Concurrent Chemoradiotherapy in Locally Advanced Head and Neck Cancer Using IMRT with SIB; NEMROCK Experience

Transcription

1 Med. J. Cairo Univ., Vol. 85, No. 4, June: , Concurrent Chemoradiotherapy in Locally Advanced Head and Neck Cancer Using IMRT with SIB; NEMROCK Experience HISHAM ATEF, M.D.; HUSSAM ZAWAM, M.D. and AHMED SELIM, M.D. The Department of Clinical Oncology and Nuclear Medicine, Kasr Al-Ainy Center, Cairo University, Cairo Egypt Abstract Background: Concurrent Chemo-Radiotherapy (CCRT) is the primary treatment modality for Locally Advanced Head and Neck Squamous Cell Carcinoma (LAHNSCC). Accelerated fractionation by Simultaneous Integrated Boost (SIB) has been shown to improve Local Control (LC). Adding chemotherapy to AF is more efficacious than RT alone. Objective: The technique of IMRT with SIB and concurrent chemotherapy is not broadly implicated in our region. This study aims at evaluation of the response and compliance of this approach in our patients. Methods: Forty patients were included and 50% received induction chemotherapy. Weekly cisplatinum (40mg/m 2 ) was administered during the radiation course. RT was administered using Intensity Modulated RT (IMRT) by step and shoot with SIB. The prescribed dose to the PTVgross disease was Gy in 2.12-Gy fractions, the dose to the PTVsubclinical disease was 59.4 Gy in 1.8-Gy fractions, and the dose to the PTVlow-risk subclinical disease was Gy in 1.64-Gy fractions. Results: With median follow-up of 18 months, LC was achieved in 33 patients (82.5% of cases) and distant control rate was 90% (36 patients). More than 5 interrupted radiation sessions and GTV volume >50 cc significantly affected LC (p=0.02 and respectively). Thirty two patients (80%) experienced grade 3 or 4 toxicities. Induction chemotherapy and PTV-70 volume >150 cc significantly affected the degree of toxicities (p=0.018 and respectively). The 2 years Disease Free Survival (DFS) is 77%. ECOG PS, large GTV volume (>50 cc) and RT interruption (>5 sessions) had negative impact on DFS (p=0.041, and respectively). The 2 years Overall Survival (OS) is 87%. Radiation interruption (>5 sessions) was the only factor which had significant detrimental effect on OS ( p=0.001). Conclusion: Induction chemotherapy seems to have a negative impact on patient's compliance to CCRT. Bulky tumors and prolonged radiation interruptions were associated with significantly lower LRC, DFS and OS. Key Words: IMRT SIB Head and neck squamous carcinoma. Correspondence to: Dr. Hisham Atef, The Department of Clinical Oncology and Nuclear Medicine, Kasr Al-Ainy Center, Cairo University, Cairo Egypt Introduction HEAD and Neck Squamous Cell Carcinoma (HNSCC) is the sixth leading cancer by incidence worldwide [1]. The Middle-East Cancer Consortium (MECC) reported that Egypt had one of the highest overall incidence rates of cancers of oral cavity and pharynx in the region [2]. This may be attributed to high rates of smoking and viral infection. Effective management of Locally Advanced Head and Neck Cancer (LA-HNC) requires comprehensive consideration of multiple competing treatment goals of locoregional control, and spectrum of toxicity. Radiotherapy (RT), with or without chemotherapy, is the primary treatment modality for locally advanced head and neck cancer patients) [3]. Accelerating the radiation treatment has been shown to improve local control on the cost of increasing acute side effects. Thus the concept of simultaneous in-field boost (or Simultaneous integrated boost-sib-) has emerged for treatment of localized primary sites. IMRT with SIB is viewed as a technically simple way and hopefully will avoid the increased late side effects related to the use of higher dose per fraction in conventional RT techniques [4]. From a radiobiological point, alteration of the fraction size and the overall treatment time using SIB can have different implications both on tumor control and toxicity [5]. SIB allows modest shortening of the overall treatment time which counteracts tumor repopulation as a major cause of radiation failure [6]. A review of 18 studies showed 15% absolute improvement in locoregional control, when using either six fraction per week or concomitant boost 1399

2 1400 Concurrent Chemoradiotherapy in Locally Advanced Head & Neck Cancer Using IMRT compared to conventional fractionation [6]. Another meta analysis showed similar improvement in LRC with altered fractionation [7]. A significant body of literature exists, including numerous randomized trials proving the benefit of adding concurrent chemotherapy to RT of advanced HNSCC which made it the current standard of care for certain patient groups. The MACH-NC (metaanalysis of chemotherapy in head and neck cancer) reported the largest and most recent update of most of these clinical trials and confirmed an absolute 5-year survival benefit of 6.5% (HR 0.81; 95% CI ) [3]. Numerous trials have shown that modified fractionation and concomitant chemotherapy are more efficacious than modified fractionation alone [8,9]. RTOG 0129 study assessed accelerated fractionation with 2 cycles of concurrent cisplatin vs standard fractionation with 3 cycles of concurrent cisplatin and there was no significant difference in OS between the 2 arms [10]. The aim of this study was to evaluate the response and toxicity of concurrent chemoradiotherapy in LA-HNC patients, by using IMRT with SIB. Another objective is to determine factors that lead to intolerance and interruption of radiation therapy sessions or delay in planned chemotherapy and how to overcome these problems. Patients and Methods Fourty patients with locally advanced carcinomas of the head and neck including those of nasopharyngeal origin (T 3 -T 4 and/or N1-3) were included. Recruitment started at the beginning of July 2013 and ended in March All the cases were presented to Kasr Al-Ainy Cancer Center (NEMROK) for treatment. Details of therapy: Patients underwent a pre-treatment evaluation, including a complete history and physical examination, CT and/or MRI of head and neck region, direct flexible fibro optic endoscopic examination, chest X-ray or thoracic Computed Tomography (CT). Associated comorbidities were assessed using the Adult Comorbidity Evaluation-27 (ACE-27) [11]. Weekly cisplatinum at a dose of 40mg/m 2 was administered during the whole course of RT in addition to the standard antiemetic therapy and hydration. Patients were set up in supine position and immobilized on a head support pad using a customized head-and-shoulder shell (S-type, Aqua plast, USA). Intravenous contrast was used in order to help in the definition of cervical nodes. All patients were CT-scanned from skull vertex to mid chest, with 2.5mm slice thickness. CT images were then transferred to the Eclipse TPS (v 8.6) via DICOM network. Treatment volume: The Gross Tumor Volume (GTV) defined as the macroscopic tumor defined after correlative analysis of CT-and MRI-scans including all involved (positive) lymph nodes. CTVgross disease is composed of GTVgross disease with a 10-mm margin to account for possible microscopic disease. A notable exception is near the brain stem or spinal cord, where normal tissue tolerances necessitate that the margin be reduced to as little as 1mm. The CTVsubclinical disease included all areas at risk for microscopic spread. A third CTVlow-risk subclinical disease may be outlined including the lower level neck nodes (levels 4 and 5b). However, in the presence of any pathologic low neck lymph node, these levels are incorporated into the CTVsubclinical disease. The PTV is generally a 5-mm expansion of all the CTVs to account for potential setup errors and patient motion. Once again, limiting the margin to 1 mm around the CTV is allowed near the brainstem and spinal cord. Treatment planning and delivery: Patients were planned for inverse IMRT with the modality of step and shoot using Eclipse TPS (Version 8.6, from Varian Medical Systems). Nine isocentric co-planner fields with equispaced gantry angles orientation in 360º around the patient (180, 220, 260, 300, 340, 20, 60, 100 and 140) were used. Megavoltage X-ray beams of 6 MV were applied. Dose and fractionation: Based on the early experience with IMRT and the consensus opinion used in the RTOG 0225 study, the prescribed dose to the PTVgross disease was Gy in 2.12-Gy fractions, the dose to the PTVsubclinical disease was 59.4 Gy in 1.8-Gy fractions, and the dose to the PTVlow-risk subclinical disease was Gy in 1.64-Gy fractions. The prescribed doses were delivered in 33, one-a-

3 Hisham Atef, et al day fractions such that the PTVgross disease is boosted at the same time as the other PTVs are irradiated. Toxicity evaluation: Evaluation of toxicity was based on the fourth version of CTCAE [12]. If weight reduction exceeds 10% during treatment, feeding through a gastrostomy tube, inserted by percutaneous fluoroscopic or endoscopic procedure, was recommended. Acute toxicity was scored from the start of radiation therapy until 3 months of follow-up. Late toxicity was scored thereafter until the end of follow-up. If multiple occurrence was documented, the most severe grade of a specific event was used for grading. Disease related functional impairments present prior to the start of chemoradiation were scored as toxicity only if worsening occurred. Statistical analysis: All statistics were performed using SPSS software (Statistical Package for Social Science) V. 19. Description statistics were presented as number and percentage (frequency distribution). Local Control (LC) was defined as absence of tumor (re)- growth in the region of the primary tumor. Regional Control (RC) was defined as absence of tumor (re)-growth in the bilateral cervical nodal areas. Distant Control (DC) was defined as absence of distant metastases. In patients without further assessment of local/ regional control, for example after development of distant spread, the date of the last information about the local/regional status was used for calculation. Disease Free Survival (DFS) was defined as absence of disease at any site or death of any cause. Cox regression models were used to estimate hazard ratios and 95% ConfiDence Intervals (CIs) for the risk of death associated with interruptions in radiotherapy. Factors were considered significant when p-value is <0.05. Results Patients' profiling: Analysis of the results showed that most of our patients were males (65%). Median age was 49 years (range 19-49). ECOG PS at presentation was 0-1 in 95% of cases. Adult comorbidity evaluation (ACE-27) grade was 0-1 in 92.5% of cases, only 3 patients had ACE grade 2 at presentation. Nasopharyngeal carcinoma represented the most common head and neck primary (62.5% of cases), followed by oropharyngeal carcinoma in 15% of cases. Other characteristics are presented in (Table 1). Table (1): Patients and tumor characteristics. Factor Variable Number Percent Gender Male Female Age <50 years >_50 years ECOG PS Smoking history Yes No ACE grading Site of primary lesion Nasopharynx Oropharynx 6 15 Larynx 4 10 Hypopharynx PNS 2 5 Stage a b Treatment details: Twenty patients (50% of cases) received induction chemotherapy. Generally induction chemotherapy was used in case of bulky disease or to avoid delay of treatment in case of long waiting list on the RT machine. Median time from simulation date to treatment date was 15.5 days, (range 5-38 days). Radiation interruption was documented in 19 patients (47.5% of cases). The total number of interrupted RT days in the 40 patients was 113 days. The main causes of interruption were unplanned machine breakdown and development of side effects. These 2 causes were responsible for interruption in 63% and 57% of cases respectively (i.e causing interruption in 37 and 36 sessions respectively). Details of RT interruption are shown in (Table 2). Median radiation time for the whole group was 50 days (range days). In patients who had interruption in their radiotherapy sessions, the median RT time was 56 days (range days) and the median number of interrupted sessions was 6 sessions (range 3-14 sessions). Total dose of cisplatin planned to be given was 280mg/m 2 (40mg/m 2 weekly for 7 weeks). Only 13 patients (32.5%) completed the planned chemo-

4 1402 Concurrent Chemoradiotherapy in Locally Advanced Head & Neck Cancer Using IMRT therapy dose, while most of our patients (23 patients representing 57.5%) have omitted 1-2 chemother- apy cycles due to either neutropenia (in 45% of cases) or severe mucositis (in 17.5% of cases). Table (2): Details of radiation interruption (values are calculated for 19 patients with RT interruption only). Factor Variable No. of patients Percentage Comment Cause of radiation interruption* No. of interrupted sessions** Machine breakdown Side effects Vacation Patient ignorance Treatment time lengthened by (N. of days) 1-5 days days 8 42 >10 days 3 16 Management of the gap Weekend sessions Extra sessions Both No special gap management *Some patients may have more than 1 cause of RT interruption. **Total number of interrupted sessions is 113. Locoregional control: With a median follow-up period of 2 years (range months), locoregional control was achieved in 33 out of 40 patients (82.5% of cases). Four patients developed distant failure (bone and lung metastases) leading to distant control rate of 90%. Analysis of the factors that affect locoregional control is shown in (Table 3). More than 5 delayed RT sessions and large GTV volume >50 cc were the only statistically significant factors. Table (3): Factors that affect locoregional control and their statistical significance. Factor Variable Ratio of CR Percentage of CR Significance* Gender M 22/ F 11/ Age group >60 5/ <60 28/ ECOG PS 0 16/ / /2 50 Smoking history No 16/ Yes 17/ Neoadjuvant chemotherpy No 17/ Yes 16/20 80 ACE grade 0 21/ / / Site of the primary NPC 18/ Other 15/ Stage 3 20/ / Omitted concomitent chemotherapy cycles No 12/ Yes 21 /28 75 Interrupted RT sessions >5 sessions 4/ sessions 29/ GTV volume >50 cc 10/ <50 cc 23/ *Significance is calculated by 2-sided chi-square test.

5 Hisham Atef, et al Acute toxicities: Eleven patients (27.5 %) developed grade 3 neutropenia. No other grade 3 or 4 hematological toxicities were noticed. High grade mucositis (grade 3 or 4) was noticed in 75% of cases. Four patients developed grade 4 (life threatening) mucositis. Those patients were hospitalized and RT sessions were interrupted. They were treated from dehydration, neutropenia, fever and oropharyngeal candidiasis. Feeding gastrostomy was inserted in 2 patients. After being successfully managed, they completed their course of treatment. High grade (grade 3-4) xerostomia occurred in 14 patients (35% of cases). Other high grade toxicities include; grade 3 oral pain in 25 patients (62.5%), grade 3 laryngitis in 13 patients (32.5%), grade 3 dysphagia in 19 patients (47.5%), and grade 3 radiation dermatitis in 6 patients (15%). Table (4): Acute non hematological toxicities. Factor Variable Number Percent Mucositis: Grade Time of highest grade mucositis Week Week Week Week Xeorstomia: Grade Time of highest grade xerostomia Week Week Week Pain: Grade Time of highest grade pain Week Week Week Week Laryngitis: Grade Time of highest grade of laryngitis Week Week Week Week Dysguesia: Grade Time of highest grade of dysguesia Week Week Week Week Dysphagia: Grade Time of highest grade of dysphagia Week Week Week Week Thickening of salivary secretions: Grade Time of highest grade of thickened salivary secretions Week Week Week Radiation dermatitis: Grade Time of highest grade of radiation dermatitis Week Week Week Week

6 1404 Concurrent Chemoradiotherapy in Locally Advanced Head & Neck Cancer Using IMRT Subacute and late radiation toxicity (after 90 days from the end of RT sessions): Only 2 patients developed grade 3 xersotomia and dysphagia after the end of RT by 3-6 months. Both of them we re hospitalized and 1 patient needed nasogastric tube insertion for proper alimentation. No grade 4 toxicities were noticed. However grade 2 xerostomia occurred in 40% of cases. Grade 2 dysguesia remained in 70% of cases. Grade 2 hoarseness of voice occurred in 17.5%. All late toxicities are summarized in (Table 5). Factors affecting development of severe toxicity (grade 3 or 4): Thirty two patients (representing 80%) have experienced grade 3 or 4 toxicities, with mucositis representing the most common toxicity occurring in 30 patients (75% of cases). Factors affecting development of severe toxicities and their statistical significance are presented in (Table 6). The only significant factors are neoadjuvant chemotherapy p-value=0.018, and large PTV-70 volume >150cc with p-value= Disease Free Survival (DFS): The 2 years DFS is estimated to be 77%. Analysis of the factors affecting DFS revealed that the only significant factors are; ECOG PS, GTV volume and >5 interrupted RT sessions. Overall Survival (OS): The 2 years OS is estimated to be 87%. Analysis of the factors affecting OS revealed that the only significant factor that has a detrimental effect on OS is more than 5 interrupted RT sessions. Table (5): Subacute and late radiation toxicities. Factor Grade Number Percentage Fatigue Myelitis Hearing impairment Tinnitus Neck edema Hoarsness Dental caries Xerostomia Dysphagia Trismus Dysguesia Fibrosis Osteonecrosis of the jaw Hypothyroidism Table (6): Factors affecting development of grade 3-4 radiation toxicities. Factor Variable Ratio of patients with severe toxicity Percentage of patients with severe toxicity Significance * Gender F 12/ M 20/ Age group >60 years 6/ <60 years 26/ Smoking history Yes 17/ No 15/ ACE grade 0 21/ / / Neoadjuvant chemotherapy Yes 19/ No 13/20 65 PTV 70 volume >150 cc 25/ <150 cc 6/ *Significance is calculated by 2-sided chi-square test.

7 Hisham Atef, et al Table (7): Factors affecting DFS and their statistical significance. Factor Survival function Delayed RT sessions Censored >5 sessions 0-5 sessions >5-censored Variable 2 years DFS p- value* ECOG PS. 0 NR Neoadjuvant chemotherapy. No Yes 72 ACE-27 grade Stage Omission of concomitant No chemo cycles. Yes 70 Interruption in RT sessions. >5 sessions sessions 87 GTV volume. >50cm <50cm 3 92 *Significance is calculated by log rank test. Percentage of patients DFS (months) Fig. (1): Kaplan Meyer survival curve showing the PFS of the whole group of patients. Percentage of patients DFS (months) 0-5-censored Fig. (2): Kaplan Meyer survival curve showing the relation between interrupted RT sessions and DFS of the whole group of patients. Percentage of patients DFS (months) GTV volume >50 cc <50 cc >50 cc-censored <50 cc-censored Fig. (3): Kaplan Meyer survival curve showing the relation between GTV volume and DFS of the whole group of patients. Table (8): Factors affecting OS and their statistical significance. Factor Variable Survival function 2 years DFS p- value* ECOG PS NR Neoadjuvant chemotherapy. No Yes 100 Stage Omission of concomitant. No chemo cycles. Yes 86 >5 sessions Interruption in RT sessions. 0-5 sessions 62.5 >50cm GTV volume. <50cm 3 96 *: Significance is calculated by log rank test. Percentage of patients OS (months) Censored Fig. (4): Kaplan Meyer plot of the OS for the whole group of patients.

8 1406 Concurrent Chemoradiotherapy in Locally Advanced Head & Neck Cancer Using IMRT Percentage of patients OS (months) Delayed RT sessions >5 sessions >5 sessions-censored 0-5 sessions 0-5 sessions-censored Percentage of patients OS (months) GTV volume >50 cc <50 cc >50 cc-censored <50 cc-censored Fig. (5): Kaplan Meyer survival curve showing the relation between interrupted RT sessions and OS of the whole group of patients. Discussion Management of SCC of head and neck represents a challenge for both the patients and the clinicians. The multiplicity of critical functions in this region greatly affects the patient's quality of life and his adherence to the treatment protocol. Locoregional recurrence is the predominant cause of failure in H & N tumors. Analysis of data from RTOG trial enrolling more than 1000 patients with LAHN-SCC revealed that the actuarial locoregional recurrence was near to 50% compared to <20% for distant metastases [13]. Consequently, efforts should focus on developing combined therapy aiming at improving locoregional control for this group of patients. One of the important features of HNSCC is the ability of these tumors to grow rapidly which may compensate for radiation-induced cell loss through the mechanism of accelerated repopulation [14]. Accelerated fractionation has been applied in several trials to overcome this problem. Hyperfractionation has been shown to provide a consistent increase in locoregional control of LAHN-SCC, with increase in acute but not late toxicity. However, delivering six fractions per week or concomitant boost (SIB) may provide similar results without significantly higher toxicity [15]. Numerous trials have shown that modified fractionation and concomitant chemotherapy are more efficacious than modified fractionation alone [2,16]. All these factors were taken in consideration in the design of this study in which concurrent chemoradiotherapy with Simultaneous Integrated Fig. (6): Kaplan Meyer survival curve showing the relation between GTV volume and OS of the whole group of patients. boost (SIB) was used for treatment of patients with locally advanced HNSCC. The epidemiological data (Table 1) reflects the general features of SCC of H & N. The majority of patients in our study were males (26/40) 65%. History of smoking was documented in 21/26 (80%) of males. Nasopharynx was the commonest site of HNSCC in our study 29/40 (64%). Nasopharyngeal carcinoma is relatively common in Mediterranean and some North African population. These areas are considered endemic areas for EBV, and the incidence outside endemic areas is much lower [17]. University of California San Francisco (UCSF) researchers were the first to report their experience with IMRT in 67 patients with nasopharyngeal cancer, including 45 patients with stage III to IV disease, treated between 1995 and Patients were prescribed 59.4 Gy in 1.8-Gy fractions to the Planning Target Volume (PTV) encompassing microscopic and gross disease and typically received 65 to Gy to the gross disease and involved lymph nodes in 2.12-to 2.25-Gy fractions. The reported 4-year estimates of local PFS, locoregional PFS, and OS were 97%, 98%, and 88%, respectively. Long-term xerostomia was minimal at 2 years, with 66% of the patients having no xerostomia and no grade 2 or higher late xerostomia [18]. Locoregional control rates above 90% in NPC have since been noted in single-institution prospective [19,20] as well as in the multiinstitutional Radiation Therapy Oncology Group (RTOG) 0225 study [21].

9 Hisham Atef, et al Similar to the UCSF regimen, the RTOG 0225 trial used a simultaneous integration of the boost, with 2.12 Gy per fraction delivered to the gross disease with a minimal 5-mm margin (PTV70). After a median follow-up of 2.6 years, the estimated 2-year local PFS, locoregional PFS, and OS rates were 92.6%, 89.3%, and 80.2%, respectively [21]. However all these series included patients with NPC only without any other locally advanced HNSCC. Montejo et al., used IMRT with SIB with concurrent cisplatin or Cetuximab to treat 43 patients with locally advanced HNSCC. They reported CR rate of 74.4% only, with 90.7% of the patients completed the prescribed treatment [22]. Locoregional control was achieved in 82.5% of our cases where 33 out of 40 patients developed CR during their follow-up CT or MRI and confirmed by endoscopy after the end of treatment by 4-6 weeks. Since we included patients with NPC together with other HNSCC, so our response rate seems quite reasonable and acceptable. We evaluated many factors which might influence the quality of response. Large GTV volume (>50 cc) and >5 delayed RT sessions were the only statistically significant factors. It is expected that concurrent chemoradiotherapy increases acute toxicity compared to radiation alone. Altered fractionation and/or multiagent chemotherapy may further increase the toxicity burden. The time of highest grade of toxicity in our study was the 5 th to 6 th week, which is a wellknown radiobiological finding [23]. Studer et al., studied 115 patients treated with SIB-IMRT with concurrent weekly cisplatin 40mg/m 2. Xerostomia grade 3 was observed in 10% of patients at completion of treatment and mucositis (grade 3) in 15 %. Grade 3 dysphagia developed in only 20 % of the cases. No grade 4 early reaction occurred [24]. In our series, high grade mucositis (grade 3 or 4) occurred in 75% of cases. Four patients developed grade 4 mucositis. Grade 3-4 xerostomia occurred in 14 patients (35% of cases) and grade 3 dysphagia in 19 patients (47.5%). Those results are quite high compared to the results of Studer et al., this is most probably related to the use of different scales for assessment of the grade of mucositis, e.g. WHO scale vs. CTCAE. In addition the former study was retrospective, 30% of their patients were post-operatively treated and 62% only of their patients had stage 3-4 diseases. The difference in development of high grade toxicities between PTV-70 values >150cc vs. <150cc was highly significant (p-value=0.0001), therefore it is expected to have high incidence of grade 3-4 mucositis in patients with more advanced stages. Subgroup analysis of our patients showed that grade 3-4 mucositis was nearly universal in patients receiving induction chemotherapy 95% (19/20), compared to 65% (13/20) in patients not receiving induction therapy, p-value= Importantly, while providing similar or better locoregional tumor control in comparison with conventional irradiation techniques, IMRT has resulted in significantly lower rates of late complications. Results of the RTOG 0225 showed that only nine patients (13.5%) had grade 2 xerostomia at 1 year from the start of IMRT, two patients had grade 3 xerostomia, and none had grade 4 xerostomia [21]. Studer et al., reported 18% grade 3/4 subacute or late effects (included 2 cases with a grade 3 xerostomia, 2 cases with grade 3 dysphagia, and mucosal ulcers in 12 cases) [24]. In our series, grade 3-4 late radiation toxicities were noted in 10% of cases. Only 2 patients developed grade 3 xersotomia and 2 patients continued to suffer from grade 3 dysphagia after 3-6 months from the end of RT. No grade 4 toxicities were noticed. However grade 2 xerostomia occurred in 40% of cases. Grade 2 dysguesia remained in 70% of cases. Those results are comparable with data from RTOG and Studer et al. Analysis of factors affecting development of severe toxicities in our series revealed that the only significant factors were neoadjuvant chemotherapy (p-value=0.018), and large PTV-70 volume >150cc (p-value=0.0001). Ninety percent (18/20) of patients who received neoadjuvant chemotherapy have omitted one or more cycles of the concomitant chemotherapy and 75% of those patients (15/20) had interruption in their radiotherapy schedule, with statistically significant differences from other patients who didn't receive induction therapy ( p- values and respectively). The role of induction chemotheray in HNSCC is still controversial, and its indications differ from site to site. Thus in NCCN guidelines 2015; induction chemothery has a category 3 recommendation (i.e.major disagreement) for the management of both locally and regionally advanced oropharyngeal cancer. However in other sites category 2A and 2B are recommended based on the updates from RTOG trial. For selected patients with hypopharyngeal and laryngeal cancers less than T4a

10 1408 Concurrent Chemoradiotherapy in Locally Advanced Head & Neck Cancer Using IMRT in extent, induction chemotherapy as part of larynx preservation protocol is category 2A [25]. It is clear that induction chemotherapy may aggravate the toxicity of concurrent chemoradiotherapy, therefore it should be done in specialized centers after proper patient selection. Adding induction chemotherapy to regimens including concurrent chemoradiotherapy particularly with altered fractionation seems to be inappropriate. Furthermore weekly cetuximab or carboplatin instead of cisplatin are reasonable agents to use if concurrent chemoradiotherapy is chosen [25]. Adding induction chemotherapy was not a preplanned policy in our study, however it was not an exclusion criteria. Failure to adhere to the planned protocol was significantly higher in this group due to the significant toxicity of neoadjuvant chemotherapy. Longer follow is required to assess the effect of neoadjuvanvt chemotherapy on DFS and OS. The effect of the GTV volume on tumor contro lwas described in various studies, for example in the study of Studer et al., [24], the mean GTV volume in patients who failed locally was 63cc compared to 32cc in locally controlled patients (p<0.01). This effect was more obvious in our study where patients with large GTV volume (>50cc) were found to have significantly lower local control rate (95.8% vs. 62.5%), 2 years DFS (92% vs. 50%) and borderline significantly lower OS (96% vs. 75%) than those with smaller GTV volume (p-values 0.001, and 0.06 respectively). Medical record of 3864 patients with HNSCC were studied by Fesinmeyer et al.; to evaluate the influence of RT interruption on survival. They concluded that interruption may influence survival time among patients completing a full course of RT [26]. Mathematical modeling of data from patients with HNSCC suggest that unscheduled interruption of 1 day if left uncompensated results in absolute reduction of local control by 1-1.4% [27]. However the exact effect of concurrent chemotherapy and altered schedules of fractionation on radiation interruption is still not clear. In our study; long radiation interruption (>5 sessions) was associated with significantly lower LC rate (90.6% vs. 50%, p=0.02), lower 2 years DFS (87% vs. 38%, p=0.001) and lower 2 years OS (93.5% vs. 62.5%, p=0.011). Conclusion: It seems that neoadjuvant chemotherapy has a negative impact on patients' compliance and tolerance to concurrent chemoradiotherapy approach, without affecting DFS or OS. Its use should be limited to patients with bulky disease or inside clinical trials. Large tumor volumes (>50cc) and long radiation interruption (>5 sessions) are associated with significantly lower locoregional control, DFS and OS. Thus encouraging patients to receive chemoradiotherapy as prescribed is of utmost importance. References 1- BOYLE P. and BERNARD LEVIN: World Cancer Report International Agency for Research on Cancer. Web 24/12/2016, FREEDMAN L.S., EDWARDS B.K., RIES L.A.G. and YOUNG J.L.: Cancer incidence in four member countries (Cyprus, Egypt, Israel, and Jordan) of the Middle East cancer consortium (MECC) compared with US SEER LEE T.F., TING H.M., CHAO P.J. and FANG F.M.: Dual Arc Volumetric-modulated Arc Radiotherapy (VMAT) of Nasopharyngeal Carcinomas: A Simultaneous Integrated Boost Treatment Plan Comparison with Intensitymodulated Radiotherapies and Single Arc VMAT. Clin. Oncol. (R. Coll. Radiol.), 24: , OLIVIER BALLIVY, RAMÓN GALIANA SANTA- MARÍA, ALICIA LOZANO BORBALAS and FERRÁN GUEDEA EDO: Clinical application of intensitymodulated radiotherapy for head and neck cancer; Clin. Transl. Oncol., 10: , TEO P.M., LEUNG S.F., TUNG S.Y., et al.: Dose-response relationship of nasopharyngeal carcinoma above conventional tumoricidal level: A study by the Hong Kong nasopharyngeal carcinoma study group (HKNPCSG). Radiother. Oncol., 79: 27-33, NGUYEN L.N. and ANG K.K.: Radiotherapy for cancer of the head and neck: Altered fractionation regimens. Lancet Oncol., 3: , BOURHIS J., OVERGAARD J., AUDRY H., et al.: Hyperfractionated or accelerated radiotherapy in head and neck cancer: A meta-analysis. Lancet, 368: , BUDACH W., HEHR T., BUDACH V., et al.: A metaanalysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck. B.M.C. Cancer, 6: 28, BENSADOUN R.J., BÉNÉZERY K., DASSONVILLE O., MAGNÉ N., et al.: French multicenter phase III randomized study testing concurrent twice-a-day radiotherapy and cisplatin/5-fluorouracil chemotherapy (BiRCF) in unresectable pharyngeal carcinoma: Results at 2 years (FNCLCC-GORTEC) Int. J. Radiat. Oncol. Biol. Phys., Mar. 15, 64 (4): , 2006.

11 Hisham Atef, et al ANG K.Z.Q., WHEELER R.H., et al.: A phase III trial (RTOG 0129) of two radiation-cisplatin regimens for head and neck carcinomas (HNC): Impact of radiation and cisplatin intensity on outcome. J. Clin. Oncol., 28: 422s, Adult Comorbidity Evaluation-27. [Online]. Available: oclatc- MufRA%3D&tabid=290. Web: 29/12/ Common Terminology Criteria for Adverse Events (CTCAE ), NIH Publication. [Online]. Available: evs.nci.nih.gov/ftp1/ctcae/ctcae_4.03_ _QuickReference_5x7.pdf, FU K.K., PAJAK T.F., TROTTI A., et al.: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: First report of RTOG Int. J. Radiat. Oncol. Biol. Phys., 48: 7-16, WITHERS H.R., TAYLOR J.M. and MACIEJEWSKI B.: The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta. Oncol., 27 (2): , GUNDERSON and TEPPER: Clinical Radiation Oncology, 3rd ed., Overview of head and neck tumors, Robert L. Foote and K. Kian Ang, ISBN: , Copyright 2012 by Saunders, an imprint of Elsevier Inc. 16- BENSADOUN R.J., BÉNÉZERY K., DASSONVILLE O., et al.: French multicenter phase III randomized study testing concurrent twice-a-day radiotherapy and cisplatin/5-fluorouracil chemotherapy (BiRCF) in unresectable pharyngeal carcinoma: Results at 2 years (FNCLCC- GORTEC) Int. J. Radiat. Oncol. Biol. Phys., Mar. 15, 64 (4): , J. FERLAY, I. SOERJOMATARAM, R. DIKSHIT, et al.: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012, Int. J. Cancer, Vol. 136, No. 5, pp. E359-E386, LEE N., XIA P., QUIVEY J.M., et al.: Intensity-modulated radiotherapy in the treatment o nasopharyngeal carcinoma: An update of the UCSF experience. Int. J. Radiat. Oncol. Biol. Phys., 53 (1): 12-22, KWONG D.L., POW E.H., SHAM J.S., et al.: Intensitymodulated radiotherapy for early-stage nasopharyngeal carcinoma. A prospective study on disease control and preservation of salivary function, Cancer, 101: , WOLDEN S.L., CHEN W.C., PFISTER D.G., et al.: Intensity-modulated radiation therapy (IMRT) for nasopharynx cancer. Update of the Memorial Sloan-Kettering experience, Int. J. Radiat. Oncol. Biol. Phys., 64: 57-62, LEE N., HARRIS J., GARDEN A.S., et al.: Intensitymodulated radiation therapy with or without chemotherapy for nasopharyngeal carcinoma. Radiation Therapy Oncology Group phase II trial 0225, J. Clin. Oncol., 27: , M. MONTEJO, D. SHRIEVE, B. BENTZ, J. HUNT, L. BUCHMAN, N. AGARWAL and Y.J. HITCHCOCK: IMRT with SIB and concurrent chemotherapy for locally advanced squamous cell carcinoma of the head and neck; Int. J. Radiation Oncology Biol. Phys., Vol. 81, No. 5, pp. e845-e852, ERIC J. HALL and AMATO J. GIACCIA: Radiobiology for the radiobiologists; 8 th ed; 2012 by Lippincott Williams and Wilkins. 24- G. STUDER, P.U. HUGUENIN, J.B. DAVIS, G. KUNZ, U.M. LÜTOLF and C. GLANZMANN: IMRT using simultaneously integrated boost (SIB) in head and neck cancer patients; Radiation Oncology, 1: 7, Doi: / X-1-7, NCCN guidelines, Head and Neck; store/login/login.aspx?returnurl= rg/professionals/physician_gls/pdf/head-and-neck.pdf, M. FESINMEYER, V. MEHTA, D. BLOUGH, L. TOCK, and S. RAMSEY: Effect of radiotherapy interruptions on survival in Medicare enrollees with local and regional head and neck cancer; Int. J. Radiation Oncology Biol. Phys., Vol. 78, No. 3, pp , Royal college of radiologists, The timely delivery of radical radiotherapy, Standards and guidelines for management of unscheduled interruptions; 3rd ed

12 1410 Concurrent Chemoradiotherapy in Locally Advanced Head & Neck Cancer Using IMRT