In recent years, a large number of studies focused on SPLC, but there were few studies on DPLC. To date, little is known about the prognostic factors and clinical characteristics of DPLC. An accurate predictive model and well-defined clinical features of DPLC are urgently needed. This study retrospectively analyzed the DPLC patients extracted from SEER database between 2004–2015. Univariate Cox regression and multivariable Cox regression analysis were used to explore the significant clinical factors and these factors were used to establish a prognostic model. Apart from that, the comparison between DPLC and SPLC was analyzed according to the information from SEER database and Provincial Hospital Affiliated to Shandong University.
In this study, we found that age, sex, histological type, stage, LN metastasis, surgery, chemotherapy were significant factors which were associated with the prognosis of DPLC patients. These results were broadly consistent with other studies, but Cong-kuan Song et al found that race, grade also had an impact on prognosis of DPLC [10].
Surgical resection is a main therapeutic method which benefits the most DPLC patients to prolong their OS [11]. Our study also showed that the survival time of patients with two operations was longer than other patients without surgery. And previous studies showed that radiation and chemotherapy emerged as the effective alternative methods for patients for whom surgery was contraindicated or was not in-line with the patient’s wishes [12, 13]. However, we found that only chemotherapy could prolong survival time of DPLP, radiotherapy was not independent diagnostic factor for DPLC patients.
Astonishingly, the OS of SPLC was shorter than DPLC (Fig. 2A). We speculated that the clinical and pathological features between SPLC and DPLC were so different that the confounding factors confounded our judgment to survival time. The key prognostic factors such as grade, LN metastasis, stage were extracted to perform the PSM analysis, considering the interference of confounding factors. And the Kaplan - Meier curve showed reasonable outcome which the OS rate of DPLC was lower after PSM analysis (Fig. 2B).
Some previous study proposed a diagnostic criterion which DPLC could be divided into synchronous DPLC and metachronous DPLC according to interval time (6 months) of the 1st and 2nd tumor of DPLC [14]. Martini and Melamed thought the interval time of mMPLC was 2 years based on 50 cases in 1975[17]. But the American College of Chest Physicians put forward the diagnostic criteria that the interval time was 4 years in 2007 [16]. Our study adopted the point of view which the time was 6 months. But it was confused that the interval time wasn’t significant prognostic factor, when it was included into Cox regression analysis. Considering the influence of confounding factors, we performed the PSM to eliminate the difference between sDPLC and mDPLC, however, there still remained some bias after PSM. And the Kaplan - Meier curve showed that there were not any differences between their OS rates after PSM (p > 0.05). Cong-kuan Song et al also found the results [10]. There were two possible reasons for this, firstly, we acknowledged the statistical limitations of the study due to the small sample size, secondly, the diagnostic criteria of interval were unreasonable. There results inspired that the further research could pay an attention to define new interval time which has more prognostic significance according to more data.
The Chi-square analysis was used to examine the differences of SPLC and DPLC. We used the data from SEER database to analyze the pathological differences, and used the data from Provincial Hospital Affiliated to Shandong University to analyze the clinical differences (Table 2 and Table 3).
Table 3
The analysis of clinical characteristics between SPLC patients and DPLC patients.
Variables
|
SPLC
|
MPLC
|
|
n
|
%
|
n
|
%
|
|
Sex
|
|
|
|
|
|
Male
|
130
|
75.14
|
88
|
50.87
|
< 0.001
|
Female
|
43
|
24.86
|
85
|
49.13
|
Age
|
|
|
|
|
|
< 60
|
82
|
47.40
|
95
|
54.91
|
0.162
|
≥ 60
|
91
|
52.60
|
78
|
45.09
|
Smoke
|
|
|
|
|
|
Yes
|
119
|
68.79
|
65
|
37.57
|
< 0.001
|
No
|
54
|
31.21
|
108
|
62.43
|
Chronic disease
|
|
|
|
|
|
Yes
|
119
|
68.79
|
54
|
31.21
|
< 0.001
|
No
|
54
|
31.21
|
119
|
68.79
|
Familial-hereditary disease
|
|
|
|
|
|
Yes
|
29
|
16.76
|
28
|
16.18
|
0.885
|
No
|
144
|
83.24
|
145
|
83.82
|
Pre-cancer symptoms
|
|
|
|
|
|
Yes
|
118
|
68.21
|
93
|
53.76
|
0.006
|
No
|
55
|
31.79
|
80
|
46.24
|
LN Metastasis
|
|
|
|
|
|
Yes
|
68
|
39.31
|
44
|
25.43
|
0.006
|
No
|
105
|
60.69
|
129
|
74.57
|
The pathological differences between the SPLC and DPLC were mainly reflected in laterality, histologic type, grade and TNM stage. The histologic type of DPLC mainly was adenocarcinoma, and this conclusion was consistent with previous research [15]. The differentiated grade of DPLC was mainly Ⅲ and Ⅳ, and the number of early-stage patients made up the majority.
The clinical differences between the DPLC and SPLC mainly were sex, smoke, chronic disease, pre-cancer symptoms. In SPLC patient’s cohort, the male patients accounted for 75.14%, the female patients accounted for 24.86%. And the 119 patients with smoking habit accounted 68.79%. In DPLC patient’s cohort, the proportion of sex was about the same, and the majority of patients hadn’t the smoking habit. Most MPLC patients didn’t have chronic diseases and pre-cancer symptoms, which brought difficulties to the timely diagnosis for patients' diseases.
It is noteworthy that there are still no specific treatment guidelines and plan for DPLC. The nomogram was widely used to predict the prognosis for cancer, primarily because of their ability to include statistical predictive factors into a multivariate visualization gram [7]. Considering the advantages of nomogram, we included aforementioned independent prognostic factors to establish a nomogram for predicting the OS of patients. The effectiveness was assessed by C-index, ROC curve and calibration plot, and the assessment results indicated that the nomogram had the excellent accuracy and predictability. Clinicians used the traditional 8th AJCC TNM system to access the progression of cancer, but the system couldn’t predict the OS of patients and provide clinical guidance. And the assessment ability of the system lacked specificity for cancer subtypes. The nomogram made up for the shortcomings of the 8th AJCC TNM system, because we included clinical factors and therapy methods into the model. DCA curves were used to certify that the predictability of the new model was better than the 8th AJCC TNM system in training and validation cohort (Fig. 4 and Figure supplement 1). The IDI values also proved these results.
Our study has the following advantages. Firstly, this study established a nomogram to predict survival time of DPLC. This model could be used to improve prediction capabilities. Then, this study was the first attempt to performed the Chi-square analysis and PSM analysis for comparing the differences of DPLC and SPLC. This work expanded our knowledge of DPLC. Certainly, there are some shortcomings in our research. We did not clearly explore the differences between sDPLC and sDPLC because of the lack of data. And the patients’ number from Provincial Hospital Affiliated to Shandong University was so insufficient that the clinical features couldn’t be explored clearly. Considering the shortcomings of this study, further prospective analysis should be recommended.