Int J Clin Oncol DOI 10.1007/s10147-015-0805-8
ORIGINAL ARTICLE
Treatment outcomes of external‑beam radiotherapy for squamous cell carcinoma of the base of the tongue Yoshifumi Kawaguchi · Kinji Nishiyama · Takerou Hirata · Kouji Konishi · Shinji Otozai · Motoyuki Suzuki · Tadashi Yoshii · Takashi Fujii · Teruki Teshima
Received: 9 October 2014 / Accepted: 12 February 2015 © Japan Society of Clinical Oncology 2015
Abstract Purpose To evaluate definitive external-beam radiotherapy (EBRT) for patients with base of the tongue (BOT) cancers. Methods We reviewed results for 26 patients with BOT cancers who were treated with EBRT. Clinical stages T1, T2, T3, and T4a were observed for 10, 7, 4, and 5 patients, respectively, and stages N0, N1, N2a, N2b, N2c, and N3 were observed for 4, 2, 5, 6, 8, and 1 patients, respectively. More than half of the patients (n = 19) were stage IVA. Standard total delivered doses were 70 Gy to primary tumors and cervical lymph node (CLN) metastases and 40–46 Gy to elective nodal regions. Eleven patients with advanced loco-regional disease received concurrent or neoadjuvant chemotherapy. Four T3 patients and one T2 patient received 2 or 3 cycles of concurrent intra-arterial cisplatin with EBRT (RADPLAT). Results Three-year overall survival was 69 % (95 % CI 47–83 %), with a median follow-up period of 33 months. Three-year local control was 100, 86, 100, and 20 % for T1, T2, T3, and T4 patients, respectively. Three-year regional control was 100 % for N0, N1, and N2a, 83 % for N2b, 75 % for N2c, and 0 % for N3 patients. Treatment failed for
Y. Kawaguchi (*) · T. Hirata · K. Konishi · T. Teshima Department of Radiation Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 3‑3, Nakamichi 1‑chome, Higashinari‑ku, Osaka 537‑8511, Japan e-mail: kawaguti‑[email protected] K. Nishiyama Department of Radiology, Yao Municipal Hospital, Osaka, Japan S. Otozai · M. Suzuki · T. Yoshii · T. Fujii Department of Head and Neck Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
7 patients. All 5 patients undergoing RADPLAT achieved complete responses and did not develop local recurrence. Conclusions We achieved favorable outcomes for patients with T1–T3 BOT cancers by use of definitive EBRT with or without chemotherapy. Keywords Base of tongue cancer · External-beam radiotherapy · Intra-arterial chemotherapy · Organ preservation
Introduction Base of tongue (BOT) cancers are relatively rare among head and neck cancers. According to a 2008 annual report from the Osaka, Japan, cancer registry, 25 patients were newly diagnosed with BOT cancer during that year, corresponding to 2 % of all patients with head and neck cancer (n = 1251) and 0.06 % of all patients with any type of cancer [1]. Hence, among treatment options, for example surgical resection (with or without postoperative radiotherapy, RT) and external-beam RT (EBRT) with or without concurrent chemotherapy, the optimum method of treatment has yet to be established. BOT cancers are frequently asymptomatic until they reach an advanced stage. Moreover, these tumors often extend across the midline, and bilateral lymph node metastases are frequently found. Therefore, many patients are diagnosed at advanced stages with cervical lymph node (CLN) metastases. Surgery for advanced BOT cancer usually involves wide resection. Some patients undergo not only glossectomy but also partial or total laryngectomy, resulting in severe speech and swallowing disorders [2]. RT can preserve the functions of these organs and is, therefore, an important therapeutic modality. However, some published data have suggested that RT alone
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yields poor outcomes for patients with locally advanced BOT cancer [3, 4]. Chemoradiotherapy (CRT) was introduced to increase the response and survival of advanced head and neck cancers, and its efficacy was proved during prospective randomized trials [5–7]. RT with concurrent intra-arterial cisplatin (RADPLAT) was also developed to enhance the effects of chemotherapeutic agents. Recently, a single-institution study reported improved tumor response and survival with RADPLAT for oropharyngeal cancers [8–10]. Thus, a variety of RT approaches are available. The results, however, have not been widely published in the medical literature, mainly because of the low prevalence of BOT cancers. In this study, we analyzed treatment outcomes of definitive EBRT, including RADPLAT, for BOT cancers.
Methods and materials Between 1995 and 2009, 37 patients with BOT squamous cell carcinoma underwent definitive RT at our institution. During this period, 11 patients received boost interstitial brachytherapy. These patients were excluded from our study, because the treatment outcomes after boost interstitial brachytherapy might differ substantially from those Table 1 Patient characteristics Characteristic
No. of patients (n = 26)
Gender Male Female Age (years) Median (range) Follow-up time (months) Median (range) Stage I II III IVA
22 4 63 (50–85) 33 (5–114) 2 1 3 19
IVB
Table 2 Stage distribution by T and N classification
13
1
T classification
after definitive EBRT. The remaining 26 patients without distant metastases were the subjects of this study. Each patient was evaluated during a joint conference of head and neck surgeons and radiation oncologists before treatment. Basically, we performed definitive EBRT for earlystage disease, surgery with or without postoperative RT for locally advanced disease, and systemic CRT for unresectable advanced disease. After 2007, we implemented RADPLAT for locally advanced cases to avoid severe speech and swallowing disorders caused by surgery. Table 1 lists the patients’ characteristics. The median age was 63 years (range 50–85 years). Of the 26 patients, 22 were men and 4 were women. Four patients had a history of metachronous cancers that were controlled at the time of treatment. Two patients had synchronous cancers (laryngeal cancer cT1aN0M0 for one and hypopharyngeal cancer cT2N2bM0 for the other) that were successfully treated with RT. Before treatment, all patients were evaluated by physical examination, laryngoscopy, chest X-ray, and computed tomography (CT) of the head and neck. Magnetic resonance imaging (MRI) was performed to assess invasion of the deep muscles of the tongue for locally advanced cases. In accordance with the International Union Against Cancer 2002 classification, the patients were classified by clinical stages as follows: stage I: 2, stage II: 1, stage III: 3, stage IVA:1 9, and stage IVB: 1 patient (Table 2). Patients were immobilized in custom masks and underwent CT-based planning. The gross tumor volume (GTV) was defined as all gross disease. The elective neck nodal areas usually included bilateral levels II, III, and IV and the retropharyngeal nodes. For patients with tumor invasion of the deep muscles of the tongue, level I nodes were included in the elective nodal areas. RT was delivered by use of 4-MV photon beams in once-daily doses of 2 Gy, 5 days per week. Typically, the primary tumor and upper neck were irradiated by use of opposed lateral fields and the lower neck by use of an anterior field. Subsequently, boost irradiation was delivered to GTV. The standard dose schedule was: 40–46 Gy to GTV and elective neck nodal areas and a boost of up to 70 Gy to GTV while shielding the spinal cord. Neck dissection (ND) before RT was undertaken for 2 patients with advanced nodal metastases.
N classification N0
N1
N2a
N2b
N2c
N3
Total
T1 T2 T3 T4a
2 1 1 0
2 0 0 0
2 3 0 0
3 2 1 0
1 1 2 4
0 0 0 1
10 7 4 5
Total
4
2
5
6
8
1
26
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One patient underwent level II lymph node resection for a primary unknown metastasis at another institution. The other patient underwent lateral ND (levels II–V). Induction or concurrent chemotherapy was used for unresectable loco-regionally advanced disease until 2006. Induction chemotherapy was indicated for patients with unresectable tumors that were considered resectable if they responded to induction chemotherapy. Induction chemotherapy with cisplatin plus 5-fluorouracil was administered to 2 patients with T4a tumors. Concurrent systemic chemotherapy was administered to 4 patients (T2: 2, T4a: 2); this comprised cisplatin alone for 2 patients, cisplatin plus 5-fluorouracil for 1, and docetaxel alone for 1. For recent cases, cisplatin alone was routinely used as concurrent systemic chemotherapy. However until 2006, we used a variety of concurrent chemotherapy regimens, because a standard regimen had not been determined. After 2007, we introduced RADPLAT for locally advanced cases. We primarily considered indication for RADPLAT to be large or infiltrating T2 tumors and T3–4 tumors. If RADPLAT was not suitable because of clinical problems, systemic CRT was indicated. In this study, we implemented RADPLAT for 1 T2 and 4 T3 patients. However, 5 T4a patients did not undergo RADPLAT. Four T4a patients were treated before we introduced RADPLAT. The remaining T4a patient had an exophytic primary tumor which we regarded as controllable by use of RT plus concurrent systemic chemotherapy. The routine arterial cisplatin infusion dose was 100 mg/m2 per week and was administered thrice during first 3 weeks of the RT course. Sodium thiosulfate was administered as an intravenous bolus of 9 g/m2 over 15–20 min, concurrently after each arterial cisplatin infusion, followed by a 12 g/m2 sodium thiosulfate intravenous infusion over 6 h. Cisplatin was infused through a selectively placed microcatheter into the bilateral lingual arteries and the superior thyroid, facial, and other feeding arteries if indicated. The proportion of infused cisplatin dose was determined on the basis of angiography and intra-arterial CT arteriography findings. Patients were followed up every 1–2 months during the first year, every 2–3 months during the second year, and every 3–6 months thereafter. At each visit, physical and laryngoscopic examinations were performed. CT or MRI of the head and neck was performed once or twice per year, and positron-emission tomography (PET) was performed when clinically indicated. The statistical analysis was performed by use of GraphPad Prism, version_5.0 (GraphPad Software, San Diego, CA, USA). Local control and overall survival (OS) were evaluated by use of the Kaplan–Meier method. Survival was calculated from the first day of RT. Toxicity was assessed in accordance with the Common Terminology Criteria for Adverse Events version 4.0.
Results The median follow-up time was 33 months (range 5–114 months). Three-year OS for all patients was 69 % (95 % confidence interval (CI) 47–83 %; Fig. 1). At the time of analysis, 9 patients had died between 5 and 114 months after RT. The causes of death were BOT cancer (n = 6), other cancers (n = 2), and non-neoplastic intercurrent disease (n = 1). Three-year local control for all patients was 81 % (95 % CI 59.8–91.5 %) (Fig. 2). Three-year local control according to T stage was 100 % for T1, 86 % for T2, 100 % for T3, and 20 % for T4. For the 14 patients with T1 or T2 tumors treated by use of RT alone, three-year local control was 93 %. Three-year regional control for all patients was 85 %. Three-year regional control according to N stage was 100 % for N0, 100 % for N1, 100 % for N2a, 83 % for N2b, 75 % for N2c, and 0 % for N3. Recurrence occurred in 7 patients (7/26, 27 %). Table 3 shows the patterns of initial failure. Most recurrence (6/7) was observed within or approximately 1 year after RT. The sites of failure were the primary site alone for 1 patient, CLN alone for 2, primary site, CLN for 3, and both primary
Fig. 1 Overall survival rate for all patients
Fig. 2 Local control rate for all patients
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Table 3 Patterns of the initial failure Pt
Clinical TN stage
Initial treatment
Failure site
Interval of failure (month)
Salvage surgery
Outcome
1 2 3 4
T2N2b T1N1 T1N2b T4aN2c
RT alone RT alone RT alone IC and RT
Primary alone CLN alone CLN alone Primary and CLN
3 56 7 4
Failure Failure Successful –
DOD DOD NED DOD
5 6
T4aN2c T4aN3
RT alone IC and RT
Primary and CLN Primary and CLN
5 1
– –
DOD DOD
7
T4aN2c
CCRT
Primary and distant
13
–
DOD
Pt patient, RT radiotherapy, IC induction chemotherapy, CCRT concurrent chemoradiotherapy, Primary primary tumor, CLN cervical lymph node, DOD died of disease, NED no evidence of disease
and distant sites for 1. Primary recurrence occurred in 4 of 5 T4a patients; however, recurrence did not occur in any of the 4 T3 patients, who were treated with RADPLAT. CLN recurrence occurred in 1 patient each from the cN1, cN2b, and cN3 groups and in 2 cN2c patients. This recurrence developed in irradiated areas in 4 patients and out-of-field alone (contralateral level III) in the fifth. Salvage surgery was attempted for 3 patients with primary failure alone or CLN recurrence alone and was successful for 1 patient with CLN recurrence alone. This patient remained alive at the time of analysis. The other 2 patients developed secondary recurrence and died from their tumors. The remaining 4 patients with recurrence and inoperable T4 at the initial presentation did not undergo salvage surgery and died from BOT cancer. Observed acute grade 3 toxicity was dysphagia for 7 patients, oral mucositis for 1, anorexia for 1, leukopenia for 1, and hypoglossal nerve palsy for 1. Hypoglossal nerve palsy developed in 1 patient treated with RADPLAT and resolved 1 month after RT. Late grade 3 toxicity was recorded for 2 patients; these involved osteoradionecrosis (ORN) [11] of the mandible, which developed shortly after dental extraction 27 and 44 months after RT. Neither acute nor late grade 4 or higher toxicity was observed in any patient.
Discussion In this we study evaluated the loco-regional control for BOT cancer provided by RT at our institute. At the University of Florida College of Medicine, Mendenhall et al. [12] treated 333 BOT cancer patients with RT alone or RT plus planned ND without chemotherapy. The median total dose delivered in that study was 70.0 Gy (range 56.6– 80.0 Gy) with conventional fractionation or 76.8 Gy (range 70.8–81.6 Gy) with hyperfractionation. In the report by Mendenhall and colleagues, 5-year local control exceeded 93 % for T1–T2 cancers. Pederson et al. [13] also evaluated
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concurrent CRT for BOT cancer. In that study, the median dose was 72.5 Gy to the gross tumor, and paclitaxel, 5-fluorouracil, and hydroxyurea were the most commonly used drugs. Five-year loco-regional control for T1–T2 cancers was very similar to that reported by Mendenhall et al.— 95 % for T1 and 91 % for T2 cancers. However, Pederson et al. excluded patients with stage I–II disease (T1–2N0) from their CRT study. In our study, among the 14 patients who were treated with RT alone, all patients achieved locoregional control except for 1 T2 patient with primary failure. Consequently, loco-regional control for T1–2 disease in our study was 93 % (13/14). These results suggest that RT alone is a reasonable option for T1 cancers and might be an option for early or well demarcated T2 cancers. We suppose that treatment for larger or infiltrating T2 cancers should be intensified by use of accelerated hyperfractionation or concurrent chemotherapy. Reportedly, RT alone could not achieve favorable local control for T3–4 BOT cancers. Brunin et al. [4] reported results for 216 patients with BOT cancers who were treated by EBRT alone and noted 5-year local control of 45 and 18 % for patients with T3 and T4 disease, respectively. Clinical outcomes of hyperfractionated radiotherapy without concurrent chemotherapy for BOT cancer were evaluated by Hinerman et al. [3], who reported improved local control of T3 and T4 cancers with twice-daily fractionation. Specifically, 5-year local control was 73 and 35 % for T3 and T4 disease, respectively. The GORTEC 94-01 study, a randomized trial that compared conventional RT with and without concurrent chemotherapy for 226 patients with stage III and IV oropharyngeal cancer, including 79 BOT cancer patients, found that 5-year locoregional control was significantly higher with CRT than with RT alone [14]. These reports demonstrate that use of accelerated hyperfractionation or concurrent chemotherapy improved the local control of locally advanced BOT cancers. However, the optimum management for T3–4 BOT cancer remains to be established. RADPLAT was introduced to increase the effects of concurrent CRT on
Int J Clin Oncol
locally advanced oropharyngeal cancer. Robbins et al. [15] reported RADPLAT treatment outcomes for 61 patients with T4 squamous cell carcinoma of the head and neck. Complete response (CR) was 85 % at the primary site and 88 % at nodal regions, with an overall CR of 80 %. Twoyear loco-regional control and disease-free survival was 57 and 46 %, respectively. Recently, some authors have reported treatment outcomes with RADPLAT for BOT cancer. Kano et al. [10] treated 13 patients with T2–4a BOT cancer with RADPLAT and reported 5-year local control and OS of 92.3 and 90.9 %, respectively, for all patients, which were much higher than the results reported by Robbins et al. In this study, we performed RADPLAT for 1 patient with T2 disease and 4 patients with T3 disease. Loco-regional control was achieved for all 5 patients. Therefore, the outcomes with RADPLAT were favorable in our study. However, these outcomes might vary. A multicenter, randomized phase III trial was performed to determine the effects of arterial chemotherapeutic drug infusion [11]. This trial compared concurrent intra-arterial and intra-venous CRT for 239 patients with T3–4 unresectable head and neck cancers and failed to show the superiority of RADPLAT. However, in an unplanned subgroup analysis, the authors found significantly higher local and loco-regional control and disease-free survival associated with RADPLAT for large (>30 mL) lateralized tumors. The effects of concurrent intra-arterial chemotherapy depend on the drug type, drug infusion dose, and use of such angiographic procedures as infusion artery selection and tumor-specific factors. Therefore, reported results with RADPLAT differ among institutions, and there is currently no general consensus on the advantage of RADPLAT over systemic CRT. Brunin et al. [4] treated BOT cancer with EBRT and reported 5-year regional control of 82, 76, and 55 % for patients with N0, N1, and N2–3 disease, respectively. Regional control was poor for patients with N2–3 nodal disease who were treated with EBRT alone. In the previously mentioned work by Mendenhall et al. [12], in which 171 of 333 BOT patients received planned post-RT ND, 5-year regional control was 100, 93, 81, and 76 % for N2a, N2b, N2c, and N3 disease, respectively. In another study [13], patients with clinical N2a–3 disease were scheduled to undergo ND after CRT. Five-year regional control was 82, 92, 77, and 84 % for N2a, N2b, N2c, and N3 disease, respectively. Therefore, improved regional control was achieved by use of radical EBRT plus planned ND compared with radical EBRT alone. Of the 17 patients with N0–N2b disease in our study, of whom only 2 patients underwent planned ND, nodal recurrence occurred in 2 patients. One of the patients underwent a right planned ND, and recurrence occurred in the left neck. Both patients were successfully salvaged with ND. Consequently, ultimate
nodal control was 100 % at these nodal stages. Of the 9 patients with N2c–N3 disease, none of whom underwent planned ND, 3 experienced nodal recurrence and did not undergo ND because of concurrent inoperable primary recurrence, i.e. these patients would not have survived even if they had undergone planned ND. We supposed that planned ND facilitated nodal control for advanced N-stage diseases. However, bilateral planned ND resulted more frequently from bilateral nodal involvement in BOT cancer cases than in other head and neck cancers, and could be a substantial burden. A multi-center randomized trial that compared RT alone, accelerated hyperfractionation RT, and concomitant CRT for patients with oropharyngeal cancer found that 30 of the 156 patients with available data experienced grade 3 or greater pharyngeal toxicity [16]. Patients treated with accelerated hyperfractionation RT and concomitant CRT more frequently experienced grade 3 or greater pharyngeal toxicity than patients treated with RT alone (23 and 24 %, respectively, vs. 11 %). In our study, the incidence of grade 3 or greater toxicity similarly doubled in patients treated with CRT vs. RT alone (44 vs. 18 %). One patient with grade 3 dysphagia suffered from hypoglossal nerve palsy. This patient had been treated with RADPLAT. According to a published study reported by Hinerman et al. [3], hypoglossal nerve palsy occurred in 2 of 134 patients with BOT cancer. Robbins et al. [15] reported grade 3 and 4 neurological toxicity of 7 and 2 %, respectively. The incidence of neurological toxicity in our study seemed similar to these published results. With regard to late complications in this study, we observed grade 3 ORN of the mandible for 2 patients (8 %). Reportedly, the incidence of ORN varies widely (range 4.7–37.5 %) in the head and neck-irradiated population [17]. Mendenhall et al. [12] reported that the incidence of ORN of the mandible was 2 %. Tooth extraction, which is a major risk factor, causes this wide range in ORN incidence. In our study, ORN developed in both patients shortly after tooth extraction. We achieved favorable local control and survival with definitive RT alone for T1 cancers. Therefore, RT alone seems a reasonable option for T1 disease. RT alone might also be an option for early or well demarcated T2 cancers. However, treatment for larger or infiltrating T2 cancers should be intensified, by use of accelerated hyperfractionation or concurrent chemotherapy. We achieved high local control for T3 cancers treated with RADPLAT. This result suggests that RADPLAT might be a promising option for locally advanced cases. However, the treatment outcomes with RADPLAT may vary among institutions and our data are limited by the small sample size and single-institution experience. Therefore, further studies are needed to confirm the effectiveness of our strategy.
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Conflict of interest The authors declare that they have no conflict of interest.
References 1. Osaka Prefectural Department of Public Health and Welfare, Osaka medical Association, Osaka Medical Center for Cancer and Cardiovascular Diseases. Annual Report of Osaka Cancer Registry No.76, Cancer Incidence and Medical Care in Osaka in 2008 and the Survival in 2006 2. Machtay M, Perch S, Markiewicz D et al (1997) Combined surgery and postoperative radiotherapy for carcinoma of the base of radiotherapy for carcinoma of the base of tongue: analysis of treatment outcome and prognostic value of margin status. Head Neck 19(6):494–499 3. Hinerman RW, Parsons JT, Mendenhall WM et al (1994) External beam irradiation alone or combined with neck dissection for base of tongue carcinoma: an alternative to primary surgery. Laryngoscope 104:1466–1470 4. Brunin F, Mosseri V, Jaulerry C et al (1999) Cancer of the base of the tongue: past and future. Head Neck 21:751–759 5. Al-Sarraf M, Pajak TF, Marcial VA et al (1987) Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG study. Cancer 59:259–265 6. Paccagnella A, Orlando A, Marchiori C et al (1994) Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst 86:265–272 7. Merlano M, Benasso M, Corvo R et al (1996) Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88:583–589 8. Oikawa H, Nakamura R, Nakasato T et al (2009) Radiotherapy and concomitant intra-arterial docetaxel combined with systemic
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Int J Clin Oncol 5-fluorouracil and cisplatin for oropharyngeal cancer: a preliminary report–improvement of locoregional control of oropharyngeal cancer. Int J Radiat Oncol Biol Phys 75:338–342 9. Rabbani A, Hinerman RW, Schmalfuss IM et al (2007) Radiotherapy and concomitant intraarterial cisplatin (RADPLAT) for advanced squamous cell carcinomas of the head and neck. Am J Clin Oncol 30:283–286 10. Kano S, Homma A, Oridate N et al (2011) Superselective arterial cisplatin infusion with concomitant radiation therapy for base of tongue cancer. Oral Oncol 47:665–670 11. Rasch CR, Hauptmann M, Schornagel J et al (2010) Intra arterial versus intravenous chemoradiation for advanced head and neck cancer: results of a randomized phase 3 trial. Cancer 116:2159–2165 12. Mendenhall WM, Morris CG, Amdur RJ et al (2006) Definitive radiotherapy for squamous cell carcinoma of the base of tongue. Am J Clin Oncol 29:32–39 13. Pederson AW, Haraf DJ, Witt ME et al (2010) Chemoradiotherapy for locoregionally advanced squamous cell carcinoma of the base of tongue. Head Neck 32:1519–1527 14. Denis F, Garaud P, Bardet E et al (2004) Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 22:69–76 15. Robbins KT, Kumar P, Harris J et al (2005) Supradose intra-arterial cisplatin and concurrent radiation therapy for the treatment of stage IV head and neck squamous cell carcinoma is feasible and efficacious in a multi-institutional setting: results of Radiation Therapy Oncology Group Trial 9615. J Clin Oncol 23:1447–1454 16. Olmi P, Crispino S, Fallai C et al (2003) Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy–a multicenter randomized trial. Int J Radiat Oncol Biol Phys 55:78–92 17. Nabil S, Samman N (2012) Risk factors for osteoradionecrosis after head and neck radiation: a systematic review. Oral Surg Oral Med Oral Pathol Oral Radiol 113:54–69
ORIGINAL ARTICLE
Treatment outcomes of external‑beam radiotherapy for squamous cell carcinoma of the base of the tongue Yoshifumi Kawaguchi · Kinji Nishiyama · Takerou Hirata · Kouji Konishi · Shinji Otozai · Motoyuki Suzuki · Tadashi Yoshii · Takashi Fujii · Teruki Teshima
Received: 9 October 2014 / Accepted: 12 February 2015 © Japan Society of Clinical Oncology 2015
Abstract Purpose To evaluate definitive external-beam radiotherapy (EBRT) for patients with base of the tongue (BOT) cancers. Methods We reviewed results for 26 patients with BOT cancers who were treated with EBRT. Clinical stages T1, T2, T3, and T4a were observed for 10, 7, 4, and 5 patients, respectively, and stages N0, N1, N2a, N2b, N2c, and N3 were observed for 4, 2, 5, 6, 8, and 1 patients, respectively. More than half of the patients (n = 19) were stage IVA. Standard total delivered doses were 70 Gy to primary tumors and cervical lymph node (CLN) metastases and 40–46 Gy to elective nodal regions. Eleven patients with advanced loco-regional disease received concurrent or neoadjuvant chemotherapy. Four T3 patients and one T2 patient received 2 or 3 cycles of concurrent intra-arterial cisplatin with EBRT (RADPLAT). Results Three-year overall survival was 69 % (95 % CI 47–83 %), with a median follow-up period of 33 months. Three-year local control was 100, 86, 100, and 20 % for T1, T2, T3, and T4 patients, respectively. Three-year regional control was 100 % for N0, N1, and N2a, 83 % for N2b, 75 % for N2c, and 0 % for N3 patients. Treatment failed for
Y. Kawaguchi (*) · T. Hirata · K. Konishi · T. Teshima Department of Radiation Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 3‑3, Nakamichi 1‑chome, Higashinari‑ku, Osaka 537‑8511, Japan e-mail: kawaguti‑[email protected] K. Nishiyama Department of Radiology, Yao Municipal Hospital, Osaka, Japan S. Otozai · M. Suzuki · T. Yoshii · T. Fujii Department of Head and Neck Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
7 patients. All 5 patients undergoing RADPLAT achieved complete responses and did not develop local recurrence. Conclusions We achieved favorable outcomes for patients with T1–T3 BOT cancers by use of definitive EBRT with or without chemotherapy. Keywords Base of tongue cancer · External-beam radiotherapy · Intra-arterial chemotherapy · Organ preservation
Introduction Base of tongue (BOT) cancers are relatively rare among head and neck cancers. According to a 2008 annual report from the Osaka, Japan, cancer registry, 25 patients were newly diagnosed with BOT cancer during that year, corresponding to 2 % of all patients with head and neck cancer (n = 1251) and 0.06 % of all patients with any type of cancer [1]. Hence, among treatment options, for example surgical resection (with or without postoperative radiotherapy, RT) and external-beam RT (EBRT) with or without concurrent chemotherapy, the optimum method of treatment has yet to be established. BOT cancers are frequently asymptomatic until they reach an advanced stage. Moreover, these tumors often extend across the midline, and bilateral lymph node metastases are frequently found. Therefore, many patients are diagnosed at advanced stages with cervical lymph node (CLN) metastases. Surgery for advanced BOT cancer usually involves wide resection. Some patients undergo not only glossectomy but also partial or total laryngectomy, resulting in severe speech and swallowing disorders [2]. RT can preserve the functions of these organs and is, therefore, an important therapeutic modality. However, some published data have suggested that RT alone
13
Int J Clin Oncol
yields poor outcomes for patients with locally advanced BOT cancer [3, 4]. Chemoradiotherapy (CRT) was introduced to increase the response and survival of advanced head and neck cancers, and its efficacy was proved during prospective randomized trials [5–7]. RT with concurrent intra-arterial cisplatin (RADPLAT) was also developed to enhance the effects of chemotherapeutic agents. Recently, a single-institution study reported improved tumor response and survival with RADPLAT for oropharyngeal cancers [8–10]. Thus, a variety of RT approaches are available. The results, however, have not been widely published in the medical literature, mainly because of the low prevalence of BOT cancers. In this study, we analyzed treatment outcomes of definitive EBRT, including RADPLAT, for BOT cancers.
Methods and materials Between 1995 and 2009, 37 patients with BOT squamous cell carcinoma underwent definitive RT at our institution. During this period, 11 patients received boost interstitial brachytherapy. These patients were excluded from our study, because the treatment outcomes after boost interstitial brachytherapy might differ substantially from those Table 1 Patient characteristics Characteristic
No. of patients (n = 26)
Gender Male Female Age (years) Median (range) Follow-up time (months) Median (range) Stage I II III IVA
22 4 63 (50–85) 33 (5–114) 2 1 3 19
IVB
Table 2 Stage distribution by T and N classification
13
1
T classification
after definitive EBRT. The remaining 26 patients without distant metastases were the subjects of this study. Each patient was evaluated during a joint conference of head and neck surgeons and radiation oncologists before treatment. Basically, we performed definitive EBRT for earlystage disease, surgery with or without postoperative RT for locally advanced disease, and systemic CRT for unresectable advanced disease. After 2007, we implemented RADPLAT for locally advanced cases to avoid severe speech and swallowing disorders caused by surgery. Table 1 lists the patients’ characteristics. The median age was 63 years (range 50–85 years). Of the 26 patients, 22 were men and 4 were women. Four patients had a history of metachronous cancers that were controlled at the time of treatment. Two patients had synchronous cancers (laryngeal cancer cT1aN0M0 for one and hypopharyngeal cancer cT2N2bM0 for the other) that were successfully treated with RT. Before treatment, all patients were evaluated by physical examination, laryngoscopy, chest X-ray, and computed tomography (CT) of the head and neck. Magnetic resonance imaging (MRI) was performed to assess invasion of the deep muscles of the tongue for locally advanced cases. In accordance with the International Union Against Cancer 2002 classification, the patients were classified by clinical stages as follows: stage I: 2, stage II: 1, stage III: 3, stage IVA:1 9, and stage IVB: 1 patient (Table 2). Patients were immobilized in custom masks and underwent CT-based planning. The gross tumor volume (GTV) was defined as all gross disease. The elective neck nodal areas usually included bilateral levels II, III, and IV and the retropharyngeal nodes. For patients with tumor invasion of the deep muscles of the tongue, level I nodes were included in the elective nodal areas. RT was delivered by use of 4-MV photon beams in once-daily doses of 2 Gy, 5 days per week. Typically, the primary tumor and upper neck were irradiated by use of opposed lateral fields and the lower neck by use of an anterior field. Subsequently, boost irradiation was delivered to GTV. The standard dose schedule was: 40–46 Gy to GTV and elective neck nodal areas and a boost of up to 70 Gy to GTV while shielding the spinal cord. Neck dissection (ND) before RT was undertaken for 2 patients with advanced nodal metastases.
N classification N0
N1
N2a
N2b
N2c
N3
Total
T1 T2 T3 T4a
2 1 1 0
2 0 0 0
2 3 0 0
3 2 1 0
1 1 2 4
0 0 0 1
10 7 4 5
Total
4
2
5
6
8
1
26
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One patient underwent level II lymph node resection for a primary unknown metastasis at another institution. The other patient underwent lateral ND (levels II–V). Induction or concurrent chemotherapy was used for unresectable loco-regionally advanced disease until 2006. Induction chemotherapy was indicated for patients with unresectable tumors that were considered resectable if they responded to induction chemotherapy. Induction chemotherapy with cisplatin plus 5-fluorouracil was administered to 2 patients with T4a tumors. Concurrent systemic chemotherapy was administered to 4 patients (T2: 2, T4a: 2); this comprised cisplatin alone for 2 patients, cisplatin plus 5-fluorouracil for 1, and docetaxel alone for 1. For recent cases, cisplatin alone was routinely used as concurrent systemic chemotherapy. However until 2006, we used a variety of concurrent chemotherapy regimens, because a standard regimen had not been determined. After 2007, we introduced RADPLAT for locally advanced cases. We primarily considered indication for RADPLAT to be large or infiltrating T2 tumors and T3–4 tumors. If RADPLAT was not suitable because of clinical problems, systemic CRT was indicated. In this study, we implemented RADPLAT for 1 T2 and 4 T3 patients. However, 5 T4a patients did not undergo RADPLAT. Four T4a patients were treated before we introduced RADPLAT. The remaining T4a patient had an exophytic primary tumor which we regarded as controllable by use of RT plus concurrent systemic chemotherapy. The routine arterial cisplatin infusion dose was 100 mg/m2 per week and was administered thrice during first 3 weeks of the RT course. Sodium thiosulfate was administered as an intravenous bolus of 9 g/m2 over 15–20 min, concurrently after each arterial cisplatin infusion, followed by a 12 g/m2 sodium thiosulfate intravenous infusion over 6 h. Cisplatin was infused through a selectively placed microcatheter into the bilateral lingual arteries and the superior thyroid, facial, and other feeding arteries if indicated. The proportion of infused cisplatin dose was determined on the basis of angiography and intra-arterial CT arteriography findings. Patients were followed up every 1–2 months during the first year, every 2–3 months during the second year, and every 3–6 months thereafter. At each visit, physical and laryngoscopic examinations were performed. CT or MRI of the head and neck was performed once or twice per year, and positron-emission tomography (PET) was performed when clinically indicated. The statistical analysis was performed by use of GraphPad Prism, version_5.0 (GraphPad Software, San Diego, CA, USA). Local control and overall survival (OS) were evaluated by use of the Kaplan–Meier method. Survival was calculated from the first day of RT. Toxicity was assessed in accordance with the Common Terminology Criteria for Adverse Events version 4.0.
Results The median follow-up time was 33 months (range 5–114 months). Three-year OS for all patients was 69 % (95 % confidence interval (CI) 47–83 %; Fig. 1). At the time of analysis, 9 patients had died between 5 and 114 months after RT. The causes of death were BOT cancer (n = 6), other cancers (n = 2), and non-neoplastic intercurrent disease (n = 1). Three-year local control for all patients was 81 % (95 % CI 59.8–91.5 %) (Fig. 2). Three-year local control according to T stage was 100 % for T1, 86 % for T2, 100 % for T3, and 20 % for T4. For the 14 patients with T1 or T2 tumors treated by use of RT alone, three-year local control was 93 %. Three-year regional control for all patients was 85 %. Three-year regional control according to N stage was 100 % for N0, 100 % for N1, 100 % for N2a, 83 % for N2b, 75 % for N2c, and 0 % for N3. Recurrence occurred in 7 patients (7/26, 27 %). Table 3 shows the patterns of initial failure. Most recurrence (6/7) was observed within or approximately 1 year after RT. The sites of failure were the primary site alone for 1 patient, CLN alone for 2, primary site, CLN for 3, and both primary
Fig. 1 Overall survival rate for all patients
Fig. 2 Local control rate for all patients
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Table 3 Patterns of the initial failure Pt
Clinical TN stage
Initial treatment
Failure site
Interval of failure (month)
Salvage surgery
Outcome
1 2 3 4
T2N2b T1N1 T1N2b T4aN2c
RT alone RT alone RT alone IC and RT
Primary alone CLN alone CLN alone Primary and CLN
3 56 7 4
Failure Failure Successful –
DOD DOD NED DOD
5 6
T4aN2c T4aN3
RT alone IC and RT
Primary and CLN Primary and CLN
5 1
– –
DOD DOD
7
T4aN2c
CCRT
Primary and distant
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–
DOD
Pt patient, RT radiotherapy, IC induction chemotherapy, CCRT concurrent chemoradiotherapy, Primary primary tumor, CLN cervical lymph node, DOD died of disease, NED no evidence of disease
and distant sites for 1. Primary recurrence occurred in 4 of 5 T4a patients; however, recurrence did not occur in any of the 4 T3 patients, who were treated with RADPLAT. CLN recurrence occurred in 1 patient each from the cN1, cN2b, and cN3 groups and in 2 cN2c patients. This recurrence developed in irradiated areas in 4 patients and out-of-field alone (contralateral level III) in the fifth. Salvage surgery was attempted for 3 patients with primary failure alone or CLN recurrence alone and was successful for 1 patient with CLN recurrence alone. This patient remained alive at the time of analysis. The other 2 patients developed secondary recurrence and died from their tumors. The remaining 4 patients with recurrence and inoperable T4 at the initial presentation did not undergo salvage surgery and died from BOT cancer. Observed acute grade 3 toxicity was dysphagia for 7 patients, oral mucositis for 1, anorexia for 1, leukopenia for 1, and hypoglossal nerve palsy for 1. Hypoglossal nerve palsy developed in 1 patient treated with RADPLAT and resolved 1 month after RT. Late grade 3 toxicity was recorded for 2 patients; these involved osteoradionecrosis (ORN) [11] of the mandible, which developed shortly after dental extraction 27 and 44 months after RT. Neither acute nor late grade 4 or higher toxicity was observed in any patient.
Discussion In this we study evaluated the loco-regional control for BOT cancer provided by RT at our institute. At the University of Florida College of Medicine, Mendenhall et al. [12] treated 333 BOT cancer patients with RT alone or RT plus planned ND without chemotherapy. The median total dose delivered in that study was 70.0 Gy (range 56.6– 80.0 Gy) with conventional fractionation or 76.8 Gy (range 70.8–81.6 Gy) with hyperfractionation. In the report by Mendenhall and colleagues, 5-year local control exceeded 93 % for T1–T2 cancers. Pederson et al. [13] also evaluated
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concurrent CRT for BOT cancer. In that study, the median dose was 72.5 Gy to the gross tumor, and paclitaxel, 5-fluorouracil, and hydroxyurea were the most commonly used drugs. Five-year loco-regional control for T1–T2 cancers was very similar to that reported by Mendenhall et al.— 95 % for T1 and 91 % for T2 cancers. However, Pederson et al. excluded patients with stage I–II disease (T1–2N0) from their CRT study. In our study, among the 14 patients who were treated with RT alone, all patients achieved locoregional control except for 1 T2 patient with primary failure. Consequently, loco-regional control for T1–2 disease in our study was 93 % (13/14). These results suggest that RT alone is a reasonable option for T1 cancers and might be an option for early or well demarcated T2 cancers. We suppose that treatment for larger or infiltrating T2 cancers should be intensified by use of accelerated hyperfractionation or concurrent chemotherapy. Reportedly, RT alone could not achieve favorable local control for T3–4 BOT cancers. Brunin et al. [4] reported results for 216 patients with BOT cancers who were treated by EBRT alone and noted 5-year local control of 45 and 18 % for patients with T3 and T4 disease, respectively. Clinical outcomes of hyperfractionated radiotherapy without concurrent chemotherapy for BOT cancer were evaluated by Hinerman et al. [3], who reported improved local control of T3 and T4 cancers with twice-daily fractionation. Specifically, 5-year local control was 73 and 35 % for T3 and T4 disease, respectively. The GORTEC 94-01 study, a randomized trial that compared conventional RT with and without concurrent chemotherapy for 226 patients with stage III and IV oropharyngeal cancer, including 79 BOT cancer patients, found that 5-year locoregional control was significantly higher with CRT than with RT alone [14]. These reports demonstrate that use of accelerated hyperfractionation or concurrent chemotherapy improved the local control of locally advanced BOT cancers. However, the optimum management for T3–4 BOT cancer remains to be established. RADPLAT was introduced to increase the effects of concurrent CRT on
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locally advanced oropharyngeal cancer. Robbins et al. [15] reported RADPLAT treatment outcomes for 61 patients with T4 squamous cell carcinoma of the head and neck. Complete response (CR) was 85 % at the primary site and 88 % at nodal regions, with an overall CR of 80 %. Twoyear loco-regional control and disease-free survival was 57 and 46 %, respectively. Recently, some authors have reported treatment outcomes with RADPLAT for BOT cancer. Kano et al. [10] treated 13 patients with T2–4a BOT cancer with RADPLAT and reported 5-year local control and OS of 92.3 and 90.9 %, respectively, for all patients, which were much higher than the results reported by Robbins et al. In this study, we performed RADPLAT for 1 patient with T2 disease and 4 patients with T3 disease. Loco-regional control was achieved for all 5 patients. Therefore, the outcomes with RADPLAT were favorable in our study. However, these outcomes might vary. A multicenter, randomized phase III trial was performed to determine the effects of arterial chemotherapeutic drug infusion [11]. This trial compared concurrent intra-arterial and intra-venous CRT for 239 patients with T3–4 unresectable head and neck cancers and failed to show the superiority of RADPLAT. However, in an unplanned subgroup analysis, the authors found significantly higher local and loco-regional control and disease-free survival associated with RADPLAT for large (>30 mL) lateralized tumors. The effects of concurrent intra-arterial chemotherapy depend on the drug type, drug infusion dose, and use of such angiographic procedures as infusion artery selection and tumor-specific factors. Therefore, reported results with RADPLAT differ among institutions, and there is currently no general consensus on the advantage of RADPLAT over systemic CRT. Brunin et al. [4] treated BOT cancer with EBRT and reported 5-year regional control of 82, 76, and 55 % for patients with N0, N1, and N2–3 disease, respectively. Regional control was poor for patients with N2–3 nodal disease who were treated with EBRT alone. In the previously mentioned work by Mendenhall et al. [12], in which 171 of 333 BOT patients received planned post-RT ND, 5-year regional control was 100, 93, 81, and 76 % for N2a, N2b, N2c, and N3 disease, respectively. In another study [13], patients with clinical N2a–3 disease were scheduled to undergo ND after CRT. Five-year regional control was 82, 92, 77, and 84 % for N2a, N2b, N2c, and N3 disease, respectively. Therefore, improved regional control was achieved by use of radical EBRT plus planned ND compared with radical EBRT alone. Of the 17 patients with N0–N2b disease in our study, of whom only 2 patients underwent planned ND, nodal recurrence occurred in 2 patients. One of the patients underwent a right planned ND, and recurrence occurred in the left neck. Both patients were successfully salvaged with ND. Consequently, ultimate
nodal control was 100 % at these nodal stages. Of the 9 patients with N2c–N3 disease, none of whom underwent planned ND, 3 experienced nodal recurrence and did not undergo ND because of concurrent inoperable primary recurrence, i.e. these patients would not have survived even if they had undergone planned ND. We supposed that planned ND facilitated nodal control for advanced N-stage diseases. However, bilateral planned ND resulted more frequently from bilateral nodal involvement in BOT cancer cases than in other head and neck cancers, and could be a substantial burden. A multi-center randomized trial that compared RT alone, accelerated hyperfractionation RT, and concomitant CRT for patients with oropharyngeal cancer found that 30 of the 156 patients with available data experienced grade 3 or greater pharyngeal toxicity [16]. Patients treated with accelerated hyperfractionation RT and concomitant CRT more frequently experienced grade 3 or greater pharyngeal toxicity than patients treated with RT alone (23 and 24 %, respectively, vs. 11 %). In our study, the incidence of grade 3 or greater toxicity similarly doubled in patients treated with CRT vs. RT alone (44 vs. 18 %). One patient with grade 3 dysphagia suffered from hypoglossal nerve palsy. This patient had been treated with RADPLAT. According to a published study reported by Hinerman et al. [3], hypoglossal nerve palsy occurred in 2 of 134 patients with BOT cancer. Robbins et al. [15] reported grade 3 and 4 neurological toxicity of 7 and 2 %, respectively. The incidence of neurological toxicity in our study seemed similar to these published results. With regard to late complications in this study, we observed grade 3 ORN of the mandible for 2 patients (8 %). Reportedly, the incidence of ORN varies widely (range 4.7–37.5 %) in the head and neck-irradiated population [17]. Mendenhall et al. [12] reported that the incidence of ORN of the mandible was 2 %. Tooth extraction, which is a major risk factor, causes this wide range in ORN incidence. In our study, ORN developed in both patients shortly after tooth extraction. We achieved favorable local control and survival with definitive RT alone for T1 cancers. Therefore, RT alone seems a reasonable option for T1 disease. RT alone might also be an option for early or well demarcated T2 cancers. However, treatment for larger or infiltrating T2 cancers should be intensified, by use of accelerated hyperfractionation or concurrent chemotherapy. We achieved high local control for T3 cancers treated with RADPLAT. This result suggests that RADPLAT might be a promising option for locally advanced cases. However, the treatment outcomes with RADPLAT may vary among institutions and our data are limited by the small sample size and single-institution experience. Therefore, further studies are needed to confirm the effectiveness of our strategy.
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Conflict of interest The authors declare that they have no conflict of interest.
References 1. Osaka Prefectural Department of Public Health and Welfare, Osaka medical Association, Osaka Medical Center for Cancer and Cardiovascular Diseases. Annual Report of Osaka Cancer Registry No.76, Cancer Incidence and Medical Care in Osaka in 2008 and the Survival in 2006 2. Machtay M, Perch S, Markiewicz D et al (1997) Combined surgery and postoperative radiotherapy for carcinoma of the base of radiotherapy for carcinoma of the base of tongue: analysis of treatment outcome and prognostic value of margin status. Head Neck 19(6):494–499 3. Hinerman RW, Parsons JT, Mendenhall WM et al (1994) External beam irradiation alone or combined with neck dissection for base of tongue carcinoma: an alternative to primary surgery. Laryngoscope 104:1466–1470 4. Brunin F, Mosseri V, Jaulerry C et al (1999) Cancer of the base of the tongue: past and future. Head Neck 21:751–759 5. Al-Sarraf M, Pajak TF, Marcial VA et al (1987) Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG study. Cancer 59:259–265 6. Paccagnella A, Orlando A, Marchiori C et al (1994) Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst 86:265–272 7. Merlano M, Benasso M, Corvo R et al (1996) Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88:583–589 8. Oikawa H, Nakamura R, Nakasato T et al (2009) Radiotherapy and concomitant intra-arterial docetaxel combined with systemic
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Int J Clin Oncol 5-fluorouracil and cisplatin for oropharyngeal cancer: a preliminary report–improvement of locoregional control of oropharyngeal cancer. Int J Radiat Oncol Biol Phys 75:338–342 9. Rabbani A, Hinerman RW, Schmalfuss IM et al (2007) Radiotherapy and concomitant intraarterial cisplatin (RADPLAT) for advanced squamous cell carcinomas of the head and neck. Am J Clin Oncol 30:283–286 10. Kano S, Homma A, Oridate N et al (2011) Superselective arterial cisplatin infusion with concomitant radiation therapy for base of tongue cancer. Oral Oncol 47:665–670 11. Rasch CR, Hauptmann M, Schornagel J et al (2010) Intra arterial versus intravenous chemoradiation for advanced head and neck cancer: results of a randomized phase 3 trial. Cancer 116:2159–2165 12. Mendenhall WM, Morris CG, Amdur RJ et al (2006) Definitive radiotherapy for squamous cell carcinoma of the base of tongue. Am J Clin Oncol 29:32–39 13. Pederson AW, Haraf DJ, Witt ME et al (2010) Chemoradiotherapy for locoregionally advanced squamous cell carcinoma of the base of tongue. Head Neck 32:1519–1527 14. Denis F, Garaud P, Bardet E et al (2004) Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 22:69–76 15. Robbins KT, Kumar P, Harris J et al (2005) Supradose intra-arterial cisplatin and concurrent radiation therapy for the treatment of stage IV head and neck squamous cell carcinoma is feasible and efficacious in a multi-institutional setting: results of Radiation Therapy Oncology Group Trial 9615. J Clin Oncol 23:1447–1454 16. Olmi P, Crispino S, Fallai C et al (2003) Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy–a multicenter randomized trial. Int J Radiat Oncol Biol Phys 55:78–92 17. Nabil S, Samman N (2012) Risk factors for osteoradionecrosis after head and neck radiation: a systematic review. Oral Surg Oral Med Oral Pathol Oral Radiol 113:54–69
