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Title: Functional outcomes in early (T1/T2) supraglottic cancer: a systematic review |
Abstract |
Objectives: Organ preserving surgery (OPS) and radiotherapy (RT) are both accepted treatment options for early stage supraglottic cancer (SGC). Radiation has supplanted surgery in most cases, because of the perception that surgery results in poorer functional outcomes. However, evidence suggests that OPS with a neck dissection may be associated with improved survival. Our objective was to conduct a systematic review of the literature to compare functional outcomes of OPS and RT for early SGC. |
Methods: We searched Medline, EMBASE and Cochrane Central Register of Controlled Trials to identify studies. Studies were included if they reported functional outcomes on 10 or more patients with early stage SGC treated with radiation or OPS, including open partial laryngectomy, transoral laser microsurgery (TLM) or transoral robotic surgery (TORS). Two reviewers independently screened articles for relevance using pre-determined criteria. |
Results: From 7720 references, we included 10 articles (n = 640 patients). 50% (n = 320) of patients were treated with surgery. Three head-to-head RT versus OPS papers were included, however different outcome measures were used for each group. Intractable aspiration management (including total laryngectomy or permanent tracheostomy) following OPS was reported in five papers representing 186 patients; the definitive intractable aspiration management rate was 2.6% (95% CI 1.0–6.8%). Four papers reported permanent G-tube rate for the surgical group (n = 198), calculating a rate of 5.3% (95% CI 2.6–10.5%), this was not reported for the RT group in any papers. One study reported quality of life. Two studies reported objective voice measures. |
Conclusions: This systematic review revealed a paucity of objective measures and significant data heterogeneity, rendering the comparison of functional outcomes following OPS versus RT for early SGC limited. Future research should include objective measures of functional outcomes including laryngectomy rate, g-tube rate, tracheostomy dependence, quality of life, and voice quality measures. |
Keywords: Early stage, Supraglottic squamous cell carcinoma, Supraglottic SCC, Outcomes, Systematic review, Functional outcomes |
Introduction |
Early stage supraglottic squamous cell carcinoma (SSCC) includes T1 tumours, isolated to one subsite of the supra- glottis with normal vocal cord function, or T2 tumours, involving more than one subsite of the supraglottis, glottis, or surrounding tissue, without evidence of regional disease spread [1]. A recent study of nearly 160,000 laryngeal can- cer SCC patients in the United States, found the incidence of SSCC to account for one third of laryngeal cancers [2]. Laryngeal cancers are the most common malignant lesions of the head and neck, with an estimated 13,150 new laryngeal cancers per year [3].The recommendations from the National Comprehensive Cancer Network (NCCN) guidelines for treatment of early stage SSCC include both organ preservation strategies – radiation (RT) or organ preservation surgery (OPS) with or without a neck dissection [3, 4]. Despite small tumour sizes, 5-year survival for early stage SSCC is 64%, and oncologic outcomes have not improved over the past 30 years [2, 5–8]. This is hypothesized to be a result of the robust lymphatic supply to the supraglottis leading to higher rates of occult metastases to regional and distant sites. When comparing the relative 5-year survival from 1985 to 1987 to 1994–1996, there was a decline from 52.2 to 47.3%. Reviewing the data from the National Cancer Database, the largest decline was identified in patients with T1 N0-T2 N0 disease. A recent meta-analysis by Patel et al. (2018) examining survival in early stage supraglottic SCC suggested that primary surgery may result in decreased disease specific survival (OR 0.43, 95% CI 0.31–0.60) and overall mortality (OR 0.40, 0.29–0.55) when compared with primary radiotherapy [9]. There are a limited number of studies, with no previ- ous meta-analysis, that have compared the functional outcomes between primary surgery and primary radio- therapy for early stage SSCC. Much of the available data focuses on survival outcomes for the two treatment modalities [7–17]. There are no prospective clinical trials, and the majority of the studies reported are small and retrospective in design. Our objectives were to systematically review the literature to find all the relevant studies about the functional outcomes for surgery and radiation for early stage SSSC, synthesize the results and perform meta-analyses where possible. |
Methods |
A systematic review protocol was developed a priori to en- sure the objectives and aims were outlined from the outset. Computerized bibliographic databases: Medline, EMBASE and Cochrane Central Register of Controlled Trials were searched to identify studies. English language records were included from January 1990 to October 2018. The search strategy was designed by three authors (B.V.W., K.B.P. and S.D.M.) and an experienced librarian. Randomized controlled trials, head-to-head comparative studies, observational studies, and case series that included 10 or more patients were reviewed. Single arm studies that reported functional results of organ preserva- tion surgeries or radiotherapy as single modality therapy were included in the review. Studies on organ preserving surgeries, including open partial laryngectomy, transoral laser microsurgery (TLM) or transoral robotic surgery (TORS), with and without neck dissection were included. The study population was limited to patients aged 18 and older, diagnosed with early stage supraglottic SCC (Tis, T1 N0, T2 N0). We excluded studies where functional results for patients with advanced T stage or node positive disease were grouped into the results and could not be reliably differentiated. We also excluded studies where functional outcomes for patients with early supra- glottic cancers were combined with early glottic cancers. Included studies were assessed for the following functional outcomes: aspiration; gastrostomy tube dependence; objective voice outcomes; and quality of life measures. Titles, abstracts, and full texts of the studies were reviewed independently by two authors (B.V.W. and K.B.P.). Disagreements were resolved by consensus. Inter-observer agreement was analyzed with Cohen’s kappa. Titles were screened for the keywords: “squamous cell carcinoma” and “supraglottic”, or “supraglottis”, or “glottic”, or “glottis”, or “larynx”, or “laryngeal”. All study abstracts that met the eligibility criteria were then screened individu- ally. The full text of studies that met inclusion criteria were then reviewed. The Newcastle-Ottawa Quality Assessment Scale for Cohort Studies was used to determine the quality of the studies (Table 2) [18]. Relevant data was extracted using a standardized data extraction form. Not all studies contained data for each of the outcome measures. Review Manager 5.3 and Comprehensive Meta-Analysis applications were used for statistical analysis. Dichotomous outcomes were compared using odds ratios (OR) or weighted incidence rates and 95% confidence intervals (CI). Heterogeneity across the studies was evaluated by the chi-square statistic and significance was set at p < 0.05. The I2 test was used to measure the extent of inconsist- ency across the results. A random effects model was used to allow for differences in the treatment effects from study to study. The Z statistic was used to test for overall pooled effect and significance was set at p < 0.05. |
Results |
The search strategy produced 7720 records. After dupli- cate records were removed from the search, 5218 unique records remained. After reviewing the titles, 1187 abstracts were deemed appropriate for abstract review. Following abstract review, 115 studies were appropriate for full text review. Ten studies met the final inclusion criteria after reviewing the full text. |
CONCLUSIONS: |
There is an overall paucity of literature available regarding functional outcomes in the treatment of early stage SSCC patients, the majority of which is moderate in overall quality and retrospective in nature. The majority of the data does not reflect the treatment algorithms of today, with the introduction of focused radiation therapies and endoscopic surgical approaches. Changes to treatment algorithms have not been reflected in head-to-head studies examining the functional outcomes. The outcome measures reported have significant heterogeneity in the current literature, which limits the ability to draw definitive conclusions. Moving forward, we propose that aspiration, intractable aspiration intervention, permanent gastrostomy tube requirements, and objective quality of life scales as objective measures that should be included in future research on this topic. Future studies and research should include well designed prospective trials with rigorous reporting of outcome measures. |
Study characteristics and methodologic quality |
There were no randomized controlled trials comparing the functional outcomes of primary surgery versus radiation. Of the 10 studies included in the analysis, 6 were retrospective cohort studies, 4 were case series. There were no prospective studies included. There were 320 patients treated with OPS, including open partial laryngectomy, transoral laser microsurgery (TLM) or trans- oral robotic surgery (TORS). For the RT arm, there were 320 patients. Altogether, 640 patients were ana- lyzed from 10 studies. There were 6 patients with early SSCC where the treatment modality was not specified and could not be included in the analyses. Characteristics of the included studies are summarized in Table 1. Overall, the quality of the included studies was moder- ate, this was for a variety of reasons, including no reference group (surgery or radiation arm only), short or unreported length of follow up, and unaccounted for patients. Table 2 summarizes the quality of the individual studies. |
Aspiration |
Aspiration was deemed a primary functional outcome measure of assessment. It was reported in 5 studies [11, 14, 19–21]. In one paper, this was evaluated under direct visualization with a functional endoscopic examination of swallowing, where the authors documented liquid penetration. The remainder of the papers reported patients with clinically evident late aspiration, and sequelae such as aspiration pneumonia. In the surgical arm, 9 out of 252 patients were reported to experience aspiration, for a pooled aspiration rate of 3.7% (95% CI 1.9–6.9%) (Fig. 2). In the RT arm, aspiration is reported in 15 out of 198 patients, for a pooled aspiration rate of 14.5% (95% CI 9.1–22.5%) (Fig. 3). The odds ratio is 1.23 (95% CI 0.14–10.86) (Fig. 4). |
Intractable aspiration management |
In many of the studies, rate of functional laryngectomy and permanent tracheostomy dependence was reported. These statistics included some, but not all, of the pa- tients who experienced late complications associated with aspiration events. This was reported in 5 studies, accounting for 186 surgical patients and 198 radiation patients. The pooled event rate for intractable aspiration management in the surgical arm is 2.6% (95% CI 1.0– 6.8%) (Fig. 5). The pooled event rate for the RT arm is 16.8% (95% CI 10.8–25.0%) (Fig. 6). The odds ratio com- paring the two groups is 1.14 (95% CI 0.04–33.45) (Fig. 7). |
Permanent gastrostomy tube and swallowing dysfunction |
The rate of permanent gastrostomy tube was reported in four studies for the OPS group. This accounted for 198 patients. This outcome measure was not reported for the radiation group in any of the studies. The pooled event ratio for permanent gastrostomy tube dependence is 5.3% (95% CI 2.6–10.5%) (Fig. 8). |
Additionally, Chun et al. compared OPS to RT with respect to functional outcomes of swallowing and speech. To evaluate swallowing, patients underwent a functional endoscopic examination of swallowing (FEES) using videoesophagofluoroscopy. The researchers looked specifically for evidence of aspiration. Liquid aspiration was identified 6% of patients in the OPS group (n = 1). There was no identified liquid aspiration in the RT co- hort [11]. |
Quality of life and voice outcomes |
Quality of life data was reported in one study. Another study reported objective voice outcome measures. Oridate et al. compared VRQOL, VHI-10, and GRBAS scores for T2 N0 SSCC against T1a, T1b, and T2 N0 glottic carcin- omas and found no significant differences in functional outcomes [22]. |
Chun et al. used stroboscopy and acoustic waveform ana- lysis to objectively evaluate voice outcomes. Abnormalities were in mucosal waveforms were identified 13% of the OPS cohort (n = 2) and 20% of the RT group (n = 2). These find- ings were not statistically significant [11]. |
Discussion |
To our knowledge, this is the first systematic review evaluating the functional outcomes of surgery versus radiother- apy for early-stage SSCC. All studies that met inclusion criteria were retrospective in design and there were 3 head-to-head comparisons of surgery versus radiation. Aspiration events, management of intractable aspiration, and permanent gastrostomy tubes are some of the major indications of laryngeal function. There was insufficient data to thoroughly meta-analyze the two modalities with respect to these outcome measures. Furthermore, object- ive voice outcomes were available in just two studies. Quality of life measures were only found in one included paper. |
Aspiration events were reported, in many cases, with little additional information. In some studies, these were clinically evident respiratory events, such as aspiration pneumonias that occurred late in the post-operative course, others reported only the number patients that experienced aspiration. Aspiration events are reported in 50% of studies (n =5), 2 of which were head-to-head comparisons. |
For intractable aspiration intervention, there was data from both the surgical and radiation cohorts from multiple studies. This was reported as permanent trache- ostomy dependence or conversion to a functional total laryngectomy. We calculated pooled event rates as well as pooled odds ratio. From the current data available, there is no strong evidence to suggest there is a differ- ence between the two modalities with respect to this outcome measure. |
With respect to permanent gastrostomy tube rate, there was no available data for the radiation cohort. Four papers reported this outcome measure for the surgical group (n = 198 patients). As a result, we were unable to make comparisons across the two treatment modalities. |
Subjective and objective measures of voice outcome were sparsely and inconsistently reported. Quality of life measures were found in just one study, which actually compared T2N0 supraglottic cancers to early glottic cancers. |
Surgery and radiotherapy for early stage SSCC |
Several factors are important in considering treatment options for patients with early laryngeal cancer. Survival outcomes are obviously at the forefront. While there is no RCT data comparing survival outcomes of patients with early SSCC, a 2016 meta-analysis by Patel et al. studying early stage SSCC suggests that patients who undergo primary surgery have better survival than those who underwent primary radiotherapy [8]. Laryngectomy rate is another important consideration, as most patients with early stage laryngeal cancer are candidates for organ preservation treatment. Finally, in the presence of equivalent survival for two treatment modalities, functional outcomes are important to assess in comparing treatment options. |
Over the last 40 years the treatment of early stage laryngeal cancer has evolved [23, 24]. Surgery, in the form of open partial laryngectomy, was initially popular how- ever many patients had poor functional outcomes including aspiration and impaired base of tongue and laryngeal movements leading to swallowing dysfunction [25]. Radiation then took over as the primary treatment modality for early stage laryngeal cancer, with the goal of mitigating many of the functional problems associated with open partial laryngectomy. However, radiation is not without its own side effects. In addition, minimally invasive surgical techniques including TORS and TLM are increasingly being used for early stage SSCC [23, 24], raising the question of whether the functional outcomes with TORS and TLM may be better than radiation. Unfortunately, there are very few studies reporting the functional outcomes of TORS and TLM for early stage supraglottic cancer. |
There are several advantages of RT. It preserves the laryngeal structures, it is generally well tolerated by patients, and increases surgical exposure to achieve excellent oncologic outcomes [26–29]. Radiation provides an effective treatment modality for patients not considered candidates for OPS due to their comorbid medical conditions. One of the disadvantages in treating early stage SSCC with RT, is that these patients are at high risk for developing a second primary and local regional recurrence [5, 6, 30]. If radiation is used as the primary treatment modality, most patients can only be salvaged with surgery, and, in the case of recurrent or new laryngeal cancer, the treatment is almost always total laryngectomy. |
Surgical approaches include open surgery or transoral surgical approaches, including laser (TLM) and robotic (TORS). Organ-preserving surgery, both open and endoscopic approaches, offer several advantages over RT. As mentioned, patients with SSCC have reasonable 5-year overall survival rates, albeit with an increased risk of developing second primary aerodigestive tract malignancy [5, 6, 30]. Surgery can therefore be utilized as the first line, and, in the setting of recurrence, radiation can be used as salvage therapy. An additional advantage of surgery is the cost benefit of surgical intervention over radiotherapy [31, 32]. Furthermore, surgical management with a neck dissection provides the opportunity to identify oc- cult metastasis; an important consideration given that up to 30% patients with SSCC may have occult nodal metastasis [32]. Identification of occult metastasis al- lows for accurate staging of patients, and subsequently treatment with multimodality therapies. |
Dombree et al. analyzed the cost of open supraglottic laryngectomy, TLM, and TORS in a Belgian model. Their study suggests the cost of open supraglottic laryn- gectomy similar to that of TLM in upfront surgical costs [31]. TORS tends to be more expensive primarily due to purchase and maintenance costs [31]. This study did not account for in-hospital costs such as length of admis- sion, complications or readmission rates. With regard to glottic cancers, a cost analysis was carried out for a Canadian model comparing TLM to radiotherapy. This showed TLM to be a more cost-effective treatment option [33]. |
There are also disadvantages of surgery, including risk of general anesthetic, particularly in patients with comor- bidities, bleeding, and infection. Pharyngocutaneous fis- tula, dysphagia and permanent tracheostomy dependence are specific risks of supraglottic laryngectomies. A criti- cism of OPS are the associated poor functional outcomes [25]. However, newer surgical techniques including TLM and TORS have gained popularity recently, and hold several advantages over open surgery and RT. In one study, TLM was compared to open surgery, resulting in reduced incidence of permanent gastrostomies and tracheostomies [20]. Since the introduction of TLM by Strong and Jako, there have been several reports investigating the role of TLM for supraglottic laryngectomy [34–48]. With respect to TORS, the majority of the stud- ies report on all stages of supraglottic SCC [20, 43, 48– 59]. With that in mind, long-term tracheostomy and gastric feeding tube rates range from 0 to 20% in patients treated with TORS [49, 52, 55]. None of the studies included in this systematic review examined the functional outcomes of TORS. |
Strengths |
There are several strengths to this review. To our know- ledge, this is the first comprehensive review of all available literature comparing functional outcomes between surgery versus radiation for patients with early stage SSCC. It was designed, conducted and reported in accordance with published guidelines (PRISMA) and the study protocol, as well as search strategy, was outlined a priori. A comprehensive search strategy was undertaken and led to the review of 5218 unique citations of which ten studies met our inclusion criteria. This resulted in the analysis of a large number of patients with early stage SSCC (n = 640). |
Limitations |
As with all systematic reviews, the strength of the conclu- sions that can be drawn from this study depend on the quality of the primary studies. The included studies were evaluated with the Newcastle-Ottawa Scale for Assessing Cohort Studies, most of which were of moderate in overall quality. Next, although we only included studies published from 1990 forward, some of the studies in our review included patients treated well before that time period. This broad recruitment period includes many patients where treatment algorithms may not reflect today’s standards. Given the improvements in medical imaging, some patients may have had regional nodal disease which was not evident on the available scans, therefore reflecting more advanced disease. Furthermore, many of the current treatment options, such intensity modulated radiotherapy (IMRT), TLM, and TORS were not in clinical practice prior to 1990. The types of radiation and protocols used were not clearly outlined in the studies included. As well, given the broad recruitment periods for some of these studies, different radiotherapy protocols would have been offered to the patients according to the available therapies at that time. |
All 10 studies that met the inclusion criteria were retrospective study designs and there were no randomized controlled trials. Retrospective studies have inherent biases including selection biases. Patient’s with medical comorbidities may not have been deemed appropriate surgical candidates and only offered radiotherapy, which may not be reflected in the results. |
Significant heterogeneity was noted between the out- come measures of the included studies. In the surgical group, not all patients may have received the same type or extent of surgery, including elective neck dissections, TLM, and TORS operations. We only considered English language studies for our systematic review, which limited the number of titles screened and studies included, how- ever, the effect of this would likely be small. |
The heterogeneity of the functional outcomes reported limited our ability to meta-analyze the data. Additionally, many of the outcomes were sparsely reported or reported for only one of the arms of study, either OPS or RT. The overall paucity of data limits our ability to draw conclusions. |
Given the lack of high level evidence guiding the opti- mal management of early stage supraglottic cancer and potential biases of retrospective studies, a head to head comparison between newer modalities such as TLM and TORS with RT is critical in determining the therapeutic algorithm that can yield better functional outcomes in early stage SSCC patient. Many studies were ruled out as part of our protocol due to the stratification of results with respect to laryngeal subsite and staging criteria (including advanced stage disease). The method in which functional results are reported, is often less rigorous than the report- ing of survival and locoregional control. The use of object- ive measures and validated tools was limited and not consistent across studies. |
Traditionally, studies comparing surgery and radiation have been challenging to accrue patients to. Ongoing efforts comparing OPS to RT for oropharyngeal cancer are underway and actively accruing [60, 61], demonstrating that a head-to-head comparison of surgery and radiation is a possibility for patients with early stage supraglottic cancer. High level of evidence is important in the development of treatment guidelines for patients with early stage disease that have a surprisingly poor prognosis, compared to other early stage head and neck cancers. Traditionally, OPS has been seen as an option with poor functional outcomes. We did not find evidence to support one modality being better than another with respect to functional outcomes. |
Conclusions |
There is an overall paucity of literature available regarding functional outcomes in the treatment of early stage SSCC patients, the majority of which is moderate in overall quality and retrospective in nature. The majority of the data does not reflect the treatment algorithms of today, with the introduction of focused radiation therapies and endoscopic surgical approaches. Changes to treatment algorithms have not been reflected in head-to-head studies examining the functional outcomes. The outcome mea- sures reported have significant heterogeneity in the current literature, which limits the ability to draw defini- tive conclusions. |
Moving forward, we propose that aspiration, intract- able aspiration intervention, permanent gastrostomy tube requirements, and objective quality of life scales as objective measures that should be included in future re- search on this topic. Future studies and research should include well designed prospective trials with rigorous reporting of outcome measures.
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Title: Cannabinoid Use in the Treatment of Laryngeal Dystonia and Vocal Tremor: A Pilot Investigation |
Abstract: |
Objectives/hypothesis. Laryngeal dystonia and vocal tremor can be debilitating conditions with
suboptimal treatment options. Botulinum toxin chemodenervation is typically the first-line treatment and is considered the gold standard. However, patient response to botulinum toxin varies widely. There is anecdotal evidence for the use of cannabinoids in treating laryngeal dystonia with a scarcity of research investigating this potential treatment option. The primary objective of this study is to survey patients with laryngeal dystonia and vocal tremor to gauge how some people are using cannabinoids to treat their condition and to ascertain patient perceptions of cannabinoid effectiveness. |
Study Design. This is a cross-sectional survey study. |
Methods. An eight-question anonymous survey was distributed to people with abductor spasmodic dysphonia adductor spasmodic dysphonia, vocal tremor, muscle tension dysphonia, and mixed laryngeal dystonia via the Dysphonia International (formerly National Spasmodic Dysphonia Association) email listserv. |
Results. 158 responses: 25 males and 133 females, (mean [range] age, 64.9 [22–95] years). 53.8% of participants had tried cannabinoids for the purposes of treating their condition at some point, with 52.9% of this subset actively using cannabis as part of their treatment. Most participants who have used cannabinoids as a treatment rank their effectiveness as somewhat effective (42.4%) or ineffective (45.9%). Participants cited a reduction in voice strain and anxiety as reasons for cannabinoid effectiveness. |
Conclusions. People with laryngeal dystonia and/or vocal tremor currently use or have tried using cannabinoids as a treatment for their condition. Cannabinoids were better received as a supplementary treatment than as a stand-alone treatment. |
Key Words: Cannabinoids–Laryngeal dystonia–Muscle tension dysphonia–Vocal tremor–Spasmodic dysphonia–Botox chemodenervation. |
INTRODUCTION |
There is currently no curative treatment for laryngeal dystonia and vocal tremor. Laryngeal dystonia is a neurogenic condition that is categorized by spasms in the adductor muscles in the vocal folds, abductor muscles, or a mix of both muscle groups.1 Adductor spasmodic dysphonia is the most commonly diagnosed condition of the three, with abductor spasmodic dysphonia and mixed spasmodic dysphonia more rarely diagnosed.2,3 Muscle tension dysphonia (MTD) is a functional condition rather than dystonia, characterized by excessive tension of the laryngeal musculature during phonation.4 Vocal tremor is characterized by involuntary regular movements of the larynx and vocal tract during phonation, with many individuals also experiencing tremors elsewhere in the body.5 Existing treatments for laryngeal dystonia seek to minimize the symptoms associated with the condition but current medications and procedures have variable efficacy among the different conditions and the individual patients diagnosed with these conditions. Chemodenervation via botulinum neurotoxin (BTX) injection is considered the standard, first-line treatment for laryngeal dystonia and vocal tremor.6,7 However, treatment is imperfect and requires repeated treatment by a skilled clinician.6,8 Besides BTX injections, voice therapy and surgery are also used to treat laryngeal dystonia and vocal tremor with inconsistent results.4,7–10 Given the vast variability in responses to different treatments for laryngeal dystonia and vocal tremor, people with these conditions often seek alternative treatment options. Cannabinoids have been used in treating dystonic conditions with varying success.11–13 Their effectiveness in treating dystonia as a whole is yet to be confirmed as reports of their benefit have been constrained to a limited number of case studies and trials with statistically small sample sizes.12,13 A recent survey, however, has shown that a sizable number of patients with vocal conditions in general use cannabinoids to manage their symptoms.14 This study aimed to survey the patterns of cannabinoid product use among patients with laryngeal dystonia/vocal tremor as well as their perspectives of the efficacy of cannabinoid products in treating their vocal condition. This research study defines cannabinoid products or cannabinoids as products or substances derived from the cannabis plant, including but not limited to Marijuana, Tetrahydrocannabinol (THC) products, and cannabidiol products (CBD). |
MATERIALS AND METHODS |
This study was approved by the Institutional Review Board of the University of Southern California (UP-21-00354). This study used a cross-sectional survey methodology utilizing a responsive questionnaire composed of eight primary questions. This electronic survey was developed using skip logic, presenting varied questions depending on the participant’s responses. The survey was created and hosted on REDCap, and distributed through the Dysphonia International (formerly the National Spasmodic Dysphonia Association) email listserv, a collection of approximately 5000 emails belonging to patients, doctors, and other healthcare professionals. The survey collected responses from December 29, 2021, to November 1, 2022. Participants were provided an informed consent instructional text before starting the survey. Participants: To be eligible to participate, participants required a diagnosis of spasmodic dysphonia or laryngeal dystonia, vocal tremor, and/or muscle tension dysphonia. To answer the survey in its entirety, participants must have reported using a cannabinoid product at least once in the past to manage their vocal symptoms specifically. Participants who had not tried a cannabinoid product at least once to treat their voice symptoms were ineligible to answer the remaining questions regarding cannabinoid use. Participation was voluntary and anonymous. Survey structure, content, and data collection The survey was composed of eight questions as well as an additional general comments box. The survey used branching conditional logic to guide participants through the questionnaire. The question format included multiple-choice, multiple-select, and open-ended written response. Participants who selected a response of “other” on any question were offered a short answer write-in text box for clarification. The first question asked participants if they had ever used cannabinoid products (Marijuana, THC products, CBD products) to treat their voice condition. If a participant selected “no”, the survey would close but would allow for participants to provide write-in responses in the general comment box. All other participants would be guided through the remaining seven primary questions with additional secondary subsections and clarification questions contingent on their responses. These participants were also able to provide write-in responses in the general comments box at the end of the survey. A facsimile of the survey can be reviewed in the supplementary section of this study (Supplementary 1). Bar graphs were created to reflect the number of responses for multiple-choice and multiple-select formatted questions. Write-in responses were reviewed for common motifs and coded for overall themes to reflect the various perspectives of the participant responses. Quotations were selected that best represented the coded themes. Demographic information was collected to gauge the diversity and overall composition of the sample population. This information included participant age, gender, and primary and ancillary dystonic diagnoses. |
RESULTS |
Participant demographics The survey included a total of 158 participants comprised of responses from 133 cisgender female participants and 25 cisgender male participants with a mean age of 64.8 years old and participant age ranging from 22 years old to 95 years old (Figure 1). Adductor spasmodic dysphonia was the most common condition with 65 participants claiming this diagnosis (Figure 1). Mixed spasmodic dysphonia was found to be the second most common with 37 responses claiming this diagnosis, and abductor spasmodic dysphonia closely followed at 30 participant responses (Figure 1). Muscle tension dysphonia, vocal tremor, and vocal dystonia otherwise not specified were less common diagnoses for this survey population (Figure 1). A majority of the respondents were not diagnosed with dystonia or tremor elsewhere in their body, though 51 of the participants (32.3%) reported experiencing dystonia or tremor beyond their vocal symptoms (Figure 1). Participants using cannabinoid products to treat vocal dystonia Of the 85 (53.8%) participants who stated they had tried using cannabinoid products at least once in the past to treat their vocal condition (Figure 2A), 45 participants (52.9%) stated they currently use cannabinoid products as treatment (Figure 2A). Among these participants, 24 participants (53.3%) used cannabinoid products daily (Figure 2B). Eight participants used cannabinoid products once a week, six participants used cannabinoid products multiple times a week, and seven participants used cannabinoid products more sparingly at once or twice a month (Figure 2B). The majority of participants reported using cannabinoid products to treat their symptoms for at least 1 year (58.8%) with 28 of these participants (32.9%) reporting use for approximately 1–2 years and 22 of these participants (25.9%) reporting using for at least 3 years (Figure 2C). Seventeen respondents reported using cannabinoid products for less than a month and 12 respondents reported several months of use (Figure 2C). Respondents were most likely to use cannabinoid products containing CBD alone (32 of 85 participants) or CBD in combination with THC (39 of 85 participants) and were less likely to use THC products alone (12 of 85 participants) (Figure 3). Among participants who actively used cannabinoids to treat their vocal condition, the most frequently used formulation of cannabinoid products was edible products, with 29 respondents (64.4%) stating they used this preparation (Figure 3). Twelve participants who selected “other” specified that they used a tincture preparation of cannabinoids and one participant specified tablets, both of which are oral formularies that can also be classified as an edible cannabinoid product (Figure 3). The second most common mode of using cannabinoid products was via smoke inhalation, with 16 participants (35.6%) using this method (Figure 3). Vaping was another common method of using cannabinoid products with 10 participants (22.2%) stating they used this formulation (Figure 3). Topical cannabinoid products were the least commonly used product with eight participants (17.8%) stating they used this preparation; one participant who selected “other” specified that they used CBD patches, which can be reclassified as a topical preparation of cannabinoids (Figure 3). Participants who did not use cannabinoid products to treat vocal dystonia Of the 158 respondents in total, 73 (46.2%) had never tried using cannabinoid products to treat laryngeal dystonia/ vocal tremor/MTD (Figure 2). Additionally, 40 respondents stated they had tried cannabinoid products to treat their condition but had since discontinued cannabinoid use (Figure 2). The most commonly cited reason for discontinuing cannabinoid use among respondents was the ineffectiveness of these products in treating their underlying vocal condition, with 31 participants (77.5%) selecting this response (Figure 4). Cost, side effects, and other reasons for discontinuing use were less frequently selected (Figure 4). The role of cannabinoid products in treating vocal dystonia in context of current treatments Cannabinoid products are overwhelmingly taken outside the care of a medical professional with 36 of the 45 participants (80.4%) who actively use these products doing so as self-directed rather than as medically prescribed. Twenty-five respondents of the 45 (55.6%) who were currently using cannabinoid products reported them as a supplementary treatment alongside medications or treatments provided by a healthcare professional (Figure 5). Botox was the most commonly used treatment alongside cannabinoid products with 15 of the 25 participants (60%) reporting that they were using this combination (Figure 5). Five participants (20%) used voice therapy in combination with cannabinoid products (Figure 5). Surgery was the least commonly reported treatment being used in combination with cannabinoid products with one participant reporting this combination |
LIMITATIONS |
As an electronic survey, this study is limited to participants who have Internet access. The electronic link was distributed exclusively through the Dystonia International (previously National Spasmodic Dysphonia Association) listserv, limiting the diversity of the sample population. The intrinsic nature of online surveys can also predispose to self-selection bias as participants choose to participate in the survey potentially based on pre-existing bias. Patients with a positive response to cannabinoids may have been more likely to respond, while those who had never considered cannabinoids may have not had as pronounced interest in responding. This may be reflected in the low percentage response rate, with only 158 responses in a collection of 5000 total emails in the listserv. However, it would be inaccurate to attribute the low response rate to selection bias alone, as the listserv was comprised of not just patients, but also physicians and healthcare professionals. Without knowing the exact number of patients in the listserv, the true response rate is difficult to calculate. As this study required participants to retrospectively recall the extent of effectiveness after using cannabinoid products, there is likely recall bias that is affecting the collected data. |
CONCLUSION |
A considerable number of patients with vocal dystonia have tried using cannabinoid products or currently use cannabinoids to treat their laryngeal dystonia, vocal tremor, and MTD. Most participants considered cannabinoids as either less effective or similarly effective to other treatments in treating their vocal dystonia. A select group of participants who used cannabinoids with Botox injections reported the combination as more effective than using Botox alone. A prospective study is warranted for further investigation to help clinicians counsel patients in their treatment journey.
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Title: Safety of Platelet-Rich Plasma Subepithelial Infusion for Vocal Fold Scar, Sulcus, and Atrophy |
Abstract |
Objective: To demonstrate the safety profile of platelet-rich plasma (PRP) as an injectable therapeutic for the treatment of vocal fold scarring and atrophy. |
Methods: Preliminary report on a prospective clinical trial of patients with vocal fold scar or atrophy undergoing unilateral vocal fold subepithelial infusion with autologous PRP. Enrolled patients underwent four sub- epithelial injections spaced 1 month apart. Adverse events were assessed peri and post-injection at each session. Patient-reported outcomes were collected at every visit using the Voice Handicap Index-10 (VHI-10) and Vocal Fatigue Index (VFI) questionnaires. |
Results: Twelve patients underwent unilateral vocal fold injection with autologous PRP prepared according to Eclipse ® |
Conclusion: This prospective study cohort demonstrated a favorable safety profile, with no adverse events or peri-procedural complications. Subjective improvements in vocal quality and reduction in vocal fatigue need to be clinically correlated with further study. |
Key Words: platelet-rich plasma, vocal fold scar, superficial lamina propria, vocal fold atrophy. Level of Evidence: 4 |
PRP system protocol. Forty-three injections were performed using a peroral or percutaneous approach. An average of 1.57 0.4 cc (range 0.6–2.0 cc) injectate was used. All patients tolerated the procedure without difficulty or peri-procedural complications. The average duration of follow-up was 3.6 1.8 months. No significant inflammatory reactions or adverse events were seen to date. There was statistically significant improvement in patient-reported outcomes at the 3 month follow up (n = 9) follow-up (mean ΔVHI-10 = 10.8, p < 0.001, mean ΔVFI = 18.9, p = 0.01, t test, paired two sample for means, two- tail). All nine patients who completed the series of four injections subjectively (yes/no) reported they were satisfied with the results. |
INTRODUCTION |
Vocal fold atrophy and scar are causes of dysphonia that pose major treatment challenges for laryngologists.1 The etiology of vocal fold scar is diverse, potentially stemming from phonotrauma, phonomicrosurgery, iatrogenic injury, malignancy, and radiation therapy.2,3 Addition- ally, loss of hyaluronic acid, elastic fibers, and lubrication during the aging process can reduce viable tissue mass.4 Underlying alterations to the superficial lamina propria (SLP) of the vocal folds drastically alter compliance.5 Con- sequently, patients endure considerable dysphonia, vocal fatigue, decreased volume, and altered pitch. These changes can contribute to depression, reduced social interaction, and decreased quality of life.6 |
The most common initial treatment for vocal fold atrophy condition is voice therapy administered by a specialized speech-language pathologist spaced out over multiple monthly sessions. Voice therapy introduces logistical strains in the elderly population, such as coordinating transportation across several sessions, and is limited by its inability to restore normal vocal fold volume and morphology.5 Alternatively, injectable filler materials (e.g., carboxymethylcellulose and micronized collagen) may be used to augment the vocal folds for patients with glottic insufficiency secondary to loss of the SLP.7 However, this treatment is temporary and fails to provide a durable effect.8 In addition, it carries the risk of worsening dysphonia due to filler inert mass effect or superficially misplaced injection.5 |
For patients with vocal fold scar, a range of surgical procedures from augmentation laryngoplasty,9 angiolytic laser procedures,10 tissue grafting,11 and Gray’s mini- thyrotomy12 have been described, which also provide inconsistent improvement.13 Recent experimental studies have explored the prospect of restoring normal SLP architecture via stem cell tissue engineering14 and growth fac- tor injections.15 Nevertheless, the paucity of controlled studies has left a void for a treatment modality that is safe, addresses the fundamental cause, and provides durable results for patients with vocal fold atrophy or scar. |
Platelet-rich plasma (PRP) consists of platelets, growth factors, cytokines, and cell adhesion molecules derived from the patient’s own blood.16 PRP is believed to activate tissue regeneration by introducing high concentrations of platelet-derived growth factors and fibrin into damaged or atrophied tissue.17 Studies in orthopedics and cosmetic surgery emphasize the breadth and safety of the therapeutic applications of PRP.18–20 Previ- ous work at our institution highlights the technical considerations for in-office PRP vocal fold injections.21 Hence, serial PRP vocal fold injections hold promise as a new treatment modality for vocal fold atrophy and scar. |
This study aims to evaluate the safety profile of autologous PRP for use as an injectable therapeutic in the vocal fold. Secondarily, we aim to determine the clini- cal efficacy of serial PRP vocal fold injections regarding patient-reported outcome measures and longevity of clinical effects from serial PRP vocal fold injections. |
MATERIALS AND METHODS |
Study Population: This study was approved by the University of Southern California Institutional Review Board. Patients were enrolled as part of an ongoing prospective clinical trial (clinicaltrials. gov APP-18-05224) consisting of a series of four unilateral vocal fold injections with autologous platelet-rich plasma. Vocal fold atrophy and lamina propria defects were diagnosed on laryngeal videostroboscopy by a fellowship-trained laryngologist. All participants were adults (age 18 years or older) with a baseline VHI-10 score ≥ 10. Patients with a his- tory of allergy or hypersensitivity to lidocaine, amide-based anesthetics, or bovine products were excluded from the trial. Patients who underwent recent laryngeal surgery or invasive procedures (e.g., vocal fold injection augmentation) within the last 3months were not permitted to enroll., Additionally, patients with active infection or inflammation in the larynx, underlying coagulopathy, thrombocytopenia, or platelet dys- function, autoimmune disease, cancer, liver disease, or respi- ratory compromise were excluded. Concomitant laryngeal conditions including but not limited to vocal tremor and laryn- geal dystonia that would otherwise warrant alternative inter- ventions for optimal treatment were also excluded. Finally, patients with a life expectancy of less than 6 months were excluded from this study. |
Clinical Protocol: The clinical protocol for this clinical trial is outlined in Figure 1. As part of the initial intake, patients completed the Voice Handicap Index-10 (VHI-10) and Vocal Fatigue Index (VFI). During their initial visit, a complete history and physical examination were performed along with voice and laryngeal videostroboscopy recordings. The first PRP vocal fold injection (Day 0) was performed within 4 weeks of the decision to partici- pate. The patient was monitored for 1 h post procedure for any potential adverse events. The following day (Day 1), the patient was re-evaluated in clinic for any side effects or adverse events. One week following the initial injection the patient was re-evaluated in clinic and VHI-10 and VFI questionnaires were collected. Subsequently, the patient returned at monthly inter- vals for repeat evaluation and re-injection for a total of four uni- lateral vocal fold injections. The patient’s subjective experience, patient-reported outcome measures, and stroboscopic examina- tion were collected at each visit. Patients continued follow-up visits at monthly intervals for 3 months following the fourth injection (Fig. 2). |
Drug/Device Information and Administration: The leukocyte poor platelet-rich plasma preparation was achieved via the Eclipse PRP® system manufactured by Eclipse® medical device (BK110035). Activation of PRP in our study is accomplished without exogenous substances by relying on shear force from injection and exposure to native collagen at the injection site.18 Patients underwent venipuncture to collect 11 ml of blood. The collected blood was placed in the Eclipse PRP centrifuge per product protocol. |
Study Agent Administration system: Unilateral injection of 1.0–2.0 cc of PRP into the membra- nous vocal fold near the area of the scar on the pre-determined side was performed using a 23-gauge needle via previously described percutaneous methods for vocal fold injection (thyrohyoid, transoral approaches).8 Trans-cervical injections were carried out through the thyro-hyoid approach with no significant leakage of PRP noted during these injections. Injections were performed throughout this study taking care to place the needle superficially into the vocal fold. The PRP then tracks throughout the entire surface of the superficial vocal fold and bulges the epi- thelium. Once material begins to extrude, commonly between 1 and 1.5 cc, the injection is concluded. All injections were per- formed in an outpatient clinic setting under local and topical anesthesia apart from one patient who requested injection 2 be performed in the operating room due to intolerance of awake in- office vocal fold injection. Due to this patient’s preference, accommodations were made to perform injections 3 and 4 in the operating room as well. The contralateral vocal fold did not undergo injection and served as an internal control. During interim periods between scheduled visits, subjects were instructed to call with any potential adverse event that may require in-person evaluation at the clinic or in an acute care setting for appropriate clinical care. |
Evaluation Criteria and Endpoint Definitions: Study completion was achieved after patients received four unilateral PRP injections and completed all follow-up post- injection clinic visits. The main objective of this study is to define the safety profile of PRP for use with serial vocal fold injections to treat vocal fold atrophy and scar. As such, the focus will be on any treatment-related adverse events that are reported during the study. Previously cited adverse events in vocal fold injection include local tissue reactivity, hemorrhage, hematoma, granuloma formation, and postprocedural airway compromise.22 Secondary endpoints included patient-reported outcome measures (VHI-10, VFI) from designated follow-up time points which are compared to baseline values prior to the first injection. Follow-up duration refers to the number of months since a patient’s first injection and continues to accumulate after all four injections have been administered. For patients with vocal fold scars, we did not include specific etiology in our demographic information as many patients had longstanding scars of unknown etiology. |
Statistical Analysis: Sample size calculations were performed based on data from prior studies for VHI-10 outcomes after vocal fold augmentation for vocal fold atrophy.23 These calculations were based on a planned comparison of VHI-10 scores before and after serial PRP injections via paired t-test statistics. All comparisons were made between baseline scores and individual post-injection time- point. The primary outcome of safety was focused on the incidence of serious adverse events related to the study material under investigation. We expected the risk of a serious adverse event to be exceedingly low and did not base our sample size calculation on that. The study cohort will be analyzed using descriptive statistics of the primary outcome. The incidence of both minor and major adverse events will be measured as a percent of total participants experiencing said adverse event. Comparison of patient-reported outcome measures from post-intervention time points to pre-intervention baseline were evaluated using parametric statistics (t-test, paired two samples for means, two-tail). |
RESULTS |
Twelve patients with vocal fold scar or atrophy under- went unilateral vocal fold injection with autologous PRP prepared according to Eclipse PRP system protocol. A total of 43 injections were performed using a peroral or percutaneous approach. An overview of study participant demo- graphics and pathology is outlined in Table I. An average of 1.57 0.4 cc (range 0.6–2.0 cc) of injectate was used. The average duration of follow-up was 3.6 1.8 months. Nine patients (75.0%) completed all four PRP injections, while two patients completed three injections and one patient received only one injection as part of the ongoing trial. At the one-month timepoint, one patient requested to receive the PRP injection in the operating room to better tolerate treatment. All other injections were per- formed in the outpatient clinic setting. No significant inflammatory reactions or adverse events were seen to date.
the earliest significantly significant decrease in both questionnaires. This significant downtrend persisted through the two-month (VHI-10 score 19.9 11.3; VFI 31.1 14.9) and three-month (VHI-10 18.9 12.4; VFI 25.1 16.2) timepoints. At the four-month timepoint, one month after the fourth injection, the VHI-10 score was 16.4 14.8 (median ΔVHI-10 = 8.4, p = 0.03) and the VFI score was 14.4 11.8 (mean ΔVFI = 23.8, p = 0.08). All patients self-reported tolerating the procedure without difficulty or immediate complications. Some patients described discomfort associated with the laryngotracheal anesthetic and mild discomfort was noted on the side of injection in two patients 1 day after the initial injection. No safety events were reported from any of the injections (n = 43) throughout the duration of the trial. |
All patients continued to experience subjectively improved voice outcomes, with the improved overall quality, loudness, vocal endurance, and less strain and breathiness at 1 month. Two patients noted that the improvements were sustained until 3 weeks following the first injection when they experienced a slight deteriora- tion but did not return to their baseline dysphonia. Eight patients continued to experience improved voice quality and resonance 1 month following the second injection. Two patients reported sustained voice quality at the level experienced after the initial injection with no notable improvement thereafter. All patients reported subjective improvement in their voice 1 month after the third injec- tion, of which three experienced their best overall voice enhancement. Two patients consistently experienced gradual deterioration in their voice quality and noted voice instability as they neared the one-month timepoint following each injection. |
DISCUSSION |
While the application of regenerative medicine techniques in laryngology holds great promise there is a pau- city of human data on the use of PRP. This prospective cohort study demonstrated a favorable safety profile for the use of serial in-office vocal fold injections of autologous PRP among patients with vocal disturbances due to vocal fold atrophy and scar. There were no adverse events or peri-procedural complications across 43 PRP injections in 12 patients. The practicality of in-office procedures has been embraced in laryngology as they circumvent the use of general anesthesia and the need for an operating room and staff.24,25 The bioactive components in PRP such as growth factors, cytokines, and cell adhesion molecules are self-renewing. Moreover, the plasma derivative tissue product is reliably reproduced via routine blood draws and minimal subsequent manipulation. In this trial, blood collection and centrifugation added approximately 10–15 min of preparation time. Blood collection, PRP product preparation, and treatment can be completed in a timely manner rendering the process feasible for the ambulatory care setting. |
Lamina propria defects found in vocal fold atrophy and scar represent challenging pathologies to treat.3 Therapeutic interventions include surgical and non-surgical options including tissue transplantation, angiolytic laser treatments, and voice therapy. Surgeons must consider the diverse roles of the larynx during respiration, phonation, and deglutination26,27 to preserve functional capacity fol- lowing treatment.2,28 Pathologic healing from scar tissue can lead to persistent dysphonia that impairs appropriate vocal fold approximation and natural dynamic oscillation required for clear resonant voice sounds.3 Moreover, there is no substance to replace the intricate framework of the SLP. Prior to trial enrollment, all patients underwent some form of previous treatment including steroid injections, injection augmentation, or surgical scar revision. |
Despite these interventions, these patients continued to have residual vocal deficits despite temporary improve- ment seen in some instances. All participants expressed dissatisfaction with their vocal capabilities during the baseline evaluation. PRP is a biological material shown to stimulate host tissue rejuvenation without eliciting immune rejection as it is derived from the patient’s own blood. The composi- tion of PRP consists primarily of a high concentration of platelets and growth factors but can also include white blood cells and other vasoactive and chemotactic agents.29 PRP releases growth factors that expedite wound healing via cell proliferation, matrix formation, osteoid produc- tion, connective tissue healing, angiogenesis, and collagen synthesis.30,31 PRP injections have been shown to have a broad range of applications in tissue sealing, stabiliza- tion, scar maturation, osteogenesis, and alopecia across various surgical specialties from orthopedics to cosmetic surgery with virtually no adverse side effects.32–34 In vivo studies revealed the effect of PRP in vocal fold healing in rabbit models following acute vocal fold injury.29 In oto- laryngology, the wound healing properties of PRP have previously been used to treat tympanic membrane perfo- ration.35 This prospective clinical report on the use of PRP in the human larynx is unique and builds on recent interest in commissioning bioactive components, includ- ing fibroblast growth factors and autologous bone marrow-derived mesenchymal stromal cells, to treat pathologies of the head and neck. Recently Woo et al. reported short-term voice improvements following in-office PRP injections with 11 patients receiving three injec- tions.26 While our preliminary work set out to show the safety and tolerability of PRP injections in an ambulatory care setting, many of the patients expressed subjective improvements occurring after a four-injection series. The standardized design of our prospective trial, formatted with consistent follow-up after four unilateral vocal fold injections, provides a unique and controlled study method. As a newly emerging therapeutic avenue in laryngology, our findings contribute to the scarcity of literature exploring the potential use of PRP injections as a suitable treatment modality for patients with vocal fold scar and atrophy. Our results are consistent with the safety of PRP injections described by Woo et al., and further support the use of PRP precisely because of their similarity. |
All patients underwent treatment without difficulty or complications. There were no accounts of laryngeal edema, local inflammatory reaction, dysphagia, or dyspnea. Mild discomfort was noted on the side of injection in two patients 1 day after the initial injection. Patients in our trial expressed a variable range of voice improve- ment. Three patients described a mild roughness in the quality of their voice for 3–5 days following the first injec- tion which subsequently resolved. One patient went on to experience a similar occurrence at their second injection. Patient experiences reflected a general trend of improve- ment with consecutive PRP injections. Three accounts across two patients described sustained improvement for 3 weeks following treatment before perceiving remission in voice quality. Generally, patients experienced vocal quality and consistency that eventually spanned the month between injections. Interestingly, three subjects experienced their best overall voice improvement after injection number three. All patients who received four PRP injections were satisfied with the improvement of their voice and expressed interest in continued treatment beyond the completion of their trial participation. |
VHI-10 and VFI scores mirror the trend of gradual improvement. At 1 week after the first PRP injection, the average VHI-10 and VFI scores began to downtrend to 27.5 10.2 and 42.9 16.4 but did not achieve the range of published minimally important clinical difference (MCID) for either questionnaire.36,37 However, by 1month, the change in the average VHI-10 and VFI scores reflected a significant decrease compared to baseline, beyond the MCID range of a four-to-six-point decrease in total score. With repeat monthly injections both the average VHI-10 and VFI scores continued to decrease significantly with sub- sequent follow-up evaluations at the two and three-month timepoints. Interestingly, at the four-month timepoint, both the VHI-10 and VFI scores continued to decrease, but only the VHI-10 score was significantly lower than baseline. It is important to note that only five patients have reached this point in the study. Therefore, it is perhaps too early to com- ment on the longevity of serial PRP injections in terms of their impact on these patient-reported outcomes. |
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