Survival outcomes in prostate cancer patients with a prior cancer
Transcript Of Survival outcomes in prostate cancer patients with a prior cancer
This article has an erratum available at: https://dx.doi.org/10.21037/tau-2021-07 and the article has been update on 2021-11-22 at here.
Original Article
Survival outcomes in prostate cancer patients with a prior cancer
Yan Zang1#, Feng Qi2#, Yifei Cheng3#, Tian Xia4, Rongrong Xiao4, Xiao Li2, Ningli Yang1
1Department of Bariatric and Metabolic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; 2Department of Urologic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China; 3Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; 4Department of Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China Contributions: (I) Conception and design: X Li, N Yang; (II) Administrative support: None; (III) Provision of study materials or patients: Y Zang, X Li, T Xia; (IV) Collection and assembly of data: F Qi, Y Zang, X Li; (V) Data analysis and interpretation: F Qi, Y Cheng, R Xiao; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. #These authors contributed equally to this work. Correspondence to: Xiao Li. Department of Urologic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China. Email: [email protected]; Ningli Yang. Department of Bariatric and Metabolic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Email: [email protected]
Background: To shed light on the survival outcomes of prostate cancer (PCa) patients diagnosed after a prior cancer and identify prognostic factors for overall survival (OS) and cancer-specific survival (CSS) in PCa patients. Methods: In the primary group, a total of 1,778 PCa patients with a prior cancer were identified in the Surveillance, Epidemiology, and End Results (SEER) database from 2005 to 2015, retrospectively. Baseline characteristics and causes of death (COD) of these patients were collected and compared. In the second group, a total of 10,296 PCa patients [5,148 patients with PCa as the only malignancy and 5,148 patients with PCa as their second primary malignancy (SPM)] diagnosed between 2010 and 2011 were extracted to investigate the impact of prior cancers on survival outcomes. Results: In PCa patients with a prior cancer, the most common type of prior cancer was from gastrointestinal system (29.92%), followed by urinary system (21.37%). Patients were more likely to die of the prior caner, and those with prior cancer from respiratory system had the worst survival outcomes. Moreover, the overall ratios in patients with stage (PCa) I–II and III–IV diseases were 0.21 and 1.65, indicating that patients with higher stage diseases were more likely to die of PCa. In the second group, patients with PCa as the SPM had worse OS than those with PCa as the first primary cancer. Lastly, prognostic factors for OS and CSS in PCa patients were explored. Conclusions: PCa remains to be an important COD for patients with a prior malignancy, especially for those with high-stage diseases. PCa patients with a prior cancer had worse survival outcomes than those without.
Keywords: Prostate cancer (PCa); Surveillance, Epidemiology, and End Results (SEER); survival; prior cancer; prognostic factor
Submitted Apr 27, 2020. Accepted for publication Dec 04, 2020. doi: 10.21037/tau-20-897 View this article at: http://dx.doi.org/10.21037/tau-20-897
Introduction
Prostate cancer (PCa) is one of the most common malignancies in genitourinary system globally (1). In
2020, the estimated newly diagnosed cases and deaths are 191,930 and 33,330 in the United States (2). In the United States and some European countries, the incidence rate of PCa has exceeded lung cancer to be the leading cause
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
742
of male malignancies. Even though, disease progression of PCa could be well controlled by surgery, radiotherapy and endocrine therapy. It was reported that the 5-year overall survival (OS) rate for PCa was up to 90% in many institutions (3-5).
Overall, the 5-year relative survival rate of cancer survivors has been increasing during the past decades (up to 66%) due to the improvement in cancer detection and treatment (6,7). As a result, the number of cancer survivors is increasing recently. Statistically, the overall estimated cancer survivors in men and women were 7,377,100 and 8,156,120 in 2016 in the United States (8), and this population showed an annual growth trend of 2% (9). Considering the increasing number of cancer survivors, the probability of developing a second primary malignancy (SPM) also increased accordingly (10). Hence, many patients may develop tumors of multiple organs or systems during their lifetime (11).
An SPM is defined as a cancer which arises in a new organ or tissue independently at least 2 months after the initial diagnosis of the prior primary malignancy (12-14). Previous studies have already discussed the critical role of SPM in many cancer types, such as breast cancer (11,15,16), Hodgkin lymphoma (17), cervical cancer (18) and so on. He et al. (19) found that there was an excessive risk of developing an SPM in young-onset (age ≤50 years old) colorectal cancer survivors. Additionally, the risk of developing SPMs was reversely correlated to age. Donin et al. (20) demonstrated that about 1 in 12 patients would develop a second malignancy during their lifetime, and the most common type of SPMs was lung cancer. Moreover, they discovered that more than half of patients with two primary cancers died of the second malignancy totally.
Most previous studies have focused on the risk of developing an SPM after a known tumor. However, the risk of a specific tumor as an SPM in patients with a prior cancer and survival outcomes for these patients have not been widely discussed. Ji et al. (12) found that the most common type of prior cancer in breast cancer patients was gynecologic cancer, followed by gastrointestinal cancer. Besides, treatment for breast cancer significantly decreased the risk of breast cancer specific morality. As PCa was traditionally considered to be an indolent cancer, many cancer survivors or clinicians may not feel it worth treating after weighing the risks and benefits when it was diagnosed after another malignancy (21), and there were rare studies on this topic. Hence, we developed this study on the basis of the Surveillance, Epidemiology, and End Results (SEER) database to achieve a deeper understanding of the survival
Zang et al. Prognosis of subsequent PCa patients
patterns and risk factors for patients with subsequent PCa. Additionally, we present the following article in accordance with the STROBE reporting checklist (available at http:// dx.doi.org/10.21037/tau-20-897).
Methods
All the raw data utilized in this study were retrospectively extracted from the SEER database. SEER registry is a public database supported by the US National Cancer Institute to collect relevant information of cancer patients, including demographic characteristics, incidence rates, treatments and survival outcomes. In the beginning, there were only nine regions participated in this project, while approximately 30% of the US population are covered in the database till now. In our study, we signed the user agreement and gained access to the database with the username of 15440-Nov2018. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Additionally, this study was exempt by Institutional Review Board (IRB) approval because the original data were from a public database and individual consent for this retrospective analysis was waived.
Primary group
In the primary group, PCa patients with a prior cancer were extracted from the SEER 9 registry using the “multiple primary-standard incidence ratio” function via the SEER*Stat software (Version 8.3.6; NCI, Bethesda, USA). The initial inclusion criteria were as follows: (I) PCa was the second malignancy of each patient, (II) patients with active follow-up after cancer diagnosis, (III) year of PCa diagnosis was from 2005 to 2015. Additionally, the exclusion criteria were as below: (I) patients with missing or unknown data [race =13, prostate-specific antigen (PSA) =2,586, Gleason score =3,336, stage =2,334, T stage =255, N stage =17, M stage =1, cause of death (COD) =1 and the administration of surgery =5], (II) patients with three or more malignancies in total (n=3), (III) diagnosed by autopsy or death certificate only, (IV) diagnosis interval between PCa and the prior cancer was less than two months.
Afterwards, baseline characteristics and clinicopathological data were extracted for each patient, including age at diagnosis, race, histological type, marital status, types of the prior cancers, American Joint Committee on Cancer (AJCC) 6th TNM stage, Gleason score, PSA level, diagnosis intervals between two cancers, administration of surgery, COD and
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
Translational Andrology and Urology, Vol 10, No 2 February 2021
follow-up. In this study, age at diagnosis was divided into <65 and ≥65 years old. Race was classified into Black, White and Other (including American Indian/AK Native, Asian/ Pacific Islander). PSA was categorized into ≤4, 4–10, 10–20 and >20 ng/mL. Gleason score fell into three categories: ≤6, 7 and 8–10. Furthermore, prior cancers were classified based on different systems, such as gastrointestinal system, urinary system, respiratory system, oral cavity and so on. Finally, for patients who died during the follow-up, COD were categorized into PCa, the prior cancer and other causes.
Firstly, the 5 most common types of the prior cancers were identified according to the frequency of occurrence, and Kaplan-Meier (KM) analyses were performed to probe the survival impacts of these cancers. Then, we calculated the percentage of PCa-related deaths and prior cancerrelated deaths in different cancer types. Furthermore, basic and pathological outcomes between patients who died of PCa and those died of the prior cancer were compared. Finally, the ratio of PCa deaths to prior cancer deaths was obtained for each prior cancer type, further stratified by PCa TNM stage.
Second group
In the second group, patients with histologically confirmed, stage I–III PCa from 2010 to 2011 were identified from the SEER 18 registry utilizing the “case listing session” tool. The enrolled patients were grouped into primary prostate cancer (PPC) and subsequent prostate cancer (SPC) according to whether there was a prior cancer before PCa diagnosis. The propensity score matching (PSM) method was developed with a ratio of 1:1 to balance the baseline characteristics. Comparisons between patients with PPC and SPC in survival outcomes were made to explore the impact of the prior cancers on survival. Finally, uni- and multivariate Cox regression analyses were constructed to identify the prognostic factors in PCa patients.
Statistical analysis
Student’s t-test and chi-square analyses were used for the comparisons in baseline characteristics and clinicopathological data, respectively. Survival outcomes were compared utilizing the KM analyses. The whole analysis was performed via SPSS 23.0 software (SPSS Inc, Chicago, IL, USA) and R software (Version 3.4.1). A twosided P<0.05 was considered to be statistically significant.
743
Results
Baseline characteristics of the primary group
A total of 1,778 eligible patients were included in the primary group. The median (interquartile range, IQR) ages at diagnosis of the prior caner and PCa were 64 [58–70] and 68 [63–74] years old. The median (IQR) diagnosis interval between two cancers was 40.5 [19–66] months. Overall, the majority of enrolled patients had their cancer diagnosed at earlier TNM stage (I–II: 76.94% and 86.33% for the prior cancer and PCa, respectively). Besides, the median (IQR) follow-up after PCa diagnosis was 42 (23.00–63.75) months (Table 1). In the primary group, the 5 most common types of prior cancer were from gastrointestinal system (29.92%), urinary system (21.37%), skin (19.97%), respiratory system (11.59%) and oral cavity and pharynx (7.31%) (Table 2). On the whole, a total of 299 patients died during the follow-up, and patients with prior cancer of respiratory system had the highest mortality (30.58%).
Survival outcomes in the primary group
As shown in Figure 1, OS was significantly different in patients with different types of prior cancer (P<0.001). PCa patients with prior cancers of respiratory system had the worst survival outcomes [10-year OS: 59.1%, 95% confidence interval (CI), 50.9–68.8%], while those with prior cancers of skin owned the longest OS (10-year OS: 85.8%, 95% CI, 80.9–90.9%).
On COD, 38.13% of patients died of the prior cancer and 16.05% of patients died of PCa (Figure 2A). When stratified by cancer types, we found that in patients with cancers of respiratory system, the prior cancer-related death rate was the highest (44.44%) and the PCa-related death rate was relatively lower (12.70%). The highest PCarelated death rate (19.64%) was found in patients with prior urological cancers. Hence, conclusions could be drawn that died of prior cancers was the main COD in these patients. Then, we compared the ratio of PCa deaths to prior cancer deaths in patients. As shown in Figure 2B, the overall ratios in patients with stage (PCa) I–II and III–IV diseases were 0.21 and 1.65, indicating that patients with higher stage diseases were more likely to die of PCa. Analogously, similar trends were detected in the majority of cancer types. However, in patients with prior cancers of respiratory system, they may be more likely to die of the first primary malignancy regardless of the PCa TNM stage (the ratio was 0.22 and 0.60 in stage I–II and III–IV diseases, respectively).
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
744
Zang et al. Prognosis of subsequent PCa patients
Table 1 Demographic and clinical factors of PCa patients with a prior cancer (n=1,778)
Variables
At prior cancer diagnosis
Age, year
Mean (SD)
64.31 (8.64)
Median (IQR)
64.00 (58.00, 70.00)
Race, n (%)
White
1,415 (79.58)
Black
277 (15.58)
Other
86 (4.84)
Marital status, n (%)
Married
1,411 (79.36)
Unmarried
189 (10.63)
Unknown
178 (10.01)
TNM stage, n (%)
I–II
1,368 (76.94)
III–IV
410 (23.06)
Interval between diagnoses, months
Mean (SD)
45.46 (31.83)
Median (IQR)
40.50 (19.00, 66.00)
Time from PCa diagnosis to death or end of study months
Mean (SD)
Median (IQR)
IQR, interquartile range; PCa, prostate cancer; SD, standard deviation.
At PCa diagnosis
68.09 (8.33) 68.00 (63.00, 74.00)
1,415 (79.58) 277 (15.58) 86 (4.84)
1,400 (78.74) 167 (9.39) 211 (11.87)
1,535 (86.33) 243 (13.67)
44.09 (23.42) 42.00 (23.00, 63.75)
Table 2 Classification of the prior malignancy, stratified by system
Systems
N (%)
Detailed cancers
Gastrointestinal system
532 (29.92)
Esophagus, stomach, liver, colon, rectum and so on
Urinary system
380 (21.37)
Bladder, kidney, renal pelvic and ureter
Skin
355 (19.97)
Melanoma and other non-epithelial skin cancers
Respiratory system
206 (11.59)
Lung, bronchus, larynx and nose
Oral cavity and pharynx
130 (7.31)
Tongue, tonsil, mouth and pharynx
Others
175 (9.84)
Others
Overall
1,778 (100.00)
All of the above
Death, n (%) 94 (17.67) 56 (14.74) 39 (10.99) 63 (30.58) 33 (18.86) 14 (8.00)
299 (16.82)
In Table 3, we found that age at PCa diagnosis (P<0.001), the rates of PSA >20 ng/mL (P<0.001), Gleason score 8–10 (P<0.001), TNM stage III–IV (PCa) diseases (P<0.001) and Tx/N1/Mx or Tx/Nx/M1 (PCa) diseases (P=0.026)
were significantly higher in patients who died of PCa when compared with those who died of the prior cancer. Furthermore, the metastatic rate (P<0.001) of the prior cancer was significantly higher in patients who died of a prior cancer.
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
Translational Andrology and Urology, Vol 10, No 2 February 2021 1.0
Survival probability
0.8
Gastrointestinal
Urinary
Skin
Respiratory
0.6
Oral
p<0.0001
0.4
0
50
100
150
Survivar time in months
Number at risk
532
445
238
21
380
317
144
12
355
313
152
10
206
160
70
5
130
103
36
1
0
50
100
150
Survivar time in months
Figure 1 Overall survival of prostate cancer patients with a prior cancer.
Survival of patients with PCa as the prior cancer or subsequent primary cancer in the second group
A total of 72,173 patients were enrolled in the second group, including 67,025 patients had PCa as their first primary malignancy and 5,148 patients had PCa as the SPM. As shown in Table 4, significant differences were detected between two groups in many variables, including age at diagnosis, race, PSA level, Gleason score, TNM stage, marital status, administration of surgery and radiotherapy (all P<0.05). To reduce the selection bias, a 1:1 PSM was developed and a total of 5,148 pairs of patients were eventually enrolled. As shown in Figure 3A,B, better survival outcomes were detected in patients with PPC when compared with those with SPC (P<0.05). After PSM, no significant difference was detected in prostate cancer-specific survival (PCSS) between two groups (P=0.66, Figure 3C), while significant shorter OS was found in patients with SPC when compared with those with PPC (P<0.001, Figure 3D). Lastly, uni- and multivariate Cox regression analyses were conducted to explore prognostic factors associated to OS and PCSS in PCa patients. Multivariate analysis revealed that age at diagnosis, Gleason score, PSA level, TNM stage and administration of surgery were risk factors for cancer-specific survival (CSS) (all P<0.05, Table 5). Similarly, age at diagnosis,
745
A
Overall
Oral
Respiratory
Skin
Urinary
Gastrointestinal
16.05 (n=48) 9.09 (n=3)
12.70 (n=8) 17.95 (n=7) 19.64 (n=11) 18.09 (n=17)
38.13 (n=114) 33.33 (n=11)
44.44 (n=28) 30.77 (n=12)
32.14 (n=18) 40.43 (n=38)
0
5 10 15 20 25 30 35 40 45 50
Died of Prior cancer
B
Overall
0.21 (20/97)
Oral Respiratory
0 (0/10)
0.60 (3/5) 0.22 (5/23)
Skin
0.36 (4/11)
Urinary
0.40 (6/15)
Gastrointestinal 0.15 (5/33)
Died of PCa 1.65 (28/17)
3.00 (3/1)
3.00 (3/1) 1.67 (5/3)
2.40 (12/5)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
I–II
III–IV
Figure 2 Survival outcomes among patients with different types of prior cancer. (A) The percentage of deaths related to prostate cancer or prior cancer among patients with different types of prior cancer, (B) ratio of prostate cancer deaths to prior cancer deaths.
race, Gleason score, PSA level, sequence of PCa (PPC vs. SPC) and administration of surgery were recognized as prognostic factors for OS (all P<0.05, Table 6).
Discussion
Nowadays, with the increase of cancer survivors, the risk of developing SPMs has also been increasing accordingly. Additionally, prior cancer played an important role in treatment strategies and clinical trials design (22). It was traditionally accepted that patients with prior cancers should be excluded in clinical trials, which may due to the assumption that prior cancers may impact the survival outcomes (23,24). Consequently, numerous patients with a prior cancer would be excluded from clinical trials, leading to worse accrual and generalizability of clinical trials (22). For example, up to about 20% of lung cancer patients were excluded from taking part in trails if following such a restrictive criterion (25). However, no convincing evidence has been proposed to support this exclusion criteria and address the actual effect of a prior malignancy on cancer survivors. Moreover, the standard incidence ratio of
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
746
Zang et al. Prognosis of subsequent PCa patients
Table 3 Clinical and demographic factors associated with prostate cancer death vs. prior cancer death
Characteristics
Died from prior cancer
Number of patients
114
Age at PCa diagnosis, mean ± SD, year
70.97±8.61
PCa treated, n (%)
22 (19.30)
Gleason score 8–10, n (%)
42 (36.84)
PSA >20 ng/mL, n (%)
23 (20.18)
PCa, TNM stage III–IV, n (%)
17 (14.91)
Prior cancer, TNM stage III–IV, n (%)
45 (39.47)
PCa, Tx/N1/Mx or Tx/Nx/M1, n (%)
8 (7.02)
Prior cancer, Tx/N1-3/Mx or Tx/Nx/M1, n (%)
47 (41.23)
Interval between diagnoses, mean ± SD, month
34.63±28.50
Kinds of the prior cancers, n (%)
Gastrointestinal system
38 (33.33)
Urinary system
18 (15.79)
Skin
12 (10.53)
Respiratory system
28 (24.56)
Oral cavity and pharynx
11 (9.65)
Others
7 (6.14)
PCa, prostate cancer; PSA, prostate-specific antigen; SD, standard deviation.
Died from PCa 48
77.29±9.07 13 (27.08) 37 (77.08) 25 (52.08) 28 (58.33)
9 (18.75) 9 (18.75) 6 (12.50) 42.44±32.70
17 (35.41) 11 (22.92)
7 (14.58) 8 (16.67) 3 (6.25) 2 (4.17)
P value
<0.001 0.272
<0.001 <0.001 <0.001
0.011 0.026 <0.001 0.130 0.683
Table 4 Baseline characteristics of patients with PPC or SPC from the SEER database 2010–2011
Variables
PPC, n (%)
Data before PSM SPC, n (%)
P value
PPC, n (%)
N
67,025
5,148
5,148
Age (year)
<0.001
<45
427 (0.64)
18 (0.35)
15 (0.29)
45–65
32,361 (48.28)
1,582 (30.73)
1,586 (30.81)
≥65
34,237 (51.08)
3,548 (68.92)
3,547 (68.90)
Race
<0.001
White
52,811 (78.79)
4,413 (85.72)
4,414 (85.74)
Black
10,761 (16.06)
554 (10.76)
556 (10.80)
Other
3,453 (5.15)
181 (3.52)
178 (3.46)
Grade1
0.488
Grade I
873 (1.30)
61 (1.18)
59 (1.15)
Grade II
27,759 (41.42)
2,087 (40.54)
2,082 (40.44)
Grade III
38,300 (57.14)
2,994 (58.16)
2,999 (58.26)
Grade IV
93 (0.14)
6 (0.12)
8 (0.16)
Table 4 (continued)
Data after PSM SPC, n (%) 5,148
18 (0.35) 1,582 (30.73) 3,548 (68.92)
4,413 (85.72) 554 (10.76) 181 (3.52)
61 (1.18) 2,087 (40.54) 2,994 (58.16)
6 (0.12)
P value 0.870 0.986 0.954
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
Translational Andrology and Urology, Vol 10, No 2 February 2021
747
Table 4 (continued)
Variables
PPC, n (%)
Data before PSM SPC, n (%)
P value
PPC, n (%)
Data after PSM SPC, n (%)
P value
Histology
0.314
0.785
Adenocarcinoma
66,726 (99.55)
5,120 (99.46)
5,122 (99.49)
5,120 (99.46)
Non-adenocarcinoma
299 (0.45)
28 (0.54)
26 (0.51)
28 (0.54)
TNM stage
<0.001
0.999
I
17,643 (26.32)
1,413 (27.45)
1,413 (27.45)
1,413 (27.45)
II
42,331 (63.16)
3,289 (63.89)
3,288 (63.87)
3,289 (63.89)
III
7,051 (10.52)
446 (8.66)
447 (8.68)
446 (8.66)
PSA, ng/mL
<0.001
0.999
≤4
10,215 (15.24)
816 (15.85)
817 (15.87)
816 (15.85)
4–10
43,021 (64.19)
3,148 (61.15)
3,149 (61.17)
3,148 (61.15)
10–20
9,204 (13.73)
801 (15.56)
803 (15.60)
801 (15.56)
>20
4,585 (6.84)
383 (7.44)
379 (7.36)
383 (7.44)
Gleason score
<0.001
0.988
≤6
31,666 (47.25)
2,272 (44.13)
2,269 (44.08)
2,272 (44.13)
7
26,257 (39.17)
2,006 (38.97)
2,003 (38.91)
2,006 (38.97)
8–10
9,102 (13.58)
870 (16.90)
876 (17.02)
870 (16.90)
Surgery
<0.001
0.897
No
38,930 (58.08)
3,645 (70.80)
3,639 (70.69)
3,645 (70.80)
Yes
28,095 (41.92)
1,503 (29.20)
1,509 (29.31)
1,503 (29.20)
Radiation
<0.001
0.921
No/unknown
40,946 (61.09)
2,915 (56.62)
2,910 (56.53)
2,915 (56.62)
Yes
26,079 (38.91)
2,233 (43.38)
2,238 (43.47)
2,233 (43.38)
Chemotherapy
0.371
0.297
No/unknown
66,883 (99.79)
5,134 (99.73)
5,139 (99.83)
5,134 (99.73)
Yes
142 (0.21)
14 (0.27)
9 (0.17)
14 (0.27)
Marital status
<0.001
0.919
Married
59,502 (88.78)
4,674 (90.79)
4,671 (90.73)
4,674 (90.79)
Unmarried
7,523 (11.22)
474 (9.21)
477 (9.27)
474 (9.21)
1Grade I, well differentiated; Grade II, moderately differentiated; Grade III, poorly differentiated; Grade IV, undifferentiated. SEER, Surveillance, Epidemiology, and End Results; PPC, primary prostate cancer; SPC, subsequent prostate cancer; PSA, prostate-specific antigen; PSM, propensity score matching; SD, standard deviation; SPC, subsequent primary cancer.
developing PCa after a prior cancer in the United States has been increasing in the past three decades (Figure S1). Considering that there are increasing cancer survivors develop PCa during the long-term follow up, it is necessary
to investigate the survival outcomes of this population. In this study, we found that the most common
cancer type of prior cancers in PCa survivors was from gastrointestinal system. More patients died from their
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
748
Zang et al. Prognosis of subsequent PCa patients
A
1.0
PCCS before PSM
B
1.0
OS before PSM
0.9
0.9
Survival probability
Survival probability
0.8
PPC SPC 0.7
0.8
PPC SPC 0.7
0.6
0.6
P=0.0056
P<0.0001
0.5
0
10 20 30 40 50 60 70 80 90
Survival time in month
Number at risk
0.5
0
10 20 30 40 50 60 70 80 90
Survival time in month
Number at risk
67025 66120 65185 64054 62705 60901 58494 33682 9325 0 5148 5036 4892 4739 4553 4363 4140 2332 619 0
67025 66120 65185 64054 62705 60901 58494 33682 9325 0 5148 5036 4892 4739 4553 4363 4140 2332 619 0
0
C
1.0
10 20 30 40 50 60 70 80 90
0
Survival time in month
PCCS after PSM
D
1.0
10 20 30 40 50 60 70 80 90 Survival time in month
OS after PSM
0.9
0.9
Survival probability
Survival probability
0.8
PPC SPC 0.7
0.8
PPC SPC 0.7
0.6
P=0.66
0.5
0
10 20 30 40 50 60 70 80 90
Survival time in month
Number at risk
5148 5080 4988 4872 4754 4585 4389 2538 668 0 5148 5036 4892 4739 4553 4363 4140 2332 619 0
0
10 20 30 40 50 60 70 80 90
Survival time in month
0.6
P<0.0001
0.5
0
10 20 30 40 50 60 70 80 90
Survival time in month
Number at risk
5148 5080 4988 4872 4754 4585 4389 2538 668 0 5148 5036 4892 4739 4553 4363 4140 2332 619 0
0
10 20 30 40 50 60 70 80 90
Survival time in month
Figure 3 Kaplan-Meier survival curves of patients with prostate cancer as the second primary cancer or the prior cancer. (A,B) PCSS and overall survival before PSM; (C,D) PCSS and overall survival after PSM. PCSS, prostate cancer-specific survival; PSM, propensity score matching.
prior cancer rather than PCa (38.13% vs. 16.05%) with a median follow-up of 42 months, and this tendency existed in various systems. However, the ratio of PCa deaths to prior cancer deaths was greater than 1 in all systems except for respiratory system, suggesting that PCa remained to be an important COD in men with a prior caner, especially for those with stage III–IV PCa diseases. Nevertheless, in patients with a prior cancer of respiratory system, both patients and clinicians should focus on the treatment of the prior cancer rather than PCa, regardless of the stage of PCa. Certainly, PCa patients with prior cancer of respiratory system had the shortest OS, while those with prior cancers
of skin owned the longest OS. Similarly, Ji et al. (12) reported that breast cancer patients with prior cancers of lung had the worst OS, and those with prior melanoma had the best OS, with a median follow-up of 20.96 months. It was due to the fact that lung cancer was more lethal than many other cancers (26) and prior skin cancer in PCa patients could only affect the OS slightly. Laccetti et al. (24) demonstrated that the most common type of prior cancer in patients with locally advanced lung cancer was PCa (25%), and prior PCa did not adversely affect OS in those patients. They claimed that locally advanced lung cancer patients with a prior cancer should not be excluded from clinical
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
Translational Andrology and Urology, Vol 10, No 2 February 2021
Table 5 Uni- and multivariate Cox regression model analysis of CSS
Variables
Univariate
HR
95% CI
Age, year
<65
Reference
≥65
2.777
1.985–3.885
Race
White
Reference
Black
0.598
0.371–0.965
Other
0.612
0.272–1.376
Grade1
Grade I–II
Reference
Grade III–IV
3.851
2.789–5.319
Marital status
Married
Reference
Unmarried
0.764
0.479–1.217
Gleason score
≤6
Reference
7
1.956
1.351–2.830
8–10
9.800
7.025–13.673
PSA, ng/mL
≤4
Reference
4–10
1.210
0.755–1.939
10–20
3.817
2.349–6.202
>20
9.855
6.094–15.938
TNM stage
I
Reference
II
4.137
2.690–6.363
III
5.245
3.125–8.804
Histology
Adenocarcinoma
Reference
Non-adenocarcinoma
2.300
0.737–7.176
Diagnosis
PPC
Reference
SPC
0.948
0.747–1.203
Table 5 (continued)
P value <0.001
<0.001 0.059
0.035 0.235 <0.001
<0.001 0.257
0.257 <0.001
<0.001 <0.001 <0.001
0.428 <0.001 <0.001 <0.001
<0.001 <0.001
0.151
0.151 0.660
0.660
749
Multivariate
HR
95% CI
Reference 1.562
1.104–2.211
P value 0.012
0.012
Reference 1.548
0.763–3.137
0.226 0.226
Reference 1.018 3.363
Reference 0.958 2.028 3.613
Reference 1.300 1.986
0.492–2.105 1.600–7.063
0.597–1.538 1.225–3.356 2.180–5.989
0.690–2.452 0.936–4.211
<0.001
0.962 0.001 <0.001
0.860 0.006 <0.001 0.070
0.417 0.074
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
750
Zang et al. Prognosis of subsequent PCa patients
Table 5 (continued)
Variables
Univariate
HR
95% CI
P value
Multivariate
HR
95% CI
P value
Surgery
<0.001
<0.001
No
Reference
Reference
Yes
0.297
0.205–0.430
<0.001
0.366
0.239–0.561
<0.001
1Grade I, well differentiated; Grade II, moderately differentiated; Grade III, poorly differentiated; Grade IV, undifferentiated. CI, confidence interval; CSS, cancer-specific survival; HR, hazard ratio; PPC, primary prostate cancer; PSA, prostate-specific antigen; PSM, propensity score matching; SD, standard deviation; SPC, subsequent primary cancer.
Table 6 Uni- and multivariate Cox regression model analysis of OS
Variables
Univariate
HR
95% CI
Age, year
<65
Reference
≥65
2.971
2.599–3.396
Race
White
Reference
Black
1.227
1.067–1.411
Other
0.948
0.728–1.235
Grade1
Grade I–II
Reference
Grade III–IV
1.582
1.433–1.747
Marital status
Married
Reference
Unmarried
1.120
0.960–1.307
Gleason score
≤6
Reference
7
1.465
1.311–1.637
8–10
2.756
2.448–3.103
PSA, ng/mL
≤4
Reference
4–10
1.146
0.986–1.332
10–20
2.100
1.776–2.483
>20
3.381
2.824–4.049
Table 6 (continued)
P value <0.001
<0.001 0.014
0.004 0.691 <0.001
<0.001 0.150
0.150 <0.001
<0.001 <0.001 <0.001
0.077 <0.001 <0.001
Multivariate
HR
95% CI
Reference 2.008
1.747–2.307
Reference 1.155 0.760
1.003–1.330 0.583–0.991
Reference 1.035
0.829–1.292
P value <0.001
<0.001 0.013
0.046 0.042 0.763
0.763
Reference 1.235 1.854
Reference 0.963 1.378 1.877
<0.001
0.972–1.569 1.435–2.395
0.084 <0.001 <0.001
0.828–1.120 1.152–1.648 1.548–2.277
0.625 <0.001 <0.001
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
Original Article
Survival outcomes in prostate cancer patients with a prior cancer
Yan Zang1#, Feng Qi2#, Yifei Cheng3#, Tian Xia4, Rongrong Xiao4, Xiao Li2, Ningli Yang1
1Department of Bariatric and Metabolic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; 2Department of Urologic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China; 3Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; 4Department of Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China Contributions: (I) Conception and design: X Li, N Yang; (II) Administrative support: None; (III) Provision of study materials or patients: Y Zang, X Li, T Xia; (IV) Collection and assembly of data: F Qi, Y Zang, X Li; (V) Data analysis and interpretation: F Qi, Y Cheng, R Xiao; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. #These authors contributed equally to this work. Correspondence to: Xiao Li. Department of Urologic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China. Email: [email protected]; Ningli Yang. Department of Bariatric and Metabolic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Email: [email protected]
Background: To shed light on the survival outcomes of prostate cancer (PCa) patients diagnosed after a prior cancer and identify prognostic factors for overall survival (OS) and cancer-specific survival (CSS) in PCa patients. Methods: In the primary group, a total of 1,778 PCa patients with a prior cancer were identified in the Surveillance, Epidemiology, and End Results (SEER) database from 2005 to 2015, retrospectively. Baseline characteristics and causes of death (COD) of these patients were collected and compared. In the second group, a total of 10,296 PCa patients [5,148 patients with PCa as the only malignancy and 5,148 patients with PCa as their second primary malignancy (SPM)] diagnosed between 2010 and 2011 were extracted to investigate the impact of prior cancers on survival outcomes. Results: In PCa patients with a prior cancer, the most common type of prior cancer was from gastrointestinal system (29.92%), followed by urinary system (21.37%). Patients were more likely to die of the prior caner, and those with prior cancer from respiratory system had the worst survival outcomes. Moreover, the overall ratios in patients with stage (PCa) I–II and III–IV diseases were 0.21 and 1.65, indicating that patients with higher stage diseases were more likely to die of PCa. In the second group, patients with PCa as the SPM had worse OS than those with PCa as the first primary cancer. Lastly, prognostic factors for OS and CSS in PCa patients were explored. Conclusions: PCa remains to be an important COD for patients with a prior malignancy, especially for those with high-stage diseases. PCa patients with a prior cancer had worse survival outcomes than those without.
Keywords: Prostate cancer (PCa); Surveillance, Epidemiology, and End Results (SEER); survival; prior cancer; prognostic factor
Submitted Apr 27, 2020. Accepted for publication Dec 04, 2020. doi: 10.21037/tau-20-897 View this article at: http://dx.doi.org/10.21037/tau-20-897
Introduction
Prostate cancer (PCa) is one of the most common malignancies in genitourinary system globally (1). In
2020, the estimated newly diagnosed cases and deaths are 191,930 and 33,330 in the United States (2). In the United States and some European countries, the incidence rate of PCa has exceeded lung cancer to be the leading cause
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
742
of male malignancies. Even though, disease progression of PCa could be well controlled by surgery, radiotherapy and endocrine therapy. It was reported that the 5-year overall survival (OS) rate for PCa was up to 90% in many institutions (3-5).
Overall, the 5-year relative survival rate of cancer survivors has been increasing during the past decades (up to 66%) due to the improvement in cancer detection and treatment (6,7). As a result, the number of cancer survivors is increasing recently. Statistically, the overall estimated cancer survivors in men and women were 7,377,100 and 8,156,120 in 2016 in the United States (8), and this population showed an annual growth trend of 2% (9). Considering the increasing number of cancer survivors, the probability of developing a second primary malignancy (SPM) also increased accordingly (10). Hence, many patients may develop tumors of multiple organs or systems during their lifetime (11).
An SPM is defined as a cancer which arises in a new organ or tissue independently at least 2 months after the initial diagnosis of the prior primary malignancy (12-14). Previous studies have already discussed the critical role of SPM in many cancer types, such as breast cancer (11,15,16), Hodgkin lymphoma (17), cervical cancer (18) and so on. He et al. (19) found that there was an excessive risk of developing an SPM in young-onset (age ≤50 years old) colorectal cancer survivors. Additionally, the risk of developing SPMs was reversely correlated to age. Donin et al. (20) demonstrated that about 1 in 12 patients would develop a second malignancy during their lifetime, and the most common type of SPMs was lung cancer. Moreover, they discovered that more than half of patients with two primary cancers died of the second malignancy totally.
Most previous studies have focused on the risk of developing an SPM after a known tumor. However, the risk of a specific tumor as an SPM in patients with a prior cancer and survival outcomes for these patients have not been widely discussed. Ji et al. (12) found that the most common type of prior cancer in breast cancer patients was gynecologic cancer, followed by gastrointestinal cancer. Besides, treatment for breast cancer significantly decreased the risk of breast cancer specific morality. As PCa was traditionally considered to be an indolent cancer, many cancer survivors or clinicians may not feel it worth treating after weighing the risks and benefits when it was diagnosed after another malignancy (21), and there were rare studies on this topic. Hence, we developed this study on the basis of the Surveillance, Epidemiology, and End Results (SEER) database to achieve a deeper understanding of the survival
Zang et al. Prognosis of subsequent PCa patients
patterns and risk factors for patients with subsequent PCa. Additionally, we present the following article in accordance with the STROBE reporting checklist (available at http:// dx.doi.org/10.21037/tau-20-897).
Methods
All the raw data utilized in this study were retrospectively extracted from the SEER database. SEER registry is a public database supported by the US National Cancer Institute to collect relevant information of cancer patients, including demographic characteristics, incidence rates, treatments and survival outcomes. In the beginning, there were only nine regions participated in this project, while approximately 30% of the US population are covered in the database till now. In our study, we signed the user agreement and gained access to the database with the username of 15440-Nov2018. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Additionally, this study was exempt by Institutional Review Board (IRB) approval because the original data were from a public database and individual consent for this retrospective analysis was waived.
Primary group
In the primary group, PCa patients with a prior cancer were extracted from the SEER 9 registry using the “multiple primary-standard incidence ratio” function via the SEER*Stat software (Version 8.3.6; NCI, Bethesda, USA). The initial inclusion criteria were as follows: (I) PCa was the second malignancy of each patient, (II) patients with active follow-up after cancer diagnosis, (III) year of PCa diagnosis was from 2005 to 2015. Additionally, the exclusion criteria were as below: (I) patients with missing or unknown data [race =13, prostate-specific antigen (PSA) =2,586, Gleason score =3,336, stage =2,334, T stage =255, N stage =17, M stage =1, cause of death (COD) =1 and the administration of surgery =5], (II) patients with three or more malignancies in total (n=3), (III) diagnosed by autopsy or death certificate only, (IV) diagnosis interval between PCa and the prior cancer was less than two months.
Afterwards, baseline characteristics and clinicopathological data were extracted for each patient, including age at diagnosis, race, histological type, marital status, types of the prior cancers, American Joint Committee on Cancer (AJCC) 6th TNM stage, Gleason score, PSA level, diagnosis intervals between two cancers, administration of surgery, COD and
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
Translational Andrology and Urology, Vol 10, No 2 February 2021
follow-up. In this study, age at diagnosis was divided into <65 and ≥65 years old. Race was classified into Black, White and Other (including American Indian/AK Native, Asian/ Pacific Islander). PSA was categorized into ≤4, 4–10, 10–20 and >20 ng/mL. Gleason score fell into three categories: ≤6, 7 and 8–10. Furthermore, prior cancers were classified based on different systems, such as gastrointestinal system, urinary system, respiratory system, oral cavity and so on. Finally, for patients who died during the follow-up, COD were categorized into PCa, the prior cancer and other causes.
Firstly, the 5 most common types of the prior cancers were identified according to the frequency of occurrence, and Kaplan-Meier (KM) analyses were performed to probe the survival impacts of these cancers. Then, we calculated the percentage of PCa-related deaths and prior cancerrelated deaths in different cancer types. Furthermore, basic and pathological outcomes between patients who died of PCa and those died of the prior cancer were compared. Finally, the ratio of PCa deaths to prior cancer deaths was obtained for each prior cancer type, further stratified by PCa TNM stage.
Second group
In the second group, patients with histologically confirmed, stage I–III PCa from 2010 to 2011 were identified from the SEER 18 registry utilizing the “case listing session” tool. The enrolled patients were grouped into primary prostate cancer (PPC) and subsequent prostate cancer (SPC) according to whether there was a prior cancer before PCa diagnosis. The propensity score matching (PSM) method was developed with a ratio of 1:1 to balance the baseline characteristics. Comparisons between patients with PPC and SPC in survival outcomes were made to explore the impact of the prior cancers on survival. Finally, uni- and multivariate Cox regression analyses were constructed to identify the prognostic factors in PCa patients.
Statistical analysis
Student’s t-test and chi-square analyses were used for the comparisons in baseline characteristics and clinicopathological data, respectively. Survival outcomes were compared utilizing the KM analyses. The whole analysis was performed via SPSS 23.0 software (SPSS Inc, Chicago, IL, USA) and R software (Version 3.4.1). A twosided P<0.05 was considered to be statistically significant.
743
Results
Baseline characteristics of the primary group
A total of 1,778 eligible patients were included in the primary group. The median (interquartile range, IQR) ages at diagnosis of the prior caner and PCa were 64 [58–70] and 68 [63–74] years old. The median (IQR) diagnosis interval between two cancers was 40.5 [19–66] months. Overall, the majority of enrolled patients had their cancer diagnosed at earlier TNM stage (I–II: 76.94% and 86.33% for the prior cancer and PCa, respectively). Besides, the median (IQR) follow-up after PCa diagnosis was 42 (23.00–63.75) months (Table 1). In the primary group, the 5 most common types of prior cancer were from gastrointestinal system (29.92%), urinary system (21.37%), skin (19.97%), respiratory system (11.59%) and oral cavity and pharynx (7.31%) (Table 2). On the whole, a total of 299 patients died during the follow-up, and patients with prior cancer of respiratory system had the highest mortality (30.58%).
Survival outcomes in the primary group
As shown in Figure 1, OS was significantly different in patients with different types of prior cancer (P<0.001). PCa patients with prior cancers of respiratory system had the worst survival outcomes [10-year OS: 59.1%, 95% confidence interval (CI), 50.9–68.8%], while those with prior cancers of skin owned the longest OS (10-year OS: 85.8%, 95% CI, 80.9–90.9%).
On COD, 38.13% of patients died of the prior cancer and 16.05% of patients died of PCa (Figure 2A). When stratified by cancer types, we found that in patients with cancers of respiratory system, the prior cancer-related death rate was the highest (44.44%) and the PCa-related death rate was relatively lower (12.70%). The highest PCarelated death rate (19.64%) was found in patients with prior urological cancers. Hence, conclusions could be drawn that died of prior cancers was the main COD in these patients. Then, we compared the ratio of PCa deaths to prior cancer deaths in patients. As shown in Figure 2B, the overall ratios in patients with stage (PCa) I–II and III–IV diseases were 0.21 and 1.65, indicating that patients with higher stage diseases were more likely to die of PCa. Analogously, similar trends were detected in the majority of cancer types. However, in patients with prior cancers of respiratory system, they may be more likely to die of the first primary malignancy regardless of the PCa TNM stage (the ratio was 0.22 and 0.60 in stage I–II and III–IV diseases, respectively).
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
744
Zang et al. Prognosis of subsequent PCa patients
Table 1 Demographic and clinical factors of PCa patients with a prior cancer (n=1,778)
Variables
At prior cancer diagnosis
Age, year
Mean (SD)
64.31 (8.64)
Median (IQR)
64.00 (58.00, 70.00)
Race, n (%)
White
1,415 (79.58)
Black
277 (15.58)
Other
86 (4.84)
Marital status, n (%)
Married
1,411 (79.36)
Unmarried
189 (10.63)
Unknown
178 (10.01)
TNM stage, n (%)
I–II
1,368 (76.94)
III–IV
410 (23.06)
Interval between diagnoses, months
Mean (SD)
45.46 (31.83)
Median (IQR)
40.50 (19.00, 66.00)
Time from PCa diagnosis to death or end of study months
Mean (SD)
Median (IQR)
IQR, interquartile range; PCa, prostate cancer; SD, standard deviation.
At PCa diagnosis
68.09 (8.33) 68.00 (63.00, 74.00)
1,415 (79.58) 277 (15.58) 86 (4.84)
1,400 (78.74) 167 (9.39) 211 (11.87)
1,535 (86.33) 243 (13.67)
44.09 (23.42) 42.00 (23.00, 63.75)
Table 2 Classification of the prior malignancy, stratified by system
Systems
N (%)
Detailed cancers
Gastrointestinal system
532 (29.92)
Esophagus, stomach, liver, colon, rectum and so on
Urinary system
380 (21.37)
Bladder, kidney, renal pelvic and ureter
Skin
355 (19.97)
Melanoma and other non-epithelial skin cancers
Respiratory system
206 (11.59)
Lung, bronchus, larynx and nose
Oral cavity and pharynx
130 (7.31)
Tongue, tonsil, mouth and pharynx
Others
175 (9.84)
Others
Overall
1,778 (100.00)
All of the above
Death, n (%) 94 (17.67) 56 (14.74) 39 (10.99) 63 (30.58) 33 (18.86) 14 (8.00)
299 (16.82)
In Table 3, we found that age at PCa diagnosis (P<0.001), the rates of PSA >20 ng/mL (P<0.001), Gleason score 8–10 (P<0.001), TNM stage III–IV (PCa) diseases (P<0.001) and Tx/N1/Mx or Tx/Nx/M1 (PCa) diseases (P=0.026)
were significantly higher in patients who died of PCa when compared with those who died of the prior cancer. Furthermore, the metastatic rate (P<0.001) of the prior cancer was significantly higher in patients who died of a prior cancer.
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
Translational Andrology and Urology, Vol 10, No 2 February 2021 1.0
Survival probability
0.8
Gastrointestinal
Urinary
Skin
Respiratory
0.6
Oral
p<0.0001
0.4
0
50
100
150
Survivar time in months
Number at risk
532
445
238
21
380
317
144
12
355
313
152
10
206
160
70
5
130
103
36
1
0
50
100
150
Survivar time in months
Figure 1 Overall survival of prostate cancer patients with a prior cancer.
Survival of patients with PCa as the prior cancer or subsequent primary cancer in the second group
A total of 72,173 patients were enrolled in the second group, including 67,025 patients had PCa as their first primary malignancy and 5,148 patients had PCa as the SPM. As shown in Table 4, significant differences were detected between two groups in many variables, including age at diagnosis, race, PSA level, Gleason score, TNM stage, marital status, administration of surgery and radiotherapy (all P<0.05). To reduce the selection bias, a 1:1 PSM was developed and a total of 5,148 pairs of patients were eventually enrolled. As shown in Figure 3A,B, better survival outcomes were detected in patients with PPC when compared with those with SPC (P<0.05). After PSM, no significant difference was detected in prostate cancer-specific survival (PCSS) between two groups (P=0.66, Figure 3C), while significant shorter OS was found in patients with SPC when compared with those with PPC (P<0.001, Figure 3D). Lastly, uni- and multivariate Cox regression analyses were conducted to explore prognostic factors associated to OS and PCSS in PCa patients. Multivariate analysis revealed that age at diagnosis, Gleason score, PSA level, TNM stage and administration of surgery were risk factors for cancer-specific survival (CSS) (all P<0.05, Table 5). Similarly, age at diagnosis,
745
A
Overall
Oral
Respiratory
Skin
Urinary
Gastrointestinal
16.05 (n=48) 9.09 (n=3)
12.70 (n=8) 17.95 (n=7) 19.64 (n=11) 18.09 (n=17)
38.13 (n=114) 33.33 (n=11)
44.44 (n=28) 30.77 (n=12)
32.14 (n=18) 40.43 (n=38)
0
5 10 15 20 25 30 35 40 45 50
Died of Prior cancer
B
Overall
0.21 (20/97)
Oral Respiratory
0 (0/10)
0.60 (3/5) 0.22 (5/23)
Skin
0.36 (4/11)
Urinary
0.40 (6/15)
Gastrointestinal 0.15 (5/33)
Died of PCa 1.65 (28/17)
3.00 (3/1)
3.00 (3/1) 1.67 (5/3)
2.40 (12/5)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
I–II
III–IV
Figure 2 Survival outcomes among patients with different types of prior cancer. (A) The percentage of deaths related to prostate cancer or prior cancer among patients with different types of prior cancer, (B) ratio of prostate cancer deaths to prior cancer deaths.
race, Gleason score, PSA level, sequence of PCa (PPC vs. SPC) and administration of surgery were recognized as prognostic factors for OS (all P<0.05, Table 6).
Discussion
Nowadays, with the increase of cancer survivors, the risk of developing SPMs has also been increasing accordingly. Additionally, prior cancer played an important role in treatment strategies and clinical trials design (22). It was traditionally accepted that patients with prior cancers should be excluded in clinical trials, which may due to the assumption that prior cancers may impact the survival outcomes (23,24). Consequently, numerous patients with a prior cancer would be excluded from clinical trials, leading to worse accrual and generalizability of clinical trials (22). For example, up to about 20% of lung cancer patients were excluded from taking part in trails if following such a restrictive criterion (25). However, no convincing evidence has been proposed to support this exclusion criteria and address the actual effect of a prior malignancy on cancer survivors. Moreover, the standard incidence ratio of
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
746
Zang et al. Prognosis of subsequent PCa patients
Table 3 Clinical and demographic factors associated with prostate cancer death vs. prior cancer death
Characteristics
Died from prior cancer
Number of patients
114
Age at PCa diagnosis, mean ± SD, year
70.97±8.61
PCa treated, n (%)
22 (19.30)
Gleason score 8–10, n (%)
42 (36.84)
PSA >20 ng/mL, n (%)
23 (20.18)
PCa, TNM stage III–IV, n (%)
17 (14.91)
Prior cancer, TNM stage III–IV, n (%)
45 (39.47)
PCa, Tx/N1/Mx or Tx/Nx/M1, n (%)
8 (7.02)
Prior cancer, Tx/N1-3/Mx or Tx/Nx/M1, n (%)
47 (41.23)
Interval between diagnoses, mean ± SD, month
34.63±28.50
Kinds of the prior cancers, n (%)
Gastrointestinal system
38 (33.33)
Urinary system
18 (15.79)
Skin
12 (10.53)
Respiratory system
28 (24.56)
Oral cavity and pharynx
11 (9.65)
Others
7 (6.14)
PCa, prostate cancer; PSA, prostate-specific antigen; SD, standard deviation.
Died from PCa 48
77.29±9.07 13 (27.08) 37 (77.08) 25 (52.08) 28 (58.33)
9 (18.75) 9 (18.75) 6 (12.50) 42.44±32.70
17 (35.41) 11 (22.92)
7 (14.58) 8 (16.67) 3 (6.25) 2 (4.17)
P value
<0.001 0.272
<0.001 <0.001 <0.001
0.011 0.026 <0.001 0.130 0.683
Table 4 Baseline characteristics of patients with PPC or SPC from the SEER database 2010–2011
Variables
PPC, n (%)
Data before PSM SPC, n (%)
P value
PPC, n (%)
N
67,025
5,148
5,148
Age (year)
<0.001
<45
427 (0.64)
18 (0.35)
15 (0.29)
45–65
32,361 (48.28)
1,582 (30.73)
1,586 (30.81)
≥65
34,237 (51.08)
3,548 (68.92)
3,547 (68.90)
Race
<0.001
White
52,811 (78.79)
4,413 (85.72)
4,414 (85.74)
Black
10,761 (16.06)
554 (10.76)
556 (10.80)
Other
3,453 (5.15)
181 (3.52)
178 (3.46)
Grade1
0.488
Grade I
873 (1.30)
61 (1.18)
59 (1.15)
Grade II
27,759 (41.42)
2,087 (40.54)
2,082 (40.44)
Grade III
38,300 (57.14)
2,994 (58.16)
2,999 (58.26)
Grade IV
93 (0.14)
6 (0.12)
8 (0.16)
Table 4 (continued)
Data after PSM SPC, n (%) 5,148
18 (0.35) 1,582 (30.73) 3,548 (68.92)
4,413 (85.72) 554 (10.76) 181 (3.52)
61 (1.18) 2,087 (40.54) 2,994 (58.16)
6 (0.12)
P value 0.870 0.986 0.954
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
Translational Andrology and Urology, Vol 10, No 2 February 2021
747
Table 4 (continued)
Variables
PPC, n (%)
Data before PSM SPC, n (%)
P value
PPC, n (%)
Data after PSM SPC, n (%)
P value
Histology
0.314
0.785
Adenocarcinoma
66,726 (99.55)
5,120 (99.46)
5,122 (99.49)
5,120 (99.46)
Non-adenocarcinoma
299 (0.45)
28 (0.54)
26 (0.51)
28 (0.54)
TNM stage
<0.001
0.999
I
17,643 (26.32)
1,413 (27.45)
1,413 (27.45)
1,413 (27.45)
II
42,331 (63.16)
3,289 (63.89)
3,288 (63.87)
3,289 (63.89)
III
7,051 (10.52)
446 (8.66)
447 (8.68)
446 (8.66)
PSA, ng/mL
<0.001
0.999
≤4
10,215 (15.24)
816 (15.85)
817 (15.87)
816 (15.85)
4–10
43,021 (64.19)
3,148 (61.15)
3,149 (61.17)
3,148 (61.15)
10–20
9,204 (13.73)
801 (15.56)
803 (15.60)
801 (15.56)
>20
4,585 (6.84)
383 (7.44)
379 (7.36)
383 (7.44)
Gleason score
<0.001
0.988
≤6
31,666 (47.25)
2,272 (44.13)
2,269 (44.08)
2,272 (44.13)
7
26,257 (39.17)
2,006 (38.97)
2,003 (38.91)
2,006 (38.97)
8–10
9,102 (13.58)
870 (16.90)
876 (17.02)
870 (16.90)
Surgery
<0.001
0.897
No
38,930 (58.08)
3,645 (70.80)
3,639 (70.69)
3,645 (70.80)
Yes
28,095 (41.92)
1,503 (29.20)
1,509 (29.31)
1,503 (29.20)
Radiation
<0.001
0.921
No/unknown
40,946 (61.09)
2,915 (56.62)
2,910 (56.53)
2,915 (56.62)
Yes
26,079 (38.91)
2,233 (43.38)
2,238 (43.47)
2,233 (43.38)
Chemotherapy
0.371
0.297
No/unknown
66,883 (99.79)
5,134 (99.73)
5,139 (99.83)
5,134 (99.73)
Yes
142 (0.21)
14 (0.27)
9 (0.17)
14 (0.27)
Marital status
<0.001
0.919
Married
59,502 (88.78)
4,674 (90.79)
4,671 (90.73)
4,674 (90.79)
Unmarried
7,523 (11.22)
474 (9.21)
477 (9.27)
474 (9.21)
1Grade I, well differentiated; Grade II, moderately differentiated; Grade III, poorly differentiated; Grade IV, undifferentiated. SEER, Surveillance, Epidemiology, and End Results; PPC, primary prostate cancer; SPC, subsequent prostate cancer; PSA, prostate-specific antigen; PSM, propensity score matching; SD, standard deviation; SPC, subsequent primary cancer.
developing PCa after a prior cancer in the United States has been increasing in the past three decades (Figure S1). Considering that there are increasing cancer survivors develop PCa during the long-term follow up, it is necessary
to investigate the survival outcomes of this population. In this study, we found that the most common
cancer type of prior cancers in PCa survivors was from gastrointestinal system. More patients died from their
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
748
Zang et al. Prognosis of subsequent PCa patients
A
1.0
PCCS before PSM
B
1.0
OS before PSM
0.9
0.9
Survival probability
Survival probability
0.8
PPC SPC 0.7
0.8
PPC SPC 0.7
0.6
0.6
P=0.0056
P<0.0001
0.5
0
10 20 30 40 50 60 70 80 90
Survival time in month
Number at risk
0.5
0
10 20 30 40 50 60 70 80 90
Survival time in month
Number at risk
67025 66120 65185 64054 62705 60901 58494 33682 9325 0 5148 5036 4892 4739 4553 4363 4140 2332 619 0
67025 66120 65185 64054 62705 60901 58494 33682 9325 0 5148 5036 4892 4739 4553 4363 4140 2332 619 0
0
C
1.0
10 20 30 40 50 60 70 80 90
0
Survival time in month
PCCS after PSM
D
1.0
10 20 30 40 50 60 70 80 90 Survival time in month
OS after PSM
0.9
0.9
Survival probability
Survival probability
0.8
PPC SPC 0.7
0.8
PPC SPC 0.7
0.6
P=0.66
0.5
0
10 20 30 40 50 60 70 80 90
Survival time in month
Number at risk
5148 5080 4988 4872 4754 4585 4389 2538 668 0 5148 5036 4892 4739 4553 4363 4140 2332 619 0
0
10 20 30 40 50 60 70 80 90
Survival time in month
0.6
P<0.0001
0.5
0
10 20 30 40 50 60 70 80 90
Survival time in month
Number at risk
5148 5080 4988 4872 4754 4585 4389 2538 668 0 5148 5036 4892 4739 4553 4363 4140 2332 619 0
0
10 20 30 40 50 60 70 80 90
Survival time in month
Figure 3 Kaplan-Meier survival curves of patients with prostate cancer as the second primary cancer or the prior cancer. (A,B) PCSS and overall survival before PSM; (C,D) PCSS and overall survival after PSM. PCSS, prostate cancer-specific survival; PSM, propensity score matching.
prior cancer rather than PCa (38.13% vs. 16.05%) with a median follow-up of 42 months, and this tendency existed in various systems. However, the ratio of PCa deaths to prior cancer deaths was greater than 1 in all systems except for respiratory system, suggesting that PCa remained to be an important COD in men with a prior caner, especially for those with stage III–IV PCa diseases. Nevertheless, in patients with a prior cancer of respiratory system, both patients and clinicians should focus on the treatment of the prior cancer rather than PCa, regardless of the stage of PCa. Certainly, PCa patients with prior cancer of respiratory system had the shortest OS, while those with prior cancers
of skin owned the longest OS. Similarly, Ji et al. (12) reported that breast cancer patients with prior cancers of lung had the worst OS, and those with prior melanoma had the best OS, with a median follow-up of 20.96 months. It was due to the fact that lung cancer was more lethal than many other cancers (26) and prior skin cancer in PCa patients could only affect the OS slightly. Laccetti et al. (24) demonstrated that the most common type of prior cancer in patients with locally advanced lung cancer was PCa (25%), and prior PCa did not adversely affect OS in those patients. They claimed that locally advanced lung cancer patients with a prior cancer should not be excluded from clinical
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
Translational Andrology and Urology, Vol 10, No 2 February 2021
Table 5 Uni- and multivariate Cox regression model analysis of CSS
Variables
Univariate
HR
95% CI
Age, year
<65
Reference
≥65
2.777
1.985–3.885
Race
White
Reference
Black
0.598
0.371–0.965
Other
0.612
0.272–1.376
Grade1
Grade I–II
Reference
Grade III–IV
3.851
2.789–5.319
Marital status
Married
Reference
Unmarried
0.764
0.479–1.217
Gleason score
≤6
Reference
7
1.956
1.351–2.830
8–10
9.800
7.025–13.673
PSA, ng/mL
≤4
Reference
4–10
1.210
0.755–1.939
10–20
3.817
2.349–6.202
>20
9.855
6.094–15.938
TNM stage
I
Reference
II
4.137
2.690–6.363
III
5.245
3.125–8.804
Histology
Adenocarcinoma
Reference
Non-adenocarcinoma
2.300
0.737–7.176
Diagnosis
PPC
Reference
SPC
0.948
0.747–1.203
Table 5 (continued)
P value <0.001
<0.001 0.059
0.035 0.235 <0.001
<0.001 0.257
0.257 <0.001
<0.001 <0.001 <0.001
0.428 <0.001 <0.001 <0.001
<0.001 <0.001
0.151
0.151 0.660
0.660
749
Multivariate
HR
95% CI
Reference 1.562
1.104–2.211
P value 0.012
0.012
Reference 1.548
0.763–3.137
0.226 0.226
Reference 1.018 3.363
Reference 0.958 2.028 3.613
Reference 1.300 1.986
0.492–2.105 1.600–7.063
0.597–1.538 1.225–3.356 2.180–5.989
0.690–2.452 0.936–4.211
<0.001
0.962 0.001 <0.001
0.860 0.006 <0.001 0.070
0.417 0.074
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897
750
Zang et al. Prognosis of subsequent PCa patients
Table 5 (continued)
Variables
Univariate
HR
95% CI
P value
Multivariate
HR
95% CI
P value
Surgery
<0.001
<0.001
No
Reference
Reference
Yes
0.297
0.205–0.430
<0.001
0.366
0.239–0.561
<0.001
1Grade I, well differentiated; Grade II, moderately differentiated; Grade III, poorly differentiated; Grade IV, undifferentiated. CI, confidence interval; CSS, cancer-specific survival; HR, hazard ratio; PPC, primary prostate cancer; PSA, prostate-specific antigen; PSM, propensity score matching; SD, standard deviation; SPC, subsequent primary cancer.
Table 6 Uni- and multivariate Cox regression model analysis of OS
Variables
Univariate
HR
95% CI
Age, year
<65
Reference
≥65
2.971
2.599–3.396
Race
White
Reference
Black
1.227
1.067–1.411
Other
0.948
0.728–1.235
Grade1
Grade I–II
Reference
Grade III–IV
1.582
1.433–1.747
Marital status
Married
Reference
Unmarried
1.120
0.960–1.307
Gleason score
≤6
Reference
7
1.465
1.311–1.637
8–10
2.756
2.448–3.103
PSA, ng/mL
≤4
Reference
4–10
1.146
0.986–1.332
10–20
2.100
1.776–2.483
>20
3.381
2.824–4.049
Table 6 (continued)
P value <0.001
<0.001 0.014
0.004 0.691 <0.001
<0.001 0.150
0.150 <0.001
<0.001 <0.001 <0.001
0.077 <0.001 <0.001
Multivariate
HR
95% CI
Reference 2.008
1.747–2.307
Reference 1.155 0.760
1.003–1.330 0.583–0.991
Reference 1.035
0.829–1.292
P value <0.001
<0.001 0.013
0.046 0.042 0.763
0.763
Reference 1.235 1.854
Reference 0.963 1.378 1.877
<0.001
0.972–1.569 1.435–2.395
0.084 <0.001 <0.001
0.828–1.120 1.152–1.648 1.548–2.277
0.625 <0.001 <0.001
© Translational Andrology and Urology. All rights reserved.
Transl Androl Urol 2021;10(2):741-753 | http://dx.doi.org/10.21037/tau-20-897