Incidence, Treatment and Outcomes of Patients with Synchronous Lung and Colorectal Malignancies: A Nationwide Inpatient Sample Database (NIS) Analysis

doi:10.21203/rs.3.rs-4971114/v1

Purpose:

Our study aims to describe the incidence, treatment and clinical outcomes of patients with synchronous lung, and colorectal cancer (CRC).

Methods:

We conducted an 11-years analysis of the Nationwide Inpatient Sample (NIS) database (2002–2012). All adult (age ≥ 18y) patients admitted with a diagnosis of CRC were included. Data abstracted include demographics, malignancy-related variables, treatment, and operative interventions. We excluded patients who had lung metastasis from CRC. Our primary outcome measures were the incidence of synchronous CRC and lung cancer, operative treatment patterns, and mortality.

Results:

Out of 1,198,421 patients admitted with a CRC diagnosis, 6,231 (0.52%) had synchronous lung cancer. Overall, mean age was 61 ± 15y, 75% were male, and 63% were white. Most patients with synchronous malignancies (56%) had advanced CRC with non-small cell lung cancer (76%). The majority of CRC patients (79%) had recto-sigmoid tumors. Only 11.2% underwent surgical management. No significant difference was noted in the proportion of patients first treated for their CRC relative to those treated for their lung cancer first (p = 0.21). The overall mortality rate was 54%.

Conclusion:

The incidence of synchronous occurrence of CRC and lung cancer is low, but the mortality is very high. Diagnosis of synchronous cancer is typically incidental. Treatment options for these patients should be tailored to the individual patient. Genetic and epidemiological studies are required to elucidate the potential connection between lung and colon cancer.

Synchronous

Colorectal

Lung

Cancer

Lung Cancer (LC) remains the leading cause of cancer-related deaths, with Colorectal Cancer (CRC) being the third leading cause of cancer-related deaths in the US [1, 2]. Patients diagnosed with metastatic CRC may have tumors arising in locations such as the liver, lungs, and peritoneum [3]. Although CRC and lung cancer are among the most common cancers worldwide, synchronous presentation of these cancers are not very common and not well studied.

Clinically, synchronous cancers refer to the onset of a second primary cancer within 6 months of an initial cancer diagnosis or co-occurring. Although the condition is uncommon, there has been a rise in synchronous CRC cases in recent years. Insufficient data is available on the onset of synchronous cancer that this disease remains poorly understood [4]. The rarity of this clinical presentation at the onset can often lead to delay of treatment or misdiagnosis of metastasis, rather than finding the cancers to be coinciding [13].

Improvements in diagnostic modalities have contributed to the increased detection of synchronous CRCs [4]. Reported incidences range from 2.3–12.4%. [4] Additionally, the prevalence of synchronous CRC ranges from 1.1–8.1% among all CRCs [5]. Despite the increased prevalence of the disease, the most appropriate treatment options, including surgical, remain uncertain. Previous studies have shown that the treatment for synchronous cancer is different in that it is done according to the distribution of lesions [4].

Synchronous CRC differs from single origin cancer with regards to gender, age, location, as well as pathologic features [4]. Risk factors for this disease include inflammatory bowel disease, familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, hyperplastic polyposis, and microsatellite instability [6, 7]. A few case studies have demonstrated synchronous CRC in patients with liver, kidney, prostate, and lung cancers [8–11]. A majority of synchronous CRC cancers occur in the liver, followed by the lung [20].

Few case reports have indicated synchronous CRC and LC with lesions located in the rectum and the lungs; nonetheless, this identified patient population remains low, and outcomes in patients with synchronous lung and CRC are not well described [11]. Our study aimed to describe the incidence, treatment, and outcomes of patients with synchronous lung and CRC. It is important to develop a better understanding of synchronous lung and CRC in order to further advance treatment options for those affected.

Dataset

We used the Nationwide Inpatient Sample (NIS) to analyze data from 2002 to 2012 retrospectively. The NIS is one of the largest all-payer national databases in the United States developed and maintained as a part of the Health Care Cost and Utilization Project (HCUP). The NIS database includes inpatient care information from community hospitals, and teaching medical centers; however, this database does not include data from long-term facilities. Every year, the NIS provides information on nearly 7 million unweighted discharges nationally. The use of the NIS database for this study followed regulations according to the data-use agreement from the HCUP. Ultimately, this study was reviewed by the University of Arizona’s Institutional Review Board and was determined to be exempt from the need for approval. Figure 1 shows a flowchart classifying patients based on the development of colorectal cancer (CRC) alone or synchronous CRC with simultaneous lung cancer from 2002 to 2012, as listed in the NIS database. Among the 1,198,421 patients admitted with a CRC diagnosis, 6,231 had synchronous lung cancer. The patients were further categorized by tumor stage and treatment strategies.

Patient population and Stratification

Patients older the age of 18 presenting with CRC alone or synchronous CRC with simultaneous Lung Cancer were included in this study. Additionally, the codes for colon, rectal, and lung cancer were used for stratification using Ninth Revision of the International Classification of Disease Diagnosis (ICD-9 codes). To ascertain that only synchronous lung cancer patients were analyzed, metastatic lung cancer patients were excluded from the analysis. Thus, patients with ICD-9 CM code 197.0 were excluded from the analysis. 197.0: Secondary malignant neoplasm of the lung.

Variables analyzed and Outcome Measures

From the database analysis, we retrieved information on patient demographics (age, gender, race), insurance (Medicare, Medicaid, private/self-pay, other), income (lowest quartile vs. highest quartile), CRC location (hepatic flexure, transverse colon descending colon, sigmoid colon, cecum, appendix, ascending colon, splenic flexure, rectosigmoid, rectum, and anus), tumor stage (I, II, III, IV), treatment (chemotherapy, radiotherapy, colectomy, lobectomy), as well as treatment sequence (treatment of CRC first versus treatment of lung cancer first or supportive care alone).

Statistical analysis

Data with a normal distribution is reported as mean ± standard deviation (SD) for continuous variables, as median [interquartile range (IQR)] for continuous variables without normal distribution, and as proportions (% percentage) for the categorical variables. To analyze the differences between the two patient groups, we used a chi-square test for categorical variables, the Mann-Whitney U test for continuous nonparametric data, and an independent Student’s t-test for continuous parametric data.

A multivariate logistic regression was used to control for the following covariates: patient’s demographics, type of cancer, location of tumor, and the treatment sequencing and modality. First, we assessed the association between each covariate and the binary outcomes on a univariate level. Variables detected to have a p-value < 0.2 after performing the univariate analysis were selected for inclusion in the multivariable logistic regression model. Hosmer-Lemeshow goodness of fit test was used to assess the model fitness. The Hosmer-Lemeshow test exceeded 0.05 and the tolerance was greater than 0.1 for all independent variables with a variance inflation factor of less than 10.0. In this study, alpha was set at 5% and a value of p < 0.05 was considered statistically significant. All statistical analyses in our study were performed using the Statistical Package for Social Sciences (SPSS, version 24; SPSS, Inc).

A total of 1,198,421 patients were admitted to a hospital with a diagnosis of CRC of which 6,231 were found to have synchronous lung cancer. In Table 1, the demographics in patients who presented with CRC alone and synchronous CRC and Lung cancers were similar in average age, gender, whites, BMI, Medicare and Medicaid. There was a significant difference in patients with private insurance with about 8% with CRC alone versus 12% with synchronous CRC and Lung Cancer (p = 0.01). In addition, there was a statistically significant difference in patients in the low-income quartile (24% vs 26%).

Table 1: Baseline Characteristics of the Study Sample
Variable	CRC N=1,192,189	CRC + Lung Cancer N=6,231	P-Value
Demographics
Age, years ± SD	60±14	61±11	0.32
Male, %	75%	74%	0.11
White, %	67%	68%	0.38
BMI≥30 kg/m²	33%	27%	0.74
Medicare	62%	61%	0.63
Medicaid	30%	27%	0.87
Private Insurance	8%	12%	0.01*
Low Income Quartile	24%	26%	0.01*
CRC Location, %
Hepatic Flexure	2.5%	2.6%	0.17
Transverse Colon	4.8%	2.9%	0.06
Descending Colon	2.5%	10%	<0.01*
Sigmoid Colon	8%	6%	0.06
Cecum	9%	7.5%	0.64
Appendix	2%	0.3%	0.13
Ascending Colon	10%	6.2%	0.87
Splenic Flexure	2%	1%	0.32
Rectosigmoid	79%	78%	0.14
Rectum	6%	8%	0.56
Anal	2.4%	2.9%	0.74
Unspecified	0.8%	2.4%	0.01*

* p-values <0.05 is statistically significant

Most CRC patients (79%) had recto-sigmoid tumors. On the other hand, in synchronous CRC and lung cancer, the CRC location most involved was the descending colon (10%) and in unspecified locations (2.4%) when being compared to CRC cancer alone (p < 0.01). Additionally, most patients with synchronous malignancies (56%) had advanced CRC with non-small cell lung cancer (p < 0.01). In Table 2, the analysis also showed that there were more patients diagnosed with stage II CRC cancer alone (42%) compared to those with synchronous CRC cancer and lung cancer (17%).

Table 2

Tumor Stage of the Study Sample
Tumor Stage	CRC N = 1,192,189	CRC + Lung Cancer N = 6,231	P-Value
I	6%	4%	0.09
II	42%	17%	< 0.01*
III	21%	23%	0.77
IV	31%	56%	< 0.01*
* p-values < 0.05 is statistically significant

In Table 3, the majority of the patients with synchronous CRC cancer and lung cancer (54%) were treated with chemotherapy (P < 0.01) while just 15% of this cohort of patients had a colectomy. In Table 4, no significant difference was noted in the proportion of patients first treated for their CRC relative to those treated for their lung cancer first (p = 0.21). Overall, there was a statistically significant difference in the mortality rate for synchronous CRC and lung cancer versus CRC alone (65% vs 54%).

Table 3

Treatments of the Study Sample
Treatment	CRC N = 1,192,189	CRC + Lung Cancer N = 6,231	P-Value
Chemotherapy	36%	54%	< 0.01*
Radiotherapy	17%	16%	0.07
Colectomy	25%	15%	< 0.01*
Lobectomy	-	16%
* p-values < 0.05 is statistically significant

Table 4

Treatment Sequence of the Study Sample
Treatment Sequence	CRC + Lung Cancer N = 6231
Treatment of Colon Cancer First	12%
Treatment of Lung Cancer First	13%
Supportive Care Alone	75%

Table 5

Outcomes for Study Sample
Outcomes	CRC N = 1,192,189	CRC + Lung Cancer N = 6,231	P-Value
Mortality, %	54%	65%	< 0.01*
* p-values < 0.05 is statistically significant

Our study showed that synchronous CRC and lung cancer is not very common but has a significant mortality rate. The independent risk factors for CRC or lung cancer have previously been established. Cigarette smoking has been shown as a generally accepted risk factor, especially within lung cancer [11]. Previous studies have also demonstrated that obesity, diabetes, and high dietary meat intake are associated with an increased risk of colon cancer [11]. Multiple risk factors have also been found to contribute to the development of synchronous CRC. African American race, advanced age, high primary tumor grade and size, perineural invasion, elevated CEA, and existing liver metastasis are associated with synchronous CRC and lung tumors [20]. The results of our study showed some differences when it comes to demographic factors that influence CRC and synchronous CRC and lung tumors (Table 1). Previous studies have also indicated a higher incidence of synchronous CRC among men, especially in patients over 70 years [14]. Our study further reinforces this significance, as the data shows a higher percentage of men (74%) than women are diagnosed with synchronous CRC and lung cancer. In our study, the average age of diagnosis for CRC alone or synchronous with lung cancer was around 60 and primarily occurring mostly in white individuals. Interestingly, our data showed that patients with private insurance and those within the low-income quartile were more likely to have synchronous CRC than CRC alone, which was statistically significant. This could be because the patients in low-income quartile might have more comorbidities due to poor health choices and because they might have less access to healthcare.

Regarding location, synchronous CRC with LC arises more commonly in the descending colon and unspecified areas in our group of patients. This differs from metastatic CRC to the lung. Previous studies have shown that rectal and left-sided colon cancer had more predilection for lung metastasis over other sites, such as liver and peritoneum (16). It is important to consider the different venous drainage systems of the colon—the inferior rectum is drained to the systemic circulation via the inferior rectal veins while the rest of the colon drains to the portal system. This may explain why rectal tumors more commonly have metastasis to the lungs [19].

Our study demonstrates that more than half the patients diagnosed with synchronous CRC and lung cancer had advanced-stage disease. This might be because these patients might have a more aggressive disease or have a predilection for cancer. The majority of synchronous CRC and lung cancer patients (75%) undergone supportive care alone. This is quite understandable because these patients had significantly advanced diseases. These patients were also more likely to undergo chemotherapy (54%) than colectomy (15%). Lung lobectomy was performed in 16% of the individuals with synchronous lung and CRC. Overall, synchronous CRC and lung cancer were found to have higher mortality rates than CRC alone. A previous study investigating treatment outcomes in synchronous CRC with lung cancer patients found that subjects who had undergone lung tumor resection had overall better survival than those who did not, with a hazard ratio of 0.482 [17]. We were not able to determine this particular outcome in our study. Another study showed that synchronous CRC patients who had undergone pulmonary metastasectomy had a 65% 5-year survival rate [18]. However, this study looked more are pulmonary metastasis and not primary lung cancer.

Regarding the treatment sequence, our study showed 12% of patients with synchronous CRC and lung cancer underwent treatment of their colorectal cancer first. In comparison, 13% underwent treatment for their lung cancer first. As previously mentioned, most patients underwent supportive care alone. In our study, we could not determine whether any of the patients underwent concurrent management of both lung and colorectal cancer. We assume that this possibly happened. Information on the time interval between colon resections and lobectomies was not available. In one case report study of synchronous CRC and lung cancer in a patient with adenocarcinoma in both locations, confirmed using immunostaining showing primary origins in each location, the patient underwent lobectomy and months later a colon resection was performed [15]. This showed that both surgical procedures could be performed in a sequential manner.

Our study also demonstrates that patients with synchronous CRC and lung cancer have a higher mortality rate than those diagnosed with CRC alone (65% vs 54%). Our results are concurrent with other synchronous cancer studies, which have demonstrated worse outcomes of survival for synchronous CRC compared to CRC alone [14]. Due to lung cancer being the leading cause of cancer-related deaths in the US, this can be considered a contributing factor to the high mortality rate observed within synchronous cancer [2]. One study of 3,102 patients followed over 76 months found that of the 9 patients that succumbed to their illness, all 9 deaths were directly associated to the patients’ lung cancer [11]. Advanced staging (56%) can be another contributor to why higher mortality rates are seen amongst patients with synchronous CRC and lung cancer, as shown in our results. Our analysis shows that patients with synchronous CRC and lung cancer are more likely to present with stage IV than CRC alone.

One of the inherent limitations of this study is that it is a retrospective analysis and there might be missing data. We could not review the histopathology of the CRC or lung cancer to determine synchronous primary lung cancer from metastatic lung cancer. However, we excluded from this study all the lung cancers that were coded with ICD-9 CM code 197.0, which represents metastatic disease to the lungs. Another limitation of this study was the lack of staging of primary lung cancer. The assumption would have been that a higher stage of lung cancer will likely have more contribution to patient mortality. This would have also been important in determining if the high mortality in the synchronous lung and colorectal cancer was due to colorectal cancer or lung cancer. Given the fact that lung cancer is the leading cause of cancer-related deaths in the US, it is reasonable to conclude a higher stage of synchronous lung cancer is more predictive of mortality than colorectal cancer is.

The incidence of synchronous occurrence of CRC and lung cancer is low, but the mortality is very high. Diagnosis of synchronous cancer is typically incidental. These patients usually present with more advanced disease and mortality might likely be accentuated by lung cancer. Treatment options for these patients should be tailored to the individual patient. Genetic and epidemiological studies are required to elucidate the potential connection between lung and colon.

Funding: No financial or proprietary interest in the subject matter or materials discussed in the manuscript.

Conflicts of interest/Competing interest: There are no conflicts of interests to report.

Availability of data and material: Nationwide Inpatient Sample database (2002-2012)

Code availability: ICD-9 CM code 197.0

Author’s contribution:

Study Design and Conception: VN, MAA, PO, AC, MH, SS, MA, MG

Data Acquisition: MAA, PO, AC, VN, MH

Statistical Analysis: MH, MAA

Manuscript Writing: MAA, AC, VN, PO, MH, SS, MA, MG

Critical Revision: VN, MAA, AC, PO, MH, SS, MA, MG

Final Approval: VN, MAA, AC, PO, MH, SS, MA, MG

^*Contributed Equally (AC and MAA).

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No competing interests reported.

Incidence, Treatment and Outcomes of Patients with Synchronous Lung and Colorectal Malignancies: A Nationwide Inpatient Sample Database (NIS) Analysis

Status:

Version 1

Abstract

Purpose:

Methods:

Results:

Conclusion:

Figures

INTRODUCTION

METHODS

Dataset

Patient population and Stratification

Variables analyzed and Outcome Measures

Statistical analysis

RESULTS

DISCUSSION

CONCLUSION

Declarations

References

Additional Declarations

Status:

Version 1