DOI: https://doi.org/10.21203/rs.2.13039/v1
Lung cancer and tuberculosis (TB) represent major public health problems worldwide, especially in developing countries. In China, the annual numbers of new cases of lung cancer and tuberculosis were estimated to be nearly 3,804,000 cases in 2014 [1] and 889,000 cases in 2017 [2], respectively.
The possible relationship between lung cancer and TB has attracted attention for several decades. An increasing number of studies have demonstrated that TB is associated with an increased risk and mortality of lung cancer and vice versa [3-6]. However, data concerning tuberculosis treatment in lung cancer patients are still incomplete, except for studies involving a small number of patients and showing inconsistent results [7, 8].
To investigate the treatment responses of TB in lung cancer patients, we performed a retrospective case-control study in a cohort of patients.
Setting
The study was performed at Anhui Provincial Chest Hospital, a tertiary referral hospital for TB in Anhui Province that has an intermediate incidence of active TB cases (58.4/100,000) [9].
Design
The study was approved by the ethics committee of our hospital. Using the electronic patient data system, patients with lung cancer and lung TB were screened from January 2013 until December 2016. According to TB treatment status, patients were divided into the TB treatment group or the TB nontreatment group. Age-, sex- and cancer stage-matched control subjects were randomly selected from lung cancer patients without TB during the same period at Anhui Provincial Chest Hospital. The diagnosis of tuberculosis was made on the basis of bacteriologic, pathologic, or clinical findings [10]. The diagnosis of cancer was confirmed by histopathological examination [11]. We excluded multidrug-resistant tuberculosis in the analysis to avoid bias caused by the cases.
The treatment of lung cancer and TB was in accordance with national guidelines [10, 11]. In brief, antituberculosis chemotherapy was initially administered with three drugs: rifampicin, isoniazid, and ethambutol for at least 6 months. Anticancer chemotherapy was administered with third-generation platinum-based regimens for non-small cell lung cancer or cisplatin plus etoposide for small cell lung cancer. No molecular targeted therapy or radiotherapy for lung cancer was given to any patient during the study period.
The responses to anticancer treatment were defined according to the response evaluation criteria in solid tumors (RECIST) [12]. The outcome of antituberculosis treatment was defined according to the national guideline [11]. The side effects of chemotherapy were graded using the National Cancer Institute Common Terminology Criteria for adverse events, version 4.0.
Statistical Analysis
Continuous variables were expressed as the median (interquartile range), and differences between groups were analyzed using the Mann-Whitney test. Categorical variables were expressed as absolute values and percentages and were analyzed using the chi-square or Fisher's exact tests. P < 0.05 was considered to be statistically significant. A statistical software package was used for the analyses (SPSS 16.0, SPSS, Chicago, USA).
During the study period, 98 consecutive lung cancer patients were diagnosed with lung tuberculosis. Among them, antituberculosis treatment was administered in 47 patients (TB treatment group). The other 51 patients did not receive tuberculosis treatment (TB nontreatment group). The lung cancer control group included 51 age-, sex- and cancer stage-matched patients without TB.
The clinical characteristics of the patients in the three groups (Table 1)
Table 1 Comparison of clinical, laboratory and cancer characteristics among three groups
variable |
With TB |
Without TB |
||||||
TB treatment |
TB nontreatment |
P value |
Lung cancer |
P value |
||||
Demographic |
|
|
|
|
|
|||
Age, years |
64.0(55.0-70.0) |
67.5(64.0-75.0) |
0.006 |
65.4(60.0-70.0) |
0.997 |
|||
Male, n (%) |
45(95.7) |
43(84.3) |
0.062 |
43(84.3) |
1.000 |
|||
BMI (kg/m2) |
20.8(19.8-21.5) |
21.0(20.3-21.3) |
0.710 |
21.9(20.5-23.0) |
0.022 |
|||
Smoker, n (%) |
32(68.1) |
31(60.8) |
0.451 |
28(54.9) |
0.547 |
|||
Laboratory |
|
|
|
|
|
|||
Hypoalbuminemia, n (%) |
19(40.4) |
13(25.5) |
0.350 |
12(23.5) |
0.818 |
|||
Anemia, n (%) |
13(27.7) |
12(23.5) |
0.639 |
17(33.3) |
0.272 |
|||
Liver dysfunction, n (%) |
5(10.6) |
5(9.8) |
0.892 |
8(15.7) |
0.373 |
|||
Renal dysfunction, n (%) |
11(23.4) |
10(19.6) |
0.647 |
12(23.5) |
0.630 |
|||
ESR elevation, n (%) |
17(43.6) |
9(21.4) |
0.033 |
13(32.5) |
0.258 |
|||
Cancer |
|
|
|
|
|
|||
Tumor burden, n (%) |
44(93.6) |
43(84.3) |
0.230 |
42(82.4) |
0.790 |
|||
Type |
|
|
|
|
|
|||
Non-small cell, n (%) |
41(87.1) |
43(84.3) |
0.705 |
37(72.6) |
0.531 |
|||
Small cell, n (%) |
6(12.8) |
8(15.7) |
14(27.5) |
|||||
Stage |
|
|
|
|
|
|||
I, n (%) |
0(0) |
2(3.9) |
0.663 |
2(3.9) |
1.000 |
|||
II, n (%) |
3(6.4) |
3(5.9) |
3(5.9) |
|||||
III, n (%) |
13(27.7) |
15(29.4) |
15(29.4) |
|||||
IV, n (%) |
24(51.1) |
26(51.0) |
26(51.0) |
|||||
Hypoalbuminemia was defined as a serum albumin concentration < 35 g/L. Anemia was defined as a hemoglobin level < 120 g/L in women and < 130 g/L in men. Liver dysfunction was defined as the total bilirubin levels ≥50 μmol/L and/or prothrombin time index <50%. Renal dysfunction was defined as serum creatinine ≥ 1.5 mg/dL. ESR (erythrocyte sedimentation rate) elevation was defined as ESR ≥ 100 mm/h
The median ages in the three groups were approximately 65 years. The age of patients in the TB nontreatment group was older than that of the patients in the TB treatment group. Male patients comprised 84%-95% of each group. Compared to the TB nontreatment group, the lung cancer patients had a higher body mass index (BMI).
The laboratory findings, including hypoalbuminemia, anemia, liver and renal dysfunction, were nearly similar among the three groups. However, the erythrocyte sedimentation rate (ESR) in the TB treatment group was higher than that in the TB nontreatment group.
The cancer type and stage were similar among the three groups. Most patients had advanced non-small cell lung cancer and had tumor burdens.
Clinical course and response to anticancer treatments (Table 2, Figure-1)
Table 2 Comparison of anticancer therapies among three groups
variable |
With TB |
Without TB |
|||||
TB treatment n (%) |
TB nontreatment n (%) |
P value |
Lung cancer, n (%) |
P value |
|||
Chemotherapy regimen |
|
|
|
|
|
||
Single agent |
6(12.8) |
10(19.6) |
0.360 |
10(19.6) |
1.000 |
||
Two agents |
41(87.2) |
41(80.4) |
41(80.4) |
||||
Treatment completion rate |
|
|
|
|
|
||
Completion |
27(57.4) |
29(56.9) |
0.306 |
40(78.4) |
0.057 |
||
Delayed completion |
7(14.9) |
4(7.8) |
4(7.8) |
||||
Early termination |
6(12.8) |
12(23.5) |
3(5.9) |
||||
Reduction in dose |
5(10.6) |
6(11.8) |
3(5.9) |
||||
Active withdrawal |
2(4.3) |
0(0) |
1(2.0) |
||||
Response |
|
|
|
|
|
||
Complete response |
0(0) |
0(0) |
0.061 |
1(2.0) |
0.001 |
||
Partial response |
5(10.6) |
5(9.8) |
4(7.8) |
||||
Stable disease |
31(66.0) |
25(49.0) |
40(78.4) |
||||
Progressive disease |
11(23.4) |
21(41.2) |
6(11.8) |
||||
Median survival(weeks) |
56(26-61) |
52(32-60) |
|
57(20-64) |
|
||
KPS change |
|
|
|
|
|
||
Increase |
6(12.8) |
14(27.5) |
0.388 |
10(19.6) |
0.645 |
||
Decrease |
3(6.4) |
1(2.0) |
1(2.0) |
||||
No change |
38(80.9) |
36(70.6) |
40(78.4) |
The anticancer chemotherapy regimens and treatment completion rates were similar among the three groups. The response rates were similar between the TB treatment and TB nontreatment groups, although more patients in the TB treatment group were in stable disease. However, the response rate was significantly higher in the lung cancer group compared to the TB nontreatment group. The median survival time and KPS changes were similar among the three groups.
Clinical course and response to antituberculosis treatments (Table 3)
Table 3 Comparison of TB characteristics and therapies
variable |
TB treatment n (%) |
TB nontreatment n (%) |
P value |
Type |
|
|
|
Active |
31(66.0) |
3(5.9) |
0.000 |
Inactive |
16(34.0) |
48(94.1) |
|
Laboratory |
|
|
|
Before cancer diagnosis |
21(44.7) |
39(76.5) |
0.000 |
At the same time |
19(40.4) |
12(23.5) |
|
During anticancer therapy |
2(4.3) |
0(0) |
|
After anticancer therapy |
5(10.6) |
0(0) |
|
Diagnose of TB Culture proven Diagnosed clinically |
18
|
1
|
|
Antituberculosis regime |
|
|
|
Single agent |
2(4.3) |
- |
|
Two agents |
10(21.3) |
- |
|
≥three agents |
35(74.4) |
- |
|
Treatment completion rate |
|
|
|
Completion |
39(83.0) |
- |
|
Delayed completion |
1(2.1) |
- |
|
Early termination |
6(12.8) |
- |
|
Reduction in dose |
1(2.1) |
- |
|
Tuberculosis treatment outcome |
|
|
|
Cure |
0(0) |
0 |
0.001 |
Improvement |
27(57.4) |
0 |
|
Stabilization |
14(29.8) |
44(86.3) |
|
Deterioration |
6(12.8) |
7(13.7) |
|
Most patients in the TB treatment group (66%) had active TB, with a significantly higher percentage than that in the TB nontreatment group (5.9%). TB was diagnosed at different time points. Most patients in the TB nontreatment group (76.5%) were diagnosed with TB before cancer diagnosis. However, 55.3% of patients in the TB treatment group were newly diagnosed with TB. Most patients in the TB treatment group received multidrug combination therapy (74.4%), completed the TB treatment (83%), and had improved outcomes (57.4%).
Side effects of treatments (Table 4)
Table 4 Comparison of side effects of therapies among three groups
variable |
With TB |
Without TB |
|||||
TB treatment n (%) |
TB nontreatment n (%) |
P value |
Lung cancer n (%) |
P value |
|||
Leukocyte deficiency |
|
|
|
|
|
||
Grade 3 |
2(4.3) |
2(3.9) |
0.460 |
4(7.8) |
0.488 |
||
Grade 4 |
2(4.3) |
1(2.0) |
0(0) |
||||
Thrombocytopenia |
|
|
|
|
|
||
Grade 3 |
1(2.1) |
1(2.0) |
0.642 |
5(9.8) |
0.769 |
||
Grade 4 |
0(0) |
1(2.0) |
2(3.9) |
||||
Renal toxic effects |
|
|
|
|
|
||
Grade 3 |
0(0) |
0(0) |
0.072 |
0(0) |
0.843 |
||
Grade 4 |
0(0) |
0(0) |
0(0) |
||||
Live toxicity |
|
|
|
|
|
||
Grade 3 |
3(8.1) |
2(3.9) |
0.255 |
0(0) |
0.377 |
||
Grade 4 |
0(0) |
1(2.0) |
0(0) |
||||
Gastrointestinal toxicity |
|
|
|
|
|
||
Grade 3 |
0(0) |
1(2.0) |
0.218 |
1(2.0) |
0.412 |
||
Grade 4 |
0(0) |
0(0) |
0(0) |
||||
Cardiac toxic effects |
8(17.0) |
6(11.8) |
0.458 |
7(13.7) |
0.767 |
||
Neuropathy |
0(0) |
1(2.0) |
0.335 |
0(0) |
0.315 |
Severe toxic complications in the three groups were similar. Patients in the TB treatment group did not have more severe toxic complications.
The main finding of the current study is that patients with coexisting lung cancer and active tuberculosis could safely receive both anticancer and antituberculosis treatments. This information will help physicians make clinical management decisions for patients with coexisting lung cancer and active tuberculosis.
Lung cancer and tuberculosis are two major public health problems in China. It was demonstrated that there were 28.49 lung cancer-related deaths per 100,000 population in 2014 [1] and 2.6 tuberculosis-related deaths per 100,000 population in 2017 in China [2]. Meanwhile, lung cancer and tuberculosis have a complicated relationship, which means that they are risk factors for each other. As a tuberculosis high-burden country, the incidence of tuberculosis in lung cancer patients was as high as 12.72% in our past research [13]. In the current study, the features of patients were elderly with advanced non-small cell lung cancer. In addition, most patients in the TB treatment group were newly diagnosed and had active tuberculosis. Hence, caution should be paid to the risk of tuberculosis in lung cancer patients.
Tuberculosis treatment in cancer patients is still not conclusive, especially for advanced non-small cell lung cancer patients with synchronous antituberculosis and anticancer treatments. Kim et al. showed that in cancer patients (including 8% with lung cancer), anticancer chemotherapy is not an obstacle to treating tuberculosis [7]. Hirashima et al demonstrated that in patients with metastatic colorectal cancer, both cancer chemotherapy and tuberculosis treatment could be concurrently administered safely and efficiently[8]. In our study, comparing patients in the TB nontreatment group to lung cancer patients, tuberculosis significantly affected the response rate of anticancer treatment in the TB nontreatment patients. On the other hand, comparing patients in the TB treatment group to patients in the TB nontreatment group, synchronous antituberculosis and anticancer treatments did not lower the response rate of the anticancer treatment and did not increase the severe side effects. Therefore, our findings suggest that both anticancer and antituberculosis treatments could be safely and effectively administered in advanced lung cancer patients with tuberculosis.
Limitations
First, this was a retrospective study with inevitable selection bias. Second, the sample size was a small cohort of patients, limiting the power of the statistical analysis. Third, patients receiving molecular targeted therapy were excluded because there were too few cases for analysis.
Our results indicate that both anticancer and antituberculosis treatments can be safely and effectively administered in lung cancer patients with tuberculosis, and attention should be paid to the risk of tuberculosis in lung cancer patients in a tuberculosis high-burden country.
TB: tuberculosis; BMI: body mass index, ESR: erythrocyte sedimentation rate
Authors’ contributions
CM performed research and analyzed data; CM and SQM Design the research. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Consent for publication
none
Ethics approval and consent to participate
The study was approved by the Ethics Committee of Anhui Chest Hosptial.
Competing interests
The authors declare that they have no competing interests.
Acknowledgements
The authors acknowledge Dr. Rui Tang for the help during preparing for the manuscript.