LC has been the most common cancer and the leading cause of cancer-related death worldwide for several decades. And a population-based study about Global patterns and trends in lung cancer incidence showed[6] the risks among recent generations have various degrees of increasing in many countries. In the past decade, significant advances have been made in the science of non-small cell lung cancer (NSCLC). In addition to conventional chemotherapy, the treatment of lung cancer has also evolved with the introduction of several lines of tyrosine kinase inhibitors (TKIs) in patients with EGFR, ALK, ROS1, and NTRK mutations. Furthermore, ICIs have dramatically changed the treatment outlook for NSCLC. LC complicated with pulmonary tuberculosis is a special group, and most of these patients are excluded from the research on ICIs. Recent research has shown that antibiotic-induced disruption of the microbiota may impact ICI efficacy[7–10]. A systematic review and meta-analysis of study displayed[11] that despite the high heterogeneity between studies, OS still revealing a significantly reduced survival in patients with NSCLC exposed to antibiotics. And the effect seems to depend on the time window of exposure with stronger effects reported when the patients took antibiotics within 60 days around ICIs initiation[11]. However, there are no separate studies on the efficacy of between anti-TB therapy and immunotherapy[12].
According to the Tuberculosis Treatment Guidelines[13], patients with active TB should be treated as soon as possible. Our patient's sputum culture was positive for Mycobacterium tuberculosis, which met the diagnostic criteria of active TB. We gave him intensive anti-TB therapy for 3 months, but CT showed that the focus in the lung was larger than before (Fig. 1A, 1B). The patient underwent a second lung biopsy, and he was eventually diagnosed with lung adenocarcinoma and active TB. But his genetic tests suggested that there were no target mutations that could benefit. Considering that his high expression of ICIs and excluding the absolute contraindication, he was given to Pembrolizumab at the same time of anti-TB. After 2 cycles of treatment, we made a comprehensive evaluation of him, and found that the primary lesions of the lung, stomach, lymph nodes were significantly reduced (Fig. 1, 3), the curative effect evaluation reached PR.
To further elucidate the impact of anti-TB on the efficacy of ICIs, we perform a systematic review of the literature using PubMed, EMBASE and meeting proceedings. Finally, ten cases were included together with the case reported in this report (Table 1). Of the ten cases included, eightt were male and two were female with a median age of 63.7. The underlying malignancies consisted of six cases of adenocarcinoma (ADC), two cases of melanoma, one case of oral squamous cell cancer (SCC) and one case of Merkel cell carcinoma (MCC). Five were treated with pembrolizumab while five were treated with nivolumab. After treatment concurrently with anti-TB and ICIs, one patient developed immune-related adverse events (irAEs) eSjogren’s syndrome, one patient developed irAEs adrenal insufficiency, four patients developed irAEs low-grade toxic hepatic, two patients were not occurred irAEs and two patients were not documented irAEs. Except for two cases whose specific information could not be obtained (Table 2), sputum smear and sputum culture of TB were negative in six cases when ICIs was started. For the total anti-TB course, except for one case who had been treated for more than 4 years when the case was reported, the choice was between 6 and 8 months (the median time was 8.6 months). In terms of treatment outcome, CR was obtained in two cases, PR was obtained in four cases, SD was obtained in 1 case, and PD was obtained in one case.
Table 1
Baseline characteristics of included patients.
Study Cancer Age Sex ICI Adverse Reaction
|
Ours
Takata[19]
Chu[20]
Eeden[21]
Inthasot[22]
Kim[18]
He[14]
Picchi[15]
Tetikkurt[16]
Daniel[17]
|
ADC
ADC
ADC
ADC
ADC
ADC
Melanoma
Melanoma
SCC
MCC
|
67
75
59
56
69
60
65
50
53
83
|
Male
Male
Male
Female
Male
Male
Female
Male
Male
Male
|
Pembrolizumab
Nivolumab
Nivolumab
Nivolumab
Nivolumab
Nivolumab
Pembrolizumab
Pembrolizumab
Pembrolizumab
Pembrolizumab
|
toxic hepatic
None
None
diarrhea
NA
toxic hepatic
Sjögren’s syndrome
toxic hepatic
NA
Adrenal insufficiency
toxic hepatic
|
ADC, Adenocarcinoma; MCC, Merkel cell carcinoma; SCC, squamous cell carcinoma; NA, not available. |
Table2. Treatment of TB and outcome.
Study
|
ECOG
|
TB
treatment
|
Time to ICI reinitiation
|
TB test results when ICI using
|
TB course
|
Outcome
|
He[14]
Ours
Takata[19]
Daniel[22]
Tetikkurt[21]
Kim[18]
Chu[20]
Eeden[16]
Inthasot[17]
Picchi[15]
|
0
1
1
1
1
1
2
3
|
HRZE→RIPE
HRZE
HRZE→RIPE
HRZE
NA
NA
NA
HRZE
|
3m
3m
4m
4m
When tumor
recurrence
1m
1m
Symptoms are slightly relieved
|
一
一
一
一
NA
一
一
|
8m
8m
12m
9m
>4 years
NA
6m
|
CR
PR
PR
PR
CR
SD
PR
PD
|
Synchronous treatment soon led to death due to tumor progression
|
NA
|
CR, Complete Response; PR, Partial Response; SD, Stable Disease; PD, Progressive Disease; NA, not available; HRZE, Isoniazide+ Rifampin+ Pyrazinamide+ Ethambutol; RIPE, streptomycin + ethambutol +moxifloxacin; 一, negative.
Summary analysis shows that anti-TB has no obviously effect on the efficacy of ICIs, with seven of the eight cases that could be analyzed achieving good results. For suitable populations selected by anti-TB combined ICIs, ECOG scores between 0 and 2 are more recommended, and generally good treatment outcomes can be achieved. When ECOG is over 2, combination therapy is not recommended, because it may accelerate disease progression. The main adverse reactions of anti-TB combined with ICIs are mainly hepatotoxicity, and the liver function can be maintained normal after liver protection therapy. According to WHO guidelines[23, 24], normal anti-TB treatment takes at least 6 months, but further clinical studies are needed to determine whether anti-TB treatment should be extended when combined with immunotherapy. And further research is needed on the timing of drug combination.
Conclusion, It can be found from our article that anti-TB may have little effect on ICIs, and it is worthwhile to conduct a larger cohort study in the future to verify the effect of anti-TB on ICIs.