Concomitant Radiochemotherapy in the Management of Nasopharyngeal Carcinoma

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1 November, ; Vol1; Issue10 Concomitant Radiochemotherapy in the Management of Nasopharyngeal Carcinoma J. Irigo, A. Maghous, E. Ogandaga, S. El Majjaoui, H. Elkacemi, T. Kebdani, N. Benjaafar Departement of Radiation Oncology, National Institute of Oncology, Mohamed V University, Rabat, Morocco Corresponding Author: Joëlle Irigo irigo78@yahoo.fr ABSTRACT Purpose: To develop the results of concomitant radiochemotherapy in management of nasopharyngeal carcinoma (NPC) to the National Institute of Oncology at Rabat. Materials and methods: Retrospective study of 81 patients with nasopharyngeal carcinoma and who were treated with concomitant radiochemotherapy to the National Institute of Oncology at Rabat in radiotherapy department, for a period of January to December Results: Median age was 43 years old with male dominance to 78.8 %. According to TNM classification passed by AJCC 2010, 43.2% were classified stage IV, 37 % stage III and 19.8 % stage II. Neoadjuvant chemotherapy was indicated in 20 patients (24.7%) or 95% in N2-N3. The Therapeutic result after the neoadjuvant chemotherapy for lymph node was complete in 31.2 %. The concomitant radiochemotherapy treatment consisted in a conformal therapy treatment with lateral 6 MV photon beams dose of 70 Gy in conventional fractioning, and in two series by excluding spinal cord after dose of 40 Gy. We used electrons treatment in addition to treat the lymph nodes. The concomitant chemotherapy consisted of a weekly cisplatin treatment 40 mg/m2. The mean spread was 57.3 days. During the concomitant chemotherapy treatment 60 % of radiomucitis and 30 % nephrotoxicity were observed in patients receiving neoadjuvant chemotherapy. Late toxicities were dominated by hyposcialie (90.1%) and otological disorders (67.9%). After an average follow-up of 30.6 months, we were able to follow the progress of 69 patients (85.2%). Forty-nine patients (75.3%) were in good locoregional control. We observed 20 relapses (24.7 %) including 14 metastatic relapses. The main prognostic factors of metastasis were lymph node involvement in 92.2% (p = 0.04) and T3-T4 stages in 64.2% (p = 0.013). At three years, overall survival at all stages were to 81.9%, survival without recurrence to 71% and local control to 79.2%. Conclusion: The nasopharyngeal carcinoma are radiosensitive and radiocurable tumors. Concomitant radiochemotherapy is the therapeutic standard for locally advanced nasopharyngeal carcinoma, and allow to obtain carcinological good results at toxicity notable disadvantage. Keywords: nasopharyngeal carcinoma, concomitant radiochemotherapy 1. INTRODUCTION The nasopharyngeal cancer (NPC) is an important issue of the public health in many countries including Morocco. According to the worldwide statistics of the International Agency for the cancer research, it is estimated approximately most of people with NPC in 2008 with 80 % in Asia and 5 % in Europe. To the National Institute of Oncology at Rabat NPC represents 6 to 10 % of the activity of the radiotherapy department. It is a cancer from the upper aerodigestive tract who show several aspects: multifactorial etiology (EBV, environment, genetic ), specific

2 histology, specific complex anatomy, radiosensitive, radiocurable. Most patients are diagnosed locally in advanced stages. The concomitant radiochemotherapy is the standard treatment over the past twenty years. However, the results of locally advanced concomitant NPC treatment are unsatisfactory. The 5-year overall survival are 53-80% for stage III and 28-61% for stages IV. Radiation therapy of NPC requires a good knowledge of the radioanatomy and the natural history of cancer.this part of anatomy is complex with many critical organs sensitive to rays. The conformal radiotherapy, with intensity modulation in particular (IMRT), reference technic, allows a highly targeted irradiation of the target volumes with better protection of the organs at risk in the vicinity while reducing as much as possible the side effects, allowing to improve the quality of life of the patients. We report in this work experience of radiotherapy department of the National Institute of Oncology (INO) on concomitant radiochemotherapy of the NPC. 2. METHODS This is a retrospective study including 81 patients affected with NPC histologically proved with cavum biopsy and who received concomitant radiochemotherapy to department of radiotherapy of INO during a period of January to December The various diagnostic and therapeutic data were collected from the clinical records, the Mosaic verification and registration system and the XiO planning software for radiotherapy. We have used TNM 2010 classification for disease staging. The various diagnostic and therapeutic data were collected from the clinical records, the Mosaic verification and registration system and the XiO planning software for radiotherapy. The concomitant radiochemotherapy consisted in a three-dimensional conformal radiotherapy (3-D) by a linear accelerator of energy 6 MV photon of two side beams dose of 70 Gy with fractioning of 2 Gy/fraction of two sets without any spinal cord after dose of 40 Gy. We used electrons treatment in addition to treat the lymph nodes. The concomitant chemotherapy consisted of a weekly cisplatin treatment 40 mg/m2. Throughout the treatment, patients were weekly monitoring to appreciate good treatment progress, to estimate weight loss and to research toxicities related to the treatment according to CTC v.03 (Commun Toxicity Criteria of EORTC) (18). Acute toxicity was defined as the side effects occurring during radiotherapy or within three months of irradiation. Late toxicity was defined as the side effects occurring or persisting three months or more after the end of radiation therapy (8). In the first two years after treatment, patients have been monitored during three months, then all 6 months during three years to once a year beyond the fifth year. A nasofibroscope otorhinolaryngeal examination and a full clinical exam have been performed. CT of nasopharyngeal and cervical reference to 6 months then once a year and if necessary supplemented according to clinical signs of calls by thoraco-abdominal CT and / or bone scintigraphy. Recurrence sites were classified according to recurrence: locoregional if recurrent to the cavum or lymph node and metastatic if recurrent at distances (hepatic, pulmonary, bone). For an analysis of statistics we used, statistical Package for the Social Sciences (SPSS) vers. 20. Quantitative variables have been expressed in measuring their trends (mean, median) and specific measures of their variability (standard deviations, quartile). Clinical and pathological features comparison was done via the Student t-test and Mann- Whitney test for quantitative variables; for qualitative variables via Pearson s chi-square test and the Fisher exact test. Global survival has been defined as the period between the histological diagnostic date and death date. Free-relapse survival has been defined as the period between the histological diagnostic date and relapse disease date, which can be a local or distant relapse or last date of patient free of the disease was known. Kaplan-Meier s statistical method was used to assess the probability of survival rates and Log-rank tests for the curves comparison. A p < 0,05 was seen as significant. 3. RESULTS Median age was 43 years (10-80) with two peaks ages, the first one to 18 years and second to 45 years (Graph 1). With male dominance to 78.8 %. The time between the onset of initial symptoms of disease and the first visit to the doctor was long period within median delay time of 6 months (1-24). In order clinical symptomatic signs were: rhinologic signs (81.5%), otologic signs (60.5 %), cervical lymphadenopathy (56.7 %) and neurological signs (44.4 %).

3 The most histological type was the undifferentiated carcinoma type III of WHO (98.8 %) followed by the keratinizing squamous cell carcinoma type I (1.2 %). As part of loco-regional extension, the CT of cavum and cervical has been performed to 98.8 %, MRI of Figure 1: Patients median age Table 1 : Stages TNM cavum to 5 % and bone scintigraphy to 80.2 %. At the end of the assessment 43.2 % of patients were classified stage IV, 37 % stage III and 19.8 % stage II (Table 1). The neo-adjuvante chemotherapy was indicated to 20 patients (24.7 %) or 95 % in N2-N3 and to 90 % in stages III-IV. The chemotherapy protocol consisted to 3 cycles of cisplatine adriamycin to 17 patients (85 %) and 3 cycles of BEC to 3 patients (15 %) under 15 years old. The Therapeutic result after the neoadjuvant chemotherapy for lymph node was complete in 31.2 %. Concomitant radiochemotherapy treatment consisted in a conformal therapy treatment dose of 70 Gy with fractioning of 2 Gy/fraction in two series by excluding spinal cord after dose of 40 Gy. We used electrons treatment in addition to treat the lymph nodes. Concomitant chemotherapy consisted of a weekly cisplatin 40 mg/m2. Mean spread was 57.3 days ± 8.2 days (49-80). Mean number of chemotherapy cycles was 5.7 ± 1.1 (2-7) and intercure interval was observed for 53 patients (65.4%). During the concomitant chemotherapy treatment 60 % of radiomucitis and 30 % nephrotoxicity were observed in patients receiving neoadjuvant chemotherapy. Acute toxicities of concomitant radiochemotherapy are listed in Table 2.

4 Table 2: Concomitant radiochemotherapy acute toxicities International Annals of Medicine Acute toxicities Neo-adjuvant chemotherapy Concomitant radiochemotherapy G2 G3 G4 G2 G3 G4 Hematological 3 (15) 4 (20) 0 (0) 15 (18.5) 8 (9.9) 0 (0) Nephrological 3 (15) 0 (0) 0 (0) 20 (24.7) 0 (0) 0 (0) Digestive 10 (50) 0 (0) 0 (0) 40 (49.4) 1 (1.2) 0 (0) Radiomucitis (65.4) 9 (11.1) 0 (0) Radiodermatitis (54.3) 8 (9.9) 0 (0) Late toxicities were dominated by hyposcialie (90.1%), otological disorders (67.9%) and trismus (17.3 %). After an average follow-up of 30.6 month ± 12 ( ), we were able to follow the progress of 69 patients (85.2%), a rate of sight loss of 14.8% (12 patients), six of which after the end of treatment. Forty-nine patients (75.3%) were in good locoregional control. We observed 20 relapses (24.7 %) by medium spreading of 14.8 months ± 9.7 (4-36): 3 local relapses including 2 (66.7 %) stage III and one (33.3 %) stage II. Three relapses lymph node including 2 (66.7 %) stage III and one (33.3 %) stage IVb. And 14 metastatic relapses including 9 (56.25 %) at bone level, 4 (25 %) at hepatic level and 3 (18.75 %) at lung level. The principle factors for the metastases prognosis were lymph node involvement within 92.2 % statistically significant (p=0.04) and stages T3-T4 within 64.2 % (p=0.013). At three years, overall survival at all stages were to 81.9%, survival without recurrence to 71% and local control to 79.2%. (Figure 2). 4. DISCUSSION Nasopharyngeal carcinomas are common in Morocco, they represent the 5th cancer at the INO and 6 to 10% of the radiotherapy department activity. The NPC affects among men aged up 50 years old. However, one first peak among years old is found in Maghreb countries. The sex-ratio is two to three men to one woman (1,2). According to the Registry of Cancer of Rabat (RECRAB) , cancer incidence of nasopharyngeal is higher to the men than women. It was estimated 3.3 cases per year per inhabitants for men and 1.8 cases per year per inhabitants for women. This incidence is close to that found in the Maghreb countries such as Tunisia. Higher in Asia (China-Shanghai) for men inhabitants with 4.1 cases per year and in Singapore reaching 17.4 cases per year for inhabitants (1). Lower in western countries (France, Switzerland, USA) for men inhabitants with 0.4 cases per year and for women inhabitants 0.2 cases per year. Median age is 58 years old, 59 to men and 50 to women according to RECRAB data. In our study, we observed lower age with median age of 43 years. Global survival all stages Global survival per stage

5 Survival without recurrence all stages Survival without recurrence per stages Local control all stages Local control per stages Figure 2: Survival curves Extension report includes a complete clinical examination with otorhinolaryngeal endoscopic examinations including a nasofibroscope examination. The superiority of the MRI of the cavum compared to the scanner is established especially for the exploration of the deep spaces of face, the endocranium and bone marrow (3). However, the CT scanner is used for the study of cortical bone of the skull base and first vertebrae. PET-scan is more and more used for the detection of distant metastasis. In an Australian series of 2011, the use of PET scans changed therapeutic management, either by detecting occult distant metastases (8%) or by modifying the nodal classification (25%) (4). In our series the extension report included an MRI of the cavum only in 5% of cases. Distant metastasis research has been by CT scan thoraco-abdominal to 16.3 % and bone scintigraphy to 80.2 %. It is a very lymphophilic cancer (75 to 90 %) (5). As see on our findings in which 56.7 % patients had clinically palpable lymphadenopathy and 78.3% had lymphadenopathy after radiological scan. Indeed, for non-metastatic forms, lymph node involvement is by far the prognostic factor determining survival in both adults and children (6). The presence of lymph node involvement simultaneous to the cervical level and retropharyngeal will be associated with a poorer prognosis. In an overview way, stages T1-2N0-1 are good prognosis, stages T3-4 N0-1 have a higher risk of local recidivism and lymph nodes stages more advanced have in addition a higher risk of distant metastatic. Which is demonstrated in our study where

6 we observed a predominance of local recurrence in stages III and IV to 66.7 % and 33.3 % respectively. The main prognostic factors for metastases were lymph nodes in 92.2%, statistically significant with p = 0.04 and T3-T4 stages in 64.2% with p = The NPC are chemosensitive, radiosensitive and radiocurable. Low evolved tumor of cavum (T1-2 N0) are effectively treated with radiotherapy, but for tumors locally developed, distant recidivism rate is 10 to 15 % at 2 years and 34 % at 4 years (7,8). Metastatic propagation risk is actually the principal death consequences. It is therefore necessary to combine effective systemic treatments. Concomitant radiochemotherapy is currently the locally advanced NPC therapeutic standard. Several randomized trials including that of the Alsaraf Intergroup in 1999 and the metaanalysis of Baujat and al. confirmed that the overall survival benefit was limited to the concomitant chemoradiotherapy group (9,10,11). Lin and al found a benefit of concomitant radiochemotherapy in overall survival of 90%, recurrence-free survival of 92% and local control of 95% at three years (12). Similar results were found to our study where we observed overall survival of 81.9 % at 3 years, recurrence-free-survival to 71 % and a local control to 79.2 % at all stages. Due to the anatomical situation of the cavum and the many major organs (especially the brain stem and the optic pathways) surrounding it, the technique of radiotherapy is complex. The conventional dose with standard fractioning (1.8 to 2 Gy per session, 5 times per week) is to70 Gy on the macroscopic tumor and Gy on all prophylactic treatment areas. This happened in our study too. By conventional irradiation, the often concave nasopharyngeal volume in front of the base of the skull is poorly included in the isodose curves unless major toxicity is accepted for healthy organs (special attention must be paid to doses received by the brainstem but also by the parotids and internal ears). At the junction areas, there is an underdosing at lymph node level. Thus the advent of the techniques of conformational radiotherapy with intensity modulation (RCMI) has allowed an improvement of the dosimetric coverage tumor with better saving of the healthy structures. RCMI is often performed with an integrated boost fractionation (dose complement on the simultaneous macroscopic target volume of prophylactic irradiation with different dose levels per fraction). The gain in salivary toxicity in RCMI is significant compared with conventional irradiation and the quality of life improved in the long term (13). RCRMI has become the new standard of treatment and should be offered to all patients subject to the availability of the technique within a perimeter considered reasonable by health authorities (14). According to our study conformational radiotherapy was performed to all patients. And the most frequent acute toxicities were radiomucitis, radiodermatitis, digestive, nephrologic and hematological toxicities as described in the literature. The chemotherapy protocol concomitant with radiotherapy is that of Alsaraf by cisplatin dose of 100 mg / m2 every three weeks or the Chen protocol (fractional dose) cisplatin dose of 40 mg / m2 weekly (9). The rational for the use of induction chemotherapy is to achieve both a reduction in tumor volume prior to the onset of radiotherapy, early treatment of micrometastatic dissemination. Generally neoadjuvant chemotherapy is better tolerated than adjuvant treatment wich allows to respect the intensity-dose. Negative arguments are that there is a risk of not performing the reference treatment of radiochemotherapy in case of limiting toxicity. The results of many non-randomized old studies are to an effective good answer, in particular if tumors are higher volume but without any survival effect clearly established. Only the randomized trial VUMCA I showed a benefit in terms of disease-free survival with neoadjuvant chemotherapy (15). Treatments are carried out with a curative aim and there are numerous sequelae. Late toxicities are dominated by xerostomia, trismus, cutaneous fibrosis, auditory toxicity and to a lesser extent neurocognitive deficit. Other more rare complications can be lethal (carotid rupture in particular in the situation of reirradiation) (16). According to our study, late toxicity in order of growth was hyposcialie (90.1%), otological disorders (67.9%) and trismus (17.3%). Most recurrences occur within three years of initial treatment (17). Second line treatments rely on surgery, re-radiation and chemotherapy. Numerous studies have been published, either in classical technique, in intensity modulation, or in stereotaxy (17). Place of concomitant chemotherapy is not defined in the context of relapses. The metastatic forms treatment require palliative chemotherapy, the protocols of which are still to be defined, the most frequently used molecules being cisplatin, 5-fluorouracil, gemcitabine and taxanes (17). 4. CONCLUSION The nasopharyngeal carcinoma are radiosensitive and radiocurable tumors. Concomitant radiochemotherapy is the therapeutic standard for locally advanced NPC

7 and allow to obtain carcinological good results at the expense of significant toxicity. The results of our work are similar those published in the literature and confirm the effectiveness of concomitant radiochemotherapy in this localization. The rationale for the use of induction chemotherapy is to obtain both a reduction in the tumor volume before the onset of radiation therapy and to treat micrometastatic dissemination early without any clearly demonstrated survival benefit. Monitoring should focus on the early detection of potentially curable local relapses and the management of long-term therapeutic sequelae. REFERENCES 1. [1] Bray F, Haugen M, Moger TA, Tretli S, Aalen OO, Grotmol T. Age-incidence curves of nasopharyngeal carcinoma worldwide: bimodality in low-risk populations and aetiologic implications. Cancer Epidemiol Biomarkers Prev 2008; 17: [2] Barnes L, Eveson JW, Reichart P, Sidransky D. World health Organization classification of tumors. Pathology and genetics of Head and Neck Tumours. IARC press L, editor, [3] Liao XB, Mao YP, Liu LZ, et al. How does magnetic resonance imaging influence staging according to AJCC staging system for nasopharyngeal carcinoma compared with computed tomography? Int J Radiat Oncol Biol Phys 2008; 72: [4] Law A, Peters LJ, Dutu G, et al. The utility of PET/CT in staging and assessment of treatment response of nasopharyngeal cancer. J Med Imaging Radiat Oncol 2011; 55: [5] King AD, Ahuja AT, Leung SF, and al. Neck node metastases from nasopharyngeal carcinoma: MR imaging of patterns of disease. Head Neck 2000; 22: [6] Ho FCH, Tham IWK, Earnest A, Lee KM, Lu JJ. Patterns of regional lymph node metastasis of nasopharyngeal carcinoma: a metaanalysis of clinical evidence. BMC Cancer 2012; 12: [7] Ng WT, Lee MCH, Hung WM, et al. Clinical outcomes and patterns of failure after intensity-modulated radiotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2011; 79: [8] Lee AWM, Ng WT, Chan YH, Sze H, Chan C, Lam TH. The battle against nasopharyngeal cancer. Radiother Oncol 2012; 104: [9] Al-Sarraf M, LeBlanc M, and al. Chemoradiotherapy vs radiotherapy in patients with advanced NPC. IG 0099 Phase III Study: Progress report. J Clin Oncol 1998; 17: [10] AWee J, Tan EH, Tai BC. Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with stage III and IV nasopharyngeal cancer. J Clin Oncol2005; 23: [11] Lin JC, Jan JS, Hsu CY. RCC versus radiotherapy alone for advanced NPC: Positive effect on overall and progression-free survival. J Clin Oncol2003; 21: [12] Lin S, Pan J, Han L, Zhang X, Liao X, Lu JJ. Nasopharyngeal carcinoma treated with reduced-volume intensity-modulated radiation therapy: report on the 3-year outcome of a prospective series. Int J Radiat Oncol Biol Phys 2009; 75: [13] Ma L, Guo Q, Zhang Y, et al. The effect of intensity-modulated radiotherapy versus conventional radiotherapy on quality of life in patients with nasopharyngeal cancer: a cross-sectional study. Head Neck Oncol 2013; 5: [14] Yoshizaki T, Ito M, Murono S,Wakisaka N, Kondo S, Endo K. Current understanding and management of nasopharyngeal carcinoma. Auris Nasus Larynx 2012; 39: [15] Chan ATC, Leung SF, Ngan RKC, et al. Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst 2005; 97: [16] Lee AWM, Ng WT, Hung WM, et al. Major late toxicities after conformal radiotherapy for nasopharyngeal carcinoma-patientand treatment-related risk factors. Int J Radiat Oncol Biol Phys 2009; 73: [17] Xu T, Tang J, Gu M, Liu L, Wei W, Yang H. Recurrent nasopharyngeal carcinoma: a clinical dilemma and challenge. Curr Oncol 2013; 20: e [18] Trotti A, Colevas AD, Setser A, et al (2003) CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 13:176 81