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The Role of the Vagus Nerve in Cancer Prognosis: A Systematic and a Comprehensive Review

The Role of the Vagus Nerve in Cancer Prognosis: A Systematic and a Comprehensive Review Hindawi Journal of Oncology Volume 2018, Article ID 1236787, 11 pages https://doi.org/10.1155/2018/1236787 Review Article The Role of the Vagus Nerve in Cancer Prognosis: A Systematic and a Comprehensive Review 1,2 3,4 5 1,6 MarijkeDeCouck , Ralf Caers, David Spiegel, and Yori Gidron Mental Health and Wellbeing Research Group, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Jette, Brussels, Belgium Faculty of Health Care, University College Odisee, Aalst, Belgium Department of Work and Organization Studies, KU Leuven, Brussels, Belgium Faculty of Business and Sustainable Development, University of Seychelles, Mahe, Seychelles Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA SCALab, Lille 3 University & Siric Oncolille, Lille, France Correspondence should be addressed to Marijke De Couck; marijke.de.couck@vub.be Received 20 April 2018; Accepted 10 June 2018; Published 2 July 2018 Academic Editor: Akira Hara Copyright © 2018 Marijke De Couck et al. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This article reviews the role of the vagus nerve in tumor modulation and cancer prognosis. We present a systematic review of 12 epidemiological studies examining the relationship between heart rate variability, the main vagus nerve index, and prognosis in cancer patients (survival and tumor markers). These studies show that initially high vagal nerve activity predicts better cancer prognosis, and, in some studies, independent of confounders such as cancer stage and treatments. Since the design of the epidemiological studies is correlational, any causal relationship between heart rate variability and cancer prognosis cannot be inferred. However, various semi-experimental cohort studies in humans and experimental studies in animals have examined this causal relationship. eTh second part of this paper presents a comprehensive review including human and animal cohort and experimental studies showing that vagotomy accelerates tumor growth, while vagal nerve activation improves cancer prognosis. Based on all reviewed studies, it is concluded that the evidence supports a protective role of the vagus nerve in cancer and specifically in the metastatic stage. 1. Introduction Two crucial etiological factors which contribute to these six hallmarks are genetic changes or instability and the immune Cancer remains the second leading cause of mortality world- inflammatory response which contributes to all stages of wide, withprostatecancer being themost prevalentcancer tumorigenesis [2, 3]. Importantly, studies have shown that type in men and breast cancer in women [1]. Cancer is three basic biological factors contribute to the onset and a complex condition since it includes several hundreds of progression of tumorigenesis, namely, (1) oxidative stress different types, and because it involves and is affected by leading to DNA damage (e.g., [4]); (2) inflammation which multiple body systems, despite beginning as uncontrolled contributes to escape from apoptosis, angiogenesis, and proliferation of a group of cells. Nevertheless, several hall- metastasis [3, 5]; and (3) excessive sympathetic activity, which marks characterize most if not all cancers including sus- aec ff ts where cancer cells will metastasize [6–8]. Can there be tained cell proliferative signalling, evasion of tumor growth one factor common to these three factors which contribute suppressors, resisting cell death (or apoptosis), enabling to cancer, which inhibits all three and which predicts cancer replicative immortality of cells, induction of angiogenesis, prognosis as well? We propose that the vagus nerve may and finally performing invasion and migration (metastasis). fulfil all these requirements. Vagus nerve stimulation reduces 2 Journal of Oncology oxidative stress [9], informs the brain about inflammation 3. Purpose of This Systematic Review [10], and profoundly inhibits inafl mmation [11], and of course Zhou and colleagues [32] recently examined the association the vagus nerve inhibits sympathetic activity since it is a between HRV and survival in cancer. They identified a major branch of the parasympathetic nervous system [12]. A total sample of 1286 patients over six studies. Overall, HRV recently discovered new pathway revealed that vagal nerve significantly predicted a reduced risk of death from various stimulation increased TFF2, a suppressor of MDSC; thus, cancers (HR = 0. 70; 95% cond fi ence interval: 0.60-0.82, p vagal nerve stimulation may increase cellular immunity [13]. < 0.001 [32]). However, they did not include studies, which For these reasons, we hypothesized that vagus nerve activity also used other clinical outcomes such as tumor markers, may have a prognostic and protective role in cancer [14, 15]. enabling more comprehensive examination of the prognostic This article will review the epidemiological evidence for its role of HRV in cancer. Furthermore, they excluded stud- protective role in cancer. ies with terminal cancer patients, but such information is also important to point at the prognostic role of HRV in 2. The Vagus Nerve the full spectrum of cancer stages and severity. Also, no th evaluation of the studies’ quality was performed, which can The vagus nerve, also called the wandering nerve, is the 10 enable one to test the HRV-prognosis relationship in the cranial nerve, descending from various sublocations within methodologically better studies only and to inform future the brain medulla, descending in the upper neck between the studies in a systematic manner how to improve scientifically. internal jugular vein and the internal carotid artery. The vagus Furthermore, no experimental studies were discussed. This nerve then innervates multiple visceral organs including review aimed to address these gaps. Since we hypothesize the heart, pancreas, lungs, and gastrointestinal tract. The that the vagus nerve may inhibit three factors that are crucial vagus nerve is a complex homeostatic system, which operates via multiple neurotransmitters and affects several systems oncogenic mechanisms (oxidative stress, inflammation, and (cardiovascular, neuroendocrine, and immunological) [11]. excessive sympathetic activity), we expect high vagus nerve It can sense peripheral inflammation and transmits action activity to be predictive of a good prognosis in cancer and potentials from the periphery to the brain stem. This in turn to slow down tumor progression. This article systematically leads to the generation of action potentials in the descending reviews the studies, which examined the relationship between vagus nerve, where proinflammatory cytokine production is HRV and cancer prognosis (survival and tumor markers; inhibited [16]. The vagus nerve is known for its protective epidemiological evidence), followed by experimental studies effects in many pathological conditions. The molecular basis testing the effects of vagotomy and vagal nerve stimulation on of this anti-inflammatory circuit, termed the cholinergic anti- cancer prognosis (experimental evidence). inflammatory pathway, includes the neurotransmitter acetyl- choline interacting with the alpha-7 nicotinic acetylcholine 4. Evidence Reviewed receptor subunit expressed on monocytes, macrophages, and other cytokine producing cells [11]. Signal transduction Studies were found by using the following key words: heart through this receptor inhibits cytokine release, suppresses rate variability; autonomic nerve system; cancer; prognosis; inflammation, and has a protective role in many conditions survival; and tumor marker. We also found studies via [15]. Many studies have shown the importance and protective references of other studies. The search was performed on effects of the vagus nerve in importance diseases such as Pubmed and the years were not restricted. cardiovascular disease, Alzheimer’s disease, and autoimmune The inclusion criteria were as follows: studies were disease [17–22]. On the other hand, low vagus nerve activ- included if they measured HRV, in patients with cancer, ity has been related to poor outcome, and vagus nerve included as clinical outcome a tumor marker specific for the stimulation with a good outcome in other conditions such cancer sampled in the study or survival, being prospective or as irritable bowel syndrome, metabolic syndrome, diabetes, historical prospective. Studies using a cross-sectional or case- sepsis, pancreatitis, depression, pain, and epilepsy [23–29]. control design were excluded. Its activity can be measured in a noninvasive manner via the measurement of variability of interbeat cardiac intervals, 5. Methodological Evaluation of Studies called heart rate variability (HRV). Indeed, HRV is strongly correlated with actual vagal nerve activity (r = 0.88; 30). We also evaluated the methodological quality of studies, Importantly, this nerve has a major homeostatic role: People in order to identify possible weaknesses to point out for with high HRV were found to recover physiologically to future studies, given the potential clinical implications of stress more rapidly on three physiological systems, namely, this line of research. Each study’s methodological quality was cardiac, hormonal, and immune, compared to those with evaluated, while considering the following issues and ratings: lower HRV [30]. In addition, in people with high, but not low (1) Was HRV measured over at least 5min? (No, Yes), (2) HRV, synchronization between brain activity and peripheral Was the design prospective (yes) or historical prospective immunity in regions that modulate homeostasis has been (No)? (3) Were patients with cardiac diseases or medication observed [31].Thus,the vagus has a crucial communicative excluded, or was this variable statistically controlled or tested and moderating homeostatic role in multiple bodily systems, for? (No, Yes), (4) Were relevant confounders (e, g., cancer and its index, HRV, has prognostic roles in various health stage, treatment, age) statistically adjusted for in the analysis? conditions. Is this the case in cancer as well? (No, Yes), (5) Were effects of HRV tested separately in each Journal of Oncology 3 cancer type If a study used various types, or was this variable SDNN, independent of confounders. However, while they controlled for statistically or methodologically by including statistically controlled for confounders, they included several types of cancer and did not statistically adjust for cancer onecancer typealone (No, Yes)? type. Chiang et al. [38], Wang et al. [36], De Couck et al. Search History in Pubmed: [33], and Kim et al. [34] also showed that HRV predicted (1) Using the words HRV heart cancer survival, 17 studies survival, and these relationships were mostly independent of were found, of whom De Couck 2016 [33]; Kim 2015 important confounders. In the study by Chiang et al. [38], [34]; Giese-Davis 2015 [35]; Wang 2013 [36] De Couck the natural log transformation of HF-HRV (high frequency 2013 [37]; Chiang 2013 [38]; Kim 2010 [39]; and Fadul heart rate variability) below 2 was a signicfi ant predictor of 2010 [40] were eligible. risk of surviving 7 days or less compared to patients with (2) Using the words HRV heart cancer prognosis, 14 ahigher HF-HRV. De Couck et al. [33] on the other hand studies were found: 1 new one: Mouton 2012 [41]. found that SDNN significantly predicted survival in patients with advanced pancreatic cancer, and that the SDNN-survival (3) Using the words “heart rate variability” cancer prog- relationship was statistically mediated by reduced levels of C- nosis, 26 studies were found, of whom only this one reactive protein (CRP). This study was the only one which was new and eligible: Hoffmann 2001 [42]. tried to reveal the possiblemechanism of theroleofthe (4) Using the words “heart rate variability” cancer sur- vagus nerve in cancer prognosis. Finally, they also found that, vival, 35 studies were found, of whom these new and in patients surviving longer than one month, HRV showed eligible studies were found: Guo 2015 [43]; Chiang the expected inverse correlation with CRP, while in patients 2010 [44]. Another study presented data of samples surviving less than one month, HRV was unrelated to CRP. used in previous studies and tested whether HRV This suggests that in patients with neuroimmunomodulation moderates the effects of cancer stage on tumor mark- (an inverse HRV-CRP relationship), survival may be longer, ers [45]. Since it was a reanalysis of other studies even in a severe cancer such as advanced pancreatic cancer. reported here, it was not included in this review. These These findings are in line with their hypothesized model 12 studies constituted the sample of studies for the where the vagus nerve may modulate cancer progression by epidemiological evidence of this review study (see inhibiting inflammation [14]. At last, Wang et al. [36] found Table 1). that SDNN predicted survival, independent of confounders, and more specicfi ally, that in patients with SDNN ≥ 10msec, 6. Studies of HRV and Cancer the median survival time was 8 months, compared to a median survival time of 1.8 months in patients with SDNN< 6.1. HRV and Cancer Survival. To date, 12 studies have 10msec. Finally, in the study by Kim et al. [34], SDNN signi-fi investigated the association between vagal nerve activity and cantly predicted poor survival by univariate analysis, though prediction of prognosis in cancer with a total sample of 1822 not multivariate analyses (e.g., age, gender, performance patients. Hoffmann et al. [42], Chiang et al. [44], and Fadul status, and stage). De Couck et al. [37] found in nonsmall et al. [40] found that heart rate variability (HRV) predicts cell lung cancer patients no significant correlation between survival time. The emerging evidence is quite consistent and SDNN or RMSSD and overall survival nor with survival demonstrates a prognostic role of vagal activity. We shall now time. However, in a further exploratory analysis, in the group describe each study in detail. below age 65, SDNN and RMSSD significantly predicted More specicfi ally, Hoffmann and colleagues [42] demon- survival time, independent of confounders (r=0.278, p = .032; strated a significantly higher mortality for patients with car- r=0.282, p=0.029, respectively), but not in people over 65. cinoid heart disease combined with reduced HRV, compared This shows that, in some cancers, perhaps in one where the to patients without carcinoid heart disease who also had HRV is obviously adversely affected by the disease and age normal HRV (p=0.04). Chiang and colleagues [44] showed such as lung cancer, the prognostic value of HRV may be a significant correlation between survival time and HF- moderated by age. Giese-Davis et al. [35] reanalyzed data from HRV (r=0.44, p=0.01) in terminal hepatocellular carcinoma an existing cohort of women with metastatic and recurrent patients. However, these three studies did not statistically breast cancer. Using the vagal nerve index of high frequency- control for the eeff cts of important confounders such as HRV (HF-HRV), they found that, in the full sample (N = treatment, cancer stage, gender, and age, and some even 87), higher HV-HRV significantly predicted longer survival included cardiac patients, which could have influenced the in a long-term follow-up. Furthermore, this result was then found to be only significant in women without visceral HRV parameters themselves. Fadul and colleagues [40] found a trend towards a significant association between overall metastases. Finally, they found that the predictive validity survival and SDNN (p=0.056) in advanced cancer. No of HF-HRV improved when dividing it by patients’ heart rate (HR), thus reflecting a more vagal/sympathetic ratio. significant associations were found between survival and the frequency domain measures (p>0.05). Furthermore, the Though attention was given to confounders, no full multiple adjusted hazard ratio for death in patients with abnormal regression analysis, controlling for all relevant confounders, in one analysis was performed. Finally, Guo et al. [43] HRV was 6.4 compared with a normal HRV, reflecting indeed a large effect size. Kim et al. [39] on the other performed a historical prospective study and examined in n = 651 cancer patients their HRV (measured during 20- hand demonstrated that terminal cancer patients with high SDNN survived significantly longer than those with low 24 hours) and its relationship with survival. They used a 4 Journal of Oncology ff Table 1: Summary of available studies of HRV and cancer. SDNN=standard deviation of normal to normal R-R intervals). Cardiac Controlled for Study Design Sample size Cancer type ECG duration patients Results SDNN QOL 1-6 confounders included? Metastatic SDNN> 100 + Carcinoid Homann 2001 Prospective 35, both genders 24-hour Holter No No CS Predicted 3 syndrome mortality (CS) SDNN predicted All types of Kim 2010 Prospective 68, both genders 5minute Yes, full No Duration of 4 primary tumours survival All types of Historical SDNN tended to Fadul 2010 47, males advanced disease 20 minute No Yes 2 Prospective predict survival (lung and gastro) Terminal HF-HRV Chiang 2010 Prospective 33, both genders Hepatocellular 5minute No Yes correlate with 4 carcinoma time-till death SDNN predicted Historical Mouton 2012 38, both genders Colorectal cancer 10 seconds Yes, full No 4 levels of CEA Prospective over 12 monts SDNN predicted 113, male Prostate cancer PSA and Historical De Couck 2013 133, both Non-small cell 10 seconds Yes, full No survival time in 4 Prospective genders lung cancer lung cancer in< 65 years Liver, colon, stomach, head & HF-HRV 138, both Chiang 2013 Prospective neck, pancreatic, 5min Yes, partial Yes predicted risk of 4 genders genitourinary, survival< 7days oesophagal Lung, breast & SDNN predicted Wang 2013 Prospective 40, both genders others with brain 5min Yes, full No 6 survival metastases Yes, but this High SDNN Historical 272, both Advanced De Couck 2016 10 seconds Yes, full variable was Predicted 4 Prospective genders pancreatic cancer controlled for Double survival Advanced 167, both SDNN predicted Kim 2015 Prospective non-small-cell 6 genders survival lung cancer SDNN and Metastatic- Giese-Davis SDNN/HR Prospective 87, only women recurrent breast ECG 5min Yes, partial Yes 3 2015 predicted cancer survival SDNN< 70ms Historical 651, both ECG, 20-24 Guo 2015 Several cancers Yes, partial predicted 4 prospective genders hours shorter survival Journal of Oncology 5 cut-off of SDNN = 70msec. Interestingly, the group of patients nerve activity predicts a better cancer prognosis. The relative with SDNN < 70msec included more men, more patients consistency in the studies reviewed above, across samples with hematological malignancies, and patients consuming with different types of cancer and stages and types of HRV antidepressants from the SSRI family. Looking at the follow- measures, point to a robust prognostic role vagal nerve up time when 25% of the sample had died, in those with activity has in cancer. Furthermore, even if we only include low SDNN this occurred after 18.7 weeks, while in those with the studies that statistically adjusted for confounders and higher SDNN this occurred at week 78.9. Finally, SDNN was hence have better methodology, 100% of these studies reached a significant predictor of survival, independent of age, cancer the same conclusion. It also seems consistent that there is stage, and performance status. However, the investigators did a significant positive association between HRV and better not statistically control for cancer type, which could aeff ct prognosis, mainly in advanced stages. It is possible that, in both HRV [46] and survival. Nevertheless, this study informs earlier tumor stages, treatments such as chemotherapy and radiotherapy are more successful in reducing tumor size us the HRV predicts survival in a heterogeneous sample of cancer, and low HRV may also be associated with more and in impacting tumor markers. Such strong therapeutic prevalence of hematological cancers. effects may leave less of a margin for vagal nerve activity to influence the process. In contrast, these treatments may have 6.2. HRV and Tumor Markers. Mouton et al. [41] and De less impact in later, advanced stages, while (systemic) vagal Couck et al. [37] extended these results to the prediction activity could possibly be of more importance in affecting of tumor burden, using serum levels of tumor markers as prognosis. It is also possible that the three factors inhibited outcome, while considering multiple confounders. While by the vagus nerve (oxidative stress, inflammation, and sym- such markers are not akin to survival, they are used by pathetic activity) may play a more important role in advanced clinicians to indicate response to treatment and do predict cancer stages, thus possibly increasing the prognostic role survival in many cancers [47]. of the vagus in later stages. Regardless of the mechanisms, Mouton et al. [41] demonstrated in a multivariate partial the studies reviewed here call for seriously considering to correlation that SDNN was a significant predictor of carci- add HRV to the clinical estimation of prognosis in oncology noembryonic antigen (CEA) levels at 1 year from diagnosis as well, given its consistent and independent role found in (r=-0.417, p=0.007) in patients with colon cancer. However, the 12 studies reviewed above. This is crucial because until when splitting the sample into palliative versus curative, the now, many of the prognostic factors are composed of clinical HRV-CEA relation occurred only in the patients receiving symptoms and signs, as well as clinician estimates. However, palliative treatment (r=-0.58, p=0.018). Furthermore, patients these are aec ff ted by physicians’ clinical experience. Hence, with low SDNN (<20ms) had signicfi antly higher CEA at 1 addition of noninvasive and objective HRV measurements for year (p=0.006) and even at study entry than patients with estimating patients’ prognosis could overcome these issues. higher initial SDNN. De Couck et al. [37] showed that SDNN Concerning the evaluation of the studies’ methodological and RMSSD were significant predictors of prostate-specific quality, the mean (SD) score was 4.00 (1.13) and the range antigen (PSA) levels at 6 months in prostate cancer patients, was between 2 and 6. The maximal possible evaluation score controlling for numerous confounders (r=-0.434, p=0.004; was 6. If we only consider the studies with≥4out of 6, 9 r=-0.437, p=0.004, respectively). RMSSD was also found to out of 12 studies (75%) had adequate-high methodology. Of be a significant predictor of PSA levels at 2 years (r=-0.381, these methodologically better studies, in all (100%), HRV p=0.0125). Furthermore, this was particularly signicfi ant in significantly predicted either tumor marker levels of patient patients with metastatic prostate cancer (r=-0.895, p<0.05), survival at follow-up. indicating moderation by stage. 8. Cohort and Experimental Evidence: 7. Summary of Study Findings Effects of Vagotomy on Cancer The 12 studies reviewed above show quite a consistent Since the design of the epidemiological studies was corre- picture: HRV has prognostic value in cancer, predicting both lational, we cannot infer any causal relationships between survival and tumor markers, in several cancers. However, HRV and cancer prognosis. Vagal nerve activity may also be several studies lacked sufficient sample sizes, some studies aec ff ted by cancer [46]. However, various semiexperimental did not statistically control for important confounders such as cancer stage, treatment, or cancer type, some used too brief cohort studies in humans and experimental studies done in measures of HRV, and finally several studies used a historical animals have examined the relationship between vagotomy prospective design. These results are in line with the meta- and cancer prognosis, with the animal studies enabling one analysis of Zhou et al. [32], which included only six studies. to infer causality. Vagotomy is a surgical sectioning of fibers However, the present review includes double the number of of the vagus nerve, previously used to diminish acid secretion studiesand extendsthese resultsto predicting tumor markers in the stomach and control a duodenal ulcer [48]. This is an irreversible procedure, whereas a temporary chemical as well. Importantly, some studies’ results also suggest that the predictive value of HRV may especially be strong in advanced denervation of the vagus can be achieved by administering stages of cancer [32, 33]. capsaicin [49]. The latter specifically activates or destroys Keeping in mind these limitations, the results of most of small diameter sensory neurons containing the capsaicin the reviewed studies demonstrate that higher initial vagus receptor. 6 Journal of Oncology It is well established that in follow-up studies of vago- ChAT and AchE in the human colon cancer cell line HT-29. tomised ulcer patients (mostly vagotomy with drainage or Importantly, they found that an inhibitor of the Ach precursor antrectomy), an increased risk of colorectal cancer [50, 51], ChAT reduced cancer cell proliferation. These results provide evidence for a causal autocrine and paracrine role of Ach prostate carcinoma [52], and stomach cancer [51, 53] has been found, as well as increased mortality from pulmonary in colon cancer cells. It is possible that, at the in situ level, carcinoma [51, 54], cerebrovascular accidents, and bronchop- the cholinergic system promotes some tumor types, while in contrast, the vagus nerve at the systemic level may slow neumonia [51]. Furthermore, in a population-based cohort study in Sweden, the ratio of observed to expected cases tumorigenesis. These issues and the conditions in which they of lung cancer was 2.20 (95% confidence interval = 1.82 occur require future serious investigation. to 2.63), with an increase in the ratio with time since the operation. However, among the patients with peptic ulcer 9. Effects of Vagus Nerve Stimulation with vagotomy, the ratio of observed to expected cases on Cancer Progression was 1.56 (1.49 to 3.67). These findings show that vagotomy increased the risk of cancer, beyond that attributed to peptic The previous studies have demonstrated an association and ulcer alone [55]. Vagotomy has quite consistently been shown experimental causal relationships between impaired vagus to enhance experimental carcinogenesis in the stomach in nerve activity and onset or worse prognosis in cancer. These various animal species [56–63]. However, in some human studies support the importance of an intact vagus nerve studies, no significant increased or decreased risk of gastric in ‘protecting’ against a poor cancer prognosis. The next cancer was found in patients vagotomised for benign gastric question of course is whether vagus nerve activation has ther- and duodenal disease [64]. Similarly, some experimental apeutic eeff cts in cancer, which has clear clinical implications studies in animals could not find an increased risk of cancer for cancer therapy. The vagus nerve can be stimulated in as well [65–67]. dieff rent ways. An implanted human vagus nerve stimulation Following these cohort and experimental vagotomy stud- (VNS) device has been FDA approved for refractory epilepsy ies, the group of Erin [68] recently conducted an experimen- for more than 10 years [73] and is undergoing clinical trials for tal study in mice bearing the 4T1 mammary carcinoma. One resistant depression [74]. Another form of an implanted VNS, week aer ft receiving a high-dose of capsaicin, female adult operating by stimulating baroreceptors, was found to increase BALB/c mice were injected orthotopically with syngeneic 4T1 HRV parameters as well, in hypertensive patients [75]. Direct mammary carcinoma cells. A dose-dependent increase in electrical stimulation of the vagus nerve attenuates TNF𝛼 - number and size of metastases to the lungs was observed as production during experimental models of endotoxaemia, a function of capsaicin. However, the primary tumor growth haemorrhagic shock, and other conditions of cytokine excess was unaffected. These results are also in line with results in [18, 25, 76–78]. However, the voltage and frequency of humans where HRV predicts prognosis in advanced cancer the stimulation required to activate the cholinergic anti- stages (see above). A subsequent study by the same group [69] inflammatory pathway are below the threshold required to investigated the effects of unilateral mid-cervical vagotomy activate cardiac vagal fibers, and so no significant effects on on the metastases of 4THMpc breast carcinoma cells, injected HR or HRV have been observed [79]. Furthermore, some orthotopically, a week after the vagotomy. Similar results were noninvasive techniques to stimulate the vagus nerve exist as found: unilateral vagotomy increased visceral metastases to well. Transcutaneous vagus nerve stimulation (t-VNS) has the lung, liver, and kidney, without affecting the growth been shown to attenuate levels of the inflammatory mediator rate of the primary tumor. These two studies propose than high mobility group box 1 (HMGB1) and improve survival an intact vagus nerve may reduce the number and size of in a murine sepsis model [25]. In a recent study, a new t- visceral metastases in the context of cancer. Since these VNS device was also found to reduce various inflammatory were experimental studies, they propose a causal relationship markers (interleukin 1 beta, interleukin-8, TNF, monocyte between vagal nerve activity and reduced metastasis of an chemoattractant protein 1, and macrophage inam fl matory existing cancer. protein 1 alpha) in humans [80]. t-VNS was also found to Novotny et al. [70] have challenged these results and reduce depression by 50%, in two recent human trials [81]. found opposite results when focusing on nonneuronal Studies have also demonstrated that multiple forms of cholinergic signals. Nonneuronal acetylcholine (Ach) plays meditation can alter the parasympathetic component of HRV a role in cellular proliferation, differentiation, and migration and can have a positive eeff ct on cardiac autonomic tone [82– (e.g., [71]), thus of high relevance to cancer. In a study 84]. Similarly, relaxation therapy and HRV-biofeedback, both of human colon cancer tissue, they found higher levels of behavioral methods, can significantly increase the parasym- the acetylcholine (ACh) precursor cholineacetyltransferace pathetic component of HRV, reflecting an increase in vagus (ChAT), higher levels of the Ach inhibitor Acetylcholine nerve activity [85–89]. Furthermore, some therapeutic agents esterase (AchE) and higher levels of the alpha 7 nicotinic targeting the cholinergic anti-inflammatory pathway through Ach receptor in tumor tissues than control tissues from the action on the vagus nerve have been developed. Examples are same people [70]. Because this was a cross-sectional study, 𝛼 7nAChR agonists, the anti-inflammatory compound GTS- no inferences can bemadeabout thedirection of association 21,orCNI-1493, also called Semapimod,which is an anti- or causality. Nevertheless, the results suggest involvement of inflammatory drug working via an intact vagus nerve. The the cholinergic system in colon cancer development. But in intact CNS-vagus nerve pathway is required for the anti- an in vitro study, Pettersson et al. [72] found the presence of inflammatory effects, since surgical vagotomy abrogates the Journal of Oncology 7 anti-inflammatory effects of Semapimod [76, 77]. Further- It is possible that, in earlier tumor stages, treatments such more, an increased efferent vagus nerve activity has been as chemotherapy and radiotherapy are more successful in observed aer ft administration of Semapimod, demonstrating reducing tumor size and in impacting tumor markers. Such its vagal activating potential [90]. strong therapeutic effects may leave less of a margin for vagal Only two studies investigated the effects of Semapimod nerve activity to influence the process. In contrast, these treatments may have less impact in later, advanced stages, and one pilot study the eeff cts of HRV-biofeedback directly while (systemic) vagal activity could possibly be of more on cancer. Kemeny et al. [91] investigated the effects of CNI- importance in aec ff ting prognosis. In addition, during the 1493 in combination with IL-2 on a hepatoma tumor. The metastatic stage, all three mechanisms thought to underlie use of IL-2 as an antineoplastic agent has been limited by the eeff cts of the vagus on tumors, namely, inafl mmation, the serious toxicities accompanied by the doses required oxidative stress, and sympathetic activation [3, 5, 6, 94], may to fight the tumor. When CNI-1493 was administered in have a greater role in prognosis. This would then potentially conjunction with continuous IL-2 to animals with preexisting enable us to observe greater impact of the vagus nerve on tumors, a 10-fold higher dose of IL-2 could be infused, and these three processes and on prognosis in the advanced stages all animals had a tumor response. u Th s, CNI-1493 did not of cancer specifically. interfere with the antitumoral activity of IL-2 but reduced The study by Magnon et al. [95] showed that the sympa- its associated toxicity. Interestingly, when they compared the thetic fibers were important at the early stages of tumorige- tumor volumes in the control group versus the group who nesis, while the parasympathetic fibers were aec ff ting tumor received CNI-1493, a smaller tumor volume was found in the progression at the later metastatic stage, however, in the other latter (though they did not statistically test this). A phase direction of our hypothesized antitumoral effects. Further I study in cancer patients demonstrated the safety of the research is needed to examine the actual role and mechanisms compound CNI-1493 and confirmed its activity in inhibiting of the vagus nerve incancer ingeneral and inthe metastatic TNF synthesis in humans [92]. stage specifically and to reveal when it has antitumor and Indeed, a more recent study conducted by Erin et al. [93] tumor-promoting eeff cts. examined the antitumoral effects of vagus nerve activation by Semapimod in mice. Balb/c mice were injected with 11. Systemic versus Local Vagal Effects CNI-1493 (4mg/kg) two days after orthotopic inoculation of 4THM breast carcinoma cells. When measuring the Most of the correlational studies testing HRV and cancer tumor weight approximately 25-28 days aer ft injection of the prognosis found a protective eeff ct of high vagal activity cells, the tumor weight was significantly decreased in the in cancer and represent a systemic influence. Furthermore, Semapimod-injected animals. Furthermore, the Semapimod the study by Erin et al. [93], which is experimental, is also animal group had significantly less macroscopic lung and performed at the systemic level. In contrasts, most of the liver metastases compared to the control group (p<0.05). studies with acetylcholine found a tumor-promoting eeff ct Interestingly, a recent matched-controlled pilot study of but represent a more local effect. our group showed positive effects of HRV-biofeedback (HRV- Given the mainly homeostatic role of this nerve in rela- B) in metastatic colon cancer patients. The patients (N = tion to multiple physiological systems [30], the vagus nerve’s 3) performed daily 20min of HRV-biofeedback for three effects at the systemic level may slow down tumorigenesis, months, in addition to receiving chemotherapy. They were while the nerve’s primary neurotransmitter acetylcholine at each retroactively matched to a control patient (N = 3 in total) the local level may promote tumors. Similar dual eeff cts can with the same cancer, same stage, same line of chemotherapy, be observed with corticotrophic releasing hormone (CRH), and similar levels of the tumor marker carcinoembryonic where it has an anti-inflammatory effect when originating antigen (CEA) at baseline. While in controls, CEA levels from the brain, but it is proinflammatory when released hardly changed, patients performing HRV-B showed a clear locally from nerve endings at sites of inflammation [96]. sharp decline in CEA levels, which by three months tended A similar dual action can be seen with norepinephrine to be significantly lower than in controls (p < 0.06). and other corticosteroids. The study of Kerzerho et al. [97] u Th s, various forms for vagus nerve activation are demonstrated that local administration of corticosteroids had available, and their effects on tumor growth and patients’ no effect on the development of immune/mucosal tolerance prognosis require careful testing in future studies. in contrast to systemically applied. Furthermore, not the con- centration, but the route of administration of corticosteroids aec ff ted the immune outcome. 10. Novel Scientific Insights Furthermore, since 80% of the vagal fibers are aer ff ent 10.1. Vagal Influences at the Metastatic Stage. The above and transmit information to the brain (e.g., influence the studies showed that vagus nerve activity is most strongly cor- HPA axis), there is a greater chance for the vagus to influence related with cancer prognosis in metastatic cancer patients. systemic, rather than local and in situ functions. Thayer et Not only the correlational studies support this, but also the al. [98] contend in a meta-analysis that dynamic connections experimental studies of Erin et al. [68, 69] in which they between the amygdala and medial prefrontal cortex, which showed that vagal denervation had most influence on the evaluate threat and safety, help regulate HRV through their metastases but not on the primary tumor. How can this be connections with the nucleus tractus solitarius (NTS). They explained? propose that vagally mediated HRV is linked to higher-level 8 Journal of Oncology executive functions. Furthermore, HRV reflects the func- reactivity predicts cancer prognosis. Importantly, all studies tional capacity of these brain structures that support working should statistically control for known confounders, when memory and emotional and physiological self-regulation. examining any new prognostic estimator. Finally, studies need to examine the mechanism. Does HRV predict cancer Interestingly, one region, namely, the anterior cingulate cortex, seems to be related to both vagal nerve activity prognosis via reducing inflammation or by increasing anti- [99] and to cellular anticancer immunity (NK cells) [100]. cancer immunity, by reducing oxidative stress or by reducing At last, the efferent vagus nerve may also have a systemic excessive sympathetic activity [15]? effect, via inhibiting cytokine production in macrophages residing in the spleen (via a mechanism that is not yet Conflicts of Interest sufficiently understood) [101]. All these factors may need to The authors declare that they have no conflicts of interest. be considered in future studies. This is why it is important to test this topic in both levels and that the conclusions of one level (systemic) may not be the same for the other level (local). Acknowledgments u Th s, the vagus nerve could affect cancer via afferent-central The authors would like to thank Professor Jacques De Gr ev ` e, neuroimmunomodulation as well. Professor Reginald Deschepper, and Professor Johan Bilsen for their help and making this review possible. For this 12. Conclusions research, wewerefunded bythe following grants: Anticancer Fund to Yori Gidron, IRP to Reginald Deschepper, and PWO This systematic review examined the evidence linking vagus Odisee to Marijke De Couck. nerve activity near diagnosis, as indexed by HRV, and prog- nosis in cancer patients. By evaluating the methodological References quality of the identified studies, we were also able to check this issue in the methodologically better studies. 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The Role of the Vagus Nerve in Cancer Prognosis: A Systematic and a Comprehensive Review

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Copyright © 2018 Marijke De Couck et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Journal of Oncology Volume 2018, Article ID 1236787, 11 pages https://doi.org/10.1155/2018/1236787 Review Article The Role of the Vagus Nerve in Cancer Prognosis: A Systematic and a Comprehensive Review 1,2 3,4 5 1,6 MarijkeDeCouck , Ralf Caers, David Spiegel, and Yori Gidron Mental Health and Wellbeing Research Group, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Jette, Brussels, Belgium Faculty of Health Care, University College Odisee, Aalst, Belgium Department of Work and Organization Studies, KU Leuven, Brussels, Belgium Faculty of Business and Sustainable Development, University of Seychelles, Mahe, Seychelles Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA SCALab, Lille 3 University & Siric Oncolille, Lille, France Correspondence should be addressed to Marijke De Couck; marijke.de.couck@vub.be Received 20 April 2018; Accepted 10 June 2018; Published 2 July 2018 Academic Editor: Akira Hara Copyright © 2018 Marijke De Couck et al. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This article reviews the role of the vagus nerve in tumor modulation and cancer prognosis. We present a systematic review of 12 epidemiological studies examining the relationship between heart rate variability, the main vagus nerve index, and prognosis in cancer patients (survival and tumor markers). These studies show that initially high vagal nerve activity predicts better cancer prognosis, and, in some studies, independent of confounders such as cancer stage and treatments. Since the design of the epidemiological studies is correlational, any causal relationship between heart rate variability and cancer prognosis cannot be inferred. However, various semi-experimental cohort studies in humans and experimental studies in animals have examined this causal relationship. eTh second part of this paper presents a comprehensive review including human and animal cohort and experimental studies showing that vagotomy accelerates tumor growth, while vagal nerve activation improves cancer prognosis. Based on all reviewed studies, it is concluded that the evidence supports a protective role of the vagus nerve in cancer and specifically in the metastatic stage. 1. Introduction Two crucial etiological factors which contribute to these six hallmarks are genetic changes or instability and the immune Cancer remains the second leading cause of mortality world- inflammatory response which contributes to all stages of wide, withprostatecancer being themost prevalentcancer tumorigenesis [2, 3]. Importantly, studies have shown that type in men and breast cancer in women [1]. Cancer is three basic biological factors contribute to the onset and a complex condition since it includes several hundreds of progression of tumorigenesis, namely, (1) oxidative stress different types, and because it involves and is affected by leading to DNA damage (e.g., [4]); (2) inflammation which multiple body systems, despite beginning as uncontrolled contributes to escape from apoptosis, angiogenesis, and proliferation of a group of cells. Nevertheless, several hall- metastasis [3, 5]; and (3) excessive sympathetic activity, which marks characterize most if not all cancers including sus- aec ff ts where cancer cells will metastasize [6–8]. Can there be tained cell proliferative signalling, evasion of tumor growth one factor common to these three factors which contribute suppressors, resisting cell death (or apoptosis), enabling to cancer, which inhibits all three and which predicts cancer replicative immortality of cells, induction of angiogenesis, prognosis as well? We propose that the vagus nerve may and finally performing invasion and migration (metastasis). fulfil all these requirements. Vagus nerve stimulation reduces 2 Journal of Oncology oxidative stress [9], informs the brain about inflammation 3. Purpose of This Systematic Review [10], and profoundly inhibits inafl mmation [11], and of course Zhou and colleagues [32] recently examined the association the vagus nerve inhibits sympathetic activity since it is a between HRV and survival in cancer. They identified a major branch of the parasympathetic nervous system [12]. A total sample of 1286 patients over six studies. Overall, HRV recently discovered new pathway revealed that vagal nerve significantly predicted a reduced risk of death from various stimulation increased TFF2, a suppressor of MDSC; thus, cancers (HR = 0. 70; 95% cond fi ence interval: 0.60-0.82, p vagal nerve stimulation may increase cellular immunity [13]. < 0.001 [32]). However, they did not include studies, which For these reasons, we hypothesized that vagus nerve activity also used other clinical outcomes such as tumor markers, may have a prognostic and protective role in cancer [14, 15]. enabling more comprehensive examination of the prognostic This article will review the epidemiological evidence for its role of HRV in cancer. Furthermore, they excluded stud- protective role in cancer. ies with terminal cancer patients, but such information is also important to point at the prognostic role of HRV in 2. The Vagus Nerve the full spectrum of cancer stages and severity. Also, no th evaluation of the studies’ quality was performed, which can The vagus nerve, also called the wandering nerve, is the 10 enable one to test the HRV-prognosis relationship in the cranial nerve, descending from various sublocations within methodologically better studies only and to inform future the brain medulla, descending in the upper neck between the studies in a systematic manner how to improve scientifically. internal jugular vein and the internal carotid artery. The vagus Furthermore, no experimental studies were discussed. This nerve then innervates multiple visceral organs including review aimed to address these gaps. Since we hypothesize the heart, pancreas, lungs, and gastrointestinal tract. The that the vagus nerve may inhibit three factors that are crucial vagus nerve is a complex homeostatic system, which operates via multiple neurotransmitters and affects several systems oncogenic mechanisms (oxidative stress, inflammation, and (cardiovascular, neuroendocrine, and immunological) [11]. excessive sympathetic activity), we expect high vagus nerve It can sense peripheral inflammation and transmits action activity to be predictive of a good prognosis in cancer and potentials from the periphery to the brain stem. This in turn to slow down tumor progression. This article systematically leads to the generation of action potentials in the descending reviews the studies, which examined the relationship between vagus nerve, where proinflammatory cytokine production is HRV and cancer prognosis (survival and tumor markers; inhibited [16]. The vagus nerve is known for its protective epidemiological evidence), followed by experimental studies effects in many pathological conditions. The molecular basis testing the effects of vagotomy and vagal nerve stimulation on of this anti-inflammatory circuit, termed the cholinergic anti- cancer prognosis (experimental evidence). inflammatory pathway, includes the neurotransmitter acetyl- choline interacting with the alpha-7 nicotinic acetylcholine 4. Evidence Reviewed receptor subunit expressed on monocytes, macrophages, and other cytokine producing cells [11]. Signal transduction Studies were found by using the following key words: heart through this receptor inhibits cytokine release, suppresses rate variability; autonomic nerve system; cancer; prognosis; inflammation, and has a protective role in many conditions survival; and tumor marker. We also found studies via [15]. Many studies have shown the importance and protective references of other studies. The search was performed on effects of the vagus nerve in importance diseases such as Pubmed and the years were not restricted. cardiovascular disease, Alzheimer’s disease, and autoimmune The inclusion criteria were as follows: studies were disease [17–22]. On the other hand, low vagus nerve activ- included if they measured HRV, in patients with cancer, ity has been related to poor outcome, and vagus nerve included as clinical outcome a tumor marker specific for the stimulation with a good outcome in other conditions such cancer sampled in the study or survival, being prospective or as irritable bowel syndrome, metabolic syndrome, diabetes, historical prospective. Studies using a cross-sectional or case- sepsis, pancreatitis, depression, pain, and epilepsy [23–29]. control design were excluded. Its activity can be measured in a noninvasive manner via the measurement of variability of interbeat cardiac intervals, 5. Methodological Evaluation of Studies called heart rate variability (HRV). Indeed, HRV is strongly correlated with actual vagal nerve activity (r = 0.88; 30). We also evaluated the methodological quality of studies, Importantly, this nerve has a major homeostatic role: People in order to identify possible weaknesses to point out for with high HRV were found to recover physiologically to future studies, given the potential clinical implications of stress more rapidly on three physiological systems, namely, this line of research. Each study’s methodological quality was cardiac, hormonal, and immune, compared to those with evaluated, while considering the following issues and ratings: lower HRV [30]. In addition, in people with high, but not low (1) Was HRV measured over at least 5min? (No, Yes), (2) HRV, synchronization between brain activity and peripheral Was the design prospective (yes) or historical prospective immunity in regions that modulate homeostasis has been (No)? (3) Were patients with cardiac diseases or medication observed [31].Thus,the vagus has a crucial communicative excluded, or was this variable statistically controlled or tested and moderating homeostatic role in multiple bodily systems, for? (No, Yes), (4) Were relevant confounders (e, g., cancer and its index, HRV, has prognostic roles in various health stage, treatment, age) statistically adjusted for in the analysis? conditions. Is this the case in cancer as well? (No, Yes), (5) Were effects of HRV tested separately in each Journal of Oncology 3 cancer type If a study used various types, or was this variable SDNN, independent of confounders. However, while they controlled for statistically or methodologically by including statistically controlled for confounders, they included several types of cancer and did not statistically adjust for cancer onecancer typealone (No, Yes)? type. Chiang et al. [38], Wang et al. [36], De Couck et al. Search History in Pubmed: [33], and Kim et al. [34] also showed that HRV predicted (1) Using the words HRV heart cancer survival, 17 studies survival, and these relationships were mostly independent of were found, of whom De Couck 2016 [33]; Kim 2015 important confounders. In the study by Chiang et al. [38], [34]; Giese-Davis 2015 [35]; Wang 2013 [36] De Couck the natural log transformation of HF-HRV (high frequency 2013 [37]; Chiang 2013 [38]; Kim 2010 [39]; and Fadul heart rate variability) below 2 was a signicfi ant predictor of 2010 [40] were eligible. risk of surviving 7 days or less compared to patients with (2) Using the words HRV heart cancer prognosis, 14 ahigher HF-HRV. De Couck et al. [33] on the other hand studies were found: 1 new one: Mouton 2012 [41]. found that SDNN significantly predicted survival in patients with advanced pancreatic cancer, and that the SDNN-survival (3) Using the words “heart rate variability” cancer prog- relationship was statistically mediated by reduced levels of C- nosis, 26 studies were found, of whom only this one reactive protein (CRP). This study was the only one which was new and eligible: Hoffmann 2001 [42]. tried to reveal the possiblemechanism of theroleofthe (4) Using the words “heart rate variability” cancer sur- vagus nerve in cancer prognosis. Finally, they also found that, vival, 35 studies were found, of whom these new and in patients surviving longer than one month, HRV showed eligible studies were found: Guo 2015 [43]; Chiang the expected inverse correlation with CRP, while in patients 2010 [44]. Another study presented data of samples surviving less than one month, HRV was unrelated to CRP. used in previous studies and tested whether HRV This suggests that in patients with neuroimmunomodulation moderates the effects of cancer stage on tumor mark- (an inverse HRV-CRP relationship), survival may be longer, ers [45]. Since it was a reanalysis of other studies even in a severe cancer such as advanced pancreatic cancer. reported here, it was not included in this review. These These findings are in line with their hypothesized model 12 studies constituted the sample of studies for the where the vagus nerve may modulate cancer progression by epidemiological evidence of this review study (see inhibiting inflammation [14]. At last, Wang et al. [36] found Table 1). that SDNN predicted survival, independent of confounders, and more specicfi ally, that in patients with SDNN ≥ 10msec, 6. Studies of HRV and Cancer the median survival time was 8 months, compared to a median survival time of 1.8 months in patients with SDNN< 6.1. HRV and Cancer Survival. To date, 12 studies have 10msec. Finally, in the study by Kim et al. [34], SDNN signi-fi investigated the association between vagal nerve activity and cantly predicted poor survival by univariate analysis, though prediction of prognosis in cancer with a total sample of 1822 not multivariate analyses (e.g., age, gender, performance patients. Hoffmann et al. [42], Chiang et al. [44], and Fadul status, and stage). De Couck et al. [37] found in nonsmall et al. [40] found that heart rate variability (HRV) predicts cell lung cancer patients no significant correlation between survival time. The emerging evidence is quite consistent and SDNN or RMSSD and overall survival nor with survival demonstrates a prognostic role of vagal activity. We shall now time. However, in a further exploratory analysis, in the group describe each study in detail. below age 65, SDNN and RMSSD significantly predicted More specicfi ally, Hoffmann and colleagues [42] demon- survival time, independent of confounders (r=0.278, p = .032; strated a significantly higher mortality for patients with car- r=0.282, p=0.029, respectively), but not in people over 65. cinoid heart disease combined with reduced HRV, compared This shows that, in some cancers, perhaps in one where the to patients without carcinoid heart disease who also had HRV is obviously adversely affected by the disease and age normal HRV (p=0.04). Chiang and colleagues [44] showed such as lung cancer, the prognostic value of HRV may be a significant correlation between survival time and HF- moderated by age. Giese-Davis et al. [35] reanalyzed data from HRV (r=0.44, p=0.01) in terminal hepatocellular carcinoma an existing cohort of women with metastatic and recurrent patients. However, these three studies did not statistically breast cancer. Using the vagal nerve index of high frequency- control for the eeff cts of important confounders such as HRV (HF-HRV), they found that, in the full sample (N = treatment, cancer stage, gender, and age, and some even 87), higher HV-HRV significantly predicted longer survival included cardiac patients, which could have influenced the in a long-term follow-up. Furthermore, this result was then found to be only significant in women without visceral HRV parameters themselves. Fadul and colleagues [40] found a trend towards a significant association between overall metastases. Finally, they found that the predictive validity survival and SDNN (p=0.056) in advanced cancer. No of HF-HRV improved when dividing it by patients’ heart rate (HR), thus reflecting a more vagal/sympathetic ratio. significant associations were found between survival and the frequency domain measures (p>0.05). Furthermore, the Though attention was given to confounders, no full multiple adjusted hazard ratio for death in patients with abnormal regression analysis, controlling for all relevant confounders, in one analysis was performed. Finally, Guo et al. [43] HRV was 6.4 compared with a normal HRV, reflecting indeed a large effect size. Kim et al. [39] on the other performed a historical prospective study and examined in n = 651 cancer patients their HRV (measured during 20- hand demonstrated that terminal cancer patients with high SDNN survived significantly longer than those with low 24 hours) and its relationship with survival. They used a 4 Journal of Oncology ff Table 1: Summary of available studies of HRV and cancer. SDNN=standard deviation of normal to normal R-R intervals). Cardiac Controlled for Study Design Sample size Cancer type ECG duration patients Results SDNN QOL 1-6 confounders included? Metastatic SDNN> 100 + Carcinoid Homann 2001 Prospective 35, both genders 24-hour Holter No No CS Predicted 3 syndrome mortality (CS) SDNN predicted All types of Kim 2010 Prospective 68, both genders 5minute Yes, full No Duration of 4 primary tumours survival All types of Historical SDNN tended to Fadul 2010 47, males advanced disease 20 minute No Yes 2 Prospective predict survival (lung and gastro) Terminal HF-HRV Chiang 2010 Prospective 33, both genders Hepatocellular 5minute No Yes correlate with 4 carcinoma time-till death SDNN predicted Historical Mouton 2012 38, both genders Colorectal cancer 10 seconds Yes, full No 4 levels of CEA Prospective over 12 monts SDNN predicted 113, male Prostate cancer PSA and Historical De Couck 2013 133, both Non-small cell 10 seconds Yes, full No survival time in 4 Prospective genders lung cancer lung cancer in< 65 years Liver, colon, stomach, head & HF-HRV 138, both Chiang 2013 Prospective neck, pancreatic, 5min Yes, partial Yes predicted risk of 4 genders genitourinary, survival< 7days oesophagal Lung, breast & SDNN predicted Wang 2013 Prospective 40, both genders others with brain 5min Yes, full No 6 survival metastases Yes, but this High SDNN Historical 272, both Advanced De Couck 2016 10 seconds Yes, full variable was Predicted 4 Prospective genders pancreatic cancer controlled for Double survival Advanced 167, both SDNN predicted Kim 2015 Prospective non-small-cell 6 genders survival lung cancer SDNN and Metastatic- Giese-Davis SDNN/HR Prospective 87, only women recurrent breast ECG 5min Yes, partial Yes 3 2015 predicted cancer survival SDNN< 70ms Historical 651, both ECG, 20-24 Guo 2015 Several cancers Yes, partial predicted 4 prospective genders hours shorter survival Journal of Oncology 5 cut-off of SDNN = 70msec. Interestingly, the group of patients nerve activity predicts a better cancer prognosis. The relative with SDNN < 70msec included more men, more patients consistency in the studies reviewed above, across samples with hematological malignancies, and patients consuming with different types of cancer and stages and types of HRV antidepressants from the SSRI family. Looking at the follow- measures, point to a robust prognostic role vagal nerve up time when 25% of the sample had died, in those with activity has in cancer. Furthermore, even if we only include low SDNN this occurred after 18.7 weeks, while in those with the studies that statistically adjusted for confounders and higher SDNN this occurred at week 78.9. Finally, SDNN was hence have better methodology, 100% of these studies reached a significant predictor of survival, independent of age, cancer the same conclusion. It also seems consistent that there is stage, and performance status. However, the investigators did a significant positive association between HRV and better not statistically control for cancer type, which could aeff ct prognosis, mainly in advanced stages. It is possible that, in both HRV [46] and survival. Nevertheless, this study informs earlier tumor stages, treatments such as chemotherapy and radiotherapy are more successful in reducing tumor size us the HRV predicts survival in a heterogeneous sample of cancer, and low HRV may also be associated with more and in impacting tumor markers. Such strong therapeutic prevalence of hematological cancers. effects may leave less of a margin for vagal nerve activity to influence the process. In contrast, these treatments may have 6.2. HRV and Tumor Markers. Mouton et al. [41] and De less impact in later, advanced stages, while (systemic) vagal Couck et al. [37] extended these results to the prediction activity could possibly be of more importance in affecting of tumor burden, using serum levels of tumor markers as prognosis. It is also possible that the three factors inhibited outcome, while considering multiple confounders. While by the vagus nerve (oxidative stress, inflammation, and sym- such markers are not akin to survival, they are used by pathetic activity) may play a more important role in advanced clinicians to indicate response to treatment and do predict cancer stages, thus possibly increasing the prognostic role survival in many cancers [47]. of the vagus in later stages. Regardless of the mechanisms, Mouton et al. [41] demonstrated in a multivariate partial the studies reviewed here call for seriously considering to correlation that SDNN was a significant predictor of carci- add HRV to the clinical estimation of prognosis in oncology noembryonic antigen (CEA) levels at 1 year from diagnosis as well, given its consistent and independent role found in (r=-0.417, p=0.007) in patients with colon cancer. However, the 12 studies reviewed above. This is crucial because until when splitting the sample into palliative versus curative, the now, many of the prognostic factors are composed of clinical HRV-CEA relation occurred only in the patients receiving symptoms and signs, as well as clinician estimates. However, palliative treatment (r=-0.58, p=0.018). Furthermore, patients these are aec ff ted by physicians’ clinical experience. Hence, with low SDNN (<20ms) had signicfi antly higher CEA at 1 addition of noninvasive and objective HRV measurements for year (p=0.006) and even at study entry than patients with estimating patients’ prognosis could overcome these issues. higher initial SDNN. De Couck et al. [37] showed that SDNN Concerning the evaluation of the studies’ methodological and RMSSD were significant predictors of prostate-specific quality, the mean (SD) score was 4.00 (1.13) and the range antigen (PSA) levels at 6 months in prostate cancer patients, was between 2 and 6. The maximal possible evaluation score controlling for numerous confounders (r=-0.434, p=0.004; was 6. If we only consider the studies with≥4out of 6, 9 r=-0.437, p=0.004, respectively). RMSSD was also found to out of 12 studies (75%) had adequate-high methodology. Of be a significant predictor of PSA levels at 2 years (r=-0.381, these methodologically better studies, in all (100%), HRV p=0.0125). Furthermore, this was particularly signicfi ant in significantly predicted either tumor marker levels of patient patients with metastatic prostate cancer (r=-0.895, p<0.05), survival at follow-up. indicating moderation by stage. 8. Cohort and Experimental Evidence: 7. Summary of Study Findings Effects of Vagotomy on Cancer The 12 studies reviewed above show quite a consistent Since the design of the epidemiological studies was corre- picture: HRV has prognostic value in cancer, predicting both lational, we cannot infer any causal relationships between survival and tumor markers, in several cancers. However, HRV and cancer prognosis. Vagal nerve activity may also be several studies lacked sufficient sample sizes, some studies aec ff ted by cancer [46]. However, various semiexperimental did not statistically control for important confounders such as cancer stage, treatment, or cancer type, some used too brief cohort studies in humans and experimental studies done in measures of HRV, and finally several studies used a historical animals have examined the relationship between vagotomy prospective design. These results are in line with the meta- and cancer prognosis, with the animal studies enabling one analysis of Zhou et al. [32], which included only six studies. to infer causality. Vagotomy is a surgical sectioning of fibers However, the present review includes double the number of of the vagus nerve, previously used to diminish acid secretion studiesand extendsthese resultsto predicting tumor markers in the stomach and control a duodenal ulcer [48]. This is an irreversible procedure, whereas a temporary chemical as well. Importantly, some studies’ results also suggest that the predictive value of HRV may especially be strong in advanced denervation of the vagus can be achieved by administering stages of cancer [32, 33]. capsaicin [49]. The latter specifically activates or destroys Keeping in mind these limitations, the results of most of small diameter sensory neurons containing the capsaicin the reviewed studies demonstrate that higher initial vagus receptor. 6 Journal of Oncology It is well established that in follow-up studies of vago- ChAT and AchE in the human colon cancer cell line HT-29. tomised ulcer patients (mostly vagotomy with drainage or Importantly, they found that an inhibitor of the Ach precursor antrectomy), an increased risk of colorectal cancer [50, 51], ChAT reduced cancer cell proliferation. These results provide evidence for a causal autocrine and paracrine role of Ach prostate carcinoma [52], and stomach cancer [51, 53] has been found, as well as increased mortality from pulmonary in colon cancer cells. It is possible that, at the in situ level, carcinoma [51, 54], cerebrovascular accidents, and bronchop- the cholinergic system promotes some tumor types, while in contrast, the vagus nerve at the systemic level may slow neumonia [51]. Furthermore, in a population-based cohort study in Sweden, the ratio of observed to expected cases tumorigenesis. These issues and the conditions in which they of lung cancer was 2.20 (95% confidence interval = 1.82 occur require future serious investigation. to 2.63), with an increase in the ratio with time since the operation. However, among the patients with peptic ulcer 9. Effects of Vagus Nerve Stimulation with vagotomy, the ratio of observed to expected cases on Cancer Progression was 1.56 (1.49 to 3.67). These findings show that vagotomy increased the risk of cancer, beyond that attributed to peptic The previous studies have demonstrated an association and ulcer alone [55]. Vagotomy has quite consistently been shown experimental causal relationships between impaired vagus to enhance experimental carcinogenesis in the stomach in nerve activity and onset or worse prognosis in cancer. These various animal species [56–63]. However, in some human studies support the importance of an intact vagus nerve studies, no significant increased or decreased risk of gastric in ‘protecting’ against a poor cancer prognosis. The next cancer was found in patients vagotomised for benign gastric question of course is whether vagus nerve activation has ther- and duodenal disease [64]. Similarly, some experimental apeutic eeff cts in cancer, which has clear clinical implications studies in animals could not find an increased risk of cancer for cancer therapy. The vagus nerve can be stimulated in as well [65–67]. dieff rent ways. An implanted human vagus nerve stimulation Following these cohort and experimental vagotomy stud- (VNS) device has been FDA approved for refractory epilepsy ies, the group of Erin [68] recently conducted an experimen- for more than 10 years [73] and is undergoing clinical trials for tal study in mice bearing the 4T1 mammary carcinoma. One resistant depression [74]. Another form of an implanted VNS, week aer ft receiving a high-dose of capsaicin, female adult operating by stimulating baroreceptors, was found to increase BALB/c mice were injected orthotopically with syngeneic 4T1 HRV parameters as well, in hypertensive patients [75]. Direct mammary carcinoma cells. A dose-dependent increase in electrical stimulation of the vagus nerve attenuates TNF𝛼 - number and size of metastases to the lungs was observed as production during experimental models of endotoxaemia, a function of capsaicin. However, the primary tumor growth haemorrhagic shock, and other conditions of cytokine excess was unaffected. These results are also in line with results in [18, 25, 76–78]. However, the voltage and frequency of humans where HRV predicts prognosis in advanced cancer the stimulation required to activate the cholinergic anti- stages (see above). A subsequent study by the same group [69] inflammatory pathway are below the threshold required to investigated the effects of unilateral mid-cervical vagotomy activate cardiac vagal fibers, and so no significant effects on on the metastases of 4THMpc breast carcinoma cells, injected HR or HRV have been observed [79]. Furthermore, some orthotopically, a week after the vagotomy. Similar results were noninvasive techniques to stimulate the vagus nerve exist as found: unilateral vagotomy increased visceral metastases to well. Transcutaneous vagus nerve stimulation (t-VNS) has the lung, liver, and kidney, without affecting the growth been shown to attenuate levels of the inflammatory mediator rate of the primary tumor. These two studies propose than high mobility group box 1 (HMGB1) and improve survival an intact vagus nerve may reduce the number and size of in a murine sepsis model [25]. In a recent study, a new t- visceral metastases in the context of cancer. Since these VNS device was also found to reduce various inflammatory were experimental studies, they propose a causal relationship markers (interleukin 1 beta, interleukin-8, TNF, monocyte between vagal nerve activity and reduced metastasis of an chemoattractant protein 1, and macrophage inam fl matory existing cancer. protein 1 alpha) in humans [80]. t-VNS was also found to Novotny et al. [70] have challenged these results and reduce depression by 50%, in two recent human trials [81]. found opposite results when focusing on nonneuronal Studies have also demonstrated that multiple forms of cholinergic signals. Nonneuronal acetylcholine (Ach) plays meditation can alter the parasympathetic component of HRV a role in cellular proliferation, differentiation, and migration and can have a positive eeff ct on cardiac autonomic tone [82– (e.g., [71]), thus of high relevance to cancer. In a study 84]. Similarly, relaxation therapy and HRV-biofeedback, both of human colon cancer tissue, they found higher levels of behavioral methods, can significantly increase the parasym- the acetylcholine (ACh) precursor cholineacetyltransferace pathetic component of HRV, reflecting an increase in vagus (ChAT), higher levels of the Ach inhibitor Acetylcholine nerve activity [85–89]. Furthermore, some therapeutic agents esterase (AchE) and higher levels of the alpha 7 nicotinic targeting the cholinergic anti-inflammatory pathway through Ach receptor in tumor tissues than control tissues from the action on the vagus nerve have been developed. Examples are same people [70]. Because this was a cross-sectional study, 𝛼 7nAChR agonists, the anti-inflammatory compound GTS- no inferences can bemadeabout thedirection of association 21,orCNI-1493, also called Semapimod,which is an anti- or causality. Nevertheless, the results suggest involvement of inflammatory drug working via an intact vagus nerve. The the cholinergic system in colon cancer development. But in intact CNS-vagus nerve pathway is required for the anti- an in vitro study, Pettersson et al. [72] found the presence of inflammatory effects, since surgical vagotomy abrogates the Journal of Oncology 7 anti-inflammatory effects of Semapimod [76, 77]. Further- It is possible that, in earlier tumor stages, treatments such more, an increased efferent vagus nerve activity has been as chemotherapy and radiotherapy are more successful in observed aer ft administration of Semapimod, demonstrating reducing tumor size and in impacting tumor markers. Such its vagal activating potential [90]. strong therapeutic effects may leave less of a margin for vagal Only two studies investigated the effects of Semapimod nerve activity to influence the process. In contrast, these treatments may have less impact in later, advanced stages, and one pilot study the eeff cts of HRV-biofeedback directly while (systemic) vagal activity could possibly be of more on cancer. Kemeny et al. [91] investigated the effects of CNI- importance in aec ff ting prognosis. In addition, during the 1493 in combination with IL-2 on a hepatoma tumor. The metastatic stage, all three mechanisms thought to underlie use of IL-2 as an antineoplastic agent has been limited by the eeff cts of the vagus on tumors, namely, inafl mmation, the serious toxicities accompanied by the doses required oxidative stress, and sympathetic activation [3, 5, 6, 94], may to fight the tumor. When CNI-1493 was administered in have a greater role in prognosis. This would then potentially conjunction with continuous IL-2 to animals with preexisting enable us to observe greater impact of the vagus nerve on tumors, a 10-fold higher dose of IL-2 could be infused, and these three processes and on prognosis in the advanced stages all animals had a tumor response. u Th s, CNI-1493 did not of cancer specifically. interfere with the antitumoral activity of IL-2 but reduced The study by Magnon et al. [95] showed that the sympa- its associated toxicity. Interestingly, when they compared the thetic fibers were important at the early stages of tumorige- tumor volumes in the control group versus the group who nesis, while the parasympathetic fibers were aec ff ting tumor received CNI-1493, a smaller tumor volume was found in the progression at the later metastatic stage, however, in the other latter (though they did not statistically test this). A phase direction of our hypothesized antitumoral effects. Further I study in cancer patients demonstrated the safety of the research is needed to examine the actual role and mechanisms compound CNI-1493 and confirmed its activity in inhibiting of the vagus nerve incancer ingeneral and inthe metastatic TNF synthesis in humans [92]. stage specifically and to reveal when it has antitumor and Indeed, a more recent study conducted by Erin et al. [93] tumor-promoting eeff cts. examined the antitumoral effects of vagus nerve activation by Semapimod in mice. Balb/c mice were injected with 11. Systemic versus Local Vagal Effects CNI-1493 (4mg/kg) two days after orthotopic inoculation of 4THM breast carcinoma cells. When measuring the Most of the correlational studies testing HRV and cancer tumor weight approximately 25-28 days aer ft injection of the prognosis found a protective eeff ct of high vagal activity cells, the tumor weight was significantly decreased in the in cancer and represent a systemic influence. Furthermore, Semapimod-injected animals. Furthermore, the Semapimod the study by Erin et al. [93], which is experimental, is also animal group had significantly less macroscopic lung and performed at the systemic level. In contrasts, most of the liver metastases compared to the control group (p<0.05). studies with acetylcholine found a tumor-promoting eeff ct Interestingly, a recent matched-controlled pilot study of but represent a more local effect. our group showed positive effects of HRV-biofeedback (HRV- Given the mainly homeostatic role of this nerve in rela- B) in metastatic colon cancer patients. The patients (N = tion to multiple physiological systems [30], the vagus nerve’s 3) performed daily 20min of HRV-biofeedback for three effects at the systemic level may slow down tumorigenesis, months, in addition to receiving chemotherapy. They were while the nerve’s primary neurotransmitter acetylcholine at each retroactively matched to a control patient (N = 3 in total) the local level may promote tumors. Similar dual eeff cts can with the same cancer, same stage, same line of chemotherapy, be observed with corticotrophic releasing hormone (CRH), and similar levels of the tumor marker carcinoembryonic where it has an anti-inflammatory effect when originating antigen (CEA) at baseline. While in controls, CEA levels from the brain, but it is proinflammatory when released hardly changed, patients performing HRV-B showed a clear locally from nerve endings at sites of inflammation [96]. sharp decline in CEA levels, which by three months tended A similar dual action can be seen with norepinephrine to be significantly lower than in controls (p < 0.06). and other corticosteroids. The study of Kerzerho et al. [97] u Th s, various forms for vagus nerve activation are demonstrated that local administration of corticosteroids had available, and their effects on tumor growth and patients’ no effect on the development of immune/mucosal tolerance prognosis require careful testing in future studies. in contrast to systemically applied. Furthermore, not the con- centration, but the route of administration of corticosteroids aec ff ted the immune outcome. 10. Novel Scientific Insights Furthermore, since 80% of the vagal fibers are aer ff ent 10.1. Vagal Influences at the Metastatic Stage. The above and transmit information to the brain (e.g., influence the studies showed that vagus nerve activity is most strongly cor- HPA axis), there is a greater chance for the vagus to influence related with cancer prognosis in metastatic cancer patients. systemic, rather than local and in situ functions. Thayer et Not only the correlational studies support this, but also the al. [98] contend in a meta-analysis that dynamic connections experimental studies of Erin et al. [68, 69] in which they between the amygdala and medial prefrontal cortex, which showed that vagal denervation had most influence on the evaluate threat and safety, help regulate HRV through their metastases but not on the primary tumor. How can this be connections with the nucleus tractus solitarius (NTS). They explained? propose that vagally mediated HRV is linked to higher-level 8 Journal of Oncology executive functions. Furthermore, HRV reflects the func- reactivity predicts cancer prognosis. Importantly, all studies tional capacity of these brain structures that support working should statistically control for known confounders, when memory and emotional and physiological self-regulation. examining any new prognostic estimator. Finally, studies need to examine the mechanism. Does HRV predict cancer Interestingly, one region, namely, the anterior cingulate cortex, seems to be related to both vagal nerve activity prognosis via reducing inflammation or by increasing anti- [99] and to cellular anticancer immunity (NK cells) [100]. cancer immunity, by reducing oxidative stress or by reducing At last, the efferent vagus nerve may also have a systemic excessive sympathetic activity [15]? effect, via inhibiting cytokine production in macrophages residing in the spleen (via a mechanism that is not yet Conflicts of Interest sufficiently understood) [101]. All these factors may need to The authors declare that they have no conflicts of interest. be considered in future studies. This is why it is important to test this topic in both levels and that the conclusions of one level (systemic) may not be the same for the other level (local). Acknowledgments u Th s, the vagus nerve could affect cancer via afferent-central The authors would like to thank Professor Jacques De Gr ev ` e, neuroimmunomodulation as well. Professor Reginald Deschepper, and Professor Johan Bilsen for their help and making this review possible. For this 12. Conclusions research, wewerefunded bythe following grants: Anticancer Fund to Yori Gidron, IRP to Reginald Deschepper, and PWO This systematic review examined the evidence linking vagus Odisee to Marijke De Couck. nerve activity near diagnosis, as indexed by HRV, and prog- nosis in cancer patients. By evaluating the methodological References quality of the identified studies, we were also able to check this issue in the methodologically better studies. 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