ORIGINAL ARTICLE. the glottic larynx is part of the spectrum of premalignant

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1 Treatment Results of Carcinoma In Situ of the Glottis An Analysis of 8 Cases ORIGINAL ARTICLE Quynh-Thu Le, MD; Robert Takamiya, MD; Hui-Kuo Shu, MD; Melanie Smitt, MD; Mark Singer, MD; David J. Terris, MD; Willard E. Fee, MD; Don R. Goffinet, MD; Karen K. Fu, MD Objectives: To evaluate the results of different treatment modalities for carcinoma in situ of the glottis, and to identify important prognostic factors for outcome. Design: Review of 8 cases treated definitively for glottic carcinoma in situ between 1958 and The median follow-up for all patients was 11 months, and 9% had more than years of follow-up Setting: Academic tertiary care referral centers. Intervention: Fifteen patients were treated with vocal cord stripping (group 1), 13 with more extensive surgery (group ) including endoscopic laser resection (11 patients) and hemilaryngectomy ( patients), and 54 with radiotherapy (group 3). Thirty patients had anterior commissure involvement and 9 had bilateral vocal cord involvement. Radiotherapy was delivered via opposed lateral fields at 1.5 to.4 Gy per fraction per day (median fraction size, Gy), 5 days per week. The median total dose was 64 Gy, and the median overall time was 47 days. Main Outcome Measures: Initial locoregional control (LRC), ultimate LRC, and larynx preservation. Results: The 1-year initial LRC rates were 56% for group 1, 71% for group, and 79% for group 3. Of those who failed, the median time to relapse was 11 months for group 1, 17 months for group, and 41 months for group 3. Univariate analysis showed that the difference in initial LRC rates between groups 1 and 3 was statistically significant (P=.), although it was not statistically significant on multivariate analysis (P=.7). Anterior commissure involvement was an important prognostic factor for LRC on both univariate (P=.3) and multivariate (P=.4; hazard ratio, 1.6) analysis, and its influence appeared to be mainly confined to the surgically treated patients (groups 1 and ). The 1-year larynx preservation rates were 9% for group 1, 7% for group, and 85% for group 3. Anterior commissure involvement was the only important prognostic factor for larynx preservation (P=.1) on univariate analysis. All but patients in whom treatment failed underwent successful salvage surgery. Voice quality was deemed good to excellent in 73% of the patients in group 1, 4% in group, and 68% in group 3. Conclusions: Treatment of carcinoma in situ of the glottis with vocal cord stripping or more extensive surgery or radiotherapy provided excellent ultimate LRC and comparable larynx preservation rates. Anterior commissure involvement was associated with poorer initial LRC and larynx preservation, particularly in the surgically treated patients. The choice of initial treatment should be individualized, depending on patient age, reliability, and tumor extent. Pretreatment and posttreatment objective evaluation of voice quality should be helpful in determining the best therapy for these patients. Arch Otolaryngol Head Neck Surg. ;16: From the Departments of Radiation Oncology (Drs Le, Smitt, and Goffinet) and Otolaryngology (Drs Terris and Fee), Stanford University, Stanford, Calif; and Departments of Radiation Oncology (Drs Takamiya, Shu, and Fu) and Otolaryngology (Dr Singer), University of California, San Francisco. CARCINOMA in situ (CIS) of the glottic larynx is part of the spectrum of premalignant changes primarily associated with cigarette smoking. 1 Histologically, it is described as a full-thickness epithelial replacement by cells with malignant cytologic features without evidence of invasion through the basement membrane. It is a relatively rare entity, with an annual incidence rate of.4 per 1 persons. 3 Approximately 5% to 3% of laryngeal CIS will progress to invasive tumors, with untreated cases transforming at the highest rates (33.3%-9.%). 4,5 The optimal approach to CIS treatment has been controversial. There has been considerable disagreement as to the initial approaches to these patients, whether it be stripping, laser surgery, cordectomy, radiotherapy (RT), or even watchful waiting. Most series reported on patients treated with either RT alone 6-1 or conservative surgery alone Those that included both treatment modalities are generally small, 3,18,19 and some included patients with early invasive T1 to T carcinomas. (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 16, NOV 135 Downloaded From: on 1/9/18 American Medical Association. All rights reserved.

2 PATIENTS AND METHODS Between May 1, 1958, and May 1, 1998, eighty-two patients received definitive treatment for CIS of the glottis at the foregoing institutions. All patients underwent direct laryngoscopy and tumor biopsy or stripping of the vocal cord at diagnosis. All pathology slides were reviewed by either Stanford or University of California, San Francisco, pathologists. Patients who were treated with stripping alone or who had more than 1 stripping procedure performed for CIS before RT were classified as the vocal cord stripping group (group 1; 15 patients). Those who underwent laser excision, cordectomy, hemilaryngectomy, or total laryngectomy immediately after a diagnostic biopsy or stripping were classified as the more extensive surgery group (group ; 13 patients). Those who received RT after biopsy or only 1 stripping procedure were classified as the RT group (group 3; 54 patients). Table 1 shows the patient and tumor characteristics for the 3 treatment groups. Group had a higher percentage of patients with anterior commissure (AC) involvement and group 3, a higher percentage of patients with bilateral vocal cord involvement. The median follow-up for all patients was 11 months (range, months), and it was similar for all 3 groups. The minimum follow-up was more than years in 74 patients (9%) and more than 5 years in 56 patients (68%). All initial treatments were delivered at either Stanford University or University of California, San Francisco. Within group 1, two patients had 1 stripping procedure, 6 had, 5 had 3, and had 4. Within group, 11 patients were treated with laser excision and with hemilaryngectomy after a pathological diagnosis of CIS. For the RT group, RT was delivered at 1.5 to.4 Gy per fraction (median, Gy per fraction), 1 fraction per day, 5 days per week. The total dose ranged from 53 to 7 Gy (median, 64 Gy). The median overall treatment time was 47 days (range, 37-6 days). All but 1 patient were treated with megavoltage photon beam: 8 with 1 MV of x-rays, 8 with 4 MV, 1 with 6 MV, and 5 with cobalt 6. One patient received part of his treatment with a 5-kV orthovoltage and the remainder with 4 MV of x-rays. All patients were treated with opposed lateral fields. The median field size was 5 cm (range, cm ). Wedges and compensators were used routinely to improve dose homogeneity after 1965 except in cases with AC involvement. For patients treated with either RT, cordectomy, or hemilaryngectomy, failure was scored when the patient was found to have either a local or a regional recurrence (whichever occurred first) after completion of treatment. For those treated with stripping or laser excision, failure was scored when the patient required salvage RT or a more extensive surgical procedure (ie, cordectomy, hemilaryngectomy, or total laryngectomy) for CIS or an invasive recurrence after or more additional procedures were performed. Estimates of LRC and survival rates were computed by means of the Kaplan-Meier product limit method. 1 Log-rank statistics were used to identify important prognostic factors for LRC. Cox proportional hazard models using the forward stepwise method were applied to all potentially significant prognostic variables in multivariate analysis. Groups 1 and were combined for multivariate analysis. Stata Statistical Software 3 was used for statistical evaluations. Table 1. Patient Characteristics by Treatment Group* Treatment Group Characteristics 1 3 patients Sex, No. (%) M 14 (93) 1 (9) 47 (87) Age, y Median Range AC involvement, No. (%) 4 (7) 7 (54) 19 (35) Bilateral TVC involvement, No. (%) 1 (7) () 8 (15) Follow-up, mo Median Range *AC indicates anterior commissure; TVC, true vocal cord. Group 1 included patients treated with vocal cord stripping alone or who had more than 1 stripping procedure performed before radiotherapy (RT) (vocal cord stripping group); group, those who underwent laser excision, cordectomy, hemilaryngectomy, or total laryngectomy immediately after diagnostic biopsy or stripping (more extensive surgery group); and group 3, those who received RT after biopsy or only 1 stripping procedure (RT group). This retrospective study was conducted at Stanford University, Stanford, Calif, and the University of California, San Francisco, to determine the impact of treatment modality on locoregional control (LRC) and larynx preservation. RESULTS LOCOREGIONAL CONTROL At last follow-up, treatment had failed in 19 patients: 6 (4%) in group 1, three (3%) in group, and 1 (18%) in group 3. Invasive cancer was found in 15 patients: 3 (%) in group 1, three (3%) in group, and 9 (16%) in group 3. The initial site of failure was in the glottis only in 17 patients (invasive cancer in 13 and CIS in 4) and in the glottis and cervical lymph nodes in patients. There was no isolated nodal failure without local recurrence, and there was no distant metastasis. Of those in whom treatment failed, the median time to relapse was 11 months for group 1 (range, 6-5 months), 17 months for group (range, 3-48 months), and 41 months for group 3 (range, months). Six patients were placed in the failure category more than 5 years after RT, and many continued to smoke after the completion of treatment. It is unclear whether these new lesions represented second primary tumors or late relapses. However, for the purpose of this analysis, they were scored as late failures. The 5- and 1-year Kaplan-Meier estimates of LRC rates were both 56% for the stripping group, 71% for the more extensive surgery group, and 9% and 79%, respectively, for the RT group (Figure 1). Within group, the 5- and 1-year LRC rates for the 11 patients treated with endoscopic laser resection were both 8%. (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 16, NOV 136 Downloaded From: on 1/9/18 American Medical Association. All rights reserved.

3 Locoregional Control, % P = Group 1 Group Group Time, y Figure 1. Kaplan-Meier estimates of locoregional control by treatment group. RT indicates radiotherapy. Groups are defined in the second footnote to Table 1. Table. Locoregional Control Rates by Potential Prognostic Factors For All Patients: Univariate Analysis* % Actuarial Failures/ Locoregional Control Variable Patients 5 y 1 y P Age, y 6 9/ / Sex F 3/ M 16/ AC involvement No 8/ Yes 11/ Bilateral TVC involved No 16/ Yes 3/ Treatment group 1 6/ / / *AC indicates anterior commissure; TVC, true vocal cord. Groups are defined in the second footnote to Table 1. P =.forpairwisecomparisonbetweenthestrippingandradiotherapygroups. Table shows the LRC rates in relation to a number of potential prognostic factors for all patients. These include age, sex, AC involvement, unilateral vs bilateral true vocal cord involvement, and type of treatment. Involvement of the AC was a significant factor on univariate analysis (P=.3). Subset analysis disclosed that the impact of AC involvement was more significant for groups 1 and than for group 3. Within the first groups, the 1-year LRC rates were 37% and 8% for patients with and without AC involvement, respectively (P=.5). Within the RT group, the rates were 73% and 8% for patients with and without AC involvement, respectively (P=.8). In addition, there was a trend toward poorer initial LRC with vocal cord stripping alone (P=.7). Pairwise comparison showed a significant difference in initial LRC between groups 1 and 3 (P=.) but not between groups and 3 or between groups 1 and Table 3. Univariate Analysis of Potential Prognostic Factors for Locoregional Control in Radiotherapy-Treated Patients* % Actuarial Locoregional Control Variable Failures/ Patients 5 y 1 y Age, y 6 6/ / AC involved Yes 5/ No 5/ TVCs involved, No. 1 7/ / Hemoglobin level, g/l (g/dl) 14 ( 14) / ( 14) 1/ 1 93 Total dose, Gy 6 3/ / Fraction size, Gy 3/ / Overall time, d 5 7/ / Field size (equivalent square), cm 4 3/ / Beam energy, MV 4 8/ / *AC indicates anterior commissure; TVC, indicates true vocal cord. Available in only 3 patients. A multivariate analysis in which the patients in groups 1 and were combined was carried out by means of the Cox regression hazard model. Involvement of the AC was found to be an independent factor for LRC, with a P value of.4 and a hazard ratio of 1.6 (95% confidence interval, 1.-.5). Although treatment modality was not a significant factor, it favored RT, with a P value of.7 and a hazard ratio of.4 (95% confidence interval,.-1.3). We evaluated a number of potentially important prognostic factors for LRC in patients treated with RT as the initial management. These included age, AC involvement, unilateral vs bilateral true vocal cord involvement, fraction size, total dose, radiation overall time, treatment field size, beam energy, and hemoglobin level. Table 3 shows the LRC in relation to these variables. None of the tested variables was significant on univariate analysis. On multivariate analysis, none of the variables reached statistical significance, except for a trend toward inferior LRC with increasing overall time (P=.1; hazard ratio, 1.18 per day). Since there was an interaction between total dose, overall time, and fraction size, we generated scatterplots (Figure ) to evaluate the impact of total dose, fraction size, and overall time on initial LRC. As shown in Figure A, there was no relationship between total dose or fraction size and initial tumor P (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 16, NOV 137 Downloaded From: on 1/9/18 American Medical Association. All rights reserved.

4 7 A B Controlled Failed LRC, 8% (8/1) LRC, 83% (5/3) LRC, 8% (9/35) LRC, 8% (4/5) Total Dose, Gy LRC, 83% (5/6) LRC, % (6/8) Fraction Size, Gy LRC, 9% (11/1) LRC, % (/) Radiation Overall Time, d Figure. Initial locoregional control in relation to total dose and fraction size (A) and total dose and irradiation overall time (B). LRC indicates locoregional control. Table 4. Results of Salvage Therapy for the 3 Treatment Groups* Salvage Treatment 1 3 RT 5 RT followed by TL 1 1 Repeated stripping 1 HL±ND TL±ND 7 Total No. (%) successfully 5 (83) 3 (1) 9 (9) salvaged control. In patients treated with an overall time of 5 days or less, the total dose, within the range evaluated, had no significant impact on LRC. Both of the patients treated with an overall time of more than 5 days and a total dose of 6 Gy or less had treatment failure. SALVAGE THERAPY Treatment Group *Data are given as number of patients unless otherwise indicated. RT indicates radiotherapy; TL, total laryngectomy; HL, hemilaryngectomy; and ND, neck dissection. Groups are defined in the second footnote to Table 1. Larynx Preserved, % P = Group Group 3 Group Time, y Figure 3. Kaplan-Meier estimates of larynx preservation for all patients. Groups are defined in the second footnote to Table 1. Salvage therapy for each treatment group and the number of cases salvaged are shown in Table 4. All but patients in whom treatment failed underwent successful salvage with either RT or more extensive surgery. Of these patients, one was initially treated with RT in He continued to smoke and drink after therapy and developed an invasive cancer involving the same true vocal cord in 1967, treated with hemilaryngectomy. He then developed nodal relapse and eventually died of locoregional progression more than 1 years after the initial diagnosis, despite additional salvage surgery and RT. In the second patient 3 stripping procedures had failed, and the patient received salvage RT for a bulky CIS relapse, although microinvasion could not be ruled out. He had treatment failure years later with invasive cancer and was treated with total laryngectomy, neck dissection, and additional RT. He eventually died of tumor progression in the base of the tongue despite the use of salvage chemotherapy. After salvage, the 1-year estimate of ultimate LRC rates were 9% for the stripping group, 1% for the more extensive surgery group, and 96% for the RT group. LARYNX PRESERVATION AND VOICE QUALITY The larynx was preserved in 14 of 15 patients in the stripping group, 1 of 13 patients in the more extensive surgery group, and 47 of 54 patients in the RT group. The 1-year larynx preservation rates were 9%, 7%, and 85% for groups 1,, and 3, respectively (Figure 3). Univariate analysis disclosed that AC involvement was a potential prognostic factor for larynx preservation, favoring patients with no AC extension. The 1-year larynx preservation rates were 71% and 93% for those with and without AC involvement, respectively (P=.1; Figure 4A). Subset analysis showed that the difference was highly significant for the surgically treated patients (groups 1 and ); the 1-year estimates of larynx preservation were 57% and 1% for those with and without AC involvement, respectively (P=.7; Figure 4B). Within the RT group, AC involvement was not a significant factor for larynx preservation; the 1-year larynx preservation rates were 89% and 93% for those with and without AC involvement, respectively (P=.3; Figure 4C). No other variables evaluated, including age, sex, bilateral vo- (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 16, NOV 138 Downloaded From: on 1/9/18 American Medical Association. All rights reserved.

5 1 A Without AC With AC 5 5 Table 5. Voice Quality by Treatment Groups Treatment Group, No. (%)* Quality 1 (n = 15) (n = 13) 3 (n = 54) Good to excellent 11 (73) 6 (46) 37 (68) Hoarse to poor 3 () 3 (3) 1 (19) Prosthesis 1 (7) 4 (31) 7 (13) *Groups are defined in the second footnote to Table 1. 1 B 5 5 Larynx Preserved, % P =.1 With AC Without AC Survived, % P = Groups 1 and Group 3 1 C 5 5 P =.7 P = Time, y cal cord involvement, and treatment type, was significant on univariate analysis. Multivariate analysis was not carried out because of the small number of events. Voice quality was scored as determined by the treating physicians and the patients. The results are shown in Table 5. It was deemed good to excellent in 11 (73%) of 15 patients in group 1, six (46%) of 13 patients in group, and 37 (69%) of 54 patients in group 3. LATE COMPLICATIONS With AC Late treatment-related complications occurred in 7 patients, 6 of whom were in the RT group. One patient had marked arytenoid scarring after multiple strippings and laser resections. One patient had marked chronic laryngeal edema for 1 year after completion of RT, requiring corticosteroid therapy. This patient received a total dose of 6 Gy in 3 fractions to a field size of 1 13 cm and Without AC Figure 4. Larynx preservation by anterior commissure (AC) involvement in all patients (A); surgically treated patients (groups 1 and ) (B); and patients who received radiotherapy (group 3) (C). Groups are defined in the second footnote to Table Time, y Figure 5. Overall survival by treatment. Groups are defined in the second footnote to Table 1. continued to smoke throughout and after treatment. Two patients developed AC webbing at and 3 years after RT, 1 patient had laryngeal fibrosis documented on biopsy associated with poor voice, 1 patient had chronic edema and a fixed true vocal cord 3 years after treatment, and 1 patient had laryngeal fibrosis after reirradiation for a second primary tumor on the epiglottis. SURVIVAL At last follow-up, 33 patients had died: of recurrences and 31 of intercurrent illnesses. The 1-year diseasespecific survival for the entire group was 98%, and the 1-year overall survival was 78%. Figure 5 shows the survival curves for the surgery (groups 1 and ) and RT groups. There was no difference in survival between the groups of patients. Secondary malignant neoplasms were documented in 3 patients, some with more than 1 site. There were skin cancers (both outside of the treatment fields), melanomas, 5 head and neck cancers (1 oral tongue cancer, 1 posterior pharyngeal wall cancer at 3 years after RT, epiglottis cancers at 1 and 8 years after RT, and 1 nasopharyngeal cancer), 1 thyroid cancer, 6 lung cancers, 8 prostate cancers, 1 bladder cancer, 1 colon cancer, and 1 meningioma. COMMENT Management of CIS of the glottis remains controversial. Treatment options include vocal cord stripping, endoscopic laser surgery, cordectomy, hemilaryngectomy, and RT. Small, previously untreated CIS lesions may be con- (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 16, NOV 139 Downloaded From: on 1/9/18 American Medical Association. All rights reserved.

6 Table 6. Locoregional Control of Glottic CIS by Treatment Types: Survey of the Literature* Source, y Stripping Laser Surgery RT Patients % ILRC % ULRC Patients % ILRC % ULRC Patients % ILRC % ULRC Miller and Fisher, NR NA NA NA NR Pene and Fletcher, NA NA NA NA NA NA Doyle et al, (3/3) 1 (3/3) NA NA NA Elman et al, (4/8) NR NA NA NA NR Sung et al, NA NA NA NA NA NA Harwood et al, NA NA NA NA NA NA Hintz et al, NA NA NA Gillis et al, NA NA NA 8 63 (5/8) 1 NA NA NA Annyas et al, NA NA NA 6 83 (5/6) 1 NA NA NA Maran and NA NA NA 5 1 (5/5) 1 Mackenzie, Wetmore et al, NA NA NA 6 67 (4/6) 1 NA NA NA Kalter et al, NA NA NA NA NA NA Crissman et al, NA NA NA 1 (/) 1 Stenersen et al, NA NA NA NR Fernberg et al, NA NA NA NA NA NA 4 9 NR MacLeod and Daniel, NA NA NA NA NA NA 7 9 Wolfensberger and Dort, NA NA NA 7 1 (7/7) 1 NA NA NA Rothfield et al, NA NA NA NA NA NA McGuirt and Browne, NA NA NA NA NA NA Eckel and Thumfart, NA NA NA 8 1 (8/8) 1 NA NA NA Fein et al, NA NA NA NA NA NA Small et al, NA NA NA NA NA NA Myssiorek et al, NA NA NA (/3) 1 Smitt and Goffinet, NA NA NA NA NA NA Nguyen et al, NA NA NA Medini et al, NA NA NA NA NA NA Present study *ILRC indicates locoregional control; ULRC, ultimate locoregional control; RT, radiotherapy; NR, not reported; and NA, not applicable. Some patients underwent biopsy only. Twelve patients underwent laser excision in addition to stripping. Seven patients had microinvasive carcinoma. Some patients underwent vocal cord stripping only. Ten-year actuarial rates. trolled by vocal cord stripping alone. Advantages of stripping procedures include a 1-session therapy (rather than a 6- to 7-week course with RT), the ability to remove all abnormal-appearing tissue to exclude invasive cancer, minimal treatment-related morbidity, and ability to preserve vocal cord function. When stripping fails, the salvage rate with RT is excellent. However, local recurrence is frequent with stripping alone (Table 6). In our series, only 56% of the patients achieved LRC by vocal cord stripping alone. We acknowledge that both our assignment of patients to the stripping group and our definition of stripping failure were not similar to definitions used in other series (see the Patients and Methods section). We considered these definitions to be fair, since multiple consecutive stripping procedures were allowed and stripping was considered to have failed only when the patient required a different type of treatment (ie, RT, laser resection, or cordectomy) for salvage. Similar to other reports in the literature, 19 most patients in this series required an average of stripping procedures to maintain LRC, and the vocal cords have the potential of becoming thickened and the voice hoarse with repeated stripping. Conservative endoscopic laser excision of vocal cord tumors was popularized in 19, when Strong 35 introduced the carbon dioxide laser for this purpose. Laser excision is convenient and exact. The lack of superficial bleeding makes it easy for the endoscopist to control surgical margins and the depth of excision. The initial control rates with endoscopic laser excision ranged from 5% to 1%, although most authors report rates higher than 8% (Table 6). In the present series, there were only local failures in the 11 patients treated with endoscopic laser surgery. Thus, the crude LRC rate was 8% and the 1-year Kaplan-Meier estimate of LRC was 8%. The majority of cases in which treatment fails can be salvaged with RT, and the ultimate LRC rates should be greater than 9%. Drawbacks of laser surgery include potentially decreased voice quality and the inability to treat large tumors with AC extension by a single procedure. In general, institutions using RT as primary therapy in these patients have reported excellent LRC rates, similar to those for T1 tumors (Table 6). 3,6-9,11,1,6,34 However, recurrence rates after RT are variable, and some authors have suggested that CIS may be intrinsically more radioresistant than invasive true vocal cord tumors. 36 The poorest RT results came from small series (by Smith and Lockey 37 and Miller and Fisher 4 ) that reported only 45% to 5% LRC rates. In Smith and Lockey s series, only patients received RT for CIS, and 1 had treatment fail- (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 16, NOV 131 Downloaded From: on 1/9/18 American Medical Association. All rights reserved.

7 ure with an invasive carcinoma. In Miller and Fisher s study, RT was used for large, extensive lesions that, in many cases, involved both true vocal cords. In addition, in a number of patients, RT was used for salvage after multiple endoscopic procedures for recurrences. In our experience, excellent LRC was achieved with definitive RT. Unlike endoscopic surgical failures, which generally occur within 1 to years after therapy, 4,6 many patients in our series had late relapses. It is unclear whether these lesions represented second primary tumors or late recurrences. In either case, long-term follow-up is important for these patients, and chemoprevention, once better defined, may have a role in their treatment. Data from our series showed that RT resulted in the highest initial LRC rate, followed by more extensive surgery and vocal cord stripping. The difference in LRC rates between RT and vocal cord stripping was statistically significant on univariate analysis but not on multivariate analysis. Most patients who had relapses underwent successful salvage with either additional surgery or RT, resulting in similar rates of larynx preservation and ultimate LRC. Voice quality, as shown in Table 5, was similar for the RT and the stripping groups. Therefore, the choice of initial treatment of a patient with CIS of the vocal cords should be individualized on the basis of patient age, reliability, and the extent of the lesion. Our recommendation for treatment of any hyperkeratotic or dysplastic lesion is complete removal via microlaryngoscopy with or without the laser, so that all abnormal tissues can be appropriately oriented and examined for proper pathological diagnosis. Assuming only CIS is found, the patient is either followed up or treated with RT, according to patient and/or physician preference. Within our group, there are differences of opinion. Some prefer to treat with repeated microlaryngoscopy and excision until or if invasive cancer is found. The patient can then be treated with either more extensive laser excision or RT, depending on tumor extent and voice quality. Others prefer RT at the onset of treatment for CIS. Involvement of the AC has been associated with a high risk of an invasive recurrence in patients treated with endoscopic surgery for CIS. Myssiorek et al 33 observed a 9% conversion rate to invasive cancer in lesions involving the AC, compared with 17% for tumors limited to the mobile portion of the vocal fold. A similar high local failure rate was observed in the present series. Only 37% and 57% of the patients with AC involvement treated surgically (groups 1 and ) had LRC and larynx preservation, respectively, at 1 years. Many patients with AC involvement may have had a larger tumor burden anteriorly and, in some cases, unrecognized subglottic extension. These patients appeared to have a higher risk of treatment failure, and their initial treatment should include RT delivered in a way that ensures adequate tumor coverage anteriorly. Our current policy is to omit the use of wedges in patients with AC involvement and to use 4 MV of x-rays whenever possible. If 6 MV of x-rays is used, bolus material is added to the skin overlying the anterior commissure to ensure adequate dosage delivery to this area. We did not observe any obvious relationship between initial LRC rates and treatment variables such as age, sex, hemoglobin level, tumor dose, fraction size, treatment field size, or beam energy in patients treated with definitive RT. However, the number of patients might be too small to allow for meaningful analysis. There was a trend toward inferior LRC with prolonged overall RT time on multivariate analysis. The dose-time scatterplot showed that neither of the patients treated with overall time of more than 5 days and total dose of 6 Gy or less achieved LRC. This suggests that higher total doses are necessary when the overall time is prolonged. For patients treated with a short overall time, a total dose of 5 Gy or more, given in fractions of greater than Gy, may be adequate for tumor control. The University of Florida at Gainsville 9 reported a 5-year LRC rate of 93% for patients treated with 56. Gy at.5 Gy per fraction per day. Recently, Spayne et al 38 reported a 98% 5-year actuarial LRC rate in 67 patients treated with 51 Gy in fractions over 4 weeks. Voice quality was deemed good to excellent in more than two thirds of the patients in both the stripping and RT groups. It was worse, however, in patients treated by more extensive resections. Since this is a retrospective study in which data on voice quality were obtained from the treatment records, the results are subjected to possible bias and should be viewed with caution. Hirano et al 39 objectively evaluated vocal function in a small group of patients treated with either RT or laser resection for invasive T1a carcinoma of the glottis. They found that laser resection, when compared with RT, was associated with a slightly higher degree of hoarseness, more incomplete vocal closure, and more diminution of vocal fold vibration, especially when the vocalis muscle was removed. However, as far as conversational voice is concerned, there was little difference in vocal function. No such study has been performed for CIS of the glottis. Prospective objective evaluation of voice quality is needed to determine voice quality before and after either RT or repeated endoscopic surgeries for these tumors. CONCLUSIONS Our data showed that either vocal stripping, or more extensive surgery or RT provided excellent LRC and larynx preservation rates for CIS of the glottis. There was a trend toward fewer local relapses in patients treated by RT in comparison with those treated by vocal cord stripping. Almost all patients in whom treatment failed underwent successful salvage. Anterior commissure involvement was associated with poorer initial LRC and larynx preservation, particularly in the surgically treated patients. The choice of initial treatment should be individualized depending on patient age, reliability, tumor extent, and physician expertise. Pretreatment and posttreatment objective evaluation of voice quality should be helpful in determining the best therapy for patients with glottic CIS. Accepted for publication March 11,. Presented at the 41st annual meeting of the American Society for Therapeutic Radiology and Oncology, San Antonio, Tex, November 3, (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 16, NOV 1311 Downloaded From: on 1/9/18 American Medical Association. All rights reserved.

8 Corresponding author: Quynh-Thu Le, MD, Department of Radiation Oncology, Stanford University Medical Center, 3 Pasteur Dr, Stanford, CA ( qle@reyes.stanford.edu). REFERENCES 1. Auerbach O, Hammond EG, Garfinkel L. Histologic changes in the larynx in relation to smoking habits. Cancer. 197;5: Hellquist H, Lundgren J, Olofsson J. Hyperplasia, keratosis, dysplasia, and carcinoma in situ of the vocal cords: a follow-up study. Clin Otolaryngol. 198;7: Nguyen C, Naghibzadeh B, Black MJ, Rochon L, Shenouda G. Carcinoma in situ of the glottic larynx: excision or irradiation? Head Neck. 1996;18: Stenersen TC, Hoel PS, Boysen M. Carcinoma in situ of the larynx: an evaluation of its natural clinical course. Clin Otolaryngol. 1991;16: Hintz BL, Kagan AR, Nussbaum H, Rao AR, Chan PYM, Miles J. A watchful waiting policy for in situ carcinoma of the vocal cords. Arch Otolaryngol. 1981;17: Pene F, Fletcher GH. Results in irradiation of the in situ carcinomas of the vocal cords. 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