Glottische larynxcarcinomen ontstaan vaak in de stembanden. Mogelijke behandelingen zijn radiotherapie en chirurgische behandeling (open chirurgie of endolaryngeale/transorale chirurgie), of een combinatie van deze twee interventies. Het is onduidelijk wat de optimale behandelstrategie is wat betreft totale overleving, ziektevrije overleving, stemkwaliteit, kwaliteit van leven en (werk)participatie.

Crucial outcome measures

Overall survival

Relapse-free survival

Functional outcomes

Important outcome measures

Larynx preservation, quality of life, secondary treatment, complications/adverse events, (work)participation

Description of studies

Randomised controlled trials

The RCT performed by Aaltonen (2014) included male patients with histologically confirmed squamous cell carcinoma, limited to one mobile vocal cord, staged as T1aN0M0. Transoral laser surgery (TLS, tumour excision with a CO₂ laser) was compared with external beam radiation therapy (RT). The outcome was voice quality, which was assessed at baseline and 6 and 24 months after treatment and was measured in three ways: an expert-rated quality of voice, self-rated quality of voice, and videolaryngostroboscopic findings. In the study, 60 male patients were randomized to TLS (n=32, of which 31 were evaluated) or radiation therapy (n=28, of which 25 were evaluated). The follow-up period was 24 months. The median age was 69 years in the TLS group and 61 years in the RT group.

Observational studies

The systematic review by Ding (2019) included 18 studies in their analysis. Of them, seven were published after 2010 and met our PICO criteria. Since none of these observational studies corrected for confounding, these results do not contribute to the body of evidence and were not graded, but only described for informative purposes.

Overall survival at five years follow-up was reported in four studies and ranged from 86 % to 97% in the laser surgery group, and from 70% to 96% in the radiotherapy group. Relapse was reported in two studies (one study reported disease-free survival and one study reported local and regional recurrence). Functional outcomes were reported in six studies (three studies acoustic parameters, four studies voice handicap index, and one study Grade, Roughness, Breathiness, Asthenia, and Strain scale), and most studies reported worse functional outcomes in laser surgery patients, compared to radiotherapy patients. The results are summarized in the evidence table.

The retrospective cohort study by Low (2016) included patients with T1aN0 glottic squamous cell carcinoma (SCC) and was performed in Australia. Transoral laser microsurgery (TLM) was compared with RT on oncologic outcomes (overall survival and relapse-free survival). In total, 105 patients were included, of whom 53 were treated with TLM and 52 with RT. The mean age was 65.4 (sd 13.0) and 70.6 (sd 11.0) years, and 42/53 (79%) and 44/52 (85%) were men in the TLM and RT group, respectively. The mean follow-up was 3.58 (sd 2.41) years in the TLM group and 4.55 (sd 3.17) years in the RT group. They concluded that patients with T1aN0 glottic SCC treated with RT or TLM have similar survival outcomes.

The retrospective cohort study by Kono (2016) included patients with T1aN0M0 glottic cancer and was performed in Japan. Laser surgery (LS) was compared with RT, on functional outcomes (acoustic parameters, voice handicap index, and auditory-perceptual evaluation). Until July 2010, the laser was used in super pulse continuous mode with 4 to 5 W power (vaporization with defocused mode using laser surgery (LS-Vap)), and from August 2010, the laser was used in super pulse continuous mode with 1 W power in focus (LS-Ex). In total 64 patients were included, of whom 37 were treated with LS and 27 with RT. The mean age was 69 (sd 9.8) and 69 (sd 9.8) years, and 33/37 (89%) and 22/27 (81%) were men in the TLM and RT group, respectively. The median follow-up period was 37 months. They concluded that early glottic cancer could be successfully treated by either RT or LS-Ex with equivalent posttherapeutic laryngeal function and quality of life.

The prospective cohort study by Taylor (2013) included patients with T1b squamous cell carcinoma (SCC) of the glottic larynx and was performed in Canada. TLS was compared with RT, on the oncologic outcomes (overall survival and disease-free survival), and functional outcomes (voice handicap index). In total, 63 patients were included, of whom 21 were treated with TLS and 42 with RT. The mean age was 64 and 69 years, and 18/21 (86%) and 39/42 (93%) were men in the TLM and RT group, respectively. Median follow-up was 34 months in both groups. They concluded that among patients with stage T1b SCC of the glottis oncological outcomes after TLM were at least equivalent to RT, and that voice quality was similar between the two groups.

The retrospective cohort study by Remmelts (2013) included patients with early stage (Tis-T2) glottic laryngeal carcinoma and was performed in the Netherlands. LS was compared with RT, on oncologic outcomes (overall survival), and functional outcomes (voice handicap index). In total, 248 patients were included, of whom 89 were treated with LS and 159 with RT. The mean age was 67 and 64 years, and 78/88 (88%) and 138/159 (87%) were men in the LS and RT group, respectively. The mean follow-up was 44 months in the LS group, and 48 months in the RT group. They concluded that oncological outcomes of both LS and RT are similar in T1a laryngeal cancer, and that numbers in this study were too small to allow any conclusions on oncological outcomes in stage T1b laryngeal cancer. According to subjective voice analysis outcomes were comparable in T1a lesions. For T1b lesions patients treated with LS had a statistically significantly higher percentage of voice deficiency (see details in the evidence tables).

The prospective cohort study by Milovanovic (2013) included patients with Tis and T1a glottic carcinoma and was performed in Serbia. TLM was compared with RT, on functional outcomes (acoustic parameters), and oncologic outcomes (overall survival). In total, 146 patients were included, of whom 72 were treated with TLM and 74 with RT. Mean age was 59.5 and 62.9 years, and 65/72 (90%) and 67/74 (91%) were men in the TLM and RT group, respectively. The follow-up ranged from 38 to 107 months. They concluded that, given that choice of treatment was also influenced by other factors, TLM was highly efficient and preferred choice of treatment for early glottic carcinoma in Serbia.

The prospective cohort study by Van Gogh (2012) included patients with T1aN0M0 glottic cancer and was performed in the Netherlands. Endoscopic laser surgery (LS) was compared with RT on functional outcomes (acoustic parameters). In total, 106 patients were included of whom 67 were treated with LS and 39 with RT. Mean age was 66 and 65 years, and 67/67 (100%) and 39/39 (100%) was men in the LS group and RT group, respectively. Median time of follow-up was comparable for patients in both groups and was maximum 24 months. They concluded that LS is the first treatment of choice in the treatment of selected cases of T1a glottic carcinomas with good functional and oncological results.

The retrospective cohort study by Kerr (2012) included patients with stage 1 or 2 glottic carcinoma and was performed in Canada. TLM was compared with RT, on oncologic outcomes (overall survival), and functional outcomes (voice handicap index). In total, 243 patients were included of whom 143 were treated with TLM, and 91 with RT. Median age was 67 in both groups, and 123/143 (86%) and 82/91 (90%) were men in the TLM and RT group, respectively. Median follow-up was 28 months in the TLM and 32 months in the RT group. They concluded that TLM patients had poorer voice quality than RT patients (see details in the evidence tables). However, the authors argued that advantages of TLM in most patients outweighed the degree of voice handicap.

Results

None of the observational studies corrected for confounding and therefore their results did not contribute to the conclusions.

Overall survival at five years (crucial)

None of the studies reported on overall survival after a minimum follow-up duration of five years.

Relapse-free survival at five years (crucial)

None of the studies reported on relapse-free survival after a minimum follow-up duration of five years.

Functional outcomes (crucial)

1. Expert-rated quality of voice

Aaltonen (2014): The mean scores in expert-rated overall voice quality (G), voice roughness (R), and strain (S) remained similar between the groups during follow-up, but patients treated with TLS had a more breathy voice (B) than those who received radiation therapy (score 1.52 versus 0.28 (on a scale from 0 (normal) to 3 (extremely abnormal) 2 years after treatment, P<0.001). A statistically significant difference emerged also in asthenia (A) (0.74 versus 0.11; P=0.003), but in both groups the absolute value was under 1, suggesting limited clinical relevance of this finding. Breathiness and asthenia improved significantly with time in the radiation therapy group (from 1.17 at baseline to 0.28 2 years after treatment, P=0.001; and from 0.56 to 0.11, P=0.001, respectively) but not in the TLS group.

The degree of voice breathiness varied between groups. In the TLS group, 5/27 (19%) had no voice breathiness (score 0), the majority (20/27, 74%) had mildly or moderately breathy voice (score 1 or 2), and 2/27 (7%) had extremely breathy voice (score 3). In the RT group, the majority of patients (14/20, 70%) had no voice breathiness (score 0), 6/20 (30%) had mildly or moderately breathy voice (score 1 or 2), and none of the patients had extremely breathy voice (score 3).

2. Self-rated quality of voice

Aaltonen (2014): Self-rated hoarseness was judged similar between the groups (P=0.144). The self-reported quality of voice improved significantly from the baseline quality during follow-up in both groups (in the TLS group, the VAS-score decreased from 59.0 to 43.1, P=0.040; and in the RT group, from 53.1 to 35.4, P=0.026). Patients assigned to RT reported less impact of hoarseness on their daily living activities than did patients assigned to TLS (P=0.007).

3. Videolaryngostroboscopic findings

Aaltonen (2014): In comparison with the RT group, patients assigned to TLS had less sufficient glottal function at videolaryngostroboscopy performed two years after study entry. They had higher scores for irregular glottal closure (P=0.025), oval closure (P=0.005), and incomplete glottal closure (P=0.018).

Larynx preservation (important)

None of the studies reported on larynx preservation.

Quality of life (important)

None of the studies reported on quality of life.

Secondary treatment (important)

None of the studies reported on secondary treatment.

Complications/adverse events (important)

None of the studies reported on complications or adverse events.

(Work)participation (important)

None of the studies reported on (work)participation.

Certainty of the evidence

None of the observational studies corrected for confounding and therefore their results could not contribute to the conclusions. GRADE was applied to assess the certainty of the evidence originating from the RCT of Aaltonen (2014).

Crucial outcome measures

Overall survival and relapse-free survival at five years

None of the studies reported on the crucial outcome measures overall survival and relapse-free survival at five years, and therefore GRADE could not be applied, and no conclusions could be drawn.

Functional outcomes (voice quality)

The certainty of the evidence regarding functional outcomes started high as the evidence originated from an RCT, and was downgraded by three levels because of study limitations: one level for risk of bias (patients and assessors were not blinded); and two levels for very serious imprecision (only one study was included, with a very small sample size). Therefore, the certainty of the evidence was very low.

Important outcome measures

None of the studies reported on any of the important outcome measures (quality of life, secondary treatment, complications/adverse events, and (work)participation) and therefore GRADE could not be applied, and no conclusions could be drawn.

A systematic review of the literature was performed to answer the following question:

What are the effects of radiotherapy compared to surgical treatment (open surgery/endolaryngeal surgery) in patients with Tis/T1 glottic laryngeal carcinomas?

P: patients with Tis/T1 glottic laryngeal carcinomas;

I: open surgery/endolaryngeal or transoral surgery;

C: radiotherapy;

O: overall survival at five years, disease-free survival at five years, voice quality, quality of life, secondary treatment, (work)participation.

Relevant outcome measures

The guideline development group considered overall survival, relapse-free survival and functional outcomes (voice quality) as crucial outcome measures for decision making; and quality of life, secondary treatment, complications/adverse events, and (work)participation as important outcome measures for decision making.

The guideline development group defined the outcome measures as follows:

Clinically relevant difference

The guideline development group defined a minimal clinically relevant difference at a minimum of a median follow-up period of three years) (in line with “NVMO-commissie ter Beoordeling van Oncologische Middelen (BOM)”) of:

• Overall survival: > 5% difference, or > 3% and HR< 0.7.
• Relapse-free survival: HR< 0.7.

And, in case of absence of a clinically relevant difference in overall survival or relapse-free survival:

• Quality of life: a minimal clinically important difference of 10 points on the quality of life instrument EORTC QLQ-C30 or a difference of a similar magnitude on other quality of life instruments.
• Complications/adverse events: statistically significant less complications/adverse events.
• Functional outcomes: statistically significant better functional outcomes.
• (Work)participation: statistically significant better (work)participation.

Search and select (Methods)

The guideline development group decided that the Cochrane review from Warner (2014) could be used as a base. After a more detailed investigation of the included study in this Cochrane review, the guideline development group decided that the interventions studied by Ogol'tsova (1990) were not relevant anno 2020, and therefore this study was excluded from the body of evidence. Literature was searched for studies published after the search date of Warner (September 2014). The databases Medline (via OVID) and Embase (via Embase.com) were searched for SRs and RCTs with relevant search term until July 10^th, 2019. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 1967 hits.

Studies were selected based on the following criteria: included patients with Tis/T1 glottic larynx carcinoma, compared radiotherapy with open or endolaryngeal surgery, reported at least one of the outcomes of interest, the study design was a systematic review (SR) or randomized controlled trial (RCT), and written in English language.

Eight studies were initially selected based on title and abstract screening. After reading the full texts and thorough assessment of the included studies, seven studies were excluded (see the table with reasons for exclusion under the tab Methods). Through the SR of Huang (2017) one RCT (Aaltonen, 2014) was included. No other, more recent, RCTs were found. Therefore, in addition to this RCT, the guideline development group decided to select the most recent SR of observational studies that could answer the PICO (Ding, 2019). The comparative observational studies described in this SR were added to the body of evidence and described in the summary of literature.

Data-synthesis

Results from RCTs and observational studies were described and synthesized (preferably by meta-analysis) separately. A priori, the guideline development group decided that observational studies should be of sufficient quality to allow a useful GRADE assessment and to allow conclusions that can guide the recommendations. The guideline development group used the following criteria for eligible observational studies of sufficient quality:

• Compared at least two interventions.
• Included at least 50 patients.
• Corrected for at least one plausible confounder, for example by matching cases and controls, stratification, or statistical correction by performing a multivariable analysis.

Results

One RCT (Aaltonen, 2014) and seven comparative observational studies were included in the analysis of the literature. They all compared laser surgery with radiation therapy (RT). Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias table. No studies were found that compared open surgery with radiotherapy.