International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation
Voice Quality After Treatment of Early Vocal Cord Cancer: A Randomized Trial Comparing Laser Surgery With Radiation Therapy Leena-Maija Aaltonen, MD, PhD,* Noora Rautiainen, MA,y Jaana Sellman, PhD,y Kauko Saarilahti, MD, PhD,z Antti Ma¨kitie, MD,* Heikki Rihkanen, MD, PhD,* Jussi Laranne, MD, PhD,x Leenamaija Kleemola, MD, PhD,x Tuija Wigren, MD, PhD,jj Eeva Sala, MD, PhD,{ Paula Lindholm, MD, PhD,# Reidar Grenman, MD,{ and Heikki Joensuu, MDz *Department of OtorhinolaryngologyeHead and Neck Surgery, Helsinki University Central Hospital, and University of Helsinki; yInstitute of Behavioural Sciences, University of Helsinki; zDepartment of Oncology, Helsinki University Central Hospital, and University of Helsinki, Helsinki, Finland; x Department of OtorhinolaryngologyeHead and Neck Surgery, Tampere University Hospital, and University of Tampere; jjDepartment of Oncology, Tampere University Hospital, and University of Tampere, Tampere, Finland; {Department of OtorhinolaryngologyeHead and Neck Surgery, Turku University Hospital, and University of Turku; and #Department of Oncology, Turku University Hospital, and University of Turku, Turku, Finland Received Apr 23, 2014, and in revised form Jun 5, 2014. Accepted for publication Jun 10, 2014.
Summary This first randomized study concerning early laryngeal cancer patient’s voice quality showed that patients treated with radiation therapy or with transoral laser surgery had similar overall voice quality, but radiation therapy resulted in a less breathy voice. Those treated with radiation therapy reported less voice-related
Objective: Early laryngeal cancer is usually treated with either transoral laser surgery or radiation therapy. The quality of voice achieved with these treatments has not been compared in a randomized trial. Methods and Materials: Male patients with carcinoma limited to 1 mobile vocal cord (T1aN0M0) were randomly assigned to receive either laser surgery (nZ32) or external beam radiation therapy (nZ28). Surgery consisted of tumor excision with a CO2 laser with the patient under general anaesthesia. External beam radiation therapy to the larynx was delivered to a cumulative dose of 66 Gy in 2-Gy daily fractions over 6.5 weeks. Voice quality was assessed at baseline and 6 and 24 months after treatment. The main outcome measures were expert-rated voice quality on a grade, roughness, breathiness, asthenia, and strain (GRBAS) scale, videolaryngostroboscopic findings, and the patients’ self-rated voice quality and its impact on activities of daily living. Results: Overall voice quality between the groups was rated similar, but voice was more breathy and the glottal gap was wider in patients treated with laser surgery than
Reprint requests to: Leena-Maija Aaltonen, MD, PhD, Department of OtorhinolaryngologyeHead and Neck Surgery, Helsinki University Central Hospital, PO Box 220, FI-00029 HUS, Finland. Tel: (þ358) 504271493; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 90, No. 2, pp. 255e260, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.06.032
Conflict of interest: none. AcknowledgmentsdThe authors thank the members of the Finnish Head and Neck Oncology Working Group and Timo Muhonen, MD, PhD for collaboration and advice, and Carol Norris, PhD for language editing.
256
International Journal of Radiation Oncology Biology Physics
Aaltonen et al.
handicap. These results suggest that radiation therapy may be a treatment of choice for patients whose requirements for voice quality are demanding. However, careful consideration of patient-related factors is essential when choosing the treatment option.
in those who received radiation therapy. Patients treated with radiation therapy reported less hoarseness-related inconvenience in daily living 2 years after treatment. Three patients in each group had local cancer recurrence within 2 years from randomization. Conclusions: Radiation therapy may be the treatment of choice for patients whose requirements for voice quality are demanding. Overall voice quality was similar in both treatment groups, however, indicating a need for careful consideration of patientrelated factors in the choice of a treatment option. Ó 2014 Elsevier Inc.
Introduction
Patients
Patients with early glottal carcinoma are usually treated with either radiation therapy or transoral laser surgery (TLS). The choice between these treatments is controversial, and treatment may vary by geographic region (1). The current evidence is insufficient to guide management decisions (2), and a recent systematic review and metaanalysis failed to identify a single randomized study comparing TLS with radiation therapy (1). The metaanalysis suggested that a higher larynx preservation rate can be achieved with TLS, but owing to the generally poor quality of the evidence, this result was considered inconclusive. The relative merits of TLS and radiation therapy for local cancer control, the functional outcomes including voice quality, and laryngeal preservation remain unknown. Inasmuch as most (85%-95%) laryngeal carcinomas limited to 1 vocal cord are cured either by TLS or by radiation therapy (3, 4), a key objective of treatment beyond recovery is maintaining good voice quality. We compared in the present randomized study the effects of TLS and external beam radiation therapy on quality of voice in a patient population with early glottal carcinoma limited to 1 vocal cord.
Eligible patients had previously untreated, histologically confirmed squamous cell carcinoma limited to 1 mobile vocal cord, staged as T1aN0M0 (5), and were capable of collaboration in voice evaluation tests. To achieve homogeneity in voice quality assessments, and because glottal cancer is infrequent in women (6), female patients were not included. The study protocol was approved by an ethics committee of the Helsinki and Uusimaa Hospital District. The patients provided written consent before entry into the study. The study was not registered (trial registration was not the norm in 1998).
Methods and Materials Design The purpose of this randomized, multicenter, parallel-group study was to compare TLS with external beam radiation therapy as the primary treatment for early glottal carcinoma limited to 1 vocal cord. The primary endpoint was voice quality 2 years after treatment.
Setting Given that the outcome of laser surgery, in particular, may depend on the operator’s skills, the study took place in large referral hospitals. The 3 largest university hospitals in Finland participated.
Randomization Study participants were randomized to the treatments at a 1:1 ratio by means of a computer program with random digits weighted according to the proportions of past randomizations to yield a roughly balanced number of randomizations between the groups in a concealed fashion. Randomization was carried out by a hospital staff member who was independent of the study. Tumor site in the vocal cord was used as a stratification factor at randomization. The result of randomization was communicated to the centers by phone.
Treatments Patients allocated to radiation therapy had their treatments started within 6 weeks after randomization. The larynx was irradiated with 6-MeV photons from 2 opposing 4.5 4.5 to 5 5 cm wedge fields to a total cumulative dose of 66 Gy in 2-Gy daily fractions over 6.5 weeks with a linear accelerator. When necessary an anterior bolus was added to achieve the desired dose at the anterior commissure. The uniformity criteria within the planned target volume were defined according to the International Commission on Radiation Units and Measurements Report 50 (7). The clinical target volume encompassed the larynx with no attempt to irradiate the regional lymphatics. Patients assigned to TLS had the tumor excised under general anesthesia within 6 weeks from randomization by
Volume 90 Number 2 2014
use of a CO2 laser. The operations were performed as described elsewhere (8, 9) by only 7 experienced senior surgeons. In short, the tumors were first split, and tumor tissue was removed down to a macroscopically healthy muscle layer. After tumor excision, small biopsy specimens were taken to ensure complete (R0) removal.
Evaluation of voice quality The patients had prescheduled follow-up visits at 2-month to 3-month intervals at the hospital otorhinolaryngology outpatient clinics. Voice samples were collected at baseline and 6 and 24 months after treatment. The larynx was examined with videolaryngostroboscopy, and the patients filled in questionnaires. Expert-rated evaluation of voice was based on 3 sentences read aloud at a comfortable speech loudness level. The sentences included 17 words and lasted about 14.5 seconds. Voice samples were uploaded onto a compact disk in a random order. A total of 150 voice samples were analyzed by 3 trained speech and language therapists with expertise in voice quality evaluation who were blinded to the treatment groups. Voice quality was assessed on the GRBAS scale, consisting of grade (G), reflecting overall voice quality; roughness (R); breathiness (B); asthenia (A); and strain (S). Ratings of these 5 aspects of voice quality varied from 0 (normal) to 3 (extremely abnormal) (10). The higher the score, the more dysphonic the voice. Interrater consistency was assessed by comparing the original ratings of all voice samples (150 items) between the raters. To assess intrarater consistency, the voice samples were randomized, after which the samples of 10 patients were randomly duplicated on a compact disk and reassessed by the raters. The patients rated their own voice quality (hoarseness) and assessed its impact on daily life using a 100-mm long visual analogue scale (VAS) with end anchors “no degree of” and “high degree of” hoarseness and inconvenience. The videolaryngostroboscopic findings were evaluated by a panel of 3 phoniatricians, who were blinded to the treatment groups and uninvolved with the treatments. Adduction and abduction movements of the vocal cords, the amplitude and the phase symmetry of the mucosal wave, glottal closure, and signs of vocal cord hyperfunction were each assessed on a scale from 0 (no pathology) to 3 (major pathology).
Statistical analysis The primary analysis was intention-to-treat and involved all eligible patients who provided informed consent, were male, and had laryngeal cancer. We found the voice quality data available in the literature to be in part conflicting and to offer little guidance for estimation of the study sample size. Therefore, we were not able to perform formal power calculations. We estimated
Voice quality in early laryngeal cancer
257
that a sample size of 30 patients per group could yield a significant difference in the primary endpoint between the groups. The statistical analyses were done with a PASW Statistics 18 computer program (SPSS Inc, Chicago, IL). Repeated measurements between the groups over time were tested with repeated-measures analysis of variance. When an assumption for sphericity was violated, the degrees of freedom were corrected with Greenhouse-Geisser estimates of sphericity. Frequency tables were compared with the c2 test or Fisher exact test. Relationships between the aspects of voice quality (the GRBAS components), self-rated quality of voice, impact of voice quality on activities of daily living, and videolaryngostroboscopic findings were analyzed by computing the Pearson correlation coefficient (r). To assess interrater and intrarater reliability in judging voice quality, Cronbach a was calculated on each of the 5 dimensions of the GRBAS scale. The P values are 2-sided.
Results Patients Sixty patients entered the study between June 1998 and October 2008. Of these, 28 were randomly assigned to radiation therapy and 32 to TLS. Four patients were excluded from the analysis (1 was female; 3 withdrew consent), leaving 25 evaluable patients in the radiation therapy group and 31 in the TLS group (Fig. 1). The median age at study entry was 65 years (Table 1).
Expert-rated quality of voice Before beginning the study treatments, the patients had generally more breathy and rough voices compared with the normal voice, but there was no significant difference between the groups. 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 than those who received radiation therapy (score 1.52 vs 0.28 2 years after treatment, P
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation
Voice Quality After Treatment of Early Vocal Cord Cancer: A Randomized Trial Comparing Laser Surgery With Radiation Therapy Leena-Maija Aaltonen, MD, PhD,* Noora Rautiainen, MA,y Jaana Sellman, PhD,y Kauko Saarilahti, MD, PhD,z Antti Ma¨kitie, MD,* Heikki Rihkanen, MD, PhD,* Jussi Laranne, MD, PhD,x Leenamaija Kleemola, MD, PhD,x Tuija Wigren, MD, PhD,jj Eeva Sala, MD, PhD,{ Paula Lindholm, MD, PhD,# Reidar Grenman, MD,{ and Heikki Joensuu, MDz *Department of OtorhinolaryngologyeHead and Neck Surgery, Helsinki University Central Hospital, and University of Helsinki; yInstitute of Behavioural Sciences, University of Helsinki; zDepartment of Oncology, Helsinki University Central Hospital, and University of Helsinki, Helsinki, Finland; x Department of OtorhinolaryngologyeHead and Neck Surgery, Tampere University Hospital, and University of Tampere; jjDepartment of Oncology, Tampere University Hospital, and University of Tampere, Tampere, Finland; {Department of OtorhinolaryngologyeHead and Neck Surgery, Turku University Hospital, and University of Turku; and #Department of Oncology, Turku University Hospital, and University of Turku, Turku, Finland Received Apr 23, 2014, and in revised form Jun 5, 2014. Accepted for publication Jun 10, 2014.
Summary This first randomized study concerning early laryngeal cancer patient’s voice quality showed that patients treated with radiation therapy or with transoral laser surgery had similar overall voice quality, but radiation therapy resulted in a less breathy voice. Those treated with radiation therapy reported less voice-related
Objective: Early laryngeal cancer is usually treated with either transoral laser surgery or radiation therapy. The quality of voice achieved with these treatments has not been compared in a randomized trial. Methods and Materials: Male patients with carcinoma limited to 1 mobile vocal cord (T1aN0M0) were randomly assigned to receive either laser surgery (nZ32) or external beam radiation therapy (nZ28). Surgery consisted of tumor excision with a CO2 laser with the patient under general anaesthesia. External beam radiation therapy to the larynx was delivered to a cumulative dose of 66 Gy in 2-Gy daily fractions over 6.5 weeks. Voice quality was assessed at baseline and 6 and 24 months after treatment. The main outcome measures were expert-rated voice quality on a grade, roughness, breathiness, asthenia, and strain (GRBAS) scale, videolaryngostroboscopic findings, and the patients’ self-rated voice quality and its impact on activities of daily living. Results: Overall voice quality between the groups was rated similar, but voice was more breathy and the glottal gap was wider in patients treated with laser surgery than
Reprint requests to: Leena-Maija Aaltonen, MD, PhD, Department of OtorhinolaryngologyeHead and Neck Surgery, Helsinki University Central Hospital, PO Box 220, FI-00029 HUS, Finland. Tel: (þ358) 504271493; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 90, No. 2, pp. 255e260, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.06.032
Conflict of interest: none. AcknowledgmentsdThe authors thank the members of the Finnish Head and Neck Oncology Working Group and Timo Muhonen, MD, PhD for collaboration and advice, and Carol Norris, PhD for language editing.
256
International Journal of Radiation Oncology Biology Physics
Aaltonen et al.
handicap. These results suggest that radiation therapy may be a treatment of choice for patients whose requirements for voice quality are demanding. However, careful consideration of patient-related factors is essential when choosing the treatment option.
in those who received radiation therapy. Patients treated with radiation therapy reported less hoarseness-related inconvenience in daily living 2 years after treatment. Three patients in each group had local cancer recurrence within 2 years from randomization. Conclusions: Radiation therapy may be the treatment of choice for patients whose requirements for voice quality are demanding. Overall voice quality was similar in both treatment groups, however, indicating a need for careful consideration of patientrelated factors in the choice of a treatment option. Ó 2014 Elsevier Inc.
Introduction
Patients
Patients with early glottal carcinoma are usually treated with either radiation therapy or transoral laser surgery (TLS). The choice between these treatments is controversial, and treatment may vary by geographic region (1). The current evidence is insufficient to guide management decisions (2), and a recent systematic review and metaanalysis failed to identify a single randomized study comparing TLS with radiation therapy (1). The metaanalysis suggested that a higher larynx preservation rate can be achieved with TLS, but owing to the generally poor quality of the evidence, this result was considered inconclusive. The relative merits of TLS and radiation therapy for local cancer control, the functional outcomes including voice quality, and laryngeal preservation remain unknown. Inasmuch as most (85%-95%) laryngeal carcinomas limited to 1 vocal cord are cured either by TLS or by radiation therapy (3, 4), a key objective of treatment beyond recovery is maintaining good voice quality. We compared in the present randomized study the effects of TLS and external beam radiation therapy on quality of voice in a patient population with early glottal carcinoma limited to 1 vocal cord.
Eligible patients had previously untreated, histologically confirmed squamous cell carcinoma limited to 1 mobile vocal cord, staged as T1aN0M0 (5), and were capable of collaboration in voice evaluation tests. To achieve homogeneity in voice quality assessments, and because glottal cancer is infrequent in women (6), female patients were not included. The study protocol was approved by an ethics committee of the Helsinki and Uusimaa Hospital District. The patients provided written consent before entry into the study. The study was not registered (trial registration was not the norm in 1998).
Methods and Materials Design The purpose of this randomized, multicenter, parallel-group study was to compare TLS with external beam radiation therapy as the primary treatment for early glottal carcinoma limited to 1 vocal cord. The primary endpoint was voice quality 2 years after treatment.
Setting Given that the outcome of laser surgery, in particular, may depend on the operator’s skills, the study took place in large referral hospitals. The 3 largest university hospitals in Finland participated.
Randomization Study participants were randomized to the treatments at a 1:1 ratio by means of a computer program with random digits weighted according to the proportions of past randomizations to yield a roughly balanced number of randomizations between the groups in a concealed fashion. Randomization was carried out by a hospital staff member who was independent of the study. Tumor site in the vocal cord was used as a stratification factor at randomization. The result of randomization was communicated to the centers by phone.
Treatments Patients allocated to radiation therapy had their treatments started within 6 weeks after randomization. The larynx was irradiated with 6-MeV photons from 2 opposing 4.5 4.5 to 5 5 cm wedge fields to a total cumulative dose of 66 Gy in 2-Gy daily fractions over 6.5 weeks with a linear accelerator. When necessary an anterior bolus was added to achieve the desired dose at the anterior commissure. The uniformity criteria within the planned target volume were defined according to the International Commission on Radiation Units and Measurements Report 50 (7). The clinical target volume encompassed the larynx with no attempt to irradiate the regional lymphatics. Patients assigned to TLS had the tumor excised under general anesthesia within 6 weeks from randomization by
Volume 90 Number 2 2014
use of a CO2 laser. The operations were performed as described elsewhere (8, 9) by only 7 experienced senior surgeons. In short, the tumors were first split, and tumor tissue was removed down to a macroscopically healthy muscle layer. After tumor excision, small biopsy specimens were taken to ensure complete (R0) removal.
Evaluation of voice quality The patients had prescheduled follow-up visits at 2-month to 3-month intervals at the hospital otorhinolaryngology outpatient clinics. Voice samples were collected at baseline and 6 and 24 months after treatment. The larynx was examined with videolaryngostroboscopy, and the patients filled in questionnaires. Expert-rated evaluation of voice was based on 3 sentences read aloud at a comfortable speech loudness level. The sentences included 17 words and lasted about 14.5 seconds. Voice samples were uploaded onto a compact disk in a random order. A total of 150 voice samples were analyzed by 3 trained speech and language therapists with expertise in voice quality evaluation who were blinded to the treatment groups. Voice quality was assessed on the GRBAS scale, consisting of grade (G), reflecting overall voice quality; roughness (R); breathiness (B); asthenia (A); and strain (S). Ratings of these 5 aspects of voice quality varied from 0 (normal) to 3 (extremely abnormal) (10). The higher the score, the more dysphonic the voice. Interrater consistency was assessed by comparing the original ratings of all voice samples (150 items) between the raters. To assess intrarater consistency, the voice samples were randomized, after which the samples of 10 patients were randomly duplicated on a compact disk and reassessed by the raters. The patients rated their own voice quality (hoarseness) and assessed its impact on daily life using a 100-mm long visual analogue scale (VAS) with end anchors “no degree of” and “high degree of” hoarseness and inconvenience. The videolaryngostroboscopic findings were evaluated by a panel of 3 phoniatricians, who were blinded to the treatment groups and uninvolved with the treatments. Adduction and abduction movements of the vocal cords, the amplitude and the phase symmetry of the mucosal wave, glottal closure, and signs of vocal cord hyperfunction were each assessed on a scale from 0 (no pathology) to 3 (major pathology).
Statistical analysis The primary analysis was intention-to-treat and involved all eligible patients who provided informed consent, were male, and had laryngeal cancer. We found the voice quality data available in the literature to be in part conflicting and to offer little guidance for estimation of the study sample size. Therefore, we were not able to perform formal power calculations. We estimated
Voice quality in early laryngeal cancer
257
that a sample size of 30 patients per group could yield a significant difference in the primary endpoint between the groups. The statistical analyses were done with a PASW Statistics 18 computer program (SPSS Inc, Chicago, IL). Repeated measurements between the groups over time were tested with repeated-measures analysis of variance. When an assumption for sphericity was violated, the degrees of freedom were corrected with Greenhouse-Geisser estimates of sphericity. Frequency tables were compared with the c2 test or Fisher exact test. Relationships between the aspects of voice quality (the GRBAS components), self-rated quality of voice, impact of voice quality on activities of daily living, and videolaryngostroboscopic findings were analyzed by computing the Pearson correlation coefficient (r). To assess interrater and intrarater reliability in judging voice quality, Cronbach a was calculated on each of the 5 dimensions of the GRBAS scale. The P values are 2-sided.
Results Patients Sixty patients entered the study between June 1998 and October 2008. Of these, 28 were randomly assigned to radiation therapy and 32 to TLS. Four patients were excluded from the analysis (1 was female; 3 withdrew consent), leaving 25 evaluable patients in the radiation therapy group and 31 in the TLS group (Fig. 1). The median age at study entry was 65 years (Table 1).
Expert-rated quality of voice Before beginning the study treatments, the patients had generally more breathy and rough voices compared with the normal voice, but there was no significant difference between the groups. 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 than those who received radiation therapy (score 1.52 vs 0.28 2 years after treatment, P
