Laryngeal cancer in Finland: A 5-year follow-up study of 366 patients

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1 ORIGINAL ARTICLE Laryngeal cancer in Finland: A 5-year follow-up study of 366 patients Aaro Haapaniemi, MD, 1 * Petri Koivunen, MD, PhD, 3 Kauko Saarilahti, MD, PhD, 7 Ilpo Kinnunen, MD, PhD, 5 Jussi Laranne, MD, PhD, 4 Leena-Maija Aaltonen, MD, PhD, 1 Mervi N arki o, MD, PhD, 2 Paula Lindholm, MD, PhD, 6 Reidar Grenman, MD, PhD, 5 Antti M akitie, MD, PhD, 1 Timo Atula, MD, PhD, 1 The Finnish Head and Neck Oncology Working Group 1 Department of Otorhinolaryngology, Head and Neck Surgery, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland, 2 Department of Otorhinolaryngology, Head and Neck Surgery, Kuopio University Hospital and University of Kuopio, Kuopio, Finland, 3 Department of Otorhinolaryngology, Head and Neck Surgery, Oulu University Hospital and University of Oulu, Oulu, Finland, 4 Department of Otorhinolaryngology, Head and Neck Surgery, Tampere University Hospital and University of Tampere, Tampere, Finland, 5 Department of Otorhinolaryngology, Head and Neck Surgery, Turku University Hospital and University of Turku, Turku, Finlan, 6 Department of Oncology, Turku University Hospital and University of Turku, Turku, Finland, 7 Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland. Accepted 30 June 2014 Published online 27 January 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to acquire nationwide data on the management and outcome of laryngeal squamous cell carcinoma (SCC) in Finnish university hospitals over a 5-year posttreatment follow-up. Methods. All records of patients diagnosed and treated for primary laryngeal SCC during 2001 to 2005 were reviewed. Results. Three hundred sixty-six patients with laryngeal cancer were identified, 360 of whom had laryngeal SCC. Three hundred forty-two patients with laryngeal SCC (95%) were treated with curative intent. Five-year disease-specific survival (DSS) for T1a, T1b, T2, T3, and T4 glottic SCC was 100%, 95%, 78%, 79%, and 53%, respectively. The corresponding figures for T1 to T4 supraglottic SCC were 68%, 54%, 72%, and 59%. Conclusion. Results of this nationwide study give a general overview of the outcome of unselected patients treated with unified guidelines. Patients with T2 tumors, usually treated with radiotherapy (RT), had a worse prognosis than expected. This patient group warrants further investigation and possibly treatment intensification. VC 2015 Wiley Periodicals, Inc. Head Neck 38: 36 43, 2016 KEY WORDS: larynx, carcinoma, treatment outcome, recurrence, chemoradiotherapy INTRODUCTION The incidence of laryngeal squamous cell carcinoma (SCC) in male populations worldwide has declined over the last decades, whereas the incidence in female populations has remained constant. A recent report based on the laryngeal cancer data of the NORDCAN database showed the same incidence trend for both sexes in the Nordic countries during 1964 to The age-adjusted incidence rate of laryngeal SCC in Finland per 100,000 persons/year in 2010 was 2.2 for men and 0.3 for women, with corresponding figures of 6.9 and 0.3 during 1962 to 1966, according to the Finnish Cancer Database (www. cancerregistry.fi/statistics). According to reports based on the National Cancer Database, the survival of patients with laryngeal SCC in the United States is declining. 2,3 Some have attributed this to the simultaneous increase in the use of organ preservation strategies in the treatment of advanced laryngeal *Corresponding author: A. Haapaniemi, Department of Otolaryngology Head and Neck Surgery, Helsinki University Central Hospital, Haartmaninkatu 4 E (P.O. Box 220), HUS, Helsinki, Finland. aaro.haapaniemi@hus.fi Contract grant sponsor: This research has received financial support from the Helsinki University Central Hospital Research Funds, the Finnish Foundation for Otolaryngological Research, and the Finnish Medical Foundation. SCC. In the Nordic countries, however, a slight improvement in treatment outcome has been observed over the last decades. 1 Laryngeal SCC comprises a heterogeneous group of tumors of the glottic, supraglottic, and, rarely, subglottic regions, each with distinct characteristics of local spread, metastatic potential, and treatment outcome. Various treatment approaches with fairly similar oncologic outcome have been presented in the literature. Early glottic cancers (ie, T1 and T2 tumors) are treated either by transoral laser surgery (TLS) or radiotherapy (RT) with comparable results More recently, concurrent chemoradiotherapy (CRT) has also become an option for T2 tumors in an attempt to improve local control. 11 Partial resection of the larynx, either by open technique or by TLS, especially for supraglottic tumors, has been advocated in some centers with results comparable to oncologic treatment. 4,5 In advanced lesions, CRT is gaining ground as the mainstay of treatment; outcome results are comparable to total laryngectomy Although these organ-sparing oncologic treatment strategies are widely replacing surgery, total laryngectomy still holds a place in treatment of the most advanced tumors and recurrent disease. The majority of patients with laryngeal SCC in Finland are treated at university hospitals according to national treatment guidelines. Based on the slight improvement of treatment outcome in the Nordic countries, in contrast to 36 HEAD & NECK DOI /HED JANUARY 2016

2 LARYNGEAL CANCER IN FINLAND Finland. Survival rates, the 5-year overall survival (OS), and disease-specific survival (DSS), were calculated using the Kaplan Meier product limit estimate. Disease-free survival (DFS) was calculated from the completion of treatment to the detection of cancer recurrence or death caused by laryngeal cancer. All statistics were calculated with the SPSS statistical package v. 16 (IBM Corporation, Armonk, NY). The Research Ethics Committee at the Helsinki University Central Hospital approved this study. Because of the study design (retrospective chart review), no informed consent was necessary, according to the Finnish Law. FIGURE 1. Overall survival of all patients with laryngeal squamous cell carcinoma treated with curative intent (n 5 342). the National Cancer Database data, the purpose of this study was to assess in detail patient characteristics, contemporary treatment approaches, and treatment outcome of laryngeal SCC in the era of organ-sparing oncologic treatment in Finland. We present a nationwide series of unselected, consecutive patients with laryngeal cancer treated at the 5 Finnish university hospitals in 2001 to 2005 over a 5-year posttreatment follow-up. PATIENTS AND METHODS Clinicopathologic data of patients primarily diagnosed and treated for invasive laryngeal cancer at the 5 Finnish university hospitals between January 1, 2001, and December 31, 2005, were extracted from hospital tumor and pathology registries. The time frame was chosen in order to achieve a minimum follow-up of 5 years. Subsequent data of patients followed up at regional hospitals after primary treatment at a university hospital were also included. However, patients with in situ malignancies were excluded. The study group comprised 366 patients (338 men and 28 women; mean age, 64.7 years; range, years). Laryngeal SCC or its histological variant was found in 360 patients (98%). Other histologies (n 5 6) included adenoid cystic carcinoma, sarcoma, mucoepidermoid carcinoma, and undifferentiated carcinoma. Only patients with laryngeal SCC were included in the final analysis. Hospital records were reviewed for details on age, sex, previous malignancies, World Health Organization performance status, tumor histology, histopathologic grade of differentiation, TNM classification, stage, intention of initial treatment (curative or palliative), indication for combined treatment when given (planned or salvage), details on surgical treatment, RT and chemotherapy, pathological TNM (in case of surgery), tumor recurrence, treatment of recurrent disease, and status at last follow-up. All patients had a minimum follow-up of 5 years. The dates and causes of death were provided by Statistics RESULTS Three hundred sixty patients with laryngeal SCC were identified, 8 (2%) of whom had histological variants of SCC. The site of the primary tumor was glottic in 253 patients (70%), supraglottic in 89 (25%), subglottic in 5 (1%), and undefinable origin (ie, transglottic) in 13 (4%). The stage distribution for glottic laryngeal SCC was as follows: stage I, 114 (45%); stage II, 61 (24%); stage III, 44 (18%); and stage IV, 34 (13%). The corresponding figures for supraglottic laryngeal SCCs were stage I, 7 (8%); stage II, 13 (15%); stage III, 26 (29%); and stage IV, 43 (48%). The transglottic tumors were of stage III in 4 cases (31%) and stage IV in 9 cases (69%). In subglottic tumors, the stage was II in 1 case, stage III in 3, and stage IV in 1 case. Treatment with curative intent was given to 342 patients (95%). The 5-year OS (Figures 1 and 2), DSS, and DFS for all patients treated with curative intent were 63%, 80%, and 76%, respectively. For the sake of clarity, detailed patient characteristics and treatment results for patients treated with curative intent are presented separately for T1 to T2 and T3 to T4 tumors. Details on oncologic treatment for both groups are presented in a separate section. FIGURE 2. Overall survival of all patients with laryngeal squamous cell carcinoma treated with curative intent according to tumor site (n 5 342). HEAD & NECK DOI /HED JANUARY

3 HAAPANIEMI ET AL. TABLE 1. Curatively intended treatment and outcome of laryngeal squamous cell carcinoma according to localization and T classification. Glottic Supraglottic Transglottic Subglottic T1a T1b T2 T3 T4 T1 T2 T3 T4 T3 T4 T2 T4 Primary treatment, no. of patients (%) RT 33 (36) 16 (73) 48 (77) 10 (22) 3 (13) 4 (40) 6 (25) 4 (14) 1 (5) 2 (50) CRT 4 (7) 18 (40) 6 (26) 6 (25) 10 (36) 8 (36) 2 (20) Surgery 52 (57) 4 (18) 3 (5) 6 (13) 2 (9) 2 (20) 1 (4) 2 (7) 2 (9) 1 (10) Combined* 7 (8) 2 (9) 7 (11) 11 (25) 12 (52) 4 (40) 11 (46) 12 (43) 11 (50) 7 (70) 2 (50) Outcome, % 5-y OS y DSS y DFS Abbreviations: RT, radiotherapy; CRT, chemoradiotherapy; OS, overall survival; DSS, disease-specific survival; DFS, disease-free survival. * Surgery preceded or followed by radiotherapy or radiochemotherapy, including primary phase salvage treatment. Empty space means absence of cases in that category. T1 to T2 tumors Of all patients treated with curative intent, 211 were classified as T1 or T2 (62%). The T classifications for early glottic laryngeal SCCs were as follows: T1a, 92 (38% of all glottic tumors); T1b, 22 (9%); and T2, 62 (25%). For early supraglottic laryngeal SCCs, the classification was T1 in 10 patients (12% of all supraglottic tumors) and T2 in 24 patients (29%). One subglottic tumor was classified as T2. Neck metastasis was absent in T1 glottic patients and was observed in only 3 glottic T2 patients (5%). Neck metastasis was more common in supraglottic laryngeal SCC: 3 T1 patients (30%) and 13 T2 patients (54%) had neck metastasis at presentation. Treatment with curative intent was given to 98% (211 of 216 patients) of all T1 to T2 patients. Glottic T1a tumors were mainly treated with laser resection alone (57%; 52 of 92). Initially unplanned combination treatment (ie, salvage surgery for tumors persisting after RT or postoperative RT for close surgical margins), was given to 7 patients (8%) in this group. Patients with glottic T1b and T2 tumors mainly received RT with or without chemotherapy (73% and 84%). Supraglottic T1 and T2 tumors were mainly treated with RT or CRT or a combination of surgery and oncologic treatment. As a primary surgical procedure, TLS was performed on 65 T1 patients (52%) and 11 T2 patients (13%). Open partial resection was rare, with only 2 procedures in the whole series. Six patients underwent total laryngectomy, 3 of which were performed for patients with persistent tumors after primary oncologic treatment. Altogether, salvage total laryngectomy for tumor persistence or later recurrence after oncologic treatment was required for 14% of patients (15 of 108) who had primary RT and 30% of patients (3 of 10) who had primary CRT. Neck dissection, including salvage neck dissection, was performed on 4 of the 62 glottic T2 patients (6%), 2 with clinically N0 nodal status. No neck dissection was performed to T1 glottic patients. For supraglottic T1 to T2 patients, neck dissection was performed on 11 patients (32%), 1 of whom had a clinically negative nodal status. Data on treatment results by T classification and overall stage are presented in Tables 1 and 2. Kaplan Meier survival curves are presented in Figures 1 through 6. No tumor persistence after primary treatment (including salvage surgery) was observed in these patients. Disease recurrence was observed in 16 T1 glottic patients (14%) and 20 T2 glottic patients (32%). In supraglottic patients with laryngeal SCC, tumor persistence or recurrence was observed in 2 T1 patients (20%) and 10 T2 patients (42%). Data on second primary tumors was available for 172 patients (82%), of which 19 developed second primary tumors during follow-up (11%). TABLE 2. Outcome of curatively intended treatment of glottic and supraglottic laryngeal squamous cell carcinoma according to stage. Glottic SCC Outcome, % Stage I (n 5 114) Stage II (n 5 59) Stage III (n 5 42) Stage Iva (n 5 26) Stage IVb (n 5 3) 5-y OS y DSS y DFS Supraglottic SCC Outcome, % Stage I (n 5 7) Stage II (n 5 13) Stage III (n 5 25) Stage Iva (n 5 37) Stage IVb (n 5 2) 5-y OS y DSS y DFS Abbreviations: SCC, squamous cell carcinoma; OS, overall survival; DSS, disease-specific survival; DFS, disease-free survival. 38 HEAD & NECK DOI /HED JANUARY 2016

4 LARYNGEAL CANCER IN FINLAND FIGURE 3. Disease-specific survival of patients with glottic laryngeal squamous cell carcinoma treated with curative intent according to T classification (n 5 244). FIGURE 5. Disease-specific survival of patients with glottic laryngeal squamous cell carcinoma treated with curative intent according to stage (n 5 244). T3 to T4 tumors Advanced laryngeal SCC (T3 or T4) was observed in 131 patients (38%) treated with curative intent. The T classifications for advanced glottic laryngeal SCCs were as follows: T3, 45 (18% of all glottic tumors) and T4, 23 (9%). For advanced supraglottic laryngeal SCCs, the classifications were T3 in 28 patients (33% of all supraglottic tumors) and T4 in 22 patients (26%). All transglottic laryngeal SCCs were of advanced T classification: T3, 3; and T4, 7. Three of the 4 subglottic laryngeal SCCs were of advanced class: T3, 2; and T4, 1. Neck metastasis was observed in 9 patients with T3 (20%) and 9 patients with T4 (39%) glottic laryngeal SCC. The metastasis rate was somewhat higher in the supraglottic group: 14 T3 patients (50%) and 14 T4 patients (63%) had nodal metastasis at presentation. In the transglottic group, neck metastasis was observed in 2 of 10 patients (20%). In the rare subglottic tumors, neck metastasis was absent. Treatment with curative intent was given to 91% of all T3 to T4 patients (131 of 144). Glottic T3 tumors mainly received RT with or without chemotherapy (73%). For T4 glottic tumors, a combined treatment approach of total FIGURE 4. Disease-specific survival of patients with supraglottic laryngeal squamous cell carcinoma treated with curative intent according to T classification (n 5 84). FIGURE 6. Disease-specific survival of patients with supraglottic laryngeal squamous cell carcinoma treated with curative intent according to stage (n 5 84). HEAD & NECK DOI /HED JANUARY

5 HAAPANIEMI ET AL. laryngectomy preceded or followed by RT with or without chemotherapy was mainly given (52%). Six patients with T4 glottic laryngeal SCC were treated with CRT, although this was not the treatment recommended for this group of patients in the national protocol. Only 1 of these patients was disease-free at the end of follow-up, 4 had died of laryngeal cancer, and 1 had died of another cause with a persistent tumor in the larynx. Advanced supraglottic tumors were most often treated with a combination of surgery and oncologic treatment, accounting for 43% and 50% of T3 and T4 tumors, respectively. Surgery alone as the primary treatment was rare. CRT as the primary treatment was used for 36% of T3 and 36% of T4 patients. Seven of 10 patients with transglottic tumors were treated with total laryngectomy combined with oncologic treatment. The 3 patients with subglottic SCC were treated with either RT (n 5 1) or a combination of total laryngectomy and postoperative RT (n 5 2). Sixty-six T3 to T4 patients (50%) had surgery in the primary treatment phase. Surgery consisted of total laryngectomy in 65 patients and laryngopharyngectomy in 1 patient. Total laryngectomy as the only treatment modality was performed on 13 patients. Combined modality treatment of surgery preceded or followed by RT with or without chemotherapy was given to 52 patients, including 2 patients who underwent salvage total laryngectomy for unsuccessful oncologic treatment and 4 patients who received postoperative oncologic treatment because of inadequate surgical margins. Salvage total laryngectomy for tumor persistence or later recurrence after oncologic treatment was required for 11% of patients (2 of 19) with primary RT and 16% of patients (7 of 44) with primary CRT. Neck dissection, including salvage neck dissection, was performed on 13 of 68 patients with glottic T3 to T4 tumors (19%), 5 of whom had a clinically negative nodal status. Twenty of 50 supraglottic T3 to T4 tumor patients (40%) underwent neck dissection, 6 of whom had a negative nodal status. Of the 3 subglottic T3 to T4 tumors, 2 underwent elective neck dissection. Two of 10 patients with transglottic T3 to T4 tumors underwent neck dissection. Disease persistence or recurrence after primary treatment was observed in 18 patients with glottic T3 tumors (40%) and 5 patients with glottic T4 tumors (22%). In patients with supraglottic laryngeal SCC, disease persistence or recurrence was observed in 6 T3 patients (21%) and 5 T4 patients (23%). Data on second primary tumors was available for 111 patients (84%), of which 12 developed second primary tumors during follow-up (11%). Radiotherapy and chemoradiotherapy Two hundred sixty-seven patients (78%) had primary RT or CRT either combined with surgery or as definitive treatment modality. One hundred twenty-seven patients were treated with RT alone, 54 with definitive CRT, and 58 with surgery followed by RT (n 5 56) or CRT (n 5 2). Twenty-eight patients received either preoperative RT (n 5 21) or CRT (n 5 7). In patients treated by postoperative RT, the median time from operation to RT was 55 days (range, days). The RT technique was conformal 3D RT in 249 patients and intensity-modulated RT (IMRT) in 18 patients. In all patients, the dose planning was performed with a CT-based RT treatmentplanning program. Sixteen patients were treated by hyperfractionated RT given twice daily and the remaining 251 patients by conventional fractionation at 2 Gy fractions given 5 times a week. In definitive RT, T1 to T2 glottic tumors were treated from 2 lateral laryngeal fields. In T3 to T4 glottic tumors also the locoregional nodal areas were irradiated. In supraglottic tumors, nodal irradiation was also given to T1 to T2 tumors because of the higher probability of nodal metastasis than in glottic tumors. In definitive RT, the median prescribed dose for macroscopic tumor was 66 Gy (range, Gy) in T1 tumors and 68 Gy (range, Gy) in T2 to T4 tumors. The median dose in nodal irradiation (n 5 42) was 50 Gy (range, Gy), the dose depending on the observed severity of nodal disease. In CRT, the median prescribed dose for macroscopic tumor was 66 Gy (range, Gy) and for elective nodal areas 50 Gy (range, Gy). In postoperative RT, the median planned dose for the laryngeal surgical area was 58 Gy (range, Gy) and for the nodal areas 50 Gy (range, Gy), with dose depending on the radicality of surgery and the extent of primary tumor and nodal disease. In preoperative RT and CRT, the median planned dose for macroscopic tumor was 66 Gy (range, Gy) and for nodal areas 50 Gy (range, Gy). In 16 patients, the RT course was interrupted because of the patient s death or deterioration of general status, the remaining 251 patients received the RT as prescribed. The mean total treatment time was 45 days. Fifty patients had a treatment gap during the RT course. In 8 patients, the gap was planned because of national holidays and in 42 the gap was unplanned. The mean duration of the treatment gap was 5 days. The concomitant chemotherapy agent used during the RT course was cisplatin in 62 patients, mitomycin in 1 patient, and cisplatin together with gefitinib in 1 patient. Cisplatin was given either as 20 to 40 mg/m 2 weekly infusions or as higher 60 to 100 mg/m 2 doses every third week during the RT. Concomitant chemotherapy was given as planned in 39 patients. In 22 patients, the chemotherapy was either interrupted or altered because of treatment-related side effects. For 2 patients, the data were missing. Palliative treatment Eighteen patients (5% of the laryngeal SCC group) with stage II to IVc disease (9 glottic, 5 supraglottic, 1 subglottic, and 3 transglottic tumors) received palliative treatment because of advanced disease or poor general condition. Two patients received RT, 1 had RT with palliative surgery and 1 had CRT. The median length of survival for this group of patients was 2.2 months. DISCUSSION In Finland, the treatment of head and neck malignancies, including laryngeal cancer, is centralized to the 5 university hospitals. All patients are managed according to common treatment guidelines set and updated by the 40 HEAD & NECK DOI /HED JANUARY 2016

6 LARYNGEAL CANCER IN FINLAND Finnish Head and Neck Oncology Working Group. These guidelines and their clinical application are similar to the practices in other Nordic countries. This study achieves the purpose of providing population-based information on the management and outcome of laryngeal SCC in Finland. All patients were reviewed and classified before treatment by the respective multidisciplinary head and neck tumor boards at the university hospitals. The treatment results for laryngeal SCCs are in line with results reported in previous studies. Patients with glottic T1a tumors had an excellent outcome. However, glottic and supraglottic T2 tumors had unexpectedly inferior results relative to the other T classifications, although our results compare favorably with other cohort-type data. 3 This study suffered from a few shortcomings. Despite centralization of the treatment of head and neck malignancies, only 67% of all cases of laryngeal SCC reported to the Finnish Cancer Database during 2001 to 2005 were included in this study. This is due to patients with laryngeal cancer also being managed in some larger nonuniversity public hospitals that follow the same national guidelines. However, because of the even geographic distribution of the 5 university hospitals in Finland, this material can be expected to depict the Finnish population as a whole. The retrospective nature of the study prevents a feasible comparison between different treatment modalities. On the other hand, this material reflects the state and results of the practical implementation of the Finnish treatment protocol. An ongoing randomized controlled study on voice quality outcome in the treatment of patients with T1a glottic carcinoma may have had a limited effect on the usual treatment decision-making in some cases (n 5 31; 34% of all T1a patients in the current study). In line with international studies, the majority of the tumors in this time period were glottic (70%), which has been the trend also in Finland after the 1960s, when supraglottic laryngeal SCC dominated the incidence statistics (65%). 15 The glottic tumors in our study were mainly classified as T1 or T2 (71%). In general, glottic tumors presented in an early stage, whereas supraglottic tumors were more advanced at presentation. Some tumors were impossible to categorize according to the site of origin because of their destructive and transglottic nature and were thus categorized as undefinable. Subglottic tumors were rare, as expected from previous reports. 16,17 Neck metastases were seldom seen in early glottic SCC, whereas even in T1 supraglottic SCC, the metastasis rate was 30%, increasing with T classification. Both TLS and RT have been widely accepted as the primary treatment for T1 glottic laryngeal SCC. The main challenge has shifted from achieving optimal local control to maintaining/improving quality of voice, as both TLS and RT have proven to provide excellent and comparable survival results. In the current study, T1a tumors were treated with either TLS or RT, whereas T1b patients received mostly RT. Seven patients in the glottic T1a laryngeal SCC group received combined treatment. In this small patient group, combined treatment was not an initially planned modality, but rather used for tumors persisting after RT or tumors with involved margins after repeated surgery. No difference in survival between TLS and RT groups was detected. The 5-year DSS of 99% and the laryngeal preservation rate of 96% compare well with results reported in previous studies. 9,18 20 In some studies, RT has been postulated to result in inferior organ preservation relative to TLS. 19,20 We also noted a significantly better organ preservation with TLS than with RT. However, clinical tumor and patient characteristics tend to weigh in with the choice between RT and TLS, making selection bias inevitable and rendering this observation as merely descriptive in nature. No significant difference in local recurrence between these treatment groups was observed. As opposed to T1 tumors, T2 glottic laryngeal SCCs had an unexpectedly poor outcome, with a 5-year DSS of 78%, similar to that of the T3 group (79%). Regarding the supraglottic tumors, the results were even worse; patients with T2 tumors had the lowest 5-year DSS (54%) for the whole subsite. The reasons for these poor outcome results remain unclear. Although the incidence of nodal metastasis in the supraglottic T2 group was high (50%), this incidence was consistent with the incidence in T3 and T4 tumors (47% and 61%, respectively). In glottic tumors, the metastasis rate in T2 tumors was low (5%). One explanation for the inferior treatment outcome may be the difficulty in distinguishing between T2 and T3 glottic tumors (ie, misdiagnosis regardless of modern imaging), leading to possible understaging and undertreatment in some cases. It is noteworthy that most of the patients in the current series with T2 tumors received RT or CRT as their primary treatment, 84% and 50% of the glottic and supraglottic T2 patients, respectively. The lack of surgery in these groups, especially the nearly complete absence of open partial resection, may have had an effect on outcome. Excellent outcomes have, however, been reported with various surgical and oncologic treatment approaches in this patient group. In contrast to our results, Peretti et al 4 reported a series of patients with glottic carcinoma treated with TLS with a 5-year DSS of 98% and laryngeal preservation rate of 95% for the subgroup of 109 T2 patients. A retrospective review on supracricoid partial laryngectomy from the University of Pennsylvania presented 35 patients with primary or recurrent T2 laryngeal SCC with an excellent 5-year DSS of 95% for patients treated for primary tumors and 100% for patients treated for radiorecurrent laryngeal SCC. 21 Frata et al 8 described a 5-year DSS of 86% and a local control rate of 73% in a series of 256 glottic T2 patients treated with RT. In studies from Japan, the addition of chemotherapy to RT was seen to improve local control and laryngeal preservation rates, with an excellent (95% to 100%) 5- year DSS with CRT. Because of the relatively small number of patients receiving CRT in our material, such a comparison could not be made. The aforementioned selective patient series have excellent results. These studies may, however, be prone to some degree of selection bias; a more feasible comparison has been made with cohort-type studies. 3 At present, IMRT has replaced conventional 3Dconformal RT in modern treatment protocols in Finland. Our study was, however, conducted in the transition period from conventional RT to IMRT. The majority of HEAD & NECK DOI /HED JANUARY

7 HAAPANIEMI ET AL. our patients were treated with conventional RT; only 18 patients received IMRT. In the literature, IMRT has been shown to produce equal or better oncologic results, with less adverse effects. 22 Cisplatinum is the chemotherapeutic agent of choice for head and neck carcinoma CRT. In our current protocol, cisplatinum is administered in weekly infusions of 40 mg/m 2. This is due to the observation of a lower incidence of side effects and equal oncologic results with weekly, smaller doses relative to higher doses administered every third week During the time frame of our study, a prospective study on the use of mitomycin in CRT was conducted. 26 No induction chemotherapy is used in Finland. The treatment of advanced laryngeal SCC has evolved over the last decades. The advent of CRT in the treatment of these tumors has shifted management from surgery to organ-sparing oncologic treatment. This change has been the subject of debate because the treatment results in some T classifications of advanced laryngeal SCCs seem to be deteriorating Unfortunately, randomized controlled trials comparing surgery followed by postoperative RT with primary CRT are few, 13,14 and modern ethical standards prevent carrying out further such studies. The results of the current study are in line with those reported in the recent literature. Mantsopoulos et al 30 described a 78% 5-year DSS and a 54% 5-year OS for 120 patients with glottic T3 tumors who had undergone primary surgical therapy. A 5-year OS of 49% was reported by Al- Mamgani et al 31 for 170 patients with T3 laryngeal SCC treated with RT with or without chemotherapy. In their study, the addition of chemotherapy was the only significant predictor of local control. A retrospective series of 223 patients with T3 to T4 laryngeal SCC by Nguyen Tan et al 32 showed a 5-year OS of 48% and a causespecific survival of 64%. Vilaseca et al 33 presented a 5- year DSS of 86% for glottic and 62% for supraglottic T3 laryngeal SCCs treated with TLS. A recent German study reported similar results for 266 T3 patients treated with primary TLS, with 83% and 84% 5-year DSS for glottic and supraglottic laryngeal SCC, respectively. 34 Although total laryngectomy with postoperative RT has been thought to be the treatment of choice for large-volume T4 laryngeal SCC, some have postulated the feasibility of CRT in this group as well. 35 According to the Finnish treatment protocol, 30 CRT is the preferred treatment for T3 laryngeal SCC and is also suitable for T4 supraglottic SCC. In our series, 6 sporadic patients with glottic T4 laryngeal SCC were treated with CRT, with disappointing results. The DSS for both advanced glottic and supraglottic laryngeal SCCs in our series was similar, with T4 tumors having an inferior outcome relative to T3 tumors. However, no apparent difference was noted in DSS between the glottic and supraglottic groups. Recently, new techniques, such as transoral robotic surgery, have been introduced in the field of laryngeal conservation surgery. 36 Although only short follow-ups are currently available, the results are encouraging. Palliative treatment of laryngeal SCC is rarely mentioned in studies reporting oncologic results in head and neck carcinoma. Only 18 patients in our series were given palliative treatment, 4 of whom were scheduled for RT, CRT, or surgery. The prognosis in this group was dire, with a median survival of only 2.2 months. A recent work by Yu et al 37 addresses the natural course of laryngeal SCC in a cohort of patients who had not received therapy for their cancer for financial or other reasons. In their study, the median OS time for all patients with laryngeal SCC after diagnosis was 16 months. The shorter survival time in our study is explained by these patients forming a highly selected 5% subgroup of the whole patient population that was beyond the reach of curative or even reasonable palliative therapies. CONCLUSIONS Nationwide series on laryngeal SCC are rare in the literature and give valuable feedback on the feasibility of the use of unified treatment guidelines in the everyday setting. Our unselected series showed that a high percentage of patients with laryngeal SCC could be treated with an initial curative intent. CRT has gained ground as the treatment of choice in many classes of advanced laryngeal cancer, excluding glottic T4 cancer, in Finland. The treatment results in this study are in line with previous publications, although T2 tumors in both glottic and supraglottic groups were found to have an unexpectedly inferior DSS. This finding warrants further studies regarding possible treatment intensification in this group of patients in Finland. Acknowledgment The authors thank our colleagues at Finnish central hospitals outside the university hospitals who provided us with essential follow-up data on several patients. REFERENCES 1. Hakulinen T, Engholm G, Gislum M, et al. Trends in the survival of patients diagnosed with cancers in the respiratory system in the Nordic countries followed up to the end of Acta Oncol 2010;49: Siegel R, Naishadham D, Jemal A. Cancer statistics, CA Cancer J Clin 2013;63: Hoffman HT, Porter K, Karnell LH, et al. Laryngeal cancer in the United States: changes in demographics, patterns of care, and survival. Laryngoscope 2006;116(9 Pt 2 Suppl): Peretti G, Piazza C, Cocco D, et al. Transoral CO(2) laser treatment for T(is)-T(3) glottic cancer: the University of Brescia experience on 595 patients. Head Neck 2010;32: Peretti G, Piazza C, Ansarin M, et al. Transoral CO2 laser microsurgery for Tis-T3 supraglottic squamous cell carcinomas. 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