+ unknown

551

1.00

 

0.044

300

1.00

 

0.318

≤ 5 cm

81

0.649

0.385–1.092

410

671.7

0.001–3.542E38

> 5 cm and ≤ 10

105

0.919

0.673–1.255

111

869.9

0.001–4.591E38

> 10

110

0.623

0.432–0.899

26

1345

0.001–7.114E38

Stage

Blank + unknown

328

1.00

 

< 0.001

297

1.00

 

< 0.001

Localized

135

0.407

0.244–0.679

390

0.001

0.001–2.763E32

Regional

45

1.093

0.631–1.894

87

0.002

0.001–9.772E32

Distant

339

1.553

1.250–1.930

73

0.002

0.001–1.007E33

Marital

Others

494

1.00

 

0.071

394

1.00

 

0.030

Married

353

0.829

0.676–1.016

453

0.723

0.539–0.969

Results

One thousand six hundred ninety-four cases with bilateral renal cancer were enrolled in this study, which included 847 cases of synchronous bilateral renal cancer and 847 cases of metachronous renal cancer. The median age was 57 years in the synchronous group and 60 years in the metachronous group. The proportion of patients whose age were higher than 45 years accounted for about 71%, while the percentage of Caucasian patients were also 78% and men were nearly 63%. More than half of the patients were married. The 5-year OS of the synchronous bilateral renal cancer is 30.8%, while 79.6% in metachronous group. Meanwhile, the 10-year CSS of the synchronous group is 18.2% while metachronous group is 54.4% (Fig. 1a). The 5-year CSS of the synchronous bilateral renal cancer is 51.5%, while 93.6% in metachronous group. Meanwhile, the 10-year CSS of the synchronous group is 49.3% while metachronous group is 87% (Fig. 1b). In addition, CS estimates are more objective than static survival probabilities. Patients who had survived more than 36 months after initial diagnosis had better 1-year CS than those who had survived no more than 36 months since diagnosis in synchronous group (Fig. 1c). Age, race, gender, behavior, tumor size, stage, and marital factors of the two groups were analyzed by multivariate COX analyses (Table 2). In the synchronous group, there exists a CSS difference among the age subgroups (p < 0.001), the behavior subgroups (p < 0.001), the tumor size subgroups (p = 0.044), and the stage subgroups (p < 0.001). And in the metachronous group, there were statistical significance among the age subgroups (p < 0.001), the stage subgroups (p < 0.001), and marital subgroups (p = 0.03). Only 5 cases were observed in the synchronous group as the second primary cancer, while 268 cases were discovered in the metachronous group in our analyses. The standard incidence was 0.34 in the synchronous group while 8.28 in the metachronous group.
Fig. 1

a Overall survival of each group. b Cancer-specific survival of each group. c Conditional survival of each group

Table 2

Risk of second primary cancer in bilateral renal cancer between 1973 and 2015

 

Synchronous

Metachronous

Variable

Categories

Observed

Expected

O/E

Observed

Expected

O/E

Total

 

5

14.54

0.34

268

32.37

8.28

Age

> 45 years

5

13.35

0.37

257

24.38

10.54

≤ 45 years

0

1.05

0.00

11

0.74

14.86

Race

Others

1

3.19

0.31

78

5.98

13.04

White

4

11.22

0.36

190

14.87

12.78

Gender

Female

1

4.42

0.23

62

4.41

14.05

Male

4

9.99

0.40

206

17.28

11.92

Behavior

Papillary

0

0.41

0.00

41

2.12

19.34

Renal cell

3

8.38

0.36

124

13.26

9.35

Nephroblastoma

0

0.48

0.00

1

0.004

250

Clear cell

1

1.71

0.59

76

7.63

9.96

Others

1

3.48

0.29

26

1.827

14.23

Tumor size

Blank + NA+ unknown

0

0.00

0.00

189

0.00

0.00

≤ 5 cm

0

0.42

0.00

50

1.80

27.78

> 5 cm and ≤ 10

2

0.85

2.34

22

1.14

19.29

> 10

3

13.26

0.23

7

4.58

1.53

Stage

Blank + unknown

4

10.85

0.37

127

14.19

8.95

Localized

0

1.04

0.00

123

4.90

25.10

Regional

0

0.24

0.00

12

0.624

19.23

Distant

1

2.41

0.42

6

0.26

23.07

Marital

Others

2

5.79

0.35

81

4.22

19.19

Married

3

8.62

0.35

187

20.95

8.93

Discussion

The study of bilateral renal cancer is so limited that urologists still know little about it. In the present study, we reported the CSS difference between synchronous bilateral renal cancer group and metachronous bilateral renal cancer group. And in previous studies, Csaba Berczi showed that the 5-year CSS were 86% in synchronous bilateral renal cancer while 75% in metachronous group [4]. Singer EA showed that overall survival was 88% and CSS was 97% after a minimum of 10-year follow-up for patients with bilateral renal cancer [5]. However, in our study, CSS of synchronous bilateral renal cancer is 51.5%, while 93.6% in metachronous group. In Csaba Berczi’s study, bilateral partial nephrectomies or unilateral nephrectomy and contralateral nephron-sparing surgery were performed in all cases. Patients included into Singer EA’s study had initial surgery at least 10 years ago. According to previous studies, the survival of patients may not be significantly different between synchronous and metachronous groups, once all the patients had surgery. However, in our study, we can observe the survival difference between the two groups. It is possible that the majority of the patients in the synchronous group of our study lost the opportunity to have surgery, which resulted in lower survival rates.

The tumor stage, size, grade, and necrosis (SSIGN) score was reported in 2002 by Frank I [6], and it was evaluated again by William P. Parker in 2017. William P. Parker showed that the C-index of the patients’ survival was up to 0.82 when evaluated by the SSIGN score [7]. Tumor size and cancer stage were both prognostic factors for the synchronous bilateral renal cancer in our study. When the data were extracted from the SEER-stat software, we did not know whether the data was from the biggest lesion of the cancer or the sum of the sizes of these bilateral lesions.

The analyses of our study showed that the synchronous bilateral renal cancer tends to be a metastatic disease, while metachronous disease was typically localized. Nearly 35% of the cases in the synchronous group were less than 46 years old while only 24% in the metachronous group. Shuch, B. indicated that early age (less than 46 years) of onset might be a sign of hereditary renal cell cancer [8]. The main pathological type in the synchronous group is renal cell cancer, and the number of cases of clear cell cancer and renal cell cancer were nearly the same in the metachronous group. Before PSM, The percentage of papillary renal cancer is higher in the metachronous group than in the synchronous group. Chandrasekar T showed that papillary renal cell cancer was associated with localized disease at the time of diagnosis [9]. This may be the main reason that there were more localized diseases in the metachronous group than the synchronous group. Each histologic type may be associated with specific gene mutations in a hereditary cancer. Shuch, B. indicated that inherited renal cancers were frequently multiple and bilateral [8]. Although we cannot get more detailed diagnostic data about these patients, we may infer that most of the incidences in our study were inherited. Hence, it may be important to conduct a gene test for patients with bilateral renal cancer, especially those younger than 46 years, in order to improve the accuracy of the diagnosis and further treatment. Meanwhile, an experienced radiologist is necessary so that the inherited disease may be identified by the CT or MRI scan.

The number of incidences of second primary cancer was apparently different after the synchronous and the metachronous renal cancer. Interestingly, the survival of patients with synchronous bilateral renal cancer is lower than that of patients from the metachronous group, while patients with second primary cancer after the synchronous renal cancer were less than patients from the metachronous group. We hypothesized that the probability of developing a second primary cancer is higher if the patients have longer survival. The diverse incidences of the second primary cancer might be explained by differences in genetic and ethnic traits, as well as life style and environment. In our study, we did not summarize the type of malignancies after the synchronous and metachronous bilateral renal cancer. Subhankar Chakraborty showed that solid tumors comprised 90% of all second malignancies in renal cell cancer patients, with the most second cancers reported in the prostate gland and the digestive and respiratory systems [10]. In previous studies, it was shown that patients with papillary renal cell carcinoma were more likely to have bladder cancer [11, 12]. There is no available study about the factors affecting the incidence of the second malignancies after the bilateral renal cancer, which merits further investigation.

The main limitation of our study was the inability to get the treatment data for each patient. Additionally, some specific and relevant data were unknown, such as on environment-lifestyle factors and comorbidities other than cancers. Therefore, further studies should be conducted to assess the influencing factors of the second primary cancer.

In conclusion, we analyzed the risk factors of the bilateral renal cancer by dividing them into two groups (synchronous and metachronous). We were surprised by the fact that the metachronous cancer had better survival but easier developed second primary cancer in comparison with the synchronous group. From a clinical perspective, these results suggest that patients with metachronous bilateral renal cancer, especially those having the factors responsible for long survival, should be monitored carefully for the development of second primary cancer. However, further studies are needed to unveil the causes of this phenomenon.

Notes

Author’s Contribution

M Abudurexiti: project development, data collection, manuscript writing

J Wang and N Shao: data collection

W Zhu and F Wan: data analysis

B Dai: manuscript editing.

Y Zhu: project development

D Ye: supervision

Funding Information

This study was sponsored by the National Natural Science Foundation of China (Nos. 81472377, 81502192, 81672544).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Ethical Approval

De-identification of SEER data was done before release and they do not contain any personally identification information. As the data are publicly available, no ethical approval is required.

Informed Consent

As the data are publicly available, no informed consent is required.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of UrologyFudan University Shanghai Cancer CenterShanghaiChina
  2. 2.Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina

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