Radiotherapy for locally advanced resectable T3–T4 laryngeal cancer—does laryngeal preservation strategy compromise survival?

Radiotherapy for locally advanced resectable T3–T4 laryngeal cancer—does laryngeal... Journal of Radiation Research, Vol. 59, No. 1, 2018, pp. 77–90 doi: 10.1093/jrr/rrx063 Advance Access Publication: 28 November 2017 Radiotherapy for locally advanced resectable T3–T4 laryngeal cancer—does laryngeal preservation strategy compromise survival? 1, 1 1 2 Hideya Yamazaki , Gen Suzuki , Satoaki Nakamura , Shigeru Hirano , 3 4 4 5 Ken Yoshida , Koji Konishi , Teruki Teshima and Kazuhiko Ogawa Department of Radiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajiicho Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan Otorhinolaryngology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajiicho Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan Department of Radiology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-City, Osaka, 569-8686, Japan Department of Radiation Oncology, Osaka International Cancer Institute, Osaka 541-8567, Japan Department of Radiation Oncology, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan *Corresponding author. Department of Radiology, Kyoto Prefectural University of Medicine, 465 Kajiicho Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566 Japan. Phone: 81-75-251-5618, Fax: 81-75-251-5840, Email: hideya10@hotmail.com (Received 2 July 2017; revised 14 August 2017; editorial decision 1 October 2017) ABSTRACT With the advancement of chemotherapy, a laryngeal preservation (LP) strategy was explored with the aim of improving maintenance of quality of life. Induction chemotherapy (ICT) following radiotherapy (RT) was con- sidered a viable option because of its high initial response rate without hampering of overall survival (OS). Subsequently, concurrent chemoradiotherapy (CCRT) using CDDP became the standard of care for LP, show- ing the best LP ratio. For enhancing treatment intensity, ICT with taxan + CDDP + 5-FU (TPF-ICT) followed by RT showed superiority over ICT with CDDP + 5-FU (PF-ICT) followed by RT. Given that almost all ran- domized controlled trials investigating ICT include not only operable (endpoint, LP) but also inoperable (end- point, OS) cases, physicians are faced with a dilemma regarding application in daily practice. In addition, increased treatment intensity causes augmentation of adverse events, which might reduce compliance. Thereafter, cetuximab, an effective drug with fewer adverse effects [bioradiotherapy (BRT)], emerged as another option. However, little evidence has confirmed its superiority over RT (or CCRT) in laryngeal cancer subpopula- tions. In spite of these developments, the OS of patients with laryngeal cancer has not improved for several decades. In fact, several studies indicated a decrease in OS during the 1990s, probably due to overuse of CCRT. Fortunately, the latter was not the case in most institutions. Currently, no other treatment has better OS than surgery. The eligi- bility criteria for LP and/or surgery largely depend upon the available expertise and experience, which differ from one institution to another. Therefore, a multidisciplinary team is required for the treatment of LP. Keywords: laryngeal cancer; larynx preservation; concurrent chemoradiotherapy; induction chemotherapy INTRODUCTION investigate this type of cancer because of its significant effects on Squamous cell carcinoma (SCC) of the head and neck is the sixth the voice, swallowing, and quality of life. Surgery has been the pri- most common type of cancer worldwide, with over 650 000 new mary treatment for locally advanced laryngeal cancer. During the diagnoses every year [1], while laryngeal cancer accounts for mid-1980s, CDDP and 5-FU (PF) before resection had been incor- ~200 000 deaths annually [2]. Although laryngeal cancer represents porated into a highly effective induction chemotherapy regimen only 2–5% of all malignancies, it is particularly important to (PF-ICT), with response rates of 85–90% and complete response © The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re- use, please contact journals.permissions@oup.com � 77 Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 78 � H. Yamazaki et al. (CR) rates of 35–55% [3, 4]. Thereafter, a combination of these has been undertaken in order to improve patient outcomes for chemotherapeutic agents with radiotherapy (RT) had been explored advanced disease. For instance, non-standard alternated fraction- as a substitute for surgical intervention for laryngeal preservation ation (acceleration of hyperfractionation, etc.) has been extensively (LP) [5, 6]. The Veterans Administration Laryngeal Cancer Study trialled in several institutions (Table 1)[15]. Mendenhall et al. Group trial (henceforth, the VA study) confirmed the compatibility reported that the probability of cure was ~65–80% for select low- of ICT → RT and surgery → RT, supporting and emphasizing the volume (≤3.5 cm ) T3 to T4 glottic SCCs after RT [16]. Shiao merits of this regimen in maintaining quality of life by avoiding lar- et al. reported that patients with a tumor volume of ≥21 cm had yngectomy [7]. Concurrent CDDP + RT (concurrent chemora- significantly inferior 5-year overall survival (OS) compared with diotherapy [CCRT] = with CDDP, unless otherwise stated) has those with a tumor volume of <21 cm (42% vs 64%; P = 0.003) also been validated for usefulness by the RTOG 99–11 trial and [17]. Moreover, Mendenhall et al. recommended that higher- became and still is a standard of care for LP [8, 9]. Subsequent ICT volume tumors, particularly those that compromised the airway, studies carried out mainly in mixed populations (unresectable and should be treated with laryngectomy and postoperative RT, because resectable diseases) established the superiority of docetaxel, CDDP RT outcomes for T4 laryngeal cancer were generally poor and occa- and 5-FU (TPF-ICT) over PF-ICT [10, 11]. Unexpectedly, after sionally resulted in a non-functioning larynx [16, 18]. the establishment of CCRT’s role in LP, several studies noted a Fuller et al. eschewed LP in patients with both T3 and T4 laryn- decline in the survival rates for laryngeal cancer patients during the geal cancer who, after a pretreatment barium swallow test and/or late 1990s [12, 13], with a trend in increasing CCRT dissemination video stroboscope evaluation, had poor baseline airway function, (and a simultaneous decrease in surgeries). The studies’ investiga- evidenced by demonstrable aspiration to a degree wherein airway tors hypothesized that overuse of CCRT may compromise survival, protection after therapy was not possible [25]. For this reason, care- which brought about wide controversy. In addition, bioradiotherapy ful multidisciplinary evaluation, including direct pretherapy assess- (BRT) emerged as an alternative treatment for cases where CDDP ment by medical oncologists, head and neck surgeons, radiation was unavailable, despite insufficient evidence for its effectiveness for oncologists, diagnostic radiologists, pathologists, and experienced laryngeal cancer subpopulations [14]. Consequently, we encoun- speech pathology personnel, is imperative. Tracheostomy or tered difficulty in selecting from the various treatment options for feeding-tube dependency is also regarded as an indicator for poor locally advanced laryngeal cancer, which ranged from laryngectomy future laryngoesophageal function; however, several experienced (surgery [S], with or without following RT) to LP treatment institutions have achieved good results for patients exhibiting these (upfront CCRT or ICT → RT/CCRT/BRT). In addition, consider- characteristics, even for those with T4 tumors [19, 20]. ing LP as the primary endpoint carries the risk of obscuring the dif- Notably, ‘unresectable’ does not always mean ‘inoperable.’ The ferences between disease control, LP rates, and quality of life. definition of ‘inoperable’ varies among institutions. Usually, the Therefore, the endpoint should be a combination of survival and term unresectable has been used for infiltrative tumors that involve laryngoesophageal function. Patients with advanced laryngeal can- the cervical vertebrae, brachial plexus, deep muscles of the neck, cer who present with poor functional status, manifested by severe and carotid artery. Poor prognostic factors have been considered to airway compromise requiring a tracheostomy or enteric feeding, include direct invasion of the skin, mediastinal structures, or prever- are poor candidates for LP. As a result, it is difficult to apply the tebral fascia. Furthermore, patients who have refused surgery have outcomes of randomized controlled trials (RCTs) directly into daily also occasionally been included in the unresectable group. clinical practice. Given the confounding nature of these considera- tions (indication, patient will, need for a multidisciplinary team, PROSPECTIVE STUDIES OF T3–T4 LARYNGEAL etc.), especially for resectable cases, we have produced this narrative CANCER review of the role of RT in locally advanced resectable laryngeal From surgery to LP treatment cancer. This review summarizes retrospective and prospective clin- The advent of systemic therapy [chemotherapy (CDDP, 5-FU, and ical data in resectable T3–4 laryngeal cancer, investigating the larynx Paclitaxel)] in the 1980s brought with it the potential for improving preservation strategy by radiotherapy, with a focus on the LP. To survival without performing functionally debilitating surgery [5, 6]. identify suitable publications, the search strategy was as follows. The During the succeeding decades, two general substitution approaches Medline database was searched by entering all possible combina- evolved for the treatment of locally advanced cancers that require tions of one of the following key words: ‘radiation/radiotherapy’, total laryngectomy (Table 2): ICT → RT (or CCRT), which is ‘laryngeal cancer’, ‘locally advanced’, ‘T3 or T4’, ‘larynx preserva- favored in Europe, and concomitant CDDP and standard fraction- tion’. Thus, the aim of this study was to raise and investigate two ation RT (CCRT), which is preferred in North America. questions for resectable T3–4 laryngeal cancer: (i) Is an LP strategy feasible? (ii) Which treatment protocol is best?’ Comparison with surgery (control arm: S ± RT) The Veterans Administration Laryngeal Cancer Study Group RETROSPECTIVE DATA ABOUT T3–T4 trial The Veterans Administration Laryngeal Cancer Study Group LARYNGEAL CANCER trial (the VA study) provided the first key evidence to demonstrate T3 tumors are good candidates for LP after early RT, depending on LP feasibility [7]. PF-ICT (CDDP 100 mg/m d1 + 5-FU patient preference (Table 1). In contrast, T4 tumors, especially large 1000 mg/m Days 1–5 every 3 weeks) → RT [66–76 Gy/1.8–2 Gy/ instances, have been treated mainly by surgery. Intensive research fractions (fr)] for chemotherapy responders was found to be a Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 RT for resectable locally advanced laryngeal cancer � 79 Table 1. Retrospective outcome of radiotherapy for T3–4 laryngeal cancer T Author (institution) PY NO PT Treatment ¶LC ¶LP ¶OS category T3 Wylie (ChH) [21] 1999 114 RT only: 50–55 Gy/ 68% NA 54% 3.3–3.4 Gy/fr (AF) Hinerman (UF) [22] 2007 87 RT only: 50–79.2 Gy/ 67% NA Stage III 52% 1.2–2 Gy/fr (AF) Wolden (Michigan U) [23] 2009 73 FP → CCRT (or S) 3-year DFS 88% 3-year LFS 62% 3-year 83% Al-Mamagami 2012 170 CCRT [70 Gy/35 6 fr/ 68% 74% 60% (Netherlands) [24] week + CDDP] Fuller (MDACC) [25] 2016 166 CCRT or ICT → RT 10-year LRC 76% 10-year 37% 67% 121 RT only 18% 50% 125 S → RT NA 46% T4 Harwood (PMC) [26] 1981 56 RT only: 50–55 Gy/ 56% NA 64.5% 2.2–2.5/fr (AF) Hinerman (UF) [22] 2007 22 RT only: 50–79.2 Gy/ 82% NA Stage IVa 67% 1.2–2 Gy/fr (AF) Wolden (Michigan U) [23] 2009 36 FP→CCRT (or S) 3-year DFS 58% 3-year LFS 58% 3-year 78% Stenson (Chicago U) [19] 2011 55 CCRT: RT 70–75 Gy FPR 67.7% 88% 49% (AF) + FHX Rosenthal (MDACC) [27] 2015 161 S → RT 78% NA MST 64 M 60 CCRT 33% MST 64 M PY = year of publication, LC = local control rate (5 years unless otherwise stated), LP = larynx preservation (rate), LRC = locoregional control rate, FPR = functional preservation rate, OS = overall survival rate, DFS = disease-free survival rate, LFS = laryngectomy-free survival, MST = median survival time, NA = not available, RT = radiotherapy, ICT = induction chemotherapy, PF = CDDP + 5FU, FHX = 5-FU + hydroxyuria, CCRT = concurrent chemoradiotherapy, S = surgery, AF = alternated fractionation, Ch H = Christie Hospital Holt Radium Institute, UF = University of Florida, MDACC = MD Anderson Cancer Center, PMH = Princess Margaret Hospital. (1.5 Gy × 2 or 2 Gy/day × 5 days → 9-day interval) × 5–7 times. better strategy compared with laryngectomy (S) → RT. The Comparison with RT alone (control arm: RT alone) ICT → RT regimen was able to preserve the larynx (62% at 3 RTOG 91–11 CCRT (concomitant CDDP 100 mg/m on Day years) without jeopardizing OS. The study revealed that the patients 1, Day 22 and Day 43 plus RT 70 Gy/35 fr) was established as a in the ICT group showed a greater number of local recurrences but standard treatment by the pivotal Intergroup RTOG 91–11 trial, fewer metastases. which demonstrated good local control and unparalleled LP with The Groupe d’Etude des Tumeurs de la Tête et du Cou this CCRT regimen [8, 30]. The primary endpoint was (GETTEC) Richard et al. presented results for patients with T3 laryngectomy-free survival (with laryngectomy or death treated as laryngeal carcinoma [29]. They compared S → RT with PF-ICT → events in this trial). After 2 years, the CCRT arm exhibited a higher RT (65–70 Gy/2 Gy/fr) in good responders (42% LP rate) and LP ratio (88%) than the ICT → RT (75%, P = 0.005) or RT (70%, S → RT in poor responders. OS and disease-free survival (DFS) P < 0.001) arm. Locoregional control rates were also significantly were significantly worse for ICT →S(P = 0.006 and P = 0.02, better with CCRT (78%) compared with ICT → RT alone (61%) respectively). The 2-year OS for the ICT → RT and S → RT and RT (56%). Moreover, 5-year OS rates for RT alone, CCRT, groups were 69% and 84%, respectively. Surgery was associated with and ICT were 54%, 55% and 58%, respectively, all of which are rela- a greater number of superior outcomes than the LP strategy. tively similar. However, the survival curves diverged after 4.5 years, with 10-year OS rates of 32%, 28% and 39% for RT only, CCRT, Singapore study Soo et al. compared CCRT (RT 66 Gy/33 fr + 2 2 and ICT → RT, respectively, thus presenting ICT as the superior CDDP 20 mg/m + 5-FU 1000 mg/m d1 × 2) with S → RT treatment. It is possible that unrecognized or under-reported late (60 Gy/30 fr) in 119 patients and found no significant difference in toxicities could have contributed to some of the non-cancer-related 3-year DFS (50% vs 40%) [29]. The overall rate for organ preserva- deaths that emerged with the long follow-up period. tion or avoidance of surgery at the primary site was 45%. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 80 � H. Yamazaki et al. Table 2. Randomized control trials for organ preservation in resectable cases Study (Tx year) Site stage %T NO Tx (% RT received) % Tx Initial response to LP¶ OS¶ Toxicity T1–2/ PT complete ICT (CCRT) T3/T4 Author PY (MF) %N ICT (×3) unless CR/RR N0/N1/ otherwise stated N2/N3 Control arm: surgery (S → RT) VA study larynx III/IV 9/65/26 166 S → RT NA 45% same OS (PF lower (1985–1988) meta, lower LC) Wolf 1991 (USA) (33 M) 54/18/ 166 PF → RT (NA) 70% RR 85% 3-year 64%, 42% mucositis LP feasible [7] 11/17 (or S) FL 39% G2 ≤ 38% GETTEC larynx II–IV all T3 30 S → RT NA 2-year 84% S OS better (1986–1989) Richard 1998 (8.3Y) 78/15/ 33 PF → RT (36%) 31% 13 PT ≥ 80% 42% 69% (P = 0.006) G2 ≤ 33% early closure: PT (France) [28] 11/7 (or S) reduction (39%) refused S Singapore study bulky T4 or 18/26/56 60 S → RT NA 3-year DFS 50% same (1996–2002) IVA Soo 2005 [29] larynx 32% 49/46/5 59 CCRT 69% 69.6%/92.8% 45% 40% mucositis early closure: poor (6Y) G3 ≤ 39% accrual Control arm: radiotherapy (RT) RTOG91–11 larynx III/ 11/79/10 173 RT 94% 5-year 66%, 5-year 54%, high grade CCRT LP best, OS (1992–2000) IV 10-year 64% 10-year 32% 81% same c b Forastiere 2013 (10.8Y) 50/21/ 172 CCRT 91% 84%, 82% 55%, 28% 82% CCRT acute worse, (USA)[8, 30] endpoint 28/2 (P < 0.001) late same LP 173 PF → RT (83%) 84% 21%/83% 71%, 68% 59%, 39% 61% (or S) (P = 0.005) Cleveland study III/IV larynx 28/39/33 50 RT NA CR 66% LP 45%, LS 34% 48% feeding tube CCRT LP better, (1990–1995) 18% 32% OS same, toxicity worse Adelstein 2000 (5 Y) 47/47/6 50 CCRT (FP) NA 94% (P < 0.001) 77% (P < 50% 58% (USA [31] 0.001), 42% (P = 0.01) (P = 0.004) Tx = treatment, PY = year of publication, MF = median follow-up period, ICT = induction chemotherapy, LP = larynx preservation (rate) (5 years unless otherwise stated), OS = overall survival, RT = radiotherapy, S = surgery, CCRT = concurrent chemoradiotherapy, PF = CDDP + 5FU, NA = not available, VA = Department of Veterans Affairs Laryngeal Cancer Study Group, GETTEC = Groupe d’Etude des Tumeurs de la Teà te et du Cou, RTOG = Radiation Therapy Oncology Group, LS = laryngectomy-free survival, FL = functioning larynx, CR = complete response, PR = partial response, RR = response rate = CR + PR. Excluding T4 with thy- b c roid cartilage or >1 cm BOT invasion. Received more than 95% of the intended dose of radiotherapy (i.e. at least 67 Gy). Probably 100%, but not exactly stated. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 RT for resectable locally advanced laryngeal cancer � 81 The Cleveland study Adelstein et al. confirmed the superiority The Spanish Head and Neck Cancer Cooperative Group The 2 2 of CCRT (5-FU 1000 mg/m /day and CDDP 20 mg/m /day, on Spanish Head and Neck Cancer Cooperative Group (TTCC) per- Day 1 and Day 22, +RT 66–72 Gy/1.8–2 Gy/fr) over RT alone formed a comparison study between PF-ICT (CDDP 100 mg/m (66–72 Gy/1.8–2 Gy/fr) for LP but not OS in 100 patients with Day 1 + 5-FU 1000 mg/m Day 1–5 every 3 weeks) and TPF-ICT 2 2 resectable American Joint Committee on Cancer Stage III and IV (paclitaxel 175 mg/m Day 1, CDDP 100 mg/m Day 2, 5-FU disease [31]. Furthermore, 82% and 98% of the patients in the RT 500 mg/m Days 2–6 every 3 weeks) [37]. Patients with a CR or and CCRT arms had been rendered disease free (P = 0.02), partial response (PR) of >80% for the primary tumor received add- respectively. For RT vs CCRT, the 5-year OS rates, OS rates with itional CCRT. The PF and TPF arms had CR rates of 14% and primary site preservation, and local control rates without surgical 33% (P < 0.001) and a median time to treatment failure (TTF) of resection were 48% vs 50% (P = 0.55), 34% vs 42% (P = 0.004) 12 and 20 months (P = 0.006), respectively. TPF-ICT patients and 45% vs 77% (P < 0.001), respectively. tended to have longer OS (37 months in the PF-ICT arm vs 43 months in the TPF-ICT arm; P = 0.06). Moreover, this difference was more evident in patients with unresectable disease (OS: 26 Induction chemotherapy months in the PF-ICT arm vs 36 months in the TPF-ICT; P = Comparison with PF-ICT (control arm: PF-ICT → RT or 0.04). PF patients experienced more instances of Grade 2–4 muco- CCRT) sitis than TPF patients (53% vs 16%; P < 0.001). To enhance treatment intensity, regimens containing taxan (doce- taxel or paclitaxel) were intensely explored. Generally, TPF-ICT showed superior outcomes compared with PF for several RCTs. Comparison with upfront CCRT (control arm: CCRT) However, a number of these RCTs were criticized for their use of Docetaxel-Based Chemotherapy Plus or Minus ICT to Decrease non-standard approaches, leaving the regimen suitable for replacing Events in Head and Neck Cancer (DeCIDE) Cohen et al. the present standard treatment. showed equivalent outcomes for TPF-ICT (×2) (docetaxel 75 mg/m 2 2 Day 1, CDDP 75 mg/m Day 1, 5-FU 750 mg/m Days 1–5) → Groupe d’Oncologie Radiothérapie Tête Et Cou (GORTEC) CCRT (docetaxel, 5-FU, and hydroxyurea + RT 1.5 Gy twice per 2000–01 Pointeu et al. confirmed that TPF-ICT (docetaxel day every other week) and upfront CCRT in N2 or N3 disease 2 2 2 75 mg/m d1, CDDP 100 mg/m Day 1, 5-FU 1000 mg/m × 4 [38]. Grade 3–4 toxicities included febrile neutropenia (11%) and days) → RT (70 Gy/35 fr) increased LP and laryngeal dysfunction- mucositis (9%) during ICT and mucositis (49%), dermatitis (21%), free survival (LDFFS) better than PF-ICT (CDDP 100 mg/m and leukopenia (18%) during CCRT (both arms combined). Day 1, 5-FU 1000 mg/m × 5 days) → RT (70 Gy/35 fr) [32, 33]. Serious adverse events were more common in the ICT arm than in For TPF-ICT and PF-ICT, the 5-year (10-year) LP rates were the CCRT arm (47% vs 28%; P = 0.002). There were no statistic- 74.0% and 70.3% (58.1% and 46.5%), whereas the 5-year (10-year) ally significant differences in OS or RFS. LDFFS rates were 67.2% and 63.7% (46.5% and 37.2%, P = 0.001), Paccagnella et al. suggested the superiority of TPF-ICT (×3) respectively. TPF-ICT did not show any significant improvement in 2 2 2 (docetaxel 75 mg/m , CDDP 80 mg/m Day 1, 5-FU 800 mg/m OS, DFS or LCR compared with PF-ICT. Statistically fewer late 96 h every 3 weeks, n = 51) → CCRT over CCRT alone (CDDP Grade 3–4 toxicities of the larynx occurred with TPF-ICT than with 2 2 20 mg/m Days 1–4, 5-FU 800 mg/m Week 1 and Week 6, PF-ICT (9.3% vs 17.1%, P = 0.038). 66–70 Gy, n = 50) in terms of initial response [39]. TPF-ICT → TAX 324 Posner and Loach et al. compared TPF-ICT with PF- CCRT achieved 50% of the primary endpoint (CR at 6–8 weeks ICT followed by 7 weeks of CCRT (RT 70–74 Gy/2 Gy/fr + car- after CCRT), whereas CCRT alone achieved 21% (P = 0.004). The boplatin AUC 1 × 5 weekly) in resectable and unresectable cases CCRT and TPF-ICT → CCRT groups had an MST of 33.3 and [34–36]. TPF-ICT had a significantly better OS than PF-ICT [haz- 39.6 months (P = 0.268), respectively. This study used a non- ard ratio (HR) 0.74, P = 0.014], with 5-year OS rates of 52% and standard chemotherapeutic drug dose for CCRT (Table 3). 42% for TPF-ICT and PF-ICT, respectively. The TPF-ICT and PF- ICT groups had a MST of 70.6 and 34.8 months, respectively. Progression-free survival (PFS) was also significantly better in Other trials patients treated with TPF-ICT than with PF-ICT (median 38.1 The CONDOR trial months vs 13.2 months). No significant difference was found for TheCONDOR trial examined theroleofalternatedRTafter dependence on gastric feeding tubes (3% vs 11%) or tracheostomies four courses of TPF-ICT → CCRT × 4 (CDDP 100 mg/m = (7% vs 11%) between the treatment groups. They also made a sub- cis100 + RT 70 Gy/35 fr including intensity-modulated RT) or population analysis limited to laryngeal (54% of entire population) CDDP 40 mg/m weekly with accelerated RT (=cis40 + acceler- and hypopharyngeal cancers (74% operable: 90 PF-ICT and 76 ated RT;ART:6 fr/wk = 70 Gy/6 wks) [40]. Unfortunately, the TPF-ICT patients) [36]. OS rates for laryngeal cancer in the PF- data safety monitoring board advised premature termination of ICT and TPF-ICT groups were 45% and 65% (P < 0.05), respect- the study, because only 22% and 41% (32% in total) of the ively. In the operable group, the 3-year laryngectomy-free survival patients treated with cis100 + RT (n = 27) and cis40 + ART rates for TPF-ICT and PF-ICT were 52% and 32% (P = 0.03), (n = 29) could receive the planned CDDP dose during CCRT, respectively. The main point of criticism was the use of a non- respectively. This trial revealed the difficulty of performing standard CCRT regimen (carboplatin). CCRT after TPF-ICT. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 82 � H. Yamazaki et al. Table 3. Randomized control trials of induction chemotherapy (ICT) including unresectable cases Study (Tx year) Stage %T–T2/T3/ NO RT (% received) Tx % Initial response LP OS¶ Toxicity T4 PT completed ICT (CCRT) Author PY (MF) %N N0/N1/ ICT (×3) if [without CR/RR (CR/ Endpoint N2/N3 otherwise stated delay or RR) reduced dose] ICT: PF vs TPF: control arm (PF-ICT → RT or CCRT) Resectable GORTEC2000–01 III/IV larynx 18/67/15 103 PF → RT (47%) 80% [32%] 30.1%/59.2% 3-year 57% 5y 50.9%, 10y G3- late 17.1% TPF better LP (2000–2005) 46% or CCRT 30.2% same OS (9%) Pointeu 2009 [32, (105 M) LP 39/23/33/4 110 TPF → RT 90% 41.8%/80% 70% (P = 0.03) 41.9%, 23.5% 9.3% (P = 0.035) 33] (61%) or [62.7%] (P = 0.002) CCRT (15%) Mix (resectable and unresectable) TAX 324 III/IV Larynx 25(T1–2)/ 245 PF → CCRT 73% 15%/64% 3-year 32%, 3- 52% feeding tube TPF better LP OS (1999–2003) 18% 32/43 (carboplatin) year LFS 32%, dependent 11%, (75%) 3-year LRC tracheostomies 70% 11% Posner 2007 [34– (72.2 M) OS 16/20/50/14 255 TPF → CCRT 68% 17%/72%(P = 52% (P = 0.02), 42% 3%, 7% 36] PFS (carboplatin) 0.07) 52%, 62% (P = 0.014) (79%) TTCC (1998–2001) III/IV larynx 11(T1–2)/ 193 PF → CCRT 36% 14%/68% NA 2-year 32%, mucositis Grade 3 TPF better LP OS 16% 34/55 (42%) (78%/88%) MST 37M ≤53% in unresectable (unresectable subpopulation 26 M) Hitt 2005 (Spain) (24 m) CR 21/19/47/13 189 T (paclitaxel) 60% 33% (P < 43% 43M 16% (P < 0.001) [37] rate PF → CCRT 0.001)/80% (P = 0.06), (60%) (88%/98%) (36M P = 0.03) 128 CCRT (92%) 71% (48.6%/90.5%) 13.8 M 27.6 M, 7.9 M 2 (1.5%) Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 RT for resectable locally advanced laryngeal cancer � 83 Upfront CCRT vs ICT(TPF) → CCRT: control arm CCRT Mix (resectable and unresectable) DECIDE N2/#3 45(T0–2)/ 135 CCRT 94% (21%/74%) NA 65% Serious adverse Same OS (2004–2009) larynx 22/22 events 28% 13.6% Cohen 2014 [38] (min 30 M) 0/0/88/11 138 TPF×2 → CCRT 86% RR 64% (26%/ 64% 47% P = 0.002 Underpowered OS (90%) 79%) Others Resectability NS CONDOR Stage III–IV 18/35/47 27 TPF (×2–4) → [22%] 6.5%/61.3% 2-year PFS 70% 72% Febrile Early closure: low- (2008–2012) larynx 8% CCRT (90% (81.5%) neutropenia feasibility allocated) 18% (during TPF) Driessen 2016 (38 M) 23/5/72 29 TPF (×2–4) → [41%] (72.4%) 78% 79% G3–4 26% (Holland) [40] feasibility CCRT cis 40 ≥90% RT (90% allocated) Tx = treatment, PY = year of publication, MF = median follow-up period, RT = radiotherapy, CCRT = concurrent chemoradiotherapy, ICT = induction chmotherapy, LP = larynx preservation rate, OS = overall survival time (5 years unless otherwise stated), PFS = progression-free survival rate, PF = CDDP + 5FU, TPF = Taxan + CDDP + 5-FU, GORTEC = Groupe d’Oncologie Radiothérapie Tête Et Cou, EORTC = European Organization for Research and Treatment of Cancer, TTCC = Spanish Head and Neck Cancer Cooperative Group, DECIDE = Docetaxel-Based Chemotherapy Plus or Minus IC to Decrease Events in Head and Neck Cancer, CR = complete response, PR = partial a b 2 response, RR = response rate = CR + PR, NA = not available, TTF = time to treatment failure. Estimated from graph. RT 72 Gy/1.8 + 1.5 Gy bid/6 wk + docetaxel 20 mg/m /wk × 4 for poor responder at TPF-ICT or RT 70 Gy/35 fr + carboplatin AUC 1·5/week × 7 weeks for good responder. Low surgical curability or LP candidate. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 84 � H. Yamazaki et al. In addition, Hitt et al. showed that ICT had significantly better 14.9 months for BRT and RT (HR 0.68; P = 0.005), respectively. PFS than CCRT alone in the per protocol population [41]. These BRT significantly prolonged PFS (HR 0.70; P = 0.006) and OS. data suggested that ICT could be beneficial for patients who can Except for acneiform rash and infusion reactions, the incidence of complete the treatment protocol. On the other hand, ICT might Grade 3 or greater toxic effects, including mucositis, did not differ only delay CCRT in those who are unable to complete the treat- significantly between the two groups. However, subpopulation ana- ment protocol, without any benefit except for additional therapeutic lysis showed that BRT was not superior to RT alone for laryngeal toxicity. Therefore, patient selection is an important issue for future cancer [53]. Although BRT has been extensively explored since this trials [42, 43]. Michigan University [43] and Popovtzer et al. pro- trial, it has thus far failed to establish its superiority in laryngeal can- posed chemotherapy selection during the first cycle of TPF-ICT [42], cer treatment. with responses being determined by examination and positron emis- sion tomography (PET)-CT. In those studies, responders (>50% Radiotherapy With Cisplatin Vs Radiotherapy With Cetuximab tumor reduction) underwent chemoradiation, whereas non-responders underwent laryngectomy. A total of 83% of the patients responded to After Induction Chemotherapy for Larynx Preservation the treatment, while 17% had stable or progressive disease. After 2 (TREMPLIN) (GORTEC + GETTEC) years, the median OS rate, LP rate and disease-specificsurvivalrate The TREMPLIN study compared CCRT and BRT for LP [50]in were 80%, 83% and 86%, respectively. Response to a single TPF cycle 153 operable patients (laryngeal or hypopharyngeal cancer, T2–T3 was associated with 2-year OS (92% vs 50%; P = 0.02). and N0–N3) after TPF-ICT. The primary endpoint was LP 3 months after treatment, with an expected rate of 80%. Secondary endpoints were laryngeal function preservation (LFP) and OS at 18 Meta-analysis of chemotherapy in head and neck cancer months. Among the 156 patients who received TPF-ICT, 126 The pivotal Meta-Analysis of Chemotherapy in Head and Neck (86%) achieved PR ≤ and 23 patients <PR (non-responders Cancer (MACH-NC) study was first reported in 2002 and updated received S [16]orRT[7]). Subsequently, 116 patients (76% of in 2009 (87 trials and 16 485 patients) [44, 45]. These studies con- those included in the TPF-ICT group) were categorized into cluded that CCRT proved to be considerably more successful than CCRT (60) (70 Gy/35 fr) or BRT (56) (70 Gy/35 fr). No signifi- alternative treatments. Adding ICT (PF-ICT) to locoregional treat- cant difference between BRT and CCRT was observed with regard ment was associated with a slight improvement in OS and distant to LP at 3 months (95% and 93%), LFP (87% and 82%) or OS at failure. The HR of death was 0.88 (P < 0.0001), with an absolute 18 months (92% and 89%). Unfortunately, considering the 24% of chemotherapy benefit of 4.5% at 5 years. CCRT showed a more patients who dropped out, the trial did not reach the expected 80% pronounced benefit compared with ICT. The HR for CCRT was LP 3 months after treatment. Though BRT was shown to be as 0.81 (P < 0.0001), with an absolute benefit of 6.5% at 5 years. toxic as CCRT, causing the same rate of Grade 3 to 4 acute mucosi- A decrease in the effects of chemotherapy was observed with age tis, it had worse in-field skin toxicity. More local failures (8.3% vs (P = 0.003, test for trend). In addition, despite current intensive 14.3% at 18 months) among patients treated with cetuximab raised efforts, no form of acceleration can potentially fully compensate for the possibility that BRT may be inferior to CCRT for achieving the lack of concurrent chemotherapy [15, 46]. local control in laryngeal cancer. This is the only RCT providing Several meta-analyses have been performed to answer subse- evidence for the similarity in the outcomes of TPF-ICT → BRT quent questions [47–49]. Comparing PF-ICT and TPF-ICT in and TPF-ICT → CCRT. 1772 patients, Blanchard et al. [9] showed that TPF-ICT had an absolute benefit of 7.4% after 5 years and was associated with a sig- nificant reduction in progression, locoregional failure, and distant RTOG0522 failure when compared with PF-ICT [9]. However, only 49% of Ang et al. made a comparison between CCRT and CCRT + cetuxi- patients treated with taxanes were able to complete sequential mab (BCCRT) [52]. RT (72 Gy/42 fr/6 weeks: twice a day for 6 CCRT as planned. Kim et al. also concluded that ICT using TPF- days) was delivered as scheduled. When IMRT was used, the proto- ICT followed by CCRT did not improve OS [11], although PFS col was changed to twice a day once a week for 5 weeks (70 Gy/35 and response rates were significantly improved. Furthermore, fr/6 weeks). Compared with CCRT, BCCRT had more frequent Gyawali et al. concluded that concurrent CCRT should be preferred RT interruptions (26.9% vs 15.1%), similar CDDP delivery (mean, over ICT at present [10] (Table 4). 2 2 185.7 mg/m vs 191.1 mg/m ) and more Grade 3–4 radiation mucositis (43.2% vs 33.3%), rash, fatigue, anorexia, and hypokalemia BRT (cetuximab)—is BRT safer than CCRT? toxicities but less late toxicity. Similar outcome was obtained; 3-year The Bonner trial PFS (61.2% vs 58.9%), 3-year OS (72.9% vs 75.8%), locoregional Bonner et al. introduced BRT (cetuximab + RT) for the treatment failure (19.9% vs 25.9%) and distant metastasis (13.0% vs 9.7%; P of advanced head and neck cancers [15, 51]. After comparing RT = 0.08). Patients with p16-positive oropharyngeal carcinoma and BRT (an initial dose of 400 mg cetuximab, a monoclonal anti- (OPC) showed better PFS (72.8% vs 49.2%; P < 0.001) and OS body against the epidermal growth factor receptor, followed by (85.6% vs 60.1%, P < 0.001) than those with p16-negative OPC. 250 mg/m weekly for the duration of RT), response rates of 64% Subpopulation analysis showed an inclination similar to that shown and 74% were found in the RT and BRT arms (P = 0.02), respect- in the Bonner trial, wherein CCRT seemed to be superior to ively. The median durations of locoregional control were 24.4 and BCCRT in patients with laryngeal cancer. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 RT for resectable locally advanced laryngeal cancer � 85 Table 4. Randomized control trials for bioradiotherapy (BRT) including unresectable cases Study (Tx year) Stage %T NO RT (% received) Tx LP OS¶ Toxicity larynx % T1–2/T3/T4 PT % completed Author PY (MF) Endpoint %N ICT (×3) unless [without delay or N0/N1/N2/N3 otherwise stated reduced dose] Resectable TREMPRIN III/IV larynx 41% 14/56/30 60 TPF → CCRT (74% 90% CCRT allocated 3 M 95%, 18 M 92% mucositis Grade 3 TPF→BRT same (2006–2008) TPF allocated) LFP ≤46% (in-field efficacy 87% 26%) Lefebvre 2013 (36 M) 3 M LP 36/26/38/0 56 TPF → BRT (74% 95% BRT allocated 93%, 82% 89% 45% (57%) BRT toxic as [50] TPF allocated) CCRT Resectability NS Bonner trial III/IV larynx 25% 31/39/30 213 RT unacceptable variation 3-year 36.4% MST acneiform rush G3 BRT OS better in (1999–2002) in RT 6% LRC 49 M ≤0.5% entire group unevaluable RT 34% 6% Bonner 2006 (54 M) NA 19/19/53/9 211 BRT 4%, 9% 47% 45.6% (P = 8% (P < 0.001) BRT not superior [14, 51] 0.03) 54 M to RT in larynx RTOG 0522 III/IV larynx 23% 39/37/24 447 CCRT radiation LRF 19.9% 3-year 72.9%, mucositis Grade 3 same PFS, OS (2005–2009) interruptions 42% PFS 61.2% ≤33.3% Ang 2014 [52] (3.8-year) PFS 11/9/75/5 444 BCCRT 51% (P < 0.001) 25.9% 75.8%, 58.9% 43.2% P16 important Italy PII III/IV larynx 26% 24/33/43 35 CCRT cis40 100% 2-year LC 2-year 78% severe 3%, RT stop 10 early closure: poor (2011–2014) 53% days <0% accrual Magrini 2016 (19.3 M) Tx 36/44/20 35 BRT 91% 80% P = 68% 19% (P = 0.044), 13% BRT toxic than [53] compliance 0.07 (P = 0.05) expected Tx = treatment, PY = year of publication, MF = median follow-up period, RT = radiotherapy, ICT = induction chemotherapy, BRT = bioradiotherapy, BCCRT = biochemoradiotherapy, CCRT = concurrent chemoradiotherapy, LP = larynx preservation (rate), OS = overall survival rate (5 years unless otherwise stated), LC = local control rate, LRC = locoregional control rate, LRF = locoregional failure rate, PFS = progression-free survival rate, LFP = larynx function preservation, SFL = survival with functioning larynx, NS = not stated. TREMPLIN = Radiotherapy With Cisplatin Vs Radiotherapy With Cetuximab After Induction Chemotherapy for Larynx Preservation, RTOG = Radiation Therapy Oncology Group. 70 Gy/35 fr or 72–76.8 Gy (1.2 Gy twice a day) concomitant boost 72 Gy. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 86 � H. Yamazaki et al. Magrini et al. made a direct comparison (Phase II trial) between DISCUSSION CCRT (70 Gy/35 fr + CDDP 40 mg/m /wk) and BRT, concluding LP strategy may decrease OS that BRT lowered compliance, increased acute toxicity rates, and Despite treatment, the 5-year OS of locally advanced laryngeal can- had similar efficacy as compared with CCRT [53]. The endpoints cer ranges from 30% to 70%. Chen et al. [12] reviewed 52 817 included compliance, toxicity and efficacy. The study was discontin- patients treated between 1985 and 2007 using the National Cancer ued early because of slow accrual after the enrollment of 70 patients. Database, noting an increase in the administration of radiation with RT discontinuation for more than 10 days occurred in 13% and 0% or without chemotherapy from <7% to 45%. Primary total laryn- of the patients receiving BRT and CDDP (P = 0.05), respectively. gectomy decreased from 42% to 32%. The 4-year OS rates for total Hematologic, renal and GI toxicities were more frequent in the laryngectomy, CCRT, and RT were 51%, 48% and 38%, respect- CDDP arm, whereas cutaneous toxicity and the need for nutritional ively. Using SEER data, Pulte et al. reported improvements in sur- support were more frequent in the BRT arm. Serious adverse events vival rates for head and neck cancer patients but not laryngeal were higher in the BRT arm than in the CDDP arm (19% vs 3%, cancer patients during the late 20th century [58]. This has also pro- P = 0.044; including 4 vs 1 toxic deaths). Although efficacies were ven to be true for a recent series of cases diagnosed in the period similar, BRT toxicity was higher than expected. 2004–2012, as reported by the National Cancer Database Analysis A German LP trial [54] utilized a protocol with three cycles of group in the USA [59, 60]. A total of 1559 cases treated with S → TPF-ICT (dose according to the TAX 323 trial) → CCRT (con- RT, 1597 with CCRT, and 386 with ICT were included. After comitant boost RT) with or without cetuximab for 16 weeks (start- adjusting for covariates, CCRT was found to be associated with ing with ICT and continuing with RT) in 180 patients. In case inferior OS compared with S → RT (HR 1.55; P < 0.01) and ICT of non-response after the first cycle, salvage laryngectomy was (HR, 1.25 P < 0.01). These reports sparked controversy. For performed. The investigators omitted 5-FU following four therapy- example, inappropriate patient selection for the LP strategy may related deaths at the beginning of the trial. The addition of cetuxi- decrease survival of locally advanced laryngeal cancer. Several mab to TPF-ICT seems to have profound effects on toxicity. important factors still need to be known before RCT outcomes can Studies attempting to add cetuximab to TPF-ICT showed excessive be translated into routine clinical work. toxicity. Therefore, current research has explored the possibility of omitting 5-FU and replacing it with cetuximab. Petrelli et al. performed a meta-analysis including 15 trials Limitations of RCTs (1808 patients) to assess the role of BRT [55]. Overall, CCRT Locally advanced (Stage III/IV) tumors are considered to include significantly improved 2-year OS (response rate = 0.66; P = 0.02), cancers of Stages T2N1 to T4N3, which are evidently different cat- 2-year PFS (response rate = 0.68; P = 0.002), and 2-year locore- egories. The aforementioned RCTs sometimes included patients gional control rate (response rate = 0.63; P = 0.005) compared with T3 tumors without cord fixation and T4 tumors with minimal with BRT. BRT had a toxicity profile similar to CCRT and was cartilage invasion. For instance, the VA study showed that <60% of difficult to deliver after TPF-ICT. The aforementioned studies the population had tumors with cord fixation, whereas all patients in (TREMPLIN, PARADIGM and DeCIDE) suggested that, despite the French GETTEC study presented with cord fixation, resulting the fascinating nature of strategies using ICT and CCRT or BRT in a superior OS after surgery. to control both locoregional and distant metastases, they have In addition, T category migration is an important confounding been difficult to implement because of their association with factor. Significant differences in the assessment of vocal cord fixation severe toxicities. have been found between experts and trainees [61], which may lead Thereafter, Mesia et al. (TTCC2007/02) reported feasible to misclassifications of T2 and T3 categories. Given that gross cartil- results for TPF-ICT (×3) → BRT in 93 patients with resectable age invasion was also difficult to detect using CT images [62], a laryngeal cancer (a Phase 2 study, with patients treated between substantial ratio of T4 tumors diagnosed using CT images may have 2008 and 2011) [56]. Among the 93 patients, 76 were responsive actually been T3 tumors after pathological examination. This is also (37 CR + 38 PR = 81% response rate), while 73 patients (78%) true for magnetic resonance imaging (MRI) usage, which improved received BRT. The 3-year actuarial rates for survival with functional the diagnostic accuracy of T4 cartilage invasion. Therefore, a dis- larynx, laryngectomy-free survival, and OS were 70%, 72% and 78%, crepancy in T category classification exists between the previously respectively. The acute toxicity observed during both ICT and BRT used CT examinations and the more recently used MRI-based was expected, with only one toxicity-related death (local bleeding) examinations. during BRT. Compliance with chemoradiotherapy (CRT) is another problem Zenda et al. also postulated the feasibility of TPF-ICT × that needs to be addressed when interpreting RCTs. The VA and 3 → BRT in a Japanese population of 54 patients, 19% of which GETTEC trials reported that only 7% and 0% of the patients dis- had laryngeal cancer (2013–2015) [57]. The response rates for continued CTX, respectively. Moreover, the RTOG 9011 trial ICT and RT were 72% and 76%, respectively. Among the 54 showed that 7% of the responders discontinued CTX after two patients, 50 (93%) received >2 courses of ICT, whereas 41 cycles of ICT, whereas 70% of those receiving CCRT completed all (76%) had full-dose RT. The rate of treatment completion was three cycles of CTX. On the other hand, Givens et al. showed that thus 76%. The frequencies of Grade 3–4 neutropenia, febrile only 48% of the patients (including 16% with larynx) completed the neutropenia, and allergic/infusion reactions were 93%, 39% and planned CTX cycles [63]. A cumulative CDDP dosage of 200 mg 11%, respectively. or more indicated better outcomes when administered concurrently Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 RT for resectable locally advanced laryngeal cancer � 87 with RT [66]. Recent results suggest that larger amount of CDDP Nedaplatin and S-1 [70]. Primary site tumors and neck lymph is associated with survival benefit in patients with human papilloma- nodes exhibited CR rates of 91% and 64.3%, respectively, with a virus (HPV)-negative but not HPV-positive LAHNC, with the 4-year OS of 85.3%. Several institutions have also explored intra- exception of the T4 or N3 subset wherein a higher cumulative cis- arterial chemotherapy with good results. Suzuki et al. reported platin dose was associated with a trend toward improved OS [64]. 3-year OS and LP rates of 92% and 93%, respectively [71]. Therefore, a huge bias exists between routine clinical practice and RCTs, such that most patients included in RCTs belong to a CONCLUSION healthier population with less severe comorbidities, better functional Regarding the first question, ‘Is an LP strategy feasible?’, the answer status, and a lesser likelihood of suffering from adverse events is ‘yes’ if the goal is set at improving the LP ratio. However, appro- related to treatments [65]. priate eligibility criteria are still emerging and currently vary depend- It is also important to emphasize that previous key trials were ing on the institution. performed using two-dimensional RT techniques and that the use Regarding the second question ‘Which treatment protocol is of more advanced RT techniques, such as IMRT and particle ther- best?’ At present, this cannot be answered because the goal can vary apy, could probably lead to less late radiation toxicity. Whether (superior OS, better Quality of Life, less morbidity), depending on today’s modern conformal radiation delivery systems reduce late patient and physician preference. normal tissue toxicity (other than that to the parotids) remains to In conclusion, options for LP, including CCRT, ICT, and BRT, be established [25]. have successfully emerged over the past several decades, without an improvement in OS. A new paradigm shift involving new systemic Surgery remains as a best treatment for T4 disease for therapies, molecular markers, and/or technology is needed to OS and requirement of multidiscipline team for LPF improve not only OS rates but also LFP. Sanabria et al. recommended that total laryngectomy be considered for advanced T4 laryngeal cancers in non-academic settings, given that its survival outcomes appear to be better than those for CCRT, CONFLICT OF INTEREST according to the results of many observational studies [65]. CCRT The authors declare that they have no competing interests. can be acceptable for patients with T3 tumors given the condition that all resources for treatment administration, follow-up, and surgi- FUNDING cal salvage are available. Nakayama et al. noted that organ-sparing The authors have no funding source. approaches require (i) a high level of skill and cooperation among various disciplines, (ii) adequate compliance from patients, and (iii) careful documentation and appropriate surveillance [66]. REFERENCES 1. Parkin DM, Bray F, Ferlay J et al. Global cancer statistics, 2002. No strategy could add a merit in elder population CA Cancer J Clin 2002;55:74–108. It should also be noted that all strategies to improve outcome, 2. Michigan Medicine. Comprehensive Cancer Centre. What including CCRT, accelerated RT, and BRT, could not establish Patients Should Know in Decision Making. http://www.mcancer. their merit with increasing age, showing no difference in survival vs org/head-and-neck-cancer/voicebox/what-patients-should-know conventional RT alone in patients older than 70 years of age [17, (10 April 2017, date last accessed). 43, 51, 67]. Therefore, elderly patients should be given special con- 3. 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Hoshikawa H, Kishino T, Mori T et al. Clinical outcomes of 66. Nakayama M, Okamoto M, Hayakawa K et al. Clinical out- nedaplatin and S-1 treatment with concurrent RT in advanced comes of 849 laryngeal cancers treated in the past 40 years: are head and neck cancer. Acta Otolaryngol 2015;135:103–8. we succeeding? Jpn J Clin Oncol 2014;44:57–64. 71. Suzuki G, Yamazaki H, Ogo E et al. Predisposing factors for lar- 67. Bourhis J, Overgaard J, Audry H et al. Hyperfractionated or ynx preservation strategies with non-surgical multimodality treat- accelerated radiotherapy in head and neck cancer: a meta- ment for locally advanced (T3–4) larynx, hypopharynx and analysis. Lancet 2006;368:843–54. cervical esophageal disease. Anticancer Res 2014;34:5205–10. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Radiation Research Oxford University Press

Radiotherapy for locally advanced resectable T3–T4 laryngeal cancer—does laryngeal preservation strategy compromise survival?

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Journal of Radiation Research, Vol. 59, No. 1, 2018, pp. 77–90 doi: 10.1093/jrr/rrx063 Advance Access Publication: 28 November 2017 Radiotherapy for locally advanced resectable T3–T4 laryngeal cancer—does laryngeal preservation strategy compromise survival? 1, 1 1 2 Hideya Yamazaki , Gen Suzuki , Satoaki Nakamura , Shigeru Hirano , 3 4 4 5 Ken Yoshida , Koji Konishi , Teruki Teshima and Kazuhiko Ogawa Department of Radiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajiicho Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan Otorhinolaryngology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajiicho Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan Department of Radiology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-City, Osaka, 569-8686, Japan Department of Radiation Oncology, Osaka International Cancer Institute, Osaka 541-8567, Japan Department of Radiation Oncology, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan *Corresponding author. Department of Radiology, Kyoto Prefectural University of Medicine, 465 Kajiicho Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566 Japan. Phone: 81-75-251-5618, Fax: 81-75-251-5840, Email: hideya10@hotmail.com (Received 2 July 2017; revised 14 August 2017; editorial decision 1 October 2017) ABSTRACT With the advancement of chemotherapy, a laryngeal preservation (LP) strategy was explored with the aim of improving maintenance of quality of life. Induction chemotherapy (ICT) following radiotherapy (RT) was con- sidered a viable option because of its high initial response rate without hampering of overall survival (OS). Subsequently, concurrent chemoradiotherapy (CCRT) using CDDP became the standard of care for LP, show- ing the best LP ratio. For enhancing treatment intensity, ICT with taxan + CDDP + 5-FU (TPF-ICT) followed by RT showed superiority over ICT with CDDP + 5-FU (PF-ICT) followed by RT. Given that almost all ran- domized controlled trials investigating ICT include not only operable (endpoint, LP) but also inoperable (end- point, OS) cases, physicians are faced with a dilemma regarding application in daily practice. In addition, increased treatment intensity causes augmentation of adverse events, which might reduce compliance. Thereafter, cetuximab, an effective drug with fewer adverse effects [bioradiotherapy (BRT)], emerged as another option. However, little evidence has confirmed its superiority over RT (or CCRT) in laryngeal cancer subpopula- tions. In spite of these developments, the OS of patients with laryngeal cancer has not improved for several decades. In fact, several studies indicated a decrease in OS during the 1990s, probably due to overuse of CCRT. Fortunately, the latter was not the case in most institutions. Currently, no other treatment has better OS than surgery. The eligi- bility criteria for LP and/or surgery largely depend upon the available expertise and experience, which differ from one institution to another. Therefore, a multidisciplinary team is required for the treatment of LP. Keywords: laryngeal cancer; larynx preservation; concurrent chemoradiotherapy; induction chemotherapy INTRODUCTION investigate this type of cancer because of its significant effects on Squamous cell carcinoma (SCC) of the head and neck is the sixth the voice, swallowing, and quality of life. Surgery has been the pri- most common type of cancer worldwide, with over 650 000 new mary treatment for locally advanced laryngeal cancer. During the diagnoses every year [1], while laryngeal cancer accounts for mid-1980s, CDDP and 5-FU (PF) before resection had been incor- ~200 000 deaths annually [2]. Although laryngeal cancer represents porated into a highly effective induction chemotherapy regimen only 2–5% of all malignancies, it is particularly important to (PF-ICT), with response rates of 85–90% and complete response © The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re- use, please contact journals.permissions@oup.com � 77 Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 78 � H. Yamazaki et al. (CR) rates of 35–55% [3, 4]. Thereafter, a combination of these has been undertaken in order to improve patient outcomes for chemotherapeutic agents with radiotherapy (RT) had been explored advanced disease. For instance, non-standard alternated fraction- as a substitute for surgical intervention for laryngeal preservation ation (acceleration of hyperfractionation, etc.) has been extensively (LP) [5, 6]. The Veterans Administration Laryngeal Cancer Study trialled in several institutions (Table 1)[15]. Mendenhall et al. Group trial (henceforth, the VA study) confirmed the compatibility reported that the probability of cure was ~65–80% for select low- of ICT → RT and surgery → RT, supporting and emphasizing the volume (≤3.5 cm ) T3 to T4 glottic SCCs after RT [16]. Shiao merits of this regimen in maintaining quality of life by avoiding lar- et al. reported that patients with a tumor volume of ≥21 cm had yngectomy [7]. Concurrent CDDP + RT (concurrent chemora- significantly inferior 5-year overall survival (OS) compared with diotherapy [CCRT] = with CDDP, unless otherwise stated) has those with a tumor volume of <21 cm (42% vs 64%; P = 0.003) also been validated for usefulness by the RTOG 99–11 trial and [17]. Moreover, Mendenhall et al. recommended that higher- became and still is a standard of care for LP [8, 9]. Subsequent ICT volume tumors, particularly those that compromised the airway, studies carried out mainly in mixed populations (unresectable and should be treated with laryngectomy and postoperative RT, because resectable diseases) established the superiority of docetaxel, CDDP RT outcomes for T4 laryngeal cancer were generally poor and occa- and 5-FU (TPF-ICT) over PF-ICT [10, 11]. Unexpectedly, after sionally resulted in a non-functioning larynx [16, 18]. the establishment of CCRT’s role in LP, several studies noted a Fuller et al. eschewed LP in patients with both T3 and T4 laryn- decline in the survival rates for laryngeal cancer patients during the geal cancer who, after a pretreatment barium swallow test and/or late 1990s [12, 13], with a trend in increasing CCRT dissemination video stroboscope evaluation, had poor baseline airway function, (and a simultaneous decrease in surgeries). The studies’ investiga- evidenced by demonstrable aspiration to a degree wherein airway tors hypothesized that overuse of CCRT may compromise survival, protection after therapy was not possible [25]. For this reason, care- which brought about wide controversy. In addition, bioradiotherapy ful multidisciplinary evaluation, including direct pretherapy assess- (BRT) emerged as an alternative treatment for cases where CDDP ment by medical oncologists, head and neck surgeons, radiation was unavailable, despite insufficient evidence for its effectiveness for oncologists, diagnostic radiologists, pathologists, and experienced laryngeal cancer subpopulations [14]. Consequently, we encoun- speech pathology personnel, is imperative. Tracheostomy or tered difficulty in selecting from the various treatment options for feeding-tube dependency is also regarded as an indicator for poor locally advanced laryngeal cancer, which ranged from laryngectomy future laryngoesophageal function; however, several experienced (surgery [S], with or without following RT) to LP treatment institutions have achieved good results for patients exhibiting these (upfront CCRT or ICT → RT/CCRT/BRT). In addition, consider- characteristics, even for those with T4 tumors [19, 20]. ing LP as the primary endpoint carries the risk of obscuring the dif- Notably, ‘unresectable’ does not always mean ‘inoperable.’ The ferences between disease control, LP rates, and quality of life. definition of ‘inoperable’ varies among institutions. Usually, the Therefore, the endpoint should be a combination of survival and term unresectable has been used for infiltrative tumors that involve laryngoesophageal function. Patients with advanced laryngeal can- the cervical vertebrae, brachial plexus, deep muscles of the neck, cer who present with poor functional status, manifested by severe and carotid artery. Poor prognostic factors have been considered to airway compromise requiring a tracheostomy or enteric feeding, include direct invasion of the skin, mediastinal structures, or prever- are poor candidates for LP. As a result, it is difficult to apply the tebral fascia. Furthermore, patients who have refused surgery have outcomes of randomized controlled trials (RCTs) directly into daily also occasionally been included in the unresectable group. clinical practice. Given the confounding nature of these considera- tions (indication, patient will, need for a multidisciplinary team, PROSPECTIVE STUDIES OF T3–T4 LARYNGEAL etc.), especially for resectable cases, we have produced this narrative CANCER review of the role of RT in locally advanced resectable laryngeal From surgery to LP treatment cancer. This review summarizes retrospective and prospective clin- The advent of systemic therapy [chemotherapy (CDDP, 5-FU, and ical data in resectable T3–4 laryngeal cancer, investigating the larynx Paclitaxel)] in the 1980s brought with it the potential for improving preservation strategy by radiotherapy, with a focus on the LP. To survival without performing functionally debilitating surgery [5, 6]. identify suitable publications, the search strategy was as follows. The During the succeeding decades, two general substitution approaches Medline database was searched by entering all possible combina- evolved for the treatment of locally advanced cancers that require tions of one of the following key words: ‘radiation/radiotherapy’, total laryngectomy (Table 2): ICT → RT (or CCRT), which is ‘laryngeal cancer’, ‘locally advanced’, ‘T3 or T4’, ‘larynx preserva- favored in Europe, and concomitant CDDP and standard fraction- tion’. Thus, the aim of this study was to raise and investigate two ation RT (CCRT), which is preferred in North America. questions for resectable T3–4 laryngeal cancer: (i) Is an LP strategy feasible? (ii) Which treatment protocol is best?’ Comparison with surgery (control arm: S ± RT) The Veterans Administration Laryngeal Cancer Study Group RETROSPECTIVE DATA ABOUT T3–T4 trial The Veterans Administration Laryngeal Cancer Study Group LARYNGEAL CANCER trial (the VA study) provided the first key evidence to demonstrate T3 tumors are good candidates for LP after early RT, depending on LP feasibility [7]. PF-ICT (CDDP 100 mg/m d1 + 5-FU patient preference (Table 1). In contrast, T4 tumors, especially large 1000 mg/m Days 1–5 every 3 weeks) → RT [66–76 Gy/1.8–2 Gy/ instances, have been treated mainly by surgery. Intensive research fractions (fr)] for chemotherapy responders was found to be a Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 RT for resectable locally advanced laryngeal cancer � 79 Table 1. Retrospective outcome of radiotherapy for T3–4 laryngeal cancer T Author (institution) PY NO PT Treatment ¶LC ¶LP ¶OS category T3 Wylie (ChH) [21] 1999 114 RT only: 50–55 Gy/ 68% NA 54% 3.3–3.4 Gy/fr (AF) Hinerman (UF) [22] 2007 87 RT only: 50–79.2 Gy/ 67% NA Stage III 52% 1.2–2 Gy/fr (AF) Wolden (Michigan U) [23] 2009 73 FP → CCRT (or S) 3-year DFS 88% 3-year LFS 62% 3-year 83% Al-Mamagami 2012 170 CCRT [70 Gy/35 6 fr/ 68% 74% 60% (Netherlands) [24] week + CDDP] Fuller (MDACC) [25] 2016 166 CCRT or ICT → RT 10-year LRC 76% 10-year 37% 67% 121 RT only 18% 50% 125 S → RT NA 46% T4 Harwood (PMC) [26] 1981 56 RT only: 50–55 Gy/ 56% NA 64.5% 2.2–2.5/fr (AF) Hinerman (UF) [22] 2007 22 RT only: 50–79.2 Gy/ 82% NA Stage IVa 67% 1.2–2 Gy/fr (AF) Wolden (Michigan U) [23] 2009 36 FP→CCRT (or S) 3-year DFS 58% 3-year LFS 58% 3-year 78% Stenson (Chicago U) [19] 2011 55 CCRT: RT 70–75 Gy FPR 67.7% 88% 49% (AF) + FHX Rosenthal (MDACC) [27] 2015 161 S → RT 78% NA MST 64 M 60 CCRT 33% MST 64 M PY = year of publication, LC = local control rate (5 years unless otherwise stated), LP = larynx preservation (rate), LRC = locoregional control rate, FPR = functional preservation rate, OS = overall survival rate, DFS = disease-free survival rate, LFS = laryngectomy-free survival, MST = median survival time, NA = not available, RT = radiotherapy, ICT = induction chemotherapy, PF = CDDP + 5FU, FHX = 5-FU + hydroxyuria, CCRT = concurrent chemoradiotherapy, S = surgery, AF = alternated fractionation, Ch H = Christie Hospital Holt Radium Institute, UF = University of Florida, MDACC = MD Anderson Cancer Center, PMH = Princess Margaret Hospital. (1.5 Gy × 2 or 2 Gy/day × 5 days → 9-day interval) × 5–7 times. better strategy compared with laryngectomy (S) → RT. The Comparison with RT alone (control arm: RT alone) ICT → RT regimen was able to preserve the larynx (62% at 3 RTOG 91–11 CCRT (concomitant CDDP 100 mg/m on Day years) without jeopardizing OS. The study revealed that the patients 1, Day 22 and Day 43 plus RT 70 Gy/35 fr) was established as a in the ICT group showed a greater number of local recurrences but standard treatment by the pivotal Intergroup RTOG 91–11 trial, fewer metastases. which demonstrated good local control and unparalleled LP with The Groupe d’Etude des Tumeurs de la Tête et du Cou this CCRT regimen [8, 30]. The primary endpoint was (GETTEC) Richard et al. presented results for patients with T3 laryngectomy-free survival (with laryngectomy or death treated as laryngeal carcinoma [29]. They compared S → RT with PF-ICT → events in this trial). After 2 years, the CCRT arm exhibited a higher RT (65–70 Gy/2 Gy/fr) in good responders (42% LP rate) and LP ratio (88%) than the ICT → RT (75%, P = 0.005) or RT (70%, S → RT in poor responders. OS and disease-free survival (DFS) P < 0.001) arm. Locoregional control rates were also significantly were significantly worse for ICT →S(P = 0.006 and P = 0.02, better with CCRT (78%) compared with ICT → RT alone (61%) respectively). The 2-year OS for the ICT → RT and S → RT and RT (56%). Moreover, 5-year OS rates for RT alone, CCRT, groups were 69% and 84%, respectively. Surgery was associated with and ICT were 54%, 55% and 58%, respectively, all of which are rela- a greater number of superior outcomes than the LP strategy. tively similar. However, the survival curves diverged after 4.5 years, with 10-year OS rates of 32%, 28% and 39% for RT only, CCRT, Singapore study Soo et al. compared CCRT (RT 66 Gy/33 fr + 2 2 and ICT → RT, respectively, thus presenting ICT as the superior CDDP 20 mg/m + 5-FU 1000 mg/m d1 × 2) with S → RT treatment. It is possible that unrecognized or under-reported late (60 Gy/30 fr) in 119 patients and found no significant difference in toxicities could have contributed to some of the non-cancer-related 3-year DFS (50% vs 40%) [29]. The overall rate for organ preserva- deaths that emerged with the long follow-up period. tion or avoidance of surgery at the primary site was 45%. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 80 � H. Yamazaki et al. Table 2. Randomized control trials for organ preservation in resectable cases Study (Tx year) Site stage %T NO Tx (% RT received) % Tx Initial response to LP¶ OS¶ Toxicity T1–2/ PT complete ICT (CCRT) T3/T4 Author PY (MF) %N ICT (×3) unless CR/RR N0/N1/ otherwise stated N2/N3 Control arm: surgery (S → RT) VA study larynx III/IV 9/65/26 166 S → RT NA 45% same OS (PF lower (1985–1988) meta, lower LC) Wolf 1991 (USA) (33 M) 54/18/ 166 PF → RT (NA) 70% RR 85% 3-year 64%, 42% mucositis LP feasible [7] 11/17 (or S) FL 39% G2 ≤ 38% GETTEC larynx II–IV all T3 30 S → RT NA 2-year 84% S OS better (1986–1989) Richard 1998 (8.3Y) 78/15/ 33 PF → RT (36%) 31% 13 PT ≥ 80% 42% 69% (P = 0.006) G2 ≤ 33% early closure: PT (France) [28] 11/7 (or S) reduction (39%) refused S Singapore study bulky T4 or 18/26/56 60 S → RT NA 3-year DFS 50% same (1996–2002) IVA Soo 2005 [29] larynx 32% 49/46/5 59 CCRT 69% 69.6%/92.8% 45% 40% mucositis early closure: poor (6Y) G3 ≤ 39% accrual Control arm: radiotherapy (RT) RTOG91–11 larynx III/ 11/79/10 173 RT 94% 5-year 66%, 5-year 54%, high grade CCRT LP best, OS (1992–2000) IV 10-year 64% 10-year 32% 81% same c b Forastiere 2013 (10.8Y) 50/21/ 172 CCRT 91% 84%, 82% 55%, 28% 82% CCRT acute worse, (USA)[8, 30] endpoint 28/2 (P < 0.001) late same LP 173 PF → RT (83%) 84% 21%/83% 71%, 68% 59%, 39% 61% (or S) (P = 0.005) Cleveland study III/IV larynx 28/39/33 50 RT NA CR 66% LP 45%, LS 34% 48% feeding tube CCRT LP better, (1990–1995) 18% 32% OS same, toxicity worse Adelstein 2000 (5 Y) 47/47/6 50 CCRT (FP) NA 94% (P < 0.001) 77% (P < 50% 58% (USA [31] 0.001), 42% (P = 0.01) (P = 0.004) Tx = treatment, PY = year of publication, MF = median follow-up period, ICT = induction chemotherapy, LP = larynx preservation (rate) (5 years unless otherwise stated), OS = overall survival, RT = radiotherapy, S = surgery, CCRT = concurrent chemoradiotherapy, PF = CDDP + 5FU, NA = not available, VA = Department of Veterans Affairs Laryngeal Cancer Study Group, GETTEC = Groupe d’Etude des Tumeurs de la Teà te et du Cou, RTOG = Radiation Therapy Oncology Group, LS = laryngectomy-free survival, FL = functioning larynx, CR = complete response, PR = partial response, RR = response rate = CR + PR. Excluding T4 with thy- b c roid cartilage or >1 cm BOT invasion. Received more than 95% of the intended dose of radiotherapy (i.e. at least 67 Gy). Probably 100%, but not exactly stated. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 RT for resectable locally advanced laryngeal cancer � 81 The Cleveland study Adelstein et al. confirmed the superiority The Spanish Head and Neck Cancer Cooperative Group The 2 2 of CCRT (5-FU 1000 mg/m /day and CDDP 20 mg/m /day, on Spanish Head and Neck Cancer Cooperative Group (TTCC) per- Day 1 and Day 22, +RT 66–72 Gy/1.8–2 Gy/fr) over RT alone formed a comparison study between PF-ICT (CDDP 100 mg/m (66–72 Gy/1.8–2 Gy/fr) for LP but not OS in 100 patients with Day 1 + 5-FU 1000 mg/m Day 1–5 every 3 weeks) and TPF-ICT 2 2 resectable American Joint Committee on Cancer Stage III and IV (paclitaxel 175 mg/m Day 1, CDDP 100 mg/m Day 2, 5-FU disease [31]. Furthermore, 82% and 98% of the patients in the RT 500 mg/m Days 2–6 every 3 weeks) [37]. Patients with a CR or and CCRT arms had been rendered disease free (P = 0.02), partial response (PR) of >80% for the primary tumor received add- respectively. For RT vs CCRT, the 5-year OS rates, OS rates with itional CCRT. The PF and TPF arms had CR rates of 14% and primary site preservation, and local control rates without surgical 33% (P < 0.001) and a median time to treatment failure (TTF) of resection were 48% vs 50% (P = 0.55), 34% vs 42% (P = 0.004) 12 and 20 months (P = 0.006), respectively. TPF-ICT patients and 45% vs 77% (P < 0.001), respectively. tended to have longer OS (37 months in the PF-ICT arm vs 43 months in the TPF-ICT arm; P = 0.06). Moreover, this difference was more evident in patients with unresectable disease (OS: 26 Induction chemotherapy months in the PF-ICT arm vs 36 months in the TPF-ICT; P = Comparison with PF-ICT (control arm: PF-ICT → RT or 0.04). PF patients experienced more instances of Grade 2–4 muco- CCRT) sitis than TPF patients (53% vs 16%; P < 0.001). To enhance treatment intensity, regimens containing taxan (doce- taxel or paclitaxel) were intensely explored. Generally, TPF-ICT showed superior outcomes compared with PF for several RCTs. Comparison with upfront CCRT (control arm: CCRT) However, a number of these RCTs were criticized for their use of Docetaxel-Based Chemotherapy Plus or Minus ICT to Decrease non-standard approaches, leaving the regimen suitable for replacing Events in Head and Neck Cancer (DeCIDE) Cohen et al. the present standard treatment. showed equivalent outcomes for TPF-ICT (×2) (docetaxel 75 mg/m 2 2 Day 1, CDDP 75 mg/m Day 1, 5-FU 750 mg/m Days 1–5) → Groupe d’Oncologie Radiothérapie Tête Et Cou (GORTEC) CCRT (docetaxel, 5-FU, and hydroxyurea + RT 1.5 Gy twice per 2000–01 Pointeu et al. confirmed that TPF-ICT (docetaxel day every other week) and upfront CCRT in N2 or N3 disease 2 2 2 75 mg/m d1, CDDP 100 mg/m Day 1, 5-FU 1000 mg/m × 4 [38]. Grade 3–4 toxicities included febrile neutropenia (11%) and days) → RT (70 Gy/35 fr) increased LP and laryngeal dysfunction- mucositis (9%) during ICT and mucositis (49%), dermatitis (21%), free survival (LDFFS) better than PF-ICT (CDDP 100 mg/m and leukopenia (18%) during CCRT (both arms combined). Day 1, 5-FU 1000 mg/m × 5 days) → RT (70 Gy/35 fr) [32, 33]. Serious adverse events were more common in the ICT arm than in For TPF-ICT and PF-ICT, the 5-year (10-year) LP rates were the CCRT arm (47% vs 28%; P = 0.002). There were no statistic- 74.0% and 70.3% (58.1% and 46.5%), whereas the 5-year (10-year) ally significant differences in OS or RFS. LDFFS rates were 67.2% and 63.7% (46.5% and 37.2%, P = 0.001), Paccagnella et al. suggested the superiority of TPF-ICT (×3) respectively. TPF-ICT did not show any significant improvement in 2 2 2 (docetaxel 75 mg/m , CDDP 80 mg/m Day 1, 5-FU 800 mg/m OS, DFS or LCR compared with PF-ICT. Statistically fewer late 96 h every 3 weeks, n = 51) → CCRT over CCRT alone (CDDP Grade 3–4 toxicities of the larynx occurred with TPF-ICT than with 2 2 20 mg/m Days 1–4, 5-FU 800 mg/m Week 1 and Week 6, PF-ICT (9.3% vs 17.1%, P = 0.038). 66–70 Gy, n = 50) in terms of initial response [39]. TPF-ICT → TAX 324 Posner and Loach et al. compared TPF-ICT with PF- CCRT achieved 50% of the primary endpoint (CR at 6–8 weeks ICT followed by 7 weeks of CCRT (RT 70–74 Gy/2 Gy/fr + car- after CCRT), whereas CCRT alone achieved 21% (P = 0.004). The boplatin AUC 1 × 5 weekly) in resectable and unresectable cases CCRT and TPF-ICT → CCRT groups had an MST of 33.3 and [34–36]. TPF-ICT had a significantly better OS than PF-ICT [haz- 39.6 months (P = 0.268), respectively. This study used a non- ard ratio (HR) 0.74, P = 0.014], with 5-year OS rates of 52% and standard chemotherapeutic drug dose for CCRT (Table 3). 42% for TPF-ICT and PF-ICT, respectively. The TPF-ICT and PF- ICT groups had a MST of 70.6 and 34.8 months, respectively. Progression-free survival (PFS) was also significantly better in Other trials patients treated with TPF-ICT than with PF-ICT (median 38.1 The CONDOR trial months vs 13.2 months). No significant difference was found for TheCONDOR trial examined theroleofalternatedRTafter dependence on gastric feeding tubes (3% vs 11%) or tracheostomies four courses of TPF-ICT → CCRT × 4 (CDDP 100 mg/m = (7% vs 11%) between the treatment groups. They also made a sub- cis100 + RT 70 Gy/35 fr including intensity-modulated RT) or population analysis limited to laryngeal (54% of entire population) CDDP 40 mg/m weekly with accelerated RT (=cis40 + acceler- and hypopharyngeal cancers (74% operable: 90 PF-ICT and 76 ated RT;ART:6 fr/wk = 70 Gy/6 wks) [40]. Unfortunately, the TPF-ICT patients) [36]. OS rates for laryngeal cancer in the PF- data safety monitoring board advised premature termination of ICT and TPF-ICT groups were 45% and 65% (P < 0.05), respect- the study, because only 22% and 41% (32% in total) of the ively. In the operable group, the 3-year laryngectomy-free survival patients treated with cis100 + RT (n = 27) and cis40 + ART rates for TPF-ICT and PF-ICT were 52% and 32% (P = 0.03), (n = 29) could receive the planned CDDP dose during CCRT, respectively. The main point of criticism was the use of a non- respectively. This trial revealed the difficulty of performing standard CCRT regimen (carboplatin). CCRT after TPF-ICT. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 82 � H. Yamazaki et al. Table 3. Randomized control trials of induction chemotherapy (ICT) including unresectable cases Study (Tx year) Stage %T–T2/T3/ NO RT (% received) Tx % Initial response LP OS¶ Toxicity T4 PT completed ICT (CCRT) Author PY (MF) %N N0/N1/ ICT (×3) if [without CR/RR (CR/ Endpoint N2/N3 otherwise stated delay or RR) reduced dose] ICT: PF vs TPF: control arm (PF-ICT → RT or CCRT) Resectable GORTEC2000–01 III/IV larynx 18/67/15 103 PF → RT (47%) 80% [32%] 30.1%/59.2% 3-year 57% 5y 50.9%, 10y G3- late 17.1% TPF better LP (2000–2005) 46% or CCRT 30.2% same OS (9%) Pointeu 2009 [32, (105 M) LP 39/23/33/4 110 TPF → RT 90% 41.8%/80% 70% (P = 0.03) 41.9%, 23.5% 9.3% (P = 0.035) 33] (61%) or [62.7%] (P = 0.002) CCRT (15%) Mix (resectable and unresectable) TAX 324 III/IV Larynx 25(T1–2)/ 245 PF → CCRT 73% 15%/64% 3-year 32%, 3- 52% feeding tube TPF better LP OS (1999–2003) 18% 32/43 (carboplatin) year LFS 32%, dependent 11%, (75%) 3-year LRC tracheostomies 70% 11% Posner 2007 [34– (72.2 M) OS 16/20/50/14 255 TPF → CCRT 68% 17%/72%(P = 52% (P = 0.02), 42% 3%, 7% 36] PFS (carboplatin) 0.07) 52%, 62% (P = 0.014) (79%) TTCC (1998–2001) III/IV larynx 11(T1–2)/ 193 PF → CCRT 36% 14%/68% NA 2-year 32%, mucositis Grade 3 TPF better LP OS 16% 34/55 (42%) (78%/88%) MST 37M ≤53% in unresectable (unresectable subpopulation 26 M) Hitt 2005 (Spain) (24 m) CR 21/19/47/13 189 T (paclitaxel) 60% 33% (P < 43% 43M 16% (P < 0.001) [37] rate PF → CCRT 0.001)/80% (P = 0.06), (60%) (88%/98%) (36M P = 0.03) 128 CCRT (92%) 71% (48.6%/90.5%) 13.8 M 27.6 M, 7.9 M 2 (1.5%) Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 RT for resectable locally advanced laryngeal cancer � 83 Upfront CCRT vs ICT(TPF) → CCRT: control arm CCRT Mix (resectable and unresectable) DECIDE N2/#3 45(T0–2)/ 135 CCRT 94% (21%/74%) NA 65% Serious adverse Same OS (2004–2009) larynx 22/22 events 28% 13.6% Cohen 2014 [38] (min 30 M) 0/0/88/11 138 TPF×2 → CCRT 86% RR 64% (26%/ 64% 47% P = 0.002 Underpowered OS (90%) 79%) Others Resectability NS CONDOR Stage III–IV 18/35/47 27 TPF (×2–4) → [22%] 6.5%/61.3% 2-year PFS 70% 72% Febrile Early closure: low- (2008–2012) larynx 8% CCRT (90% (81.5%) neutropenia feasibility allocated) 18% (during TPF) Driessen 2016 (38 M) 23/5/72 29 TPF (×2–4) → [41%] (72.4%) 78% 79% G3–4 26% (Holland) [40] feasibility CCRT cis 40 ≥90% RT (90% allocated) Tx = treatment, PY = year of publication, MF = median follow-up period, RT = radiotherapy, CCRT = concurrent chemoradiotherapy, ICT = induction chmotherapy, LP = larynx preservation rate, OS = overall survival time (5 years unless otherwise stated), PFS = progression-free survival rate, PF = CDDP + 5FU, TPF = Taxan + CDDP + 5-FU, GORTEC = Groupe d’Oncologie Radiothérapie Tête Et Cou, EORTC = European Organization for Research and Treatment of Cancer, TTCC = Spanish Head and Neck Cancer Cooperative Group, DECIDE = Docetaxel-Based Chemotherapy Plus or Minus IC to Decrease Events in Head and Neck Cancer, CR = complete response, PR = partial a b 2 response, RR = response rate = CR + PR, NA = not available, TTF = time to treatment failure. Estimated from graph. RT 72 Gy/1.8 + 1.5 Gy bid/6 wk + docetaxel 20 mg/m /wk × 4 for poor responder at TPF-ICT or RT 70 Gy/35 fr + carboplatin AUC 1·5/week × 7 weeks for good responder. Low surgical curability or LP candidate. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 84 � H. Yamazaki et al. In addition, Hitt et al. showed that ICT had significantly better 14.9 months for BRT and RT (HR 0.68; P = 0.005), respectively. PFS than CCRT alone in the per protocol population [41]. These BRT significantly prolonged PFS (HR 0.70; P = 0.006) and OS. data suggested that ICT could be beneficial for patients who can Except for acneiform rash and infusion reactions, the incidence of complete the treatment protocol. On the other hand, ICT might Grade 3 or greater toxic effects, including mucositis, did not differ only delay CCRT in those who are unable to complete the treat- significantly between the two groups. However, subpopulation ana- ment protocol, without any benefit except for additional therapeutic lysis showed that BRT was not superior to RT alone for laryngeal toxicity. Therefore, patient selection is an important issue for future cancer [53]. Although BRT has been extensively explored since this trials [42, 43]. Michigan University [43] and Popovtzer et al. pro- trial, it has thus far failed to establish its superiority in laryngeal can- posed chemotherapy selection during the first cycle of TPF-ICT [42], cer treatment. with responses being determined by examination and positron emis- sion tomography (PET)-CT. In those studies, responders (>50% Radiotherapy With Cisplatin Vs Radiotherapy With Cetuximab tumor reduction) underwent chemoradiation, whereas non-responders underwent laryngectomy. A total of 83% of the patients responded to After Induction Chemotherapy for Larynx Preservation the treatment, while 17% had stable or progressive disease. After 2 (TREMPLIN) (GORTEC + GETTEC) years, the median OS rate, LP rate and disease-specificsurvivalrate The TREMPLIN study compared CCRT and BRT for LP [50]in were 80%, 83% and 86%, respectively. Response to a single TPF cycle 153 operable patients (laryngeal or hypopharyngeal cancer, T2–T3 was associated with 2-year OS (92% vs 50%; P = 0.02). and N0–N3) after TPF-ICT. The primary endpoint was LP 3 months after treatment, with an expected rate of 80%. Secondary endpoints were laryngeal function preservation (LFP) and OS at 18 Meta-analysis of chemotherapy in head and neck cancer months. Among the 156 patients who received TPF-ICT, 126 The pivotal Meta-Analysis of Chemotherapy in Head and Neck (86%) achieved PR ≤ and 23 patients <PR (non-responders Cancer (MACH-NC) study was first reported in 2002 and updated received S [16]orRT[7]). Subsequently, 116 patients (76% of in 2009 (87 trials and 16 485 patients) [44, 45]. These studies con- those included in the TPF-ICT group) were categorized into cluded that CCRT proved to be considerably more successful than CCRT (60) (70 Gy/35 fr) or BRT (56) (70 Gy/35 fr). No signifi- alternative treatments. Adding ICT (PF-ICT) to locoregional treat- cant difference between BRT and CCRT was observed with regard ment was associated with a slight improvement in OS and distant to LP at 3 months (95% and 93%), LFP (87% and 82%) or OS at failure. The HR of death was 0.88 (P < 0.0001), with an absolute 18 months (92% and 89%). Unfortunately, considering the 24% of chemotherapy benefit of 4.5% at 5 years. CCRT showed a more patients who dropped out, the trial did not reach the expected 80% pronounced benefit compared with ICT. The HR for CCRT was LP 3 months after treatment. Though BRT was shown to be as 0.81 (P < 0.0001), with an absolute benefit of 6.5% at 5 years. toxic as CCRT, causing the same rate of Grade 3 to 4 acute mucosi- A decrease in the effects of chemotherapy was observed with age tis, it had worse in-field skin toxicity. More local failures (8.3% vs (P = 0.003, test for trend). In addition, despite current intensive 14.3% at 18 months) among patients treated with cetuximab raised efforts, no form of acceleration can potentially fully compensate for the possibility that BRT may be inferior to CCRT for achieving the lack of concurrent chemotherapy [15, 46]. local control in laryngeal cancer. This is the only RCT providing Several meta-analyses have been performed to answer subse- evidence for the similarity in the outcomes of TPF-ICT → BRT quent questions [47–49]. Comparing PF-ICT and TPF-ICT in and TPF-ICT → CCRT. 1772 patients, Blanchard et al. [9] showed that TPF-ICT had an absolute benefit of 7.4% after 5 years and was associated with a sig- nificant reduction in progression, locoregional failure, and distant RTOG0522 failure when compared with PF-ICT [9]. However, only 49% of Ang et al. made a comparison between CCRT and CCRT + cetuxi- patients treated with taxanes were able to complete sequential mab (BCCRT) [52]. RT (72 Gy/42 fr/6 weeks: twice a day for 6 CCRT as planned. Kim et al. also concluded that ICT using TPF- days) was delivered as scheduled. When IMRT was used, the proto- ICT followed by CCRT did not improve OS [11], although PFS col was changed to twice a day once a week for 5 weeks (70 Gy/35 and response rates were significantly improved. Furthermore, fr/6 weeks). Compared with CCRT, BCCRT had more frequent Gyawali et al. concluded that concurrent CCRT should be preferred RT interruptions (26.9% vs 15.1%), similar CDDP delivery (mean, over ICT at present [10] (Table 4). 2 2 185.7 mg/m vs 191.1 mg/m ) and more Grade 3–4 radiation mucositis (43.2% vs 33.3%), rash, fatigue, anorexia, and hypokalemia BRT (cetuximab)—is BRT safer than CCRT? toxicities but less late toxicity. Similar outcome was obtained; 3-year The Bonner trial PFS (61.2% vs 58.9%), 3-year OS (72.9% vs 75.8%), locoregional Bonner et al. introduced BRT (cetuximab + RT) for the treatment failure (19.9% vs 25.9%) and distant metastasis (13.0% vs 9.7%; P of advanced head and neck cancers [15, 51]. After comparing RT = 0.08). Patients with p16-positive oropharyngeal carcinoma and BRT (an initial dose of 400 mg cetuximab, a monoclonal anti- (OPC) showed better PFS (72.8% vs 49.2%; P < 0.001) and OS body against the epidermal growth factor receptor, followed by (85.6% vs 60.1%, P < 0.001) than those with p16-negative OPC. 250 mg/m weekly for the duration of RT), response rates of 64% Subpopulation analysis showed an inclination similar to that shown and 74% were found in the RT and BRT arms (P = 0.02), respect- in the Bonner trial, wherein CCRT seemed to be superior to ively. The median durations of locoregional control were 24.4 and BCCRT in patients with laryngeal cancer. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 RT for resectable locally advanced laryngeal cancer � 85 Table 4. Randomized control trials for bioradiotherapy (BRT) including unresectable cases Study (Tx year) Stage %T NO RT (% received) Tx LP OS¶ Toxicity larynx % T1–2/T3/T4 PT % completed Author PY (MF) Endpoint %N ICT (×3) unless [without delay or N0/N1/N2/N3 otherwise stated reduced dose] Resectable TREMPRIN III/IV larynx 41% 14/56/30 60 TPF → CCRT (74% 90% CCRT allocated 3 M 95%, 18 M 92% mucositis Grade 3 TPF→BRT same (2006–2008) TPF allocated) LFP ≤46% (in-field efficacy 87% 26%) Lefebvre 2013 (36 M) 3 M LP 36/26/38/0 56 TPF → BRT (74% 95% BRT allocated 93%, 82% 89% 45% (57%) BRT toxic as [50] TPF allocated) CCRT Resectability NS Bonner trial III/IV larynx 25% 31/39/30 213 RT unacceptable variation 3-year 36.4% MST acneiform rush G3 BRT OS better in (1999–2002) in RT 6% LRC 49 M ≤0.5% entire group unevaluable RT 34% 6% Bonner 2006 (54 M) NA 19/19/53/9 211 BRT 4%, 9% 47% 45.6% (P = 8% (P < 0.001) BRT not superior [14, 51] 0.03) 54 M to RT in larynx RTOG 0522 III/IV larynx 23% 39/37/24 447 CCRT radiation LRF 19.9% 3-year 72.9%, mucositis Grade 3 same PFS, OS (2005–2009) interruptions 42% PFS 61.2% ≤33.3% Ang 2014 [52] (3.8-year) PFS 11/9/75/5 444 BCCRT 51% (P < 0.001) 25.9% 75.8%, 58.9% 43.2% P16 important Italy PII III/IV larynx 26% 24/33/43 35 CCRT cis40 100% 2-year LC 2-year 78% severe 3%, RT stop 10 early closure: poor (2011–2014) 53% days <0% accrual Magrini 2016 (19.3 M) Tx 36/44/20 35 BRT 91% 80% P = 68% 19% (P = 0.044), 13% BRT toxic than [53] compliance 0.07 (P = 0.05) expected Tx = treatment, PY = year of publication, MF = median follow-up period, RT = radiotherapy, ICT = induction chemotherapy, BRT = bioradiotherapy, BCCRT = biochemoradiotherapy, CCRT = concurrent chemoradiotherapy, LP = larynx preservation (rate), OS = overall survival rate (5 years unless otherwise stated), LC = local control rate, LRC = locoregional control rate, LRF = locoregional failure rate, PFS = progression-free survival rate, LFP = larynx function preservation, SFL = survival with functioning larynx, NS = not stated. TREMPLIN = Radiotherapy With Cisplatin Vs Radiotherapy With Cetuximab After Induction Chemotherapy for Larynx Preservation, RTOG = Radiation Therapy Oncology Group. 70 Gy/35 fr or 72–76.8 Gy (1.2 Gy twice a day) concomitant boost 72 Gy. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 86 � H. Yamazaki et al. Magrini et al. made a direct comparison (Phase II trial) between DISCUSSION CCRT (70 Gy/35 fr + CDDP 40 mg/m /wk) and BRT, concluding LP strategy may decrease OS that BRT lowered compliance, increased acute toxicity rates, and Despite treatment, the 5-year OS of locally advanced laryngeal can- had similar efficacy as compared with CCRT [53]. The endpoints cer ranges from 30% to 70%. Chen et al. [12] reviewed 52 817 included compliance, toxicity and efficacy. The study was discontin- patients treated between 1985 and 2007 using the National Cancer ued early because of slow accrual after the enrollment of 70 patients. Database, noting an increase in the administration of radiation with RT discontinuation for more than 10 days occurred in 13% and 0% or without chemotherapy from <7% to 45%. Primary total laryn- of the patients receiving BRT and CDDP (P = 0.05), respectively. gectomy decreased from 42% to 32%. The 4-year OS rates for total Hematologic, renal and GI toxicities were more frequent in the laryngectomy, CCRT, and RT were 51%, 48% and 38%, respect- CDDP arm, whereas cutaneous toxicity and the need for nutritional ively. Using SEER data, Pulte et al. reported improvements in sur- support were more frequent in the BRT arm. Serious adverse events vival rates for head and neck cancer patients but not laryngeal were higher in the BRT arm than in the CDDP arm (19% vs 3%, cancer patients during the late 20th century [58]. This has also pro- P = 0.044; including 4 vs 1 toxic deaths). Although efficacies were ven to be true for a recent series of cases diagnosed in the period similar, BRT toxicity was higher than expected. 2004–2012, as reported by the National Cancer Database Analysis A German LP trial [54] utilized a protocol with three cycles of group in the USA [59, 60]. A total of 1559 cases treated with S → TPF-ICT (dose according to the TAX 323 trial) → CCRT (con- RT, 1597 with CCRT, and 386 with ICT were included. After comitant boost RT) with or without cetuximab for 16 weeks (start- adjusting for covariates, CCRT was found to be associated with ing with ICT and continuing with RT) in 180 patients. In case inferior OS compared with S → RT (HR 1.55; P < 0.01) and ICT of non-response after the first cycle, salvage laryngectomy was (HR, 1.25 P < 0.01). These reports sparked controversy. For performed. The investigators omitted 5-FU following four therapy- example, inappropriate patient selection for the LP strategy may related deaths at the beginning of the trial. The addition of cetuxi- decrease survival of locally advanced laryngeal cancer. Several mab to TPF-ICT seems to have profound effects on toxicity. important factors still need to be known before RCT outcomes can Studies attempting to add cetuximab to TPF-ICT showed excessive be translated into routine clinical work. toxicity. Therefore, current research has explored the possibility of omitting 5-FU and replacing it with cetuximab. Petrelli et al. performed a meta-analysis including 15 trials Limitations of RCTs (1808 patients) to assess the role of BRT [55]. Overall, CCRT Locally advanced (Stage III/IV) tumors are considered to include significantly improved 2-year OS (response rate = 0.66; P = 0.02), cancers of Stages T2N1 to T4N3, which are evidently different cat- 2-year PFS (response rate = 0.68; P = 0.002), and 2-year locore- egories. The aforementioned RCTs sometimes included patients gional control rate (response rate = 0.63; P = 0.005) compared with T3 tumors without cord fixation and T4 tumors with minimal with BRT. BRT had a toxicity profile similar to CCRT and was cartilage invasion. For instance, the VA study showed that <60% of difficult to deliver after TPF-ICT. The aforementioned studies the population had tumors with cord fixation, whereas all patients in (TREMPLIN, PARADIGM and DeCIDE) suggested that, despite the French GETTEC study presented with cord fixation, resulting the fascinating nature of strategies using ICT and CCRT or BRT in a superior OS after surgery. to control both locoregional and distant metastases, they have In addition, T category migration is an important confounding been difficult to implement because of their association with factor. Significant differences in the assessment of vocal cord fixation severe toxicities. have been found between experts and trainees [61], which may lead Thereafter, Mesia et al. (TTCC2007/02) reported feasible to misclassifications of T2 and T3 categories. Given that gross cartil- results for TPF-ICT (×3) → BRT in 93 patients with resectable age invasion was also difficult to detect using CT images [62], a laryngeal cancer (a Phase 2 study, with patients treated between substantial ratio of T4 tumors diagnosed using CT images may have 2008 and 2011) [56]. Among the 93 patients, 76 were responsive actually been T3 tumors after pathological examination. This is also (37 CR + 38 PR = 81% response rate), while 73 patients (78%) true for magnetic resonance imaging (MRI) usage, which improved received BRT. The 3-year actuarial rates for survival with functional the diagnostic accuracy of T4 cartilage invasion. Therefore, a dis- larynx, laryngectomy-free survival, and OS were 70%, 72% and 78%, crepancy in T category classification exists between the previously respectively. The acute toxicity observed during both ICT and BRT used CT examinations and the more recently used MRI-based was expected, with only one toxicity-related death (local bleeding) examinations. during BRT. Compliance with chemoradiotherapy (CRT) is another problem Zenda et al. also postulated the feasibility of TPF-ICT × that needs to be addressed when interpreting RCTs. The VA and 3 → BRT in a Japanese population of 54 patients, 19% of which GETTEC trials reported that only 7% and 0% of the patients dis- had laryngeal cancer (2013–2015) [57]. The response rates for continued CTX, respectively. Moreover, the RTOG 9011 trial ICT and RT were 72% and 76%, respectively. Among the 54 showed that 7% of the responders discontinued CTX after two patients, 50 (93%) received >2 courses of ICT, whereas 41 cycles of ICT, whereas 70% of those receiving CCRT completed all (76%) had full-dose RT. The rate of treatment completion was three cycles of CTX. On the other hand, Givens et al. showed that thus 76%. The frequencies of Grade 3–4 neutropenia, febrile only 48% of the patients (including 16% with larynx) completed the neutropenia, and allergic/infusion reactions were 93%, 39% and planned CTX cycles [63]. A cumulative CDDP dosage of 200 mg 11%, respectively. or more indicated better outcomes when administered concurrently Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/77/4670788 by Ed 'DeepDyve' Gillespie user on 16 March 2018 RT for resectable locally advanced laryngeal cancer � 87 with RT [66]. Recent results suggest that larger amount of CDDP Nedaplatin and S-1 [70]. Primary site tumors and neck lymph is associated with survival benefit in patients with human papilloma- nodes exhibited CR rates of 91% and 64.3%, respectively, with a virus (HPV)-negative but not HPV-positive LAHNC, with the 4-year OS of 85.3%. Several institutions have also explored intra- exception of the T4 or N3 subset wherein a higher cumulative cis- arterial chemotherapy with good results. Suzuki et al. reported platin dose was associated with a trend toward improved OS [64]. 3-year OS and LP rates of 92% and 93%, respectively [71]. Therefore, a huge bias exists between routine clinical practice and RCTs, such that most patients included in RCTs belong to a CONCLUSION healthier population with less severe comorbidities, better functional Regarding the first question, ‘Is an LP strategy feasible?’, the answer status, and a lesser likelihood of suffering from adverse events is ‘yes’ if the goal is set at improving the LP ratio. However, appro- related to treatments [65]. priate eligibility criteria are still emerging and currently vary depend- It is also important to emphasize that previous key trials were ing on the institution. performed using two-dimensional RT techniques and that the use Regarding the second question ‘Which treatment protocol is of more advanced RT techniques, such as IMRT and particle ther- best?’ At present, this cannot be answered because the goal can vary apy, could probably lead to less late radiation toxicity. Whether (superior OS, better Quality of Life, less morbidity), depending on today’s modern conformal radiation delivery systems reduce late patient and physician preference. normal tissue toxicity (other than that to the parotids) remains to In conclusion, options for LP, including CCRT, ICT, and BRT, be established [25]. have successfully emerged over the past several decades, without an improvement in OS. A new paradigm shift involving new systemic Surgery remains as a best treatment for T4 disease for therapies, molecular markers, and/or technology is needed to OS and requirement of multidiscipline team for LPF improve not only OS rates but also LFP. Sanabria et al. recommended that total laryngectomy be considered for advanced T4 laryngeal cancers in non-academic settings, given that its survival outcomes appear to be better than those for CCRT, CONFLICT OF INTEREST according to the results of many observational studies [65]. CCRT The authors declare that they have no competing interests. can be acceptable for patients with T3 tumors given the condition that all resources for treatment administration, follow-up, and surgi- FUNDING cal salvage are available. Nakayama et al. noted that organ-sparing The authors have no funding source. approaches require (i) a high level of skill and cooperation among various disciplines, (ii) adequate compliance from patients, and (iii) careful documentation and appropriate surveillance [66]. REFERENCES 1. Parkin DM, Bray F, Ferlay J et al. Global cancer statistics, 2002. No strategy could add a merit in elder population CA Cancer J Clin 2002;55:74–108. It should also be noted that all strategies to improve outcome, 2. Michigan Medicine. Comprehensive Cancer Centre. What including CCRT, accelerated RT, and BRT, could not establish Patients Should Know in Decision Making. http://www.mcancer. their merit with increasing age, showing no difference in survival vs org/head-and-neck-cancer/voicebox/what-patients-should-know conventional RT alone in patients older than 70 years of age [17, (10 April 2017, date last accessed). 43, 51, 67]. Therefore, elderly patients should be given special con- 3. 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