Treatment outcomes of the patients with early glottic cancer treated with initial radiotherapy and salvaged by conservative surgery

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1 Japanese Journal of Clinical Oncology, 2015, 45(3) doi: /jjco/hyu203 Advance Access Publication Date: 11 December 2014 Original Article Original Article Treatment outcomes of the patients with early glottic cancer treated with initial radiotherapy and salvaged by conservative surgery Aya Harada 1, Ryohei Sasaki 1, *, Daisuke Miyawaki 1, Kenji Yoshida 1, Hideki Nishimura 1, Yasuo Ejima 1, Kazuhiro Kitajima 2, Miki Saito 3, Naoki Otsuki 3, and Ken-Ichi Nibu 3 1 Division of Radiation Oncology, Kobe University Graduate School of Medicine, Kobe, 2 Department of Radiology, Kobe University Graduate School of Medicine, Kobe, and 3 Department of Otolaryngology-Head and Neck Surgery, Kobe University Graduate School of Medicine, Kobe, Japan *For reprints and all correspondence: Ryohei Sasaki, Division of Radiation Oncology, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe-city, , Hyogo, Japan. rsasaki@med.kobe-u.ac.jp Received 6 June 2014; Accepted 9 November 2014 Abstract Objective: This retrospective study analyzed the oncological and treatment outcomes of the patients with T1 T2N0 glottic cancer, who were treated with radiotherapy as initial treatment and salvaged by conservative surgery for radiation failure. Methods: Between May 1999 and December 2010, 115 patients with glottic laryngeal cancer were treated at Kobe University Hospital. At presentation, 54 patients had stage T1a disease, 26 had stage T1b disease and 35 had stage T2 disease. Seventy-nine patients were treated with conventional radiotherapy and 36 patients were treated with hyperfractionated radiotherapy as initial treatment. Results: Median duration of follow-up was 61 months. Five-year local control rates of radiotherapy were 92% in T1a, 83% in T1b and 86% in T2. Of 12 patients who developed local, larynx was successfully preserved in 3 patients by laryngomicrosurgery, 7 patients by vertical partial laryngectomy and one patient by subtotal laryngectomy. Ultimate 5-year laryngeal preservation rate and local control rate of all cases were 99 and 100%, respectively. Conclusions: Present results suggest that initial treatment with radiotherapy salvaged by organ preservation surgery is an effective strategy for laryngeal preservation in the treatment of T1 T2N0 glottic laryngeal cancer. Key words: glottic cancer, radiotherapy, salvage therapy, organ preservation Introduction Squamous cell carcinoma (SCC) accounts for most laryngeal cancers, of which 67% arise in the glottic region, 31% in the supraglottic region, and 2% in the subglottic region (1). Since larynx plays important roles in phonation, respiration and deglutition, the treatment goal of laryngeal cancer is not only to control the disease but also to preserve the functional larynx. In terms of quality of voice, both transoral laser microsurgery (LMS) and radiotherapy provide favorable quality in T1 and T2 glottic cancer, while open vertical partial laryngectomy (VPL) results in poorer voice (2 7). During the past decade, radiotherapy has been successfully employed for the treatment of T1 glottic cancer (8 12). However, conventional radiotherapy still results in unsatisfactory outcomes for T2 disease (8,9,12 14), prompting researchers to explore more aggressive treatment regimens. Recent trends in radiotherapy for early glottic cancers involve a better understanding of the role of fractionation, The Author Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com 248

2 Jpn J Clin Oncol, 2015, Vol. 45, No which considers both, the dose administered at each treatment and the frequency of treatments (12,15 19). Selection of the initial treatment for early glottic cancer depends on patient factors and availability of expertise and appropriate support and rehabilitation services. Although several reports have demonstrated that initial radiotherapy for early glottic cancer is associated with high rates of local control (20), few details are available on the subsequent clinical course of patients whose primary cancers were not controlled by this radiotherapy. Accordingly, the appropriate larynx preservation strategy, including both initial treatment and salvage therapy, should be proposed by a team of physicians that includes surgeons, medical oncologists and radiation oncologists. Since 1999, we have held multidisciplinary cancer board conferences for head and neck cancers, including discussions of treatment options for early laryngeal cancer. We carefully determined radiotherapy methods for initial treatment of early-stage laryngeal cancer, reserving surgery for salvage treatment. All patients were followed up by both radiation oncologists and head and neck surgeons. In this retrospective study, we describe the oncological and functional outcomes of our treatments for T1 and T2 glottic SCC. Patients and methods Patients A total of 115 consecutive patients with histologically proven SCC of the glottis (T1 T2N0M0, Union for International Cancer Control 6th edition) were assessed. These patients were primarily treated with radiotherapy as an initial treatment between May 1999 and December Patients treated by transoral laser surgery were excluded from this study. Details of the patients and tumor characteristics are presented in Table 1. All patients provided written informed consent for this study and the use of any accompanying images. This retrospective study was approved by the institutional review board of the Kobe University Hospital. Decision-making process to determine the initial therapeutic strategy is as follows. Each new case was introduced at the Head and Neck Cancer Board Conference of Kobe University Hospital, which consisted of head and neck surgeons, radiation oncologists, medical oncologists and radiologists. Staging and treatment choices were discussed at this board conference to determine the best treatment Table 1. Patient and tumor characteristics Characteristics Number of patients n = 115 (%) Age Median (range) 69 years (36 92) Gender Male Female 7 6 Performance status Unknown 4 3 T stage T1a T1b T Tumor bulk Yes No Anterior commissure involvement Yes No strategy to preserve the functional larynx. Staging work-up included physical examination, video laryngoscope, complete blood counts, chest radiography and computed tomography (CT) of the neck and thorax. Careful assessments were made of the tumor location, tumor volume, age, presence of other cancers, other conditions (including intercurrent diseases) and performance status. Our general policy for the initial treatment of T1N0 glottic cancer was conventional radiotherapy (once daily) (RT). However, when the tumor was bulky or involved anterior commissure, hyperfractionated radiotherapy (twice daily) (HRT) was adopted. Following Reddy et al. (11), we defined bulky tumors as large and/or infiltrative lesions involving an entire true vocal cord, as well as horseshoe-shaped lesions involving more than the anterior one-third of both true vocal cords. The treatment policy for T2N0 glottic cancer was HRT. Possible salvage methods were discussed at choosing the initial radiotherapy regimen. During the board conference, to avoid total laryngectomy was the most important factor in our decisions regarding voicepreservation strategies for early glottis cancers. Radiotherapy All patients were treated with external-beam radiotherapy using highenergy photons from a 4 MV X-ray linear accelerator. Patients were immobilized using a thermoplastic mask, and CT images were acquired in the treatment position. Radiation treatments were delivered with parallel opposed laryngeal ports with appropriate wedges employed to assure homogenous dose distribution in the glottic area. Especially, dose of anterior commissure were carefully considered and planned to obtain a homogenous dose distribution. Bolus was not used for these patients with T1 T2 tumors. Elective irradiation was not performed for neck lymph nodes. The median total dose was 66 Gy (range, Gy) among patients with T1aN0 cancer, 70 Gy (range, Gy) among patients with T1bN0 cancer and 74.4 Gy (range, Gy) among patients with T2N0 cancer. Seventy-nine patients (69%) received once-daily (conventional) fractionation (2 Gy per fraction), whereas 36 patients (31%) received twice-daily fractionation (1.2 Gy per fraction at 6 h intervals). The median overall treatment time was 46 days (range, days). Salvage surgery In general, we follow the criteria for partial laryngectomy set by Biller et al. (21): (i) subglottic extension not exceeding 5 mm; (ii) no invasion of the cartilage; (iii) tumor extension to the contralateral vocal cord not exceeding 3 mm; (iv) the arytenoid, except for the vocal process, being cancer free; (v) mobility of the vocal cord; (vi) supraglottic extension extending not further than the lateral extension of the sinus of Morgagni; frontolateral laryngectomy consisted of removal of the frontolateral part of the ala of the thyroid cartilage with the anterior commissure and the ipsilateral vocal cord, including the paraglottic space. Additional excision of part of the opposite vocal cord was performed according to the extent of the tumor. In the extended frontolateral laryngectomy, part or all of the arytenoids was removed in addition to that described for the frontolateral laryngectomy (22). Follow-up evaluation for the early detection of local After completion of radiotherapy, all patients were evaluated using video laryngoscope every month for the first year, every 2 months for the next 2 years, and every 3 months thereafter, for a total of at least 5 years, by both radiation oncologists and head and neck surgeons. When was suspected, biopsy was performed for confirmation.

3 250 Radiotherapy for early glottic cancer Statistical analyses Statistical analyses were performed using StatView Ver5.0 (SAS Institute Japan, Tokyo). Time to event was calculated from the starting date of radiotherapy to the event of interest. For overall survival, the event of interest was death due to any cause, and for rates, the event of interest was the confirmation of local based on biopsy results. The Kaplan Meier method was used to plot survival and curves. Follow-up durations were estimated for surviving patients. The log-rank test was used to assess differences in local rates according to the various factors. Results Patients Representative examples of our criteria are presented in Fig. 1 (a for T1 tumors; b for T2 tumors). Thirty patients had bulky tumors (T1: 18, Figure 1. Representative cases of T1/T2 stage glottic cancer and their treatment methods. (a) Left upper panel shows a T1a tumor without tumor bulk or AC involvement. Left lower panel shows a T1b tumor without tumor bulk but with AC involvement. (b) Right upper panel shows a T2 tumor with a tumor bulk and without AC involvement. Right lower panel shows a T2 tumor with a tumor bulk and AC involvement. (c and d) Decision trees for T1 or T2 tumors according to tumor bulk or AC involvement.

4 Jpn J Clin Oncol, 2015, Vol. 45, No T2: 12), and 50 (T1: 27, T2: 23) patients tumors with anterior commissure (AC) involvement (Table 1). Among the 18 patients with bulky T1 tumors, 4 (22%) patients with AC involvement and 3 (17%) patients without AC involvement were treated with twice-daily fractionated radiotherapy (Fig. 1c). Among the 12 patients with bulky T2 tumors, 5 (42%) patients with AC involvement and 5 (42%) patients without AC involvement were treated with twice-daily fractionated radiotherapy. Among the 23 patients with T2 tumors that were not bulky, 12 (52%) patients with AC involvement and 5 (22%) patients without AC involvement were treated with twice-daily fractionated radiotherapy (Fig. 1d). Survival The median duration of follow-up was 61 months ranging from 2 months to 151 months. Overall 5-year survival rates were 100% in patients with T1a disease, 96% in patients with T1b disease, 91% in patients with T2 disease and 96% in patients with all T stage (Fig. 2). During follow-up period, 7 patients died. One patient (1%) died of laryngeal cancer due to pulmonary metastases but local disease was controlled until death. Of the other 6 patients (5%), 3 died of other cancers (lung cancer 2, hepatocellular carcinoma 1) and 3 died of other intercurrent diseases. Local control rates by initial radiotherapy Local s developed in 12 (10%) patients during the followup period (Table 3). Among these patients, the initial T stage was T1a in 4 cases, T1b in 4 cases, and T2 in 4 cases. Three patients (2 with T1b tumors and 1 with a T2 tumor) were diagnosed with bulky tumors, and7patients(4witht1btumorsand3witht2tumors)showed AC involvement. Although the T stage at first was T2 or lower (T1a: 4, T1b: 4 and T2: 4), pathological T stages varied (Tis: 3, T1a: 2, T1b: 3, T2: 3; and T3: 1). The 5-year local control rates by initial radiotherapy were 92% in patients with T1a disease, 83% in patients with T1b disease, 86% in patients with T2 disease and 88% in patients with all T stage (Table 2, Fig.3). Of the 12 patients who developed local s, none died of the disease. Although we assessed the prognostic significance of T stage, tumor bulk and AC involvement, none of the factors were found to be significantly prognostic for local control (T stage: P = 0.47; tumor bulk: P = 0.93; and AC involvement: P = 0.25). Ultimate laryngeal preservation rates All the 12 patients who developed local s underwent salvage surgery for local control. At first, LMS was performed in 5 patients, VPL in 6 patients and supracricoid laryngectomy (SCL) in 1 patient. Of 5 patients salvaged by LMS, 2 patients subsequently experienced second. A 69-year-old male patient (Table 3, No.5) with second 47 months after LMS treatment was salvaged by VPL. A 71-year-old male patient (Table 3, No.10) who experienced at 20 months was treated with LMS. However, he had local relapse again 6 months after LMS and was successfully salvaged by total laryngectomy. Ultimately, larynx was preserved in 11 out of 12 patients who had local after initial radiotherapy and local was controlled in all cases. Thus, ultimate laryngeal preservation rate and local control rate of all cases (T1a, T1b, T2 and all T stage) were 100, 100, 97% and 99%, respectively Figure 2. Kaplan Meier curves for overall survival according to T stage. Figure 3. Kaplan Meier curves for local control according to T stage. Table 2. Outcomes of initial radiation therapy and salvage treatments in 115 patients with early-stage glottic cancer T stage Number of patients Radiation dose Gy (range) Radiation method Local control rate (%) Ultimate local control rate (%) Laryngeal preservation rate (%) T1a ( ) Once daily: 51 Twice daily: 3 T1b ( ) Once daily: 20 Twice daily: 6 T ( ) Once daily: 8 Twice daily:

5 252 Radiotherapy for early glottic cancer Table 3. Details of 12 patients who experienced a local Details of Salvage surgery Controlled periods (m) Pathological T stage at T stage at 1st Radiation dose (Gy) T stage of second Treatment policy ptis AC involvement pt4a Tumor bulk No. Gender Age Initial T stage 1 Male 71 T1a No No Once daily 66 T1a ptis 6 LMS 2 Male 66 T1a No No Once daily 70 T1a pt1a 14 LMS 3 Male 61 T1a No No Once daily 66 T1b pt1b 13 VPL 4 Male 69 T1a No No Once daily 66 T2 pt2 42 VPL 5 Male 69 T1b No Yes Once daily 70 T1a pt1a 11 LMS VPL At 47 months second 6 Male 58 T1b No Yes Once daily 70 T1b pt1b 13 LMS 7 Male 55 T1b Yes Yes Twice daily 75.6 T1b ptis 24 VPL 8 Male 61 T1b Yes Yes Once daily 70 T1b pt1b 36 VPL 9 Male 47 T2 Yes No Twice daily 74.4 T1a pt2 8 VPL 10 Male 71 T2 No Yes Twice daily 74.4 T2 pt2 20 LMS TL At 6 months second 11 Male 66 T2 No Yes Once daily 72 T2 ptis 32 VPL 12 Male 61 T2 No Yes Twice daily 74.4 T2 pt3 35 STL AC, anterior commissure; LMS, laser microsurgery; VPL, vertical partial laryngectomy; STL, subtotal laryngectomy; TL, total laryngectomy. Figure 4. Kaplan Meier curves for laryngeal preservation according to T stage. (Table 2, Fig. 4). Finally, overall laryngectomy-free survival rate was 99%. Tracheostomy was successfully closed in all the patients who had salvage surgery except one patient who had total laryngectomy. All the patients have normal diet without aspiration. Treatment-related complications Acute adverse events were evaluated according to the Common Terminology Criteria for Adverse Events version 3.0. Radiation mucositis was observed in 23 patients (Grade 2: 23), and radiation dermatitis was observed in 17 patients (Grade 2: 16, Grade 3: 1). All the patients who had Grade 3 dermatitis had undergone twice-daily fractionated radiotherapy as initial treatment. No significant late toxicity was observed. Regarding surgical complications, 2 (17%) of these patients experienced a minor complication (airway complication: 1, wound infection: 1). Discussion For SCC of the glottis, prospects of achieving local control with radiotherapy depend on both tumor-related and treatment-related factors. Among the tumor-related factors, AC involvement and tumor bulk are especially concerning because of their strong influences on the local control rate. For patients who have laryngeal cancer with AC involvement, the optimal methods of staging and treatment are debatable. Approximately 20% of all glottic cancers are reported to involve AC, while only 1% of these arise purely from AC (23). AC is attached to the thyroid cartilage, and AC involvement is considered as poor prognostic factor for radiotherapy outcomes. CT and magnetic resonance imaging criteria to optimize the diagnosis of thyroid cartilage invasion are still being assessed. Understaging or overstaging still occurs in 25 50% of cases (24 27). It is also important to note that AC involvement for T1 tumors includes several subtypes that are not accounted for in the TNM classification. Although partial laryngectomy has been preferred for a particular subset of patients (7,28), many reports have indicated the usefulness of radiotherapy (29,30). To our knowledge, no study has directly compared the efficacy of treatment modalities such as radiotherapy, open surgery or transoral LMS in cases with AC involvement. In a review, Bradley et al. (24) identified two studies that showed no influence of AC involvement on rates (31,32). However, most studies identified AC involvement as one of the poorest independent prognostic factors, as determined using

6 Jpn J Clin Oncol, 2015, Vol. 45, No Table 4. Treatment outcomes for T1 glottic cancer compared with previous reports Author Year reported Number Stage Radiation dose (Gy) 5-year local control (%) Ultimate local control rate (%) 5-year laryngeal preservation (%) Le (8) a T median 63 Thariat (9) b T1a T1b median 67 Yamazaki (10) c T1 60, 66 (2 Gy/Fr), , 63 (2.25 Gy/Fr) Reddy (42) d T1 small T1 bulky median 66 Present study T1a T1b median NA NA, not assessed; AJCC, American Joint Committee on Cancer; UICC, International Union Against Cancer. a AJCC 1992 classification. b UICC 2002 classification. c UICC d AJCC Table 5. Treatment outcomes for T2 glottic cancer compared with previous reports Author Year reported Number Stage Radiation dose (Gy) 5-year local control (%) Ultimate local control rate (%) 5-year laryngeal preservation (%) Lesnicar (13) a T Le (8) b T median, 65.2 Medini (14) b T Garden (15) c T NA median, 70 Thariat (9) d T NA 75 median, 67 Tateya (16) e T Present study T median, a UICC b AJCC 1992 classification. c Non-specific TNM d UICC 2002 classification. e AJCC multivariate analysis (33 41). They concluded that AC involvement is a predictor of poor response to radiotherapy in terms of local control, possibly because the treatment strategy was underpowered. In our series of patients, strategies for cases with AC involvement were carefully discussed from multidisciplinary perspective. In both T1 and T2 cases with AC involvement, more aggressive radiotherapeutic regimens were preferred as initial treatment to avoid total laryngectomy at. As a result of this individualized planning, satisfactory laryngeal preservation rate was achieved (Tables 4 and 5). In addition to AC involvement, tumor bulk also has an important influence on laryngeal cancer outcomes (11, 40, 42). Reddy et al. (11,42) demonstrated that, when using radiotherapy, the likelihood of achieving local control and preservation of laryngeal function is related to tumor volume. They investigated several factors affecting the local control achieved by radiotherapy in patients with T1 glottic cancer. In univariate analysis, Reddy et al. found that tumor bulk, AC involvement, treatment duration and fractional dose were significant prognostic factors. However, only tumor bulk remained significantly associated with local control in multivariate analysis. In our series, neither AC nor tumor bulk were identified as prognostic factors for local control. This could be explained by the more aggressive methods of radiotherapy that were applied to cases with AC involvement and/or tumor bulk, which may have improved the outcomes of these cases. There has been a great deal of discussion about the potential of optimized fractionation to improve the outcomes of radiotherapy, particularly against T2 glottic cancer. Burke et al. (17) reported an 80% local control rate for 10 cases of T2 glottic cancer with hyperfractionation in Fein et al. (18) also reported the effectiveness of hyperfractionation for T2 glottic cancer, obtaining a local control rate of 91% in 35 cases. Further, Parsons et al. (19) reported 93% local control rate after initial treatment of 28 T2 glottic cancers with hyperfractionation. Tateya et al. (16) also reported favorable results using this technique with 5-year laryngeal preservation rate of 95%, which was significantly better than that in our once-a-day radiation group. In 2003, Garden et al. (15) reported that twice-daily radiotherapy nearly significantly increased the local control rate from 68 to 79% among

7 254 Radiotherapy for early glottic cancer T2N0 patients (P = 0.06). In our series, 66% of patients with T2 glottic cancers were treated with hyperfractionation, resulting in a favorable local control rate of 86%. Thus, we will therefore continue our current strategy for early glottic cancers (Table 5). Moreover, our ultimate laryngeal preservation rate was quite satisfactory in comparison with previous studies. The laryngeal preservation was successfully preserved either by LMS, VPL or SCL in all the radiation-failure cases except one. These results again support the rationale for conservative surgery as a salvage surgery of irradiation failure in the treatment of early glottic cancers. In addition, we believe that this extremely high functional laryngeal preservation rate is a consequence of the careful follow-up by both radiation oncologists and head and neck surgeons after initial radiotherapy. Conclusions The selection of treatment for early glottic cancers with bulky volume or AC involvement should be based on the clinical, endoscopic and imaging findings of individual case. These findings provide the precise definition of the extent of individual cancer, resulting in an appropriate choice of therapeutic strategy. When radiotherapy is applied as initial treatments for early glottic cancers with bulky volume or AC involvement, hyperfractionated radiotherapy contributes to improve laryngeal preservation rates. Careful follow-up after initial radiotherapy is mandatory for early detection of radiation failure and for conservative salvage surgery. Additional study is necessary to clarify the efficacy of our multidisciplinary approach for early glottic laryngeal cancer. Conflict of interest statement None declared. References 1. Shaha AR, Shah JP. Carcinoma of the subglottic larynx. Am J Surg 1982;144: Mendenhall WM, Werning JW, Hinerman RW, Amdur RJ, Villaret DB. 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