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The concept of larynx preservation in locally advanced laryngeal or hypopharyngeal squamous cell carcinoma, has evolved during the last three decades, especially with the improvement of nonsurgical strategies. These approaches include: 1) radiotherapy alone, 2) concomitant chemoradiotherapy (CCRT), or 3) induction chemotherapy followed by radiotherapy or CCRT and more recently concurrent anti-EGFR. To date, the best protocol has yet to be defined. We review and discuss the most important and recent randomized phase II/III trials that impact our daily practice concerning this concept to make the selection of an appropriate strategy easier. However, the decision of larynx preservation should always be a multidisciplinary approach.
Keywords: Larynx preservation; radiotherapy; induction chemotherapy; concomitant; targeted therapy. 












1.Introduction:
Head and neck cancer is the sixth most common cancer worldwide [1]. There are around 160,000 cases of cancer of the larynx per year [1], and most of them are locally advanced (LA) disease (stage III or IV). Until the early 1990s, the standard treatment for LA larynx or hypopharynx squamous cell carcinoma (SCC) unfit for functional surgery was total laryngectomy and lymph node dissection followed by radiotherapy (RT). However, this surgical procedure is among the most feared by patients. It has a negative impact with tracheotomy, loss of natural voice, social isolation, loss of employment and depression.
Larynx preservation (LP) strategies have since been developed. These non surgical strategies include RT alone, concomitant chemoradiotherapy (CCRT), induction chemotherapy (ICT) followed by RT or CCRT in good responders, and more recently concomitant radiotherapy with target therapy (anti-epidermal growth factor receptor). The choice between these protocols depends on various factors and is still difficult. In fact, the decision is a multidisciplinary one. Eligibility criteria for LP are a tumor unfit for a functional surgery but potentially resectable (T2�T3 up to T4 tumors) without massive cartilage invasion or extension to soft tissues and without laryngeal dysfunction (tracheostomy, nasogastric tube, or aspiration pneumonia). Age (<70 years), performance status (WHO< 3), and comorbidities are also important considerations [2].
The aim of this review is to analyze the most important and recent randomized phase II/III clinical trials that impact our daily practice concerning the concept of LP and to discuss them in terms of outcome, feasibility and toxicity.  


2.Method:
Pub Med, Medline, Cancerlit, Embase, Ovid online, Wiley online and Cochrane were used to search for publications in English relevant to the review. The research terms were: �organ preservation�, �larynx�, �hypopharynx�, �radiotherapy�, �chemotherapy�, �target therapy�. Only articles or abstracts relevant to randomized phase II/III trials were considered . Attention has been paid to the reported endpoints, objective response rate (ORR), toxicity and salvage therapy. The last search was done October 15, 2012. Based on this final search, seven randomized phase III trials are reported here. In addition, one phase II trial has been included due to its important findings.
3. Results:
3.1-The Department of Veterans Affairs Laryngeal Cancer Study Group [3,4]:
332 patients with advanced but resectable SCC of the larynx (stage III, IV (AJCC 1985)) were enrolled in this study and were assigned in equal numbers to surgery followed by RT (arm A), or to ICT (5-Fluorourcail/Cisplatin (PF)) followed by RT if there was at least a partial response (>50%) otherwise immediate surgery and postoperative radiation therapy (arm B). Only one death directly related to chemotherapy was noted, but interruption of chemotherapy due to toxicity occurred in 12 patients. The frequency and severity of adverse events related due radiation therapy were similar in both treatment groups. The ORR to chemotherapy was 85%. The estimated 2-year survival was 68% in both treatment groups, but disease-free survival (DFS) tended to be shorter in the chemotherapy group, though this difference was not statistically significant (p=0.11). In the chemotherapy group, recurrences at the site of the primary tumor were more frequent (12% vs 2%, p=0.001) while distant metastases were less common (11% vs 17%, p=0.001).
The larynx was preserved in 107 patients (64%). Salvage laryngectomy for recurrent cancer was performed in 11 patients. The estimated rate of LP at 2 years was 66%.
The authors conclude that ICT was well tolerated and did not negatively affect the definitive treatment that followed and without compromising the overall survival (OS). The survival of nonresponding patients who underwent prompt salvage surgery was also not impaired.
3.2- EORTC 24891 (European Organization for Research and Treatment of Cancer) Head and Neck Cooperative Group) [5,6,7]:
202 patients with SCC of the pyriform sinus classified T2-T4 N0-N3 (AJCC 1987) and eligible for a classic total laryngectomy with partial pharyngectomy were enrolled in this study. They were assigned to surgery followed by RT, or to ICT (PF) followed by RT if there was complete response (92 patients) otherwise immediate surgery and postoperative radiation therapy (97 patients). 13 out of 202 initial patients did not start the planned treatment for various reasons. One death related to chemotherapy was reported, and chemotherapy was interrupted in 13 patients due to toxic effects of chemotherapy. The ORR was 86%. 
At 10.5 years median follow-up, 28 patients experienced local or/and regional failure in the surgery arm versus 32 patients in the chemotherapy arm. 34 and 38 patients experienced distant metastases in the surgery and chemotherapy group, respectively. There was no significant difference in locoregional failures (p=0.84) or distant metastases (p=0.14) between the two groups. 17 salvage surgeries were performed in the chemotherapy group.
The 5 and 10- year OS rates were 38% and 13.1% in the chemotherapy group, 32.6% and 13.8% in the surgery arm, respectively. The 5 and 10-year DFS were 31.7% and 10.8% in the chemotherapy group versus 26.4% and 8.5% in the surgery arm, respectively. The 5- and 10-year rates of survival with preserved larynx were 21.9% and
8.7%, respectively. The 5- and 10-year disease-specific survival rates with preserved larynx were 40.5% and 26.97%, respectively, when omitting deaths not due to uncontrolled local evolution and with preserved larynx.
The authors conclude that the concept of LP in advanced but resectable hypopharyngeal SCC is feasible and safe without compromising the disease control or the OS.
3.3-GETTEC (Groupe d�Etude des Tumeurs de la T�te et du Cou) [8]�:
68 patients with advanced laryngeal SCC classified as T3, N0-N2b (AJCC 1986) and considered for total laryngectomy, were included in this study. The patients were assigned to total laryngectomy followed by RT (32 patients), or to PF followed by RT in good responders (regression>80%) otherwise immediate surgery and postoperative radiation therapy (96 patients). All the patients had vocal cord-fixation, and 2/3 of patients had a glottis or trans-glottic tumor. 3 patients in the chemotherapy group did not start the planned treatment due to contra-indication to chemotherapy. Toxicity grade 3 or 4 related-chemotherapy occurred in 6 patients. The ORR to chemotherapy (e"80%) was 39%. LP rate was 42% at 2 years. Locoregional and or metastatic recurrence occurred in 19 and 11 patients in the chemotherapy and the no-chemotherapy group, respectively. The 2-year survival and 2-year DFS rates were statistically significant in favor of the no-chemotherapy group;  84% vs 69%, p=0.006 and 78% vs 60%, p=0.02, respectively. 
The authors conclude that the concept of larynx preservation should not be considered as a standard treatment but as an investigational approach. 


3.4-RTOG 91-11 (Radiation Therapy Oncology Group) and the Head and Neck Intergroup [9,10]:
547 patients with LA glottic or supraglottic laryngeal SCC classified as T2-T4, N0-N3 (stage III or IV) and considered for total laryngectomy, were included in this study. They were balanced equally between 3 groups. In the first group, good responders to PF (regression >50%) received RT, while the others received laryngectomy and adjuvant radiotherapy (173 patients). In the second group, the patients received CCRT based on cisplatin (172 patients), and in the third group, the patients were treated with RT alone (173 patients). In more than two third of patients, the primary site of the tumor was supraglottic, and less than half of the patients had vocal cord-fixation. The primary end point was LP.  The rate of severe side effects was greater with the chemotherapy-based regimens (81% with ICT+RT, 82% with CCRT and 61% with RT alone). The mucosal toxicity in CCRT was nearly twice as frequent as the mucosal toxicity of the other 2 treatments during radiotherapy. The total of deaths related to treatment were 5(3%), 9(5%) and 5(3%) in the ICT+RT, CCRT and RT groups, respectively. The ORR was 85% in the ICT group. At 10 years, laryngectomy-free survival (LFS) was significantly better with either ICT+RT (28.9%, p=0.02) or CCRT (23.5%, p=0.03) compared to R (17.2%). There was no difference in LFS between ICT+RT and CCRT (p=0.68). Locoregional control (LRC) was significantly better with CCRT (65.3%) compared to ICT+RT (48.9%, p=0.0037) or RT (47.2%, p=0.0015). LP was significantly better with CCRT (81.7%) compared to ICT+RT (67.5%, p=0.005) or RT (63.8%, p<0.001). There was no difference in LP and LRC between ICT+RT and RT (p=0.35 and 0.72, respectively). DFS was significantly better with CCRT (21.6%) compared to R (14.8%, p=0.04), but there is no difference when compared to ICT (20.4%, p=0.88). The 10-year OS rates did not differ significantly between the 3 groups (ICT+RT 38.5% vs CCRT 27.5% (p=0.08), ICT+RT vs RT 31.5% (p=0.29), CCRT vs RT (p=0.53)). No difference in late effects was detected, but deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy (30.8% v 20.8% with induction chemotherapy and 16.9% with RT alone).
The authors conclude that CCRT is superior to sequential therapy or RT alone for achieving LRC and LP but does not improve the OS. Thus, CCRT should be considered standard care for patients desiring LP.
3.5-GORTEC 2000-01 (Groupe fran�ais d�Oncologie Radioth�rapie T�te et Cou) [11]�:
213 patients with laryngeal or hypopharyngeal SCC classified as T2-T4 N0-N3 M0 (stage III or IV (AJCC 1998)) that required total laryngectomy were enrolled in this study. They were randomly assigned to receive 3 cycles of Docetaxel/PF (TPF) (110 patients) or PF (103 patients) followed by CCRT or RT alone in good responders. Patients who did not respond to chemotherapy (regression<50%) underwent total laryngectomy followed by RT. The primary endpoint was the 3-year LP rate. In the TPF arm, patients experienced more grade 2 alopecia (19.4% vs 2%), more grade 4 neutropenia (31.5% vs 17.6%) and more febrile neutropenia (10.9% vs 5.8%). Patients treated with PF experienced more grade 3 and 4 stomatitis (7.8% vs 4.6%), more grade 3 and 4 thrombocytopenia (7.8% vs 1.8%), and grade 4 creatinine elevation (2% vs 0%). Grade 4 larynx late toxicity occurred in 6.2% and 13.6% of patients in the TPF and PF groups, respectively (p=0.1). Others toxicities were similar in both groups. During ICT, 3 patients died in the TPF group versus 2 patients in the PF group. In the TPF group, 62.7% of patients received complete treatment without delay or dose reduction versus 32% patients in the PF group (p<0.001). After ICT, the ORR was 80% and 59.2% in the TPF and PF groups, respectively (p=0.002). The 3-year LP rate was 70.3% in TPF arm and 57.5% in the PF arm (p=0.03). The 3-year OS was 60% in both arms. The 3-year DFS was 58% and 44% in TPF and PF groups, respectively (p=0.11). The rates of local and regional failures were 18.6% vs 23.7% and 14.7% vs 20.2% in the TPF and PF groups, respectively. A salvage total laryngectomy was performed in 13 and 12 patients in the TPF and PF groups, respectively (p=0.51).
The authors conclude that TPF regimen improves LP but not survival rates.
3.6- Subgroup of TAX 324 [12]:
Among 501 patients enrolled in the phase III trial TAX 324, which compares ICT with either TPF or PF followed by carboplatin-based CCRT in SCC of the head and neck, 166 patients had LA laryngeal or hypopharyngeal SCC (stage III or IV). An analysis of this subgroup was reported in 2009: 90 and 76 patients in the TPF and PF groups, respectively. The comparison between the 2 groups was not statistically significant, and 123 patients (74%) were defined as having operable tumors (67 patients in TPF vs 56 patients in PF). Estimated 3-year survival was 57% and 40% in the TPF and PF groups (p=0.024), respectively. There were total (40% vs 47%), locoregional (32% vs 38%) and distant (6% vs 7%) treatment failures in TPF vs PF groups, respectively, without any statistical significance. In the group of operable patients (74%), estimated 3-year laryngectomy-free survival was 52% and 32% in the TPF and PF groups (p=0.03), respectively, leading to an absolute improvement of 20% in favor of TPF ICT at 3 years.
However, primary sites (supraglottis, glottis, transglottic), mobility of vocal cords, ORR and DFS were not reported. As well, toxicity was only reported for all the patients enrolled initially in TAX 324 [13], where more grade 3 or 4 neutropenia was found in the TPF groups (p<0.001) and more grade 3 or 4 thrombocytopenia in the PF group (p=0.005). Treatment delays was more frequent in the PF group (p<0.001).
This analysis of TAX 324 subgroup provides evidence of a significant advantage in survival and LP for TPF compared with PF in LA laryngeal or hypopharyngeal SCC.
3.7-EORTC 24954 [14]:
450 patients with LA SCC of the larynx (T3-T4 and N0-N2 M0) or the hypopharynx (T2-T4 and N0-N2 M0) that required total laryngectomy, were enrolled in this study. They were randomly assigned to receive 2 cycles PF and then, in good responders, (response>50%), another 2 cycles PF followed by RT (sequential arm, n=224), or assigned to be treated with 4 cycles PF with RT being given between cycles of chemotherapy (alternating arm, n=226). The primary endpoint was survival with a functional larynx. Among the 218 patients with laryngeal SCC, 155(71%) had supraglottic tumors (77 and 78 patients in sequential and alternating arm, respectively) and 63(29%) had glottic or transglottic tumors (31 and 32 patients in sequential and alternating arm, respectively). Only 144 (64%) patients received all the planned chemotherapy in the sequential arm versus 156 (69%) patients in the alternating arm. Dose modification of 5Fluorouracil or cisplatin due to toxic effects was required in 142 vs 137 patients in sequential vs alternating arms, respectively. Acute radiotherapy-related toxic effects were statistically significantly higher in the sequential arm (p<0.001), however late toxicity was similar in both arms. Interruption or delay of RT due to toxic effects from RT was reported in 6 and 7 patients in the sequential and alternating arms, respectively.  Discontinuation of RT due to toxic effects from chemotherapy was reported in 36 patients in the alternating arm. Salvage surgery was performed in 68 vs 50 patients in sequential vs alternating arms, respectively. Estimated 3 and 5-year survival with a functional larynx were 39.5% and 30.5%  vs 45.4% and 36.2% for the sequential vs alternating arms, respectively (p=0.155). Estimated 3 and 5-year OS were 62.2% and 48.5%  vs 64.8% and 51.9% for the sequential vs alternating arms, respectively (p=0.446). Estimated 3 and 5-year progression-free survival (PFS) were 49.7% and 41.04%  vs 50.7% and 41.8% for the sequential vs alternating arms, respectively (p=0.750).
Both schemas of treatment are similar in term of results with slightly less acute radiotherapy-related toxic effects in the alternating treatment.
3.8- TREMPLIN study [15]:
153 patients with stage III-IV larynx or hypopharynx SCC who were all candidates for a total laryngectomy were enrolled in this study. They received initially 3 cycles TPF. In instances of response less than 50%, the patients underwent surgery; otherwise they were randomly assigned to receive cisplatin-based CCRT (arm A) or to be treated with RT and concurrent Cetuximab (arm B). The primary endpoint was LP 3 months after treatment. Only 74% patients (74%) received all the planned ICT while the others had either reduced dosages or less than 3 cycles. Toxic deaths occurred in 2 patients (1.6%) during ICT.  Grade 3 or 4 toxicity occurred in 36 patients (23.5%), in particular febrile neutropenia in 16 patients (10%) and renal toxicity in 4 patients (2.6%) patients. The dropout rate after ICT and before random assignment was substantial (24%; 37 patients): four deaths, 23 insufficient responses
to ICT, and 10 exclusions. In particular, six patients among the responders could not be randomized due to ICT-related toxicity precluding any further cisplatin. Finally, only 76% patients were randomized after ICT to larynx preserving treatment (60 patients in arm A versus 56 in the arm B). 
In arm A, only 26 (43%) patients received the complete prescribed treatment versus 40(71%) patients in arm B due to grade 3-4 toxicity. During concurrent treatment, grade 3 or 4 mucositis occurred in 27(47%) vs 25(45%) patients in arm A vs B, respectively. Grade 3 or 4 acute skin toxicity occurred in 15(26%) vs 32(57%) patients in arm A vs B, respectively (p<0.001). Grade3-4 nephrotoxicity occurred only in arm A (9 patients (15.5%). Modification of treatment protocol due to toxicity was required in 33(57%) vs 19(29%) patients in arm A vs B, respectively (p=0.02). Late toxicity was considerable in arm A (p=0.111), in particular 13 patients (22.4 %) had persistent renal dysfunction.
LP at 3 and 18 months after treatment were reported in 95% vs 93% (p=0.63) and 87% vs 82% (p=0.41) of patients in arm A vs arm B, respectively.  After a median follow-up of 36 months, OS was 75% and 73% in arm A and B, respectively. Local failures occurred in 5 pts in arm A (none were salvaged) and in 12 patients in arm B (7 were salvaged) for a similar number of local failure of 5 patients in each arm. Distant metastases were similar in the two arms (5 patients (8.3%) in arm A vs 3 (5.4%) in arm B).
The authors conclude that TPF-based ICT followed by CCRT or Cetuximab is feasible for LP, but had substantial overall toxicity. LP and survival rates are similar in both arms and there is no evidence that one treatment is superior to the other, but compliance was higher with concomitant cetuximab.
All trials are summarized in Table 1.
4. Discussion:
4.1. Optimizing patient selection and endpoints:
Though the trials mentioned above all investigate LP, it is difficult to form a definitive opinion on the practice based on any one trial considering their methodological differences. Some clinical trials considered only larynx or only hypopharynx SCC while others considered both. The trials included different stages: only T3, T3 -T4, T2-T4. Primary sites of tumors and mobility of vocal cords in the larynx SCC were different across trials as well. Some studies even failed to specify this information in their articles. Identification of good responders also varied based on different percentages of tumor regression (50%, 80% and 100%). Also, primary and secondary endpoints were different. Finally, the definition of larynx preservation itself was different in these trials: it varied from simply �larynx in place� to � functional larynx without any relapse or tracheotomy or feeding tube�. All these different eligibility criteria and clinical situations lead to an inconsistent application of the concept of larynx preservation and make the discussion quite confusing. In fact, recent epidemiological observations have shown a modest decline in survival rates for patients with laryngeal cancer, which may be ascribed to the increasing use of nonsurgical management [16,17,18].
As well, comparison between results of these different trials may be misleading.
Some authors have made recommendations concerning the concept of LP [19,20,21] in order to optimize patient selection for LP approach, to be able to compare the different studies and to make clinical trials more effective to evaluate and quantify the therapeutic benefit of novel treatment options for patients with LA SCC of the larynx or hypopharynx. Recommended eligibility criteria are patients with T2 or T3 laryngeal or hypopharyngeal SCC not considered for partial laryngectomy. Excluded should be those with laryngeal dysfunction or aged >70 years. Baseline and post-treatment functional assessments should include speech and swallowing evaluations. Furthermore, voice should be routinely assessed with a simple, validated instrument. Regarding endpoints, the primary endpoint should capture survival and function. As a result, the panel created a new endpoint of laryngoesophageal dysfunction (LED)-free survival, which includes the events of death, local relapse, total or partial laryngectomy, tracheotomy at >2 years, or feeding tube at >2 years. Recommended secondary endpoints are freedom from LED, overall survival, progression-free survival, locoregional control, time to tracheotomy, time to laryngectomy, time to discontinuation of feeding tube, and quality of life/patient-reported outcomes. Future exploratory correlative biomarker studies should include epidermal growth factor receptor, excision repair cross-complementation group 1 gene, E-cadherin and beta-catenin, epiregulin and amphiregulin, and TP53 mutation.
4.2. Therapeutic considerations:
4.2.1: Induction chemotherapy (ICT):
ICT based on PF regimen followed by RT in good responders has been reported as a valid strategy for LP for patients with LA SCC of the larynx or hypopharynx, and without compromising OS when compared to radical surgery [3,5]. In contrast, this strategy was reported with significantly worse DFS and OS rates in the GETTEC trial [8]. These results have been evaluated in the MACH-NC (meta-analysis of chemotherapy in head and neck cancer) first published in 2000 [22] on 93 randomized trials and more than 17,000 patients. This meta-analysis has specifically analyzed these 3-above mentioned trials (602 patients), and has showed evidence of two thirds percent of LP in the ICT arm at 5-years, without compromising OS (39% vs 45% in ICT vs surgery) or event-free survival (EFS) (34% vs 40% in ICT vs Surgery). These differences were not statistically significant. There were more locoregional failures but less metastatic spread and second primary in the ICT arm. These good survival rates may be explained by the efficacy of salvage surgery but also by ICT on systemic tumors cells [2]. The first conclusion is that ICT with PF based-chemotherapy followed by definitive RT in good responders is a valid option for LP.
Two clinical trials support the superiority of TPF regimen versus PF followed by RT in LP, though with more toxicity [11,12]. The second conclusion is that TPF based-chemotherapy is a good induction for LP but granulocyte colony-stimulating factor (G-CSF) prophylaxis is recommended.
4.2.2: Concomitant chemoradiotherapy (CCRT):
LP and LCR were significantly improved with CCRT when compared to ICT (PF regimen) followed by RT or to RT alone, but with a significant increase in acute toxicity [9,10]. The OS is not improved with CCRT. The update of MACH-NC in 2009 [23] compared directly and indirectly CCRT to ICT in head and neck cancer. The direct comparison (6 randomized trials and 861 patients) showed results in favor of CCRT including, OS (p=0.15) with an absolute benefit of 3.5% at 5 years, EFS (p=0.01) and loco-regional failure (p=0.005). The indirect comparison (50 concomitant chemotherapy trials vs 31 induction chemotherapy trials) showed that the benefit of chemotherapy in OS was significantly greater in the concomitant group when the analysis included only trials with PF regimen (p=0.01). The difference concerning loco regional failure was also significant in favor of CCRT (p<0.0001). Regarding the type of drugs to be combined concomitantly with radiotherapy, cisplatin alone, cisplatin or carboplatin associated with 5Fluorouracil, or other poly-chemotherapy including either platin or 5Fluorouracil had a benefit of the same order of magnitude [23]. Mono-chemotherapy with a drug other than cisplatin led to inferior results and should not be recommended in routine practice [23]. Single agent cisplatin at dose of 100 mg/m� appears to be one of the standard treatments in combination with radiotherapy. The benefit of concomitant chemotherapy appears to be similar irrespective of whether the radiotherapy was given conventionally or using altered fractionation [23]. A decreasing effect of chemotherapy with age (p<0.003) is also reported [23]. This could be partly explained by lower compliance and higher toxicity rates in older patients [2].
The third conclusion is that CCRT is a valid option for LP and is superior to ICT based-PF regimen. Patients should receive a platinum-based chemotherapy in their CCRT regimen. Due to its toxicity, CCRT should be reserved for selected patients in view of their general status and co-morbidities.
 Rapid alternation between cycles of radiation and chemotherapy is a variant of concomitant administration. The results of both sequential and alternating schemas were similar (EORTC 24954).  Thus, this trial does not con�rm the results of the RTOG 91-11. This difference might result from the fact that rapid alternation between cycles of radiation and chemotherapy does not deliver chemotherapy and radiotherapy in a fully concomitant way. Nevertheless, the absence of direct comparison prevents the drawing of any �rm conclusion on potential differences in ef�cacy results between these 2  variants  of the chemoradiation concept [24].
4.2.3: CCRT vs ICT followed by CCRT:
At this time, one question remains. Which strategy is better for LP: CCRT alone or ICT with TPF regimen followed by CCRT? A phase III trial demonstrated, however, that ICT (PF or TPF) followed by CCRT significantly increases LRC (p=0.003) and time to treatment failure (p<0.001) compared with CCRT alone in patients with unresectable locally advanced head and neck cancers (LAHNC) [25]. In a phase II randomized study, Paccagnella et al [26] reported that TPF induction chemotherapy improves clinical response and does not compromise subsequent chemoradiotherapy in LAHNC. As well, the preliminary results of two phase III trials�the DeCIDE [27] and the PARADIGM [28] trials comparing TPF induction + CCRT to CCRT alone in LAHNC�confirm the feasibility of TPF-based sequential therapy. Neither DeCIDE nor PARADIGM studies demonstrated an overall survival advantage on the induction chemotherapy arm: the 3-year OS was 75% (ICT) vs 73% (CCRT) in Decide trial (p=0.70), and 73% (ICT) vs 78% (CCRT) in PARADIGM trial (p0.77) [29]. 
4.2.4: Targeted therapies:
The TREMPLIN study showed that 3 cycles of TPF induction followed by radiation and 3 doses of concurrent cisplatin is too toxic, leading specifically to nephrotoxicity, which compromises the feasibility of concurrent cisplatin. Three cycles of TPF induction followed by RT and cetuximab is too toxic as well, specifically for the skin, compromising the feasibility of concurrent cetuximab. Both schedules are similar in terms of LP, and neither sequential regimen can be considered a treatment standard. To achieve a better LCR and due to the cytostatic activity of cetuximab, a maintenance therapy would be condisered.  Finally, it should be taken into account that the TREMPLIN study is not a comparison between CCRT versus RT+ cetuximab because the concurrent therapy was only given after TPF induction. Similarly, a randomized phase III trial (RTOG 0522) [30] reported the results of concurrent accelerated radiation plus cisplatin with or without cetuximab in LAHNC: the addition of cetuximab to the radiation-cisplatin platform did not improve PFS or OS. The triplet regimen was associated with higher rates of mucositis and cetuximab-induced skin reactions. Another randomized phase III trial [31] is ongoing and compares CCRT or RT/cetuximab versus induction TPF followed by CCRT or RT/cetuximab in LAHNC.
5.Conclusion:
To date, the acceptable and nonsurgical strategies for organ preservation in appropriate patients with advanced larynx or hypopharynx SCC are: 1) CCRT (cisplatin-based regimen), 2) TPF as ICT followed by radiation in good responders, or 3) radiation alone. Currently, concurrent radiotherapy and cisplatin is the recommended option for achieving LP in United States [32]. Chemotherapy and radiation therapy cannot be offered to all patients due to substantial acute and possible late toxicities. Improvements in radiation therapy, especially intensity-modulated radiation therapy (IMRT), may limit toxicity [33]. 
Electing nonsurgical LP treatment and deciding which one to attempt for LA laryngeal or hypopharyngeal SCC should always be discussed in a multidisciplinary concertation. This discussion should always take into account the stage of the tumor as well as the general status of the patient, his or her comorbidities, psychosocial situation and preferences to identify the most appropriate options for each individual patient [2]. Future clinical trials should try to achieve some homogeneity in eligibility criteria and endpoints to make comparison across studies easier [34]. Finally, the next generations of LP trials should compare treatment with the most effective regimens: (CCRT alone) vs (induction TPF followed by RT alone or CCRT) vs (induction TPF followed by concomitant RT and cetuximab).
6. Conflict of interest:
All the authors have no conflict of interest to declare.
7. References:
1-Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.	
2-Horn S, et al. Larynx preservation: What is the standard treatment? Crit Rev Oncol/Hematol (2011), doi:10.1016/j.critrevonc.2010.11.008
3-The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation in patients with advanced laryngeal cancer . N Engl J Med 1991;324(24):1685-1690 .
4- Spaulding MB, Fischer SG, Wolf GT, et al. Tumor response, toxicity, and survival after neoadjuvant organ preserving chemotherapy for advanced laryngeal carcinoma. J Clin Oncol 1994;12:1592-1599.
5-Lefebvre JL, Chevalier D, Luboinski B, et al. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 1996;88:890-899.
6-Lefebvre JL, Chevalier D, Luboinski B, et al. EORTC Head and Neck Cancer Cooperative Group. Is laryngeal preservation (LP) with induction chemotherapy (ICT) safe in the treatment of hypopharyngeal SCC? Final results of the phase III EORTC 24892 trial. ASCO Annual Meeting. J Clin Oncol 2004;22(No. 14S (July 15 Supplement)):5531.
7-Lefebvre JL, Andry G, Chevalier D, et al. Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. Ann oncol 2012;23:2708-2714.
8- Richard JM, Sancho-Garnier H, Pessey JJ, et al. Randomized trial of induction chemotherapy in larynx carcinoma. Oral Oncol 1998;34:224-228.
9-Forastiere AA , Goepfert H , Maor M , et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349(22):2091-2098.
10- Forastiere AA , Zhang Q, Weber RS , et al. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 2013;31:845-852.
11- Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction chemotherapy with Cisplatin and 5-Fluorouracil With or Without Docetaxel for Larynx Preservation. J natl Cancer Inst 2009;101:498-506.
12-Posner MR, Norris CM, Wirth LJ, et al. Sequential therapy for the locally advanced larynx and hypopharynx cancer subgroup in TAX 324: survival, surgery, and organ preservation. Ann Oncol 2009;20:921-927.
13-Posner MR, Hershock D, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705-15.
14- Lefebvre JL, Rolland F, Tesselaar M, et al. Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy. J Natl Cancer Inst 2009;101:142-152.
15- Lefebvre JL, Pointreau Y, Rolland F, et al. Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: The TREMPLIN Randomized Phase II Study. J Clin Oncol 2013�;31:853-859.
16-Hoffman HT, Porter K, Karnell LH, et al. Laryngeal cancer in the United States: changes in demographics, patterns of care and survival. Laryngoscope 2006;116(Suppl 11):1�13.
17-Chen AY, Halpern M. Factors predictive of survival in advanced laryngeal cancer. Arch Otolaryngol Head Neck Surg 2007;133:1270�1276.
18-Forastiere, A. A. (2010), Larynx preservation and survival trends: Should there be concern?. Head Neck, 32:�14�17
19-Lefebvre JL, Ang KK. Larynx preservation clinical trial design: key issues and recommendations-a consensus panel summary. Int J Radiat Oncol Biol Phys 2009;73:1293�1303.
20-Lefebvre JL, Ang KK. Larynx preservation clinical trial design: key issues and recommendations -a consensus panel summary. Head Neck 2009;31:429�441.
21- Ang KK. Larynx preservation clinical trial design: summary of key recommendations of a consensus panel. Oncologist 2010; 15:25�29.
22-Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-analysis of chemotherapy on head and neck cancer. Lancet 2000;355(9208):949-55.
23-Pignon JP, LeMaitre A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC)�: An update on 93 randomized trials and 17,346 patients. Radiother Oncol 2009;92:4-14.
24- Bernier J. Current State-of-the-Art for Concurrent Chemoradiation. Semin Radiat Oncol 2009�;19:3-10.
25- Hitt R, Grau J, Lopez-Pousa A, et al. final results of a randomized phase III trial comparing induction chemotherapy with cisplatin/5-FU or docetaxel/cisplatin/5-FU follow by chemoradiotherapy (CRT) vs CRT alone as first-line treatment of unresectable locally advanced head and neck cancer (LAHNC) [abstract]. J Clin Oncol 2009, 27(15S):Abstract 6009.
26- Paccagnella A, Mastromauro C, D�Amanzo P, et al. Induction Chemotherapy Before Chemoradiotherapy in Locally Advanced Head and Neck Cancer: The Future? Oncologist 2010;15(suppl 3):8-12
27-Cohen EW, Karrison T, Kocherginsky M, et al. DeCIDE: A phase III randomized trial of docetaxel (D), cisplatin (P), 5-fluorouracil (F) (TPF) induction chemotherapy (IC) in patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol 30, 2012 (suppl; abstr 5500)
28- Haddad RI, Tishler RB, Adkins D, et al. The PARADIGM trial: A phase III study comparing sequential therapy (ST) to concurrent chemoradiotherapy (CRT) in locally advanced head and neck cancer (LAHNC): Preliminary toxicity report. J Clin Oncol 2010;28(No. 15S):5563.
29- Haddad RI, Rabinowits G, Tishler RB, et al. The PARADIGM trial: A phase III study comparing sequential therapy (ST) to concurrent chemoradiotherapy (CRT) in locally advanced head and neck cancer (LANHC). J Clin Oncol 2012;30 (suppl; abstr 5501)
30-K. K. Ang, Q. E. Zhang, D. I. Rosenthal, et al. A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas (HNC). J Clin Oncol 29: 2011 (suppl; abstr 5500)
31-A. Paccagnella, M. G. Ghi, I. Floriani,et al. 
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����sH	Concomitant chemoradiation or RT/cetuximab versus induction TPF followed by chemoradiation or RT/cetuximab in locally advanced head and neck squamous cell carcinoma: A randomized phase III factorial study. J Clin Oncol 29: 2011 (suppl; abstr TPS196)
32-National Comprehensive Cancer Network. Head and neck cancers version I.2012.  HYPERLINK "http://www.nccn.org" www.nccn.org 
33- Miah AB, Bhide SA, Guerrero-Urbano MT, et al. Dose-escalated intensitymodulated radiotherapy is feasible and may improve locoregional control and laryngeal preservation in laryngo-hypopharyngeal cancers. Int J Radiat Oncol Biol Phys 2012; 82:539�547.
34-Lefebvre JL. Larynx preservation. Current opinion 2012;24(3):218-222.
Tables:
Table 1: Randomized trials of larynx preservation.










 PAGE   \* MERGEFORMAT 19




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