Introduction
Head and neck tumours account for approximately 3–5% of all malignancies diagnosed worldwide [1]. It is a heterogeneous group of tumours with a mortality rate of above 50% [1]. As most tumours are cancers of epithelial or glandular origin and by the time of diagnosis are locally advanced, radiotherapy with or without previous surgery is the treatment of choice [2]. Dry mouth, or xerostomia, is a frequent adverse effect of radiotherapy and depends on the rate of salivary gland damage and regeneration [3]. Regeneration of the gland tissue may be none or incomplete and the dry mouth may accompany the patient until death. It can profoundly affect patients’ ability to chew, swallow and speak, as well as it may affect the teeth health and overall quality of life [3].
After surgery and/or radiotherapy salivary glands lose the ability to produce saliva and 80% of all patients with head and neck cancers treated with these methods suffer from dry mouth or xerostomia [4]. Only in some of these patients, there will be enough viable gland tissue amenable to stimulation and/or able to regenerate. Besides oncology, in medicine, there is a great interest in the treatment of xerostomia and hyposalivation in Sjögren syndrome [5]. Some data on the treatment of xerostomia cited in this paper may originate from this research.
Methods
This review presents the data on the management of xerostomia after radiotherapy treatment for head and neck cancers. A combination of the terms “xerostomia”, “treatment” “radiotherapy” and “head and neck cancer” yielded in the National Library of Medicine 211 articles. Among them 26 (including systematic reviews) were about treatment methods and were published in the last 10 years. Three articles were systematic reviews of different treatments of xerostomia.
Topical agents and saliva substitutes
Taking sips of water, sometimes with ice or lemon, is the oldest treatment method for dry mouth. However, it is seldom successful in the long run as water washes out the mucus and decreases the lubrication of the mucus membrane which is then prone to drying. Therefore new formulations of artificial saliva were prepared and are already in use for decades. Artificial saliva ideally resembles a natural one and is usually a mix of buffering agents, cellulose-like derivatives and flavouring agents [6]. Saliva replacements are accessible as different agents such as liquids, sprays, gels, oils, mouthwashes, chewing gums, and toothpastes. Typically, they are not toxic and can be applied by the patient as needed, many times a day. Their main purpose is to lubricate the mucous membrane and facilitate chewing, swallowing and speaking. Some preparations may be combined with pilocarpine which stimulates the salivary glands to produce more natural saliva [7, 8]. Artificial saliva was in the past only rarely a subject of a clinical controlled trial as such. More often it was used as a placebo to be compared with [7].
Seventy-two patients with Sjögren syndrome (most of them women) and xerostomia with dry eyes were assigned randomly to receive either 10 pilocarpine drops (5 mg) or 10 drops of artificial saliva three times daily for 12 weeks [7]. The primary outcome was the measurement of non-stimulated salivary and lacrimal flow. The secondary endpoint was the patients’ subjective assessment. Patients receiving pilocarpine had a statistically significant improvement in their salivary flow (p < 0.001), lacrimal flow (p < 0.001) and subjective global assessment (p < 0.001), compared with patients who received artificial saliva. The most common side effects were sialorrhea and nausea.
Recently, several clinical trials with different formulations of artificial saliva with or without pilocarpine were published which suggests developments of new and improved preparations [8–10]. A study by Sarideechaigul et al. [8] aimed to compare the efficacy and safety of xerostomia treatment of two artificial saliva formulations containing 0.1% pilocarpine, and, either sodium carboxymethylcellulose or, sodium polyacrylate. Thirty-one xerostomia patients with xerostomia were randomly allocated into either a carboxymethylcellulose-treated group (15 patients) or, a polyacrylate-treated group (16 patients). The xerostomia could be secondary to radiotherapy but also could result from different, usually, autoimmune disorders. The artificial saliva formulations were taken at the volume of 0.5 mL four times daily for six weeks in a double-blind fashion. The results were assessed using stimulated and unstimulated salivary flow rates and xerostomia inventory and clinical oral dryness score. After treatment, the carboxymethylcellulose-treated group had significantly lower clinical dryness scores and higher unstimulated and stimulated whole salivary flow rates (p < 0.001), while the polyacrylate-treated group showed significantly lower clinical oral dryness scores only (p = 0.004). The effects of both formulas ceased after the discontinuation of therapy.
Another single-blinded randomized controlled trial concerning the efficacy of an oral moisturizing jelly and topical commercial mouth gel was tested in patients with postradiotherapy xerostomia [9]. Primary endpoints were Candida colonization, stimulated salivary flow rate, salivary buffering capacity and salivary pH. Secondary endpoints included subjective patient reports. Both tested saliva gels improved saliva pH, decreased the number of Candida species and stimulated the salivary flow rate. A total of 56 participants in the oral moisturizing jelly (n = 30) and commercial mouth gel (n = 26) groups completed the study. Oral moisturizing gel significantly increased saliva pH (p = 0.042) and buffering capacity (p = 0.013) after one month of use, while commercial mouth gel only improved saliva pH (p = 0.027). Both interventions tended to increase the stimulated salivary flow rate but only commercial gel had a significant increase at two months (p = 0.015). Both commercial gel and oral moisturizing jelly significantly decreased the number of Candida species at 1 and 2 months, but not counting. A comparison of similar preparations was performed by Nuchit et al. [10]. These authors concluded that the new oral moisturizing gel tested by them was significantly better than the control commercial mouth gel and it improved better patients’ salivary flow rate and subjective experience.
Finally, in a controlled clinical trial [11] including 94 survivors of nasopharyngeal cancer a xerostomia Oral7 mouthwash, (an immunologically active saliva substitute formulated with natural enzymes such as lactoperoxidase, lysozyme, glucose oxidase, and lactoferrin, similar to naturally occurring saliva) was compared to commercially available Colgate Plax mouthwash with biocidal properties but no immunologic active ingredients. The trial lasted for 4 weeks. The endpoints were xerostomia inventory and unstimulated whole saliva. There was a significant difference in the xerostomia inventory (p < 0.0001) and unstimulated whole saliva (p < 0.0001) between the control and interventional arm. The immunologically active mouthwash (intervention arm) was significantly better than the control mouthwash but the study lasted only for a short time and it is difficult to judge the long-term effects.
In conclusion — new developments of artificial saliva preparations, step by step, improve their palatability and efficacy. Pilocarpine added to the artificial saliva seems to have an additional effect. However, this particular aspect was not tested in the controlled trials discussed here. On the other hand, the market is flooded with different preparations (tested and untested) available without a prescription, which may leave the patient with xerostomia in great confusion.
Pharmacological treatment
Patients with head and neck cancers survive longer and also suffer xerostomia for a longer time [12], but the data on the results of pharmacological treatment cover usually short periods. Earlier months than years. A systematic review of the xerostomia pharmacological treatments had been published in the Cochrane database by Riley et al. [13].
Amifostine
Two drugs were discussed extensively in this paper [13]. The first is amifostine, a selective-target cytoprotective agent and the second was pilocarpine, an old pro-cholinergic drug (see further). Amifostine was studied in 3520 patients in 39 controlled trials. The authors conclude, that there is some low-quality evidence to suggest that the drug amifostine prevents the feeling of dry mouth in people receiving radiotherapy to the head and neck (with or without chemotherapy) in the short- (end of radiotherapy) to medium-term (three months after completion of radiotherapy). However, it is less clear whether or not this effect is sustained for 12 months after radiotherapy. The benefits of amifostine should be weighed against its high costs and frequent adverse effects. Nausea, vomiting, low blood pressure, and allergic response were all more frequent in those receiving amifostine than placebo. There was insufficient evidence to show that any other treatment is beneficial.
Pro-cholinergic drugs
Pilocarpine is an old and cheap pro-cholinergic drug used in ophthalmology and it can be used for xerostomia orally as capsules [14] or topically as drops [7, 15]. However, the controlled trials performed on only 389 patients and reviewed by Riley et al. [13] revealed data of low quality and only a minor effect, accompanied by some unpleasant adverse effects like runny nose, increased lacrimation and sweating as well as nausea and vomiting.
A study performed at the University of Sao Paulo (Brazil) [16] showed that bethanechol (another old pro-cholinergic drug, similar to pilocarpine) used to treat post-radiotherapy salivary gland dysfunction, improved xerostomia symptoms, and induces some changes in saliva composition. In this study, 45 post-radiotherapy patients complaining of xerostomia used 50 mg/day of bethanechol for 3 months, and the salivary parameters were evaluated before, and at 1, 2 and 3 months of therapy. The biochemical analysis included buffering capacity of saliva; pH; total salivary protein concentration; amylase and catalase concentrations; catalase and peroxidase activity. Patients showed improvement in xerostomia experienced before and after 1, 2 and 3 months of therapy. The percentage of severe xerostomia decreased to 80.5%, 75.7% to 70% of the pretreatment values, respectively. Inversely, the frequency of mild xerostomia increased from 19.5% (background value) to 24.3% after 1 month and to 30% after 3 months. This is despite no changes in stimulated and unstimulated salivary flows. In addition, some changes were observed in the chemical composition of saliva. In stimulated whole saliva, total protein increased significantly after one month (p < 0.0001) but decreased later on in the study. In the end, after 3 months the total protein values were similar to the background values (p = 0.51). In unstimulated whole saliva collection, there was a decrease in peroxidase activity by comparing the background values with those after 1 month (p = 0.026), 2 months (p = 0.007) and 3 months of treatment (p = 0.018). For stimulated whole saliva collections, there was also a decrease in this peroxidase activity compared to the background values. In unstimulated whole saliva, there was no significant change in catalase activity during the study (p < 0.05). However, in stimulated whole saliva, catalase was increased after 2 (p < 0.0001) and 3 months (p = 0.003). Amylase activity in unstimulated whole saliva collection was increased after 1 (p = 0.002), 2 (p < 0.0001) and 3 months (p = 0.029). In conclusion, bethanechol appeared in this study to reduce the severity of xerostomia despite the lack of an increase in salivary flow rates. It is thus possible that qualitative changes in salivary biochemistry were responsible for the observed effects.
Vitamins C and E
Vitamins C and E (alone or in combination) were used in the prevention and treatment of xerostomia for a longer time. However, these drugs were never trustworthy tested in a clinical trial. A prospective, double-blind, randomized study with the vitamins C and E [17] was studied in South Korea on 45 patients before radiotherapy due to head and neck cancers. The patients were randomized into two groups. The intervention group (n = 25) received 100 IU of vitamin E and 500 mg of vitamin C (in one capsule), administered twice daily. The control group (n = 20) received an identical capsule with a placebo, also twice daily. Both groups started treatment one week before and continued it for one month after the completion of radiotherapy. Patients were assessed with a patient-reported xerostomia questionnaire, patient-reported xerostomia score and salivary scintigraphy. The intervention group showed greater improvements in the xerostomia questionnaire and scores at 6 months post-radiotherapy when compared with those at one-month post-radiotherapy (p = 0.007 and 0.008, respectively). In contrast, the control group showed no changes between 1- and 6 months post-radiotherapy. By salivary scintigraphy, there was no difference in maximal accumulation or ejection fraction between the two groups. At the final follow-up, there was no difference in overall survival and disease-free survival between the two groups. So, it is probable that vitamins C and E may protect patients from post-radiotherapy xerostomia. More studies should be done in the future. The vitamins were not studied separately so it is not known which (if not both) vitamins are responsible for the observed effect.
Alternative treatments
Low-level laser therapy
An exciting, but not yet fully proven in clinical trials method is illumination with low-level laser therapy (LLLT). LLLT is a cheap method used for photo-bio-modulation of tissue in many medical specialities, including pain control [18]. In the study performed in Sao Paulo (Brazil) [19] on 29 patients with post-radiation hyposalivation and dry mouth a continuous wave indium-gallium-aluminium-phosphorus diode laser device was used punctually on the major salivary glands (808 nm, 0.75 W/cm2, 30 mW, illuminated area 0.04 cm2, 7.5 J/cm2, 10 s, 0.3 J). Six extraoral points were illuminated on each parotid gland and three on each submandibular gland, as well as two intraoral points on each sublingual gland. Each patient received two sessions a week for three months. Stimulated and unstimulated salivary flow rate, salivary pH, and quality of life questionnaire were assessed at baseline and the end of the treatment. There were significant increases in both mean salivary flow rates (unstimulated; p = 0.0012; stimulated; p < 0.0001), mean pH values (unstimulated; p = 0.0002 and stimulated; p = 0.0004), and mean score from the quality-of-life questionnaire (p < 0.0001). Low-level laser therapy seems to be effective to mitigate salivary hypofunction and decrease of xerostomia. One should remember that this was not a controlled study and the study lasted only for three months. There are no data on long-term effects after discontinuation of photo-bio-modulation.
In this view, it is important to mention the older but uncontrolled study by Loncar et al. [20] who showed on 16 patients that photo-bio-modulation with LLLT was not only stimulating salivation but also positively influencing the regeneration of the salivary glands. However, more recently, a well-designed placebo-controlled clinical trial did not show any effect on salivary glands in Sjögren syndrome [21]. In another uncontrolled study, exposure to photo-bio-modulation during the radiotherapy period probably limited hyposalivation [22]. So, it is possible, but not proven, that regeneration of the salivary gland may be different in Sjögren syndrome and post-radiation xerostomia.
One should also reflect on the issue that until recently the LLLT was never used in oncology as the LLLT was feared to stimulate the remaining tumour cells to grow and metastasize. The data on this issue are still preliminary and controversial [23, 24]. On the other hand, illumination with LLLT is performed on the salivary glands that did not contain any tumour. Taking all of this into account further studies and well-controlled studies are needed, but this method has its potential.
Hyperbaric oxygen
Another alternative method is the use of hyperbaric oxygen therapy. Lovelace et al. [25] in a metanalysis of the literature on this subject found that hyperbaric oxygen improves the subjective experience of xerostomia. After this, several clinical trials were performed and a systematic review confirmed the long-term effects on xerostomia [26]. What is interesting is that with this method the need for tooth extraction due to hyposalivation and caries was reduced [27]. The limitation of this method is that number of hyperbaric chambers, used in diving medicine, is limited, and many countries do not have these facilities at all.
Thyme honey
Thyme honey was used in traditional medicine for many ailments. Among others: wound healing and xerostomia. A single-centre, randomized clinical trial was performed with thyme honey on inpatients with head and neck cancers subjected to radiotherapy [28]. It was anticipated that the presence of honey in the oral cavity before and after radiotherapy can have a sialagogue effect by stimulating the salivary glands to produce more saliva and can prevent xerostomia. Seventy-two patients with head and neck cancer receiving radiotherapy or/and chemotherapy or/and surgery were recruited in a specialized cancer centre. Patients were randomized before the oncological therapy to either thyme honey or saline groups. Patients had oral rinses (20 mL of thyme honey diluted in 100 mL of purified water) just before the radiotherapy session, immediately after the radiotherapy session and 6 hours after the session. The control group received rinses with saline according to the same protocol. The study was evaluated after 1 and 6 months. Analysis of results revealed the statistically significant effect of thyme honey on xerostomia (p < 0.001) and overall quality of life (p < 0.001) in comparison to placebo. Thyme honey was safe in use and was effective in the treatment of not only xerostomia but also dysphagia, intractable pain, postradiotherapy changes in the taste and significantly improved quality of life. This is a single trial and more trials should be done before these methods, although very interesting, can be presented to the great public. In the above study blinding was not ideal as saline tastes different from honey. This could influence the final results. Also, unintended beneficiary effects on so many other symptoms should always be treated with suspicion.
Acupuncture
In the past, it was claimed that acupuncture can mitigate post-radiotherapy xerostomia in head and neck cancer patients. Ni et al. [29] performed a systematic review of acupuncture in the treatment of xerostomia in cancer patients. Eight clinical trials (725 participants) were analysed, and 3 were included in the meta-analysis. All included trials had a high risk of bias, such as selection, performance, and detection bias. Analysis indicated favourable effects of Acupuncture regarding the improvement of xerostomia symptoms (MD −3.05, p = 0.02, 95% CI −5.58 to −0.52), compared with sham acupuncture. However, there were no differences between acupuncture and sham acupuncture regarding the stimulated salivary flow rate (MD 0.37, p = 0.08, 95% CI −0.05 to 0.79) and unstimulated salivary flow rate (MD 0.09, p = 0.12, 95% CI −0.02 to 0.21), which were whole salivary flow rate compared with no acupuncture (standard oral care, usual care, or no treatment). Acupuncture produced a significant improvement in patient-reported xerostomia, without causing serious adverse effects. The authors concluded that the overall quality of the analysed data was low. In conclusion, acupuncture is probably effective against xerostomia, but its effect could be caused not by acupuncture itself but by the placebo effect. Acupuncture cannot yet be recommended for radiation-induced xerostomia in cancer patients until more solid evidence is produced.
Transcutaneous electrical nerve stimulation
Salimi et al. [30] performed a systematic review of the studies investigating the effects of transcutaneous electrical nerve stimulation (TENS) in xerostomia experienced by patients with head and neck cancer. Five studies (928 patients) were included in the systematic review. Most of the studies presented in this review suggest that there is a benefit in producing saliva by stimulating the salivary glands with TENS. However, all the studies with TENS used different protocols and this is why the results are impossible to compare.
New non-pharmacological methods in the development
Mesenchymal stem cell therapy
Mesenchymal stem cell (MSC) therapy has shown promising results in pre-clinical studies. It was hypothesized that MSCs could have a paracrine, angiogenic and antiapoptotic effect on the salivary glands [31]. In a single-centre, phase I/II, randomized, first in humans, a placebo-controlled, double-blinded clinical trial using MSCs or placebo injected directly into the submandibular salivary glands [32]. The primary endpoint was the unstimulated salivary flow rate. Secondary endpoints were subjective patient reports, safety and efficacy measures. The effects were evaluated at the baseline and 1 and 4 months after the MSC or saline injection. The results of this feasibility phase 1 study were promising and will be used to design further trials. Similar promising results were obtained with effective mononuclear cells [E-MNC] [33]. E-MNC could influence the regeneration of the atrophic cells probably better than the MSC. The results should be further validated in phase II and III trials.
Gene transfer therapy
Salivary gland gene transfer into the salivary glands is safe and can be beneficial in humans. Applications to treat and prevent radiation damage show considerable promise. A first-in-human clinical trial was recently successfully completed [34]. The results are promising as a proof-of-the concept, but we need to wait until controlled studies will be published.
Discussion
Feeling of dry mouth or xerostomia is one of the most annoying, common complications of radiotherapy due to head and neck cancers [1–4]. It influences significantly patients’ quality of life and it may last life-long. It may induce caries and result in compulsory tooth extraction and oral/gingival infections. Because treatment of established xerostomia is often unsatisfactory or incomplete and the condition lasts sometimes life-long it is important to address this in the clinical trials of the problem of prevention. Such trials are now slowly coming up and some are promising. The potential of xerostomia prevention was observed in the trial with C and E vitamins [17] and thyme honey trials [28]. But these findings need confirmation. Also, there are only a few trials which address the regeneration of the salivary glands. The potential for regeneration was suggested in the LLLT trial [20]. However, this finding could not be confirmed for the patients with xerostomia due to Sjögren syndrome [21]. Regeneration may differ in these two conditions. Although tempting, extrapolation from Sjögren syndrome to post-radiotherapy xerostomia is risky and should not be accepted without caution. Regeneration or at least maintenance of the improved glandular function after discontinuation of treatment has been evidenced for hyperbaric oxygen only [25, 26]. In contrast, many studies reviewed in this paper lasted only for a relatively short time and there is a paucity of data on xerostomia after discontinuation of therapy.
Traditionally xerostomia is treated with artificial saliva or other topical preparations which need to be applied many times a day. But the effects of these topical preparations are often disappointing. Recently, different new and improved preparations were introduced on the market and there is considerable progress in this field. Many preparations available on the market, sometimes without prescription, were never clinically tested. The patients are often overwhelmed by this and making a rational choice can be challenging. Some of the Artificial saliva preparations are combined with pilocarpine topically, while their account is still controversial [13]. In the case of the salivary glands, rest function is available stimulating measures can be tried. Here are the pro-cholinergic drugs like pilocarpine, or bethanechol applied systemically, the standard. However, the efficacy of these methods is limited, and new drugs and new methods are needed. Amifostine was the most promising new stimulating and cytoprotective drug which was expected to replace pilocarpine, but its effects are only moderate and are accompanied by frequent adverse effects [13].
Among the alternative methods of stimulation, hyperbaric oxygen looks the most promising. [26, 27]. Its lasting effect is confirmed beyond any doubt. However, the drawback of this method is the poor availability of hyperbaric oxygen chambers in countries without access to the sea. Many new clinical trials should be performed, also with emerging alternative treatments. Clinicians, however, have even now a wide choice of methods available to choose from. The new, but not yet sufficiently investigated, and hence poorly available methods, are mesenchymal cell therapy as well as gene-transfer therapy [31–33]. If the preliminary results will be confirmed, these methods may be the future of therapy for post-radiation xerostomia. Treatment methods for xerostomia are presented in the Table 1.
|
Method of treatment, how it works? |
Appearance |
How often and how should be applied? |
Availability |
Is the action proven? |
|
Formulations of artificial saliva Topical, lubricating |
Liquids, drops, sprays, gels, mouthwash, chewing gum, toothpaste |
Treatment is non-toxic so the formulations may be applied many times a day |
Very good |
Not always, there are many formulations and only a few were tested clinically. Clinical trials were probably sponsored by the pharmaceutical industry |
|
Amifostine [13] This is a well know cytoprotective drug. It generates tissue thiols. It is used during chemo- and radiotherapy |
Ampoules for parenteral use |
Intravenous injection of 200 mg/m2 before radiotherapy |
It is available in hospitals. it is quite expensive |
In many controlled clinical trials, the activity against xerostomia is only moderate and the adverse effects are frequent. It does not work against established post-radiation xerostomia |
|
Pilocarpine [7, 8, 14, 15] It is an old pro-cholinergic drug stimulating salivary production. It works only when the salivary glands are intact (not after surgery). Tablets act systemically while drops act topically with fewer adverse effects |
Tablets [14], drops [7, 8, 13, 15] |
Usually 3 × 5 mg With higher doses, frequent adverse effects such as nausea and vomiting, increased sweating and increased lacrimation. Increased production of gastric acid [13] |
Tablets and capsules are not easily accessible in pharmacies. Drops are used by ophthalmologists and are available in every pharmacy |
In the controlled studies the stimulation of the salivary glands is minimal and adverse effects are common [13] |
|
Bethanechol A pro-cholinergic drug [16] |
Tablets [16] |
50 mg a day [16] |
Fewer adverse effects in comparison to pilocarpine [16] |
In controlled studies, it has similar effects as pilocarpine but fewer adverse effects [16] |
|
Vitamin C and E [17] |
Capsules |
Vitamin C 500 mg and vitamin E 11 IU, twice daily [17] |
Cheap. Easily accessible in every pharmacy |
This was a single trial on a limited number of patients. The results should be repeated and confirmed [17] |
|
Photo-bio-modulation by the low-level laser therapy [19–21]. It works probably by biostimulation and regeneration of the salivary glands |
Exposition to the laser light beam |
Therapies in the office. Usually 20–30 minutes. Couple of times a week. Different protocols. The treatment is not toxic unless excess advised doses |
Availability is limited. LLLT is used in physiotherapy, sports and pain medicine |
The results of clinical trials are scarce and are not consistent as every author uses different equipment and doses. Stimulation of regeneration of the salivary glands is not yet proven [20, 21] |
|
Hyperbaric oxygen [25, 26] Stimulates regeneration of the salivary glands |
Oxygen is applied under high pressure in a hyperbaric tank. The session lasts 20–30 minutes |
Up to 5 times a week. [27]. This method is not suitable for claustrophobic patients. The treatment is not toxic |
Availability is limited to large cities. Some countries do not have even one chamber |
Clinical trials revealed consistent positive and long-lasting results [25, 26, 27] |
|
Thyme honey [28] The mechanism of action is unknown |
Honey dissolved in water |
A couple of times a day. Its working is limited to the prevention of xerostomia [28] |
Cheap, easily available in specialized shops |
A positive preventive effect was seen in a single-centre trial (not well-blinded) with a limited number of patients [28]. The authors reported a positive effect also on intractable pain. The trial should be repeated with a better design |
|
Acupuncture [29] It Is not clear how it works |
Needle insertion |
Twice weekly sessions |
Cheap, available |
Difficult to differentiate what is the effect of a placebo and what is the effect of true acupuncture. The results of a systematic review show that most trials used different protocols [29] |
|
Mesenchymal stem cells [31, 32, 33]. The cells can stimulate the regeneration of the salivary glands |
The cells are injected directly into the gland |
Once in the operation theatre |
Experimental. Availability is limited to research centres. Single centres in Europe |
The working, although promising, is not yet proven in clinical trials |
|
Gene transfer therapy [34] |
The genes are injected into the salivary gland |
Once in the operation theatre |
Experimental |
The results are promising but until now there is only a proof-of-the-concept trial [34] |
Declaration of conflict of interests
The authors declare that there is no conflict of interest.
Funding
None declared.
