Original Article
Concomitant boost chemoradiotherapy in locally advanced head and neck cancer: Treatment tolerance and acute side effects ABSTRACT Aim: In the present study, we evaluated treatment tolerance and side effects of 6 days a week accelerated radiation therapy using concomitant boost methods with chemotherapy in locally advanced head and neck cancer. Materials and Methods: Thirty patients suffered locally advanced head and neck malignancies were included into this clinical trial. The patients were scheduled for accelerated radiotherapy with total dose of 70 Gy 6 days a week (5 days radiotherapy and 1-day concomitant boost radiotherapy) for 5 weeks and also concurrently for chemotherapy with cisplatin and also celecoxib. Results: The average age of the patients was 51.47 ± 11.49 years. The incidence of acute mucositis at the end of the 1st week was 33.3% that was gradually increased until the end of the 5th week (93.3%) and then had a ecreasing trend within the 6th week (70.0%). The incidence of acute dysphagia was estimated 23.3% at the end of the 1st week and reached 60% at completion of treatment. Conclusion: Scheduling a treatment approach with 6 days a week, accelerated radiation therapy using concomitant boost methods with chemotherapy, and celecoxib leads to significant reducing the incidence of complications in the final weeks of therapy in patients with locally advanced head and neck cancer KEY WORDS: Accelerated radiotherapy, celecoxib, chemotherapy, concomitant boost radiotherapy, head and neck cancer
INTRODUCTION Head and neck cancer with various clinical manifestations and different pathological features are generally accompanied with a wide range of response treatment and prognosis.[1] Development of surgical techniques to repair injuries, as well as developing and improving radiotherapy treatment have result in a significant improvement in the recovery process and prognosis of patients with head and neck cancers. [2] In locally advanced head and neck cancers, chemoradiotherapy can be effectively used as initial treatment or as an adjuvant therapy.[2] Nowadays, the use of systemic methods for treatment of squamous cell carcinoma is being investigated including concurrent chemoradiotherapy, induction therapy with palliative chemotherapy, and targeted treatments with or without radiotherapy. Over the past two decades, the efforts of all health professionals have focused on improving affectivity of the treatment approaches in patients suffering squamous cell carcinoma leading to the development of combination therapy with surgery, radiation, and chemotherapy. Conventional radiation therapy is the standard approach to treat the patients with locally advanced carcinoma; however, this method has not been led to satisfactory results. Therefore, 24
more attention was directed toward the use of other methods of treatment, including hyperfractionation radiation therapy and accelerated radiotherapy. Recent studies have been evidenced the highest survival rate and the highest rate of remission using chemotherapy in combination with radiotherapy. Furthermore, simultaneous treatment with radiotherapy and chemotherapy has been found to have more improvement compared to radiotherapy alone. Accordingly, the chemoradiotherapy has been identified as a standard therapeutic method in patients with locally advanced squamous cell carcinoma of the head and neck. Simultaneous use of both radiotherapy and chemotherapy in head and neck cancers is associated with long‑term recovery rate.[3] In order to reduce treatment failure and its related toxicity, the new radiotherapy treatment options have been evaluated to prevent early or long‑term complications of these procedures as much as possible. Accelerated radiotherapy regimens have been associated with better outcomes compared to other methods of treatment in patients with head and neck cancer.[3‑5] Furthermore, it has been reported that the use of the methods with shorter duration or using concomitant boost techniques have been accompanied with lower toxicity rate and fewer side effects.[3,5] However, effectiveness of these
Mehrsa Majdaeen, Ali Kazemian1, Mohammad Babaei1, Peiman Haddad1, Farnaz Amouzegar Hashemi1 Department of Radiation Oncology, Razi Hospital, Rasht University of Medical Sciences, Rasht, 1Department of Radiation Oncology, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran For correspondence: Dr. Mohammad Babaei, Department of Radiotherapy Oncology, Cancer Institute, Imam Khomeini Hospital, Tehran University of Medical Sciences, Keshavarz Boulevard, Tehran, Iran. E-mail: m-babaei@ sina.tums.ac.ir
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.155098 PMID: *** Quick Response Code:
Journal of Cancer Research and Therapeutics - January-March 2015 - Volume 11 - Issue 1
Majdaeen, et al.: Concomitant chemoradiotherapy in head and neck cancer
methods has not been approved in some clinical studies because of their intensification effects on healthy tissues and also high treatment failure in patients with advanced head and neck cancers.[6] Besides the quality of the recommended therapies, the overall duration of treatment protocols is also an important factor that influence treatment outcomes in these patients.[7] Extending the duration of therapy in these patients is an important cause of treatment failure that is associated with increased long‑term complications.[8] In the present study, we evaluated treatment tolerance and side effects of 6 days a week accelerated radiation therapy using concomitant boost methods with chemotherapy and celecoxib in locally advanced head and neck cancer. METHODS This study was a phase I clinical trial on patients suffered locally advanced head and neck squamous cell carcinoma referred to Radiotherapy and Oncology Department of Imam Khomeini Hospital. Inclusion criteria were age ranged 18–60 years, no history of surgery, neoadjuvant chemotherapy, suitable cell blood count and renal function test for chemotherapy, Karnofsky scale index higher than 70, and documented pathological features of carcinoma. Baseline assessments including medical history, full physical examination, bone scan in cases with bone pain were done. Accelerated radiotherapy was performed with the total dose of 70 Gy. Boost was scheduled for all patients using three‑dimensional method and by determining organ at risk including spine, temporomandibular joint, optic nerve, chiasma, salivary glands. Thus, the patients’ treatment included 2 Gy daily for 5 weeks. The patients also received cisplatin (100 mg/m2) every 3 weeks and also celecoxib (100 mg) every 6 h during radiotherapy. Dysphagia was graded according to the World Health Organization as grade 0: Without mucosal changes, grade I: Sore throat, and erythema, grade II: Erythema, ulcers, ability to swallow solid food, grade III: Ulcer, ability to swallow food, liquid, and grade IV: Impaired swallowing. Mucositis was also classified as follows: Grades 0 and I: Mild mucositis, grades II and III: Moderate mucositis and grade IV: Severe mucositis. The study information was recorded in an SPSS statistical file. Results were reported as mean ± standard deviation for the quantitative variables and percentages for the categorical variables. The groups were compared using the Student’s t‑test for the continuous variables and the Chi‑square test (or Fisher’s exact test if required) for the categorical variables. Trend of the changes in study parameters was assessed by the repeated measure ANOVA test. P < 0.05 were considered statistically significant. All the statistical analyses were performed using SPSS version 16.0 (SPSS Inc., Chicago, IL, USA) for windows. RESULTS Thirty patients were enrolled with the average age of 51.47 ± 11.49 years (ranged 29–69 years) that 83% were
male. The most common type of carcinoma was laryngeal cancer (43.3%), followed by nasopharyngeal carcinoma (33.3%) and hypo pharyngeal cancer (16.7%). Stage II was not reported in none of them. 73.3% had stage III and others had stage IV. One‑third of patients were staged N0, 40% staged N1, 20% staged N2, and others staged N3. Regarding tumor grading, 16.7% were graded as I, 33.3% were graded as II, 20.0% were graded as III, and others were graded as IV. The incidence of acute mucositis at the end of the 1st week was 33.3% that was gradually increased until the end of the 5th week (93.3%) and then had a decreasing trend within the 6th week (70.0%) [Figure 1]. In the 1st week of treatment, none of the patients developed severe mucositis. At the end of the 6th week, 23.1% of patients were diagnosed with severe mucositis [Table 1]. The incidence of acute dysphagia was estimated 23.3% at the end of the 1st week, but it was gradually increased to 80.0% until the end of the 4th week. However, the incidence of this complication was reduced within the 5th and 6th week and reached 60% at completion of treatment [Figure 2]. Severe dysphagia was observed in only one patient during the 4th and 5th week that the condition improved within 6 weeks [Table 2]. Weight loss was seen in our patients during treatment. Mean weight of patients at the 1st week was 63.8 kg and reached 57.3 kg at the end of treatment. Changes in the levels of white blood cells in a 6 weeks treatment period were variable, but the trend was not significant. In general, the levels of these parameters ranged between 5176 (in 6th week) and 9360 (in 2nd week) [Figure 3]. Changes in serum hemoglobin levels had a decreasing trend
Figure 1: Changes in the incidence of severe mucositis in patients treated within 6 weeks
Table 1: Severity of mucositis within 6 weeks Treatment (week) 1st 2nd 3rd 4th 5th 6th
Journal of Cancer Research and Therapeutics - January-March 2015 - Volume 11 - Issue 1
Mild mucositis (%) 9 (34.6) 14 (53.8) 14 (53.8) 7 (26.9) 4 (15.4) 4 (15.4)
Moderate mucositis (%) 0 (0) 3 (11.5) 9 (34.6) 15 (57.7) 17 (65.4) 16 (61.5)
Severe mucositis (%) 0 1 (3.3) 3 (11.5) 4 (15.4) 5 (19.2) 6 (23.1) 25
Majdaeen, et al.: Concomitant chemoradiotherapy in head and neck cancer
during the 6 weeks of treatment so that the mean hemoglobin level was reduced from 13.9 during the 1st week to 11.9 at the end of the 6th week of treatment [Figure 4]. Furthermore, plasma platelet level was decreased from the 1st week until the end of the 6th week, and this trend was not significant [Figure 5]. Chemotherapy was discontinued in three patients because of hematologic side effects.
Severe dysphagia (%) 0 1 (3.3) 1 (3.3) 1 (3.3) 1 (3.3) 0
improvement of patients’ outcome. Despite agreement between professions in concomitantly performing these two procedures as a standard approaches in head and neck cancers, due to the toxic effects of chemotherapy drugs used in standard treatment, this issue remains controversial between radiation oncologist. While there are clear evidences on the effectiveness of cisplatin‑based chemotherapy regimen, no general agreement on the use of this regimen has been reported.[9] Some phase III trials reported that the use of high‑dose cisplatin and radiotherapy has resulted in considerable improving in these patients.[10‑13] In some studies, common side effects of this chemoradiation regimen such as mucositis, dysphagia, anemia, and renal function impairment have been identified as the main factors for regimen discontinuing as well as for prolongation of treatment.[14] Mucositis is a common acute complication of radiation usually manifested by painful lesions with dysphagia that adversely affect patient’s quality of life and may lead to discontinuation of treatment. This event may be accompanied with different problems such as treatment incompleteness due to patient intolerance that directly influence patients’ treatment response.[15] In the present study,
Figure 2: Changes in the incidence of severe dysphagia in patients treated within 6 weeks
Figure 3: Changes in serum white blood cells level in patients treated within 6 weeks
Figure 4: Changes in serum hemoglobin level in patients treated within 6 weeks
Figure 5: Changes in serum platelet level in patients treated within 6 weeks
DISCUSSION Some phase II to III clinical trials showed that concomitant radiotherapy and chemotherapy resulted in significant Table 2: Severity of dysphagia within 6 weeks Treatment (week) 1st 2nd 3rd 4th 5th 6th
26
Mild dysphagia (%) 7 (23.3) 12 (40) 14 (46.7) 18 (60) 17 (56.7) 6 (20)
Moderate dysphagia (%) 0 (0) 0 2 (6.7) 5 (16.7) 5 (16.7) 12 (40)
Journal of Cancer Research and Therapeutics - January-March 2015 - Volume 11 - Issue 1
Majdaeen, et al.: Concomitant chemoradiotherapy in head and neck cancer
although incidence of mucositis was gradually increased at the end of the 5th week of treatment (to 93.3%), but this trend was significantly reduced at the end of the 6th week and reached 70.0%. In a study by Mojahed et al., grade II mucositis was not reported in patients who received celecoxib at the 2nd week of treatment, while the incidence of mucositis reached 76.0% at the 5th week and was again decreased to 19.0% at the end of the 8th week. Furthermore, grade III mucositis was not detected in none of those who received celecoxib in the 4th week of treatment. In their study, it was finally concluded that the use of celecoxib as a cyclooxygenase‑2 (COX‑2) inhibitor not only can result in reducing incidence of grades III and IV mucositis, but also lead to delaying appearance and progression of grade I mucositis to higher grades.[16] We used COX‑2 inhibitor (celecoxib) because it is a safe and inexpensive drug and may reduce acute toxicities of chemoradiation specially mucositis in head and neck carcinoma.[16] In a study by Abitbol et al., grades III and IV mucositis was observed in 74% and 11%, respectively.[17] In Medina study in 2006, treatment radiochemotherapy protocol containing 5 days a week for 6 weeks led to the occurrence of grade III mucositis in 85% and dysphagia in 50%[18] that was consistent with other observations.[19‑22] In our study, the maximum incidence of mucositis was observed in 5th and 6th weeks of treatment that was consistent with Medina observation.[18] However, higher incidence of this phenomenon was also reported by Staar et al.[23] that was higher than that reported with similar standard protocol[ 20,24,25] or Radiation Therapy Oncology Group protocol.[26] In Fu et al. study in 1995 with standard treatment protocol, the incidence of mucositis was estimated 56%.[27] In another study by Tsao et al., mucositis was occurred in 81%.[28] The incidence of mucositis in Regine et al. study was 69% in grade III and 7% in grade IV states.[29] Vees and Allal reported early mucositis in 80% of patients,[30] and de Arruda et al. detected grades I to III of mucositis in 8%, 54%, and 38%, respectively.[31] In current study, the incidence of acute dysphagia was estimated 23.3% at the end of the 1st week, but it was gradually increased to 80.0% until the end of the 4th week. However, the incidence of this complication was reduced within the 5th and 6th week and reached 60% at completion of treatment, and this event may be due to celecoxib. In Mojahed et al. study, incidence of dysphagia was significantly lower in the celecoxib group than the control group.[16] In another study by Garden et al., acute similar complications in these patients were more severe.[32] in Vivek et al. survey in 2006, 12.5% of patients undergoing chemoradiotherapy suffered dysphagia.[33] In our study, changes in serum level of white blood cells were fluctuating during the 6 weeks of treatment. However, the trend of these changes was not meaningful. Furthermore, despite decreasing trends of serum hemoglobin and platelet levels, these trends were not also significant. In Abitbol et al. survey, decrease in hemoglobin level was observed in 15%, decrease in platelet level was observed in 11%, and decrease
in white blood cell concentration was reported in 22% of treated patients.[17] In chemotherapy, cisplatin has been considered as the gold standard,[34] and additional concurrent chemotherapy may lead to acute toxicity due to radiation.[35,36] In some clinical meta‑analyses, the risk of acute mucositis can be increased by chemotherapy >3 times of radiotherapy alone.[37] It seems that the present studied protocol was accompanied with lower acute toxicity in comparison with the previous studies, and none of the patients faced with a recurrence. According to our study results, despite appearing acute complications in some of the patients who receiving accelerated regimen, this treatment method has a high efficiency compared to other methods. In the studied 6 weeks treatment protocol, in addition to reducing the duration of treatment, the incidence of complications might be decreased in the final weeks of treatment by adding COX‑2 selective inhibitor drugs. Thus, considering treatment protocol including concomitant radiotherapy and chemotherapy 6 days a week is recommended in patients with advanced head and neck cancers. This treatment protocol is tolerable by the patients and has no relapse. For definitive clinical recommendations for clinical radiotherapists and oncologists, future studies should be conducted with a larger sample sizes. REFERENCES 1. Clark J, Busse P, Deschler D. Head and neck cancer. In: Chabner B, Lynch T, Longo D, editors. Harrison’s Manual of Oncology. New York, NY: McGraw Hill; 2008. p. 593‑609. 2. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Head and Neck Cancer. 2014. Available from: http:// www.nccn.org/professionals/physician_gls/. 3. Krstevska V. Radiotherapy and chemotherapy in locally advanced head and neck squamous cell carcinoma. J BUON 2009;14:361‑73. 4. Vokes EE, Weichselbaum RR, Lippman SM, Hong WK. Head and neck cancer. N Engl J Med 1993;328:184‑94. 5. Katori H, Tsukuda M, Taguchi T. Analysis of efficacy and toxicity of chemotherapy with cisplatin, 5‑fluorouracil, methotrexate and leucovorin (PFML) and radiotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck. Cancer Chemother Pharmacol 2007;59:789‑94. 6. Bourhis J, Wibault P, Lusinchi A, Bobin S, Luboinski B, Eschwege F. Status of accelerated fractionation radiotherapy in head and neck squamous cell carcinomas. Curr Opin Oncol 1997;9:262‑6. 7. Jackson SM, Weir LM, Hay JH, Tsang VH, Durham JS. A randomised trial of accelerated versus conventional radiotherapy in head and neck cancer. Radiother Oncol 1997;43:39‑46. 8. Dobrowsky W, Dobrowsky E, Naudé J, Millesi W, Pavelka R, Kautzky M, et al. Conventional vs accelerated fractionation in head and neck cancer. Br J Cancer Suppl 1996;27:S279‑81. 9. Bourhis J, Guigay J, Temam S, Pignon JP. Chemo‑radiotherapy in head and neck cancer. Ann Oncol 2006;17 Suppl 10:X39‑41. 10. Adelstein DJ, Li Y, Adams GL, Wagner H Jr, Kish JA, Ensley JF, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92‑8.
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11. Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091‑8. 12. Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945‑52. 13. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy for high‑risk squamous‑cell carcinoma of the head and neck. N Engl J Med 2004;350:1937‑44. 14. Wilkes JD. Prevention and treatment of oral mucositis following cancer chemotherapy. Semin Oncol 1998;25:538‑51. 15. Shih A, Miaskowski C, Dodd MJ, Stotts NA, MacPhail L. Mechanisms for radiation‑induced oral mucositis and the consequences. Cancer Nurs 2003;26:222‑9. 16. Mojahed MM, Aghili M, Kazemian A, Farshid F, Izadi S. Celecoxib - Chemoradiation therapy for reducing mucositis and other acute side effects in advance head and neck carcinoma. Tehran University Medical Journal 2009;66:797-803. 17. Abitbol A, Abdel‑Wahab M, Lewin A, Troner M, Rodrigues MA, Hamilton‑Nelson KL, et al. Phase II study of tolerance and efficacy of hyperfractionated radiotherapy and 5‑fluorouracil, cisplatin, and paclitaxel (Taxol) in stage III and IV inoperable and/or unresectable head‑and‑neck squamous cell carcinoma: A‑2 protocol. Int J Radiat Oncol Biol Phys 2002;53:942‑7. 18. Medina JA, Rueda A, de Pasos AS, Contreras J, Cobo M, Moreno P, et al. A phase II study of concomitant boost radiation plus concurrent weekly cisplatin for locally advanced unresectable head and neck carcinomas. Radiother Oncol 2006;79:34‑8. 19. Beckmann GK, Hoppe F, Pfreundner L, Flentje MP. Hyperfractionated accelerated radiotherapy in combination with weekly cisplatin for locally advanced head and neck cancer. Head Neck 2005;27:36‑43. 20. Allal AS, Taussky D, Mach N, Becker M, Bieri S, Dulguerov P. Can concomitant‑boost accelerated radiotherapy be adopted as routine treatment for head‑and‑neck cancers? A 10‑year single‑institution experience. Int J Radiat Oncol Biol Phys 2004;58:1431‑6. 21. Harrison LB, Raben A, Pfister DG, Zelefsky M, Strong E, Shah JP, et al. A prospective phase II trial of concomitant chemotherapy and radiotherapy with delayed accelerated fractionation in unresectable tumors of the head and neck. Head Neck 1998;20:497‑503. 22. Widder J, Dobrowsky W, Schmid R, Pokrajac B, Selzer E, Pötter R. Hyperfractionated accelerated radiochemotherapy (HFA‑RCT) with mitomycin C for advanced head and neck cancer. Radiother Oncol 2004;73:173‑7. 23. Staar S, Rudat V, Stuetzer H, Dietz A, Volling P, Schroeder M, et al. Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy – Results of a multicentric randomized German trial in advanced head‑and‑neck cancer. Int J Radiat Oncol Biol Phys 2001;50:1161‑71. 24. Ang KK, Harris J, Garden AS, Trotti A, Jones CU, Carrascosa L, et al. Concomitant boost radiation plus concurrent cisplatin for advanced head and neck carcinomas: Radiation therapy oncology group phase II trial 99‑14. J Clin Oncol 2005;23:3008‑15. 25. Kumar S, Pandey M, Lal P, Rastogi N, Maria Das KJ, Dimri K. Concomitant boost radiotherapy with concurrent weekly cisplatin
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in advanced head and neck cancers: A phase II trial. Radiother Oncol 2005;75:186‑92. 26. Forastiere AA. Cisplatin and radiotherapy in the management of locally advanced head and neck cancer. Int J Radiat Oncol Biol Phys 1993;27:465‑70. 27. Fu KK, Clery M, Ang KK, Byhardt RW, Maor MH, Beitler JJ. Randomized phase I/II trial of two variants of accelerated fractionated radiotherapy regimens for advanced head and neck cancer: Results of RTOG 88‑09. Int J Radiat Oncol Biol Phys 1995;32:589‑97. 28. Tsao AS, Garden AS, Kies MS, Morrison W, Feng L, Lee JJ, et al. Phase I/II study of docetaxel, cisplatin, and concomitant boost radiation for locally advanced squamous cell cancer of the head and neck. J Clin Oncol 2006;24:4163‑9. 29. Regine WF, Valentino J, Arnold SM, Haydon RC, Sloan D, Kenady D, et al. High‑dose intra‑arterial cisplatin boost with hyperfractionated radiation therapy for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 2001;19:3333‑9. 30. Vees H, Allal AS. Carbogen breathing combined with radical radiotherapy in advanced head and neck cancer patients with severe co‑morbidities. Clin Oncol (R Coll Radiol) 2006;18:493‑6. 31. de Arruda FF, Puri DR, Zhung J, Narayana A, Wolden S, Hunt M, et al. Intensity‑modulated radiation therapy for the treatment of oropharyngeal carcinoma: The Memorial Sloan‑Kettering Cancer Center experience. Int J Radiat Oncol Biol Phys 2006;64:363‑73. 32. Garden AS, Harris J, Vokes EE, Forastiere AA, Ridge JA, Jones C, et al. Preliminary results of Radiation Therapy Oncology Group 97‑03: A randomized phase ii trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck. J Clin Oncol 2004;22:2856‑64. 33. Vivek RS, Baludavid M, Mohanram R, Chitra, Amanullah, Vijayalakshmi, et al. Concurrent chemo-irradiation using accelerated concomitant boost radiation therapy in loco-regionally advanced head and neck squamous cell carcinomas. J Cancer Res Ther 2006;2:90‑6. 34. Pignon JP, Bourhis J, Domenge C, Designé 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;355:949‑55. 35. Trotti A, Bellm LA, Epstein JB, Frame D, Fuchs HJ, Gwede CK, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: A systematic literature review. Radiother Oncol 2003;66:253‑62. 36. Henk JM. Controlled trials of synchronous chemotherapy with radiotherapy in head and neck cancer: Overview of radiation morbidity. Clin Oncol (R Coll Radiol) 1997;9:308‑12. 37. El‑Sayed S, Nelson N. Adjuvant and adjunctive chemotherapy in the management of squamous cell carcinoma of the head and neck region. A meta‑analysis of prospective and randomized trials. J Clin Oncol 1996;14:838‑47. Cite this article as: Majdaeen M, Kazemian A, Babaei M, Haddad P, Hashemi FA. Concomitant boost chemoradiotherapy in locally advanced head and neck cancer: Treatment tolerance and acute side effects. J Can Res Ther 2015;11:24-8. Source of Support: Nil, Conflict of Interest: None declared.
Journal of Cancer Research and Therapeutics - January-March 2015 - Volume 11 - Issue 1
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Concomitant boost chemoradiotherapy in locally advanced head and neck cancer: Treatment tolerance and acute side effects ABSTRACT Aim: In the present study, we evaluated treatment tolerance and side effects of 6 days a week accelerated radiation therapy using concomitant boost methods with chemotherapy in locally advanced head and neck cancer. Materials and Methods: Thirty patients suffered locally advanced head and neck malignancies were included into this clinical trial. The patients were scheduled for accelerated radiotherapy with total dose of 70 Gy 6 days a week (5 days radiotherapy and 1-day concomitant boost radiotherapy) for 5 weeks and also concurrently for chemotherapy with cisplatin and also celecoxib. Results: The average age of the patients was 51.47 ± 11.49 years. The incidence of acute mucositis at the end of the 1st week was 33.3% that was gradually increased until the end of the 5th week (93.3%) and then had a ecreasing trend within the 6th week (70.0%). The incidence of acute dysphagia was estimated 23.3% at the end of the 1st week and reached 60% at completion of treatment. Conclusion: Scheduling a treatment approach with 6 days a week, accelerated radiation therapy using concomitant boost methods with chemotherapy, and celecoxib leads to significant reducing the incidence of complications in the final weeks of therapy in patients with locally advanced head and neck cancer KEY WORDS: Accelerated radiotherapy, celecoxib, chemotherapy, concomitant boost radiotherapy, head and neck cancer
INTRODUCTION Head and neck cancer with various clinical manifestations and different pathological features are generally accompanied with a wide range of response treatment and prognosis.[1] Development of surgical techniques to repair injuries, as well as developing and improving radiotherapy treatment have result in a significant improvement in the recovery process and prognosis of patients with head and neck cancers. [2] In locally advanced head and neck cancers, chemoradiotherapy can be effectively used as initial treatment or as an adjuvant therapy.[2] Nowadays, the use of systemic methods for treatment of squamous cell carcinoma is being investigated including concurrent chemoradiotherapy, induction therapy with palliative chemotherapy, and targeted treatments with or without radiotherapy. Over the past two decades, the efforts of all health professionals have focused on improving affectivity of the treatment approaches in patients suffering squamous cell carcinoma leading to the development of combination therapy with surgery, radiation, and chemotherapy. Conventional radiation therapy is the standard approach to treat the patients with locally advanced carcinoma; however, this method has not been led to satisfactory results. Therefore, 24
more attention was directed toward the use of other methods of treatment, including hyperfractionation radiation therapy and accelerated radiotherapy. Recent studies have been evidenced the highest survival rate and the highest rate of remission using chemotherapy in combination with radiotherapy. Furthermore, simultaneous treatment with radiotherapy and chemotherapy has been found to have more improvement compared to radiotherapy alone. Accordingly, the chemoradiotherapy has been identified as a standard therapeutic method in patients with locally advanced squamous cell carcinoma of the head and neck. Simultaneous use of both radiotherapy and chemotherapy in head and neck cancers is associated with long‑term recovery rate.[3] In order to reduce treatment failure and its related toxicity, the new radiotherapy treatment options have been evaluated to prevent early or long‑term complications of these procedures as much as possible. Accelerated radiotherapy regimens have been associated with better outcomes compared to other methods of treatment in patients with head and neck cancer.[3‑5] Furthermore, it has been reported that the use of the methods with shorter duration or using concomitant boost techniques have been accompanied with lower toxicity rate and fewer side effects.[3,5] However, effectiveness of these
Mehrsa Majdaeen, Ali Kazemian1, Mohammad Babaei1, Peiman Haddad1, Farnaz Amouzegar Hashemi1 Department of Radiation Oncology, Razi Hospital, Rasht University of Medical Sciences, Rasht, 1Department of Radiation Oncology, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran For correspondence: Dr. Mohammad Babaei, Department of Radiotherapy Oncology, Cancer Institute, Imam Khomeini Hospital, Tehran University of Medical Sciences, Keshavarz Boulevard, Tehran, Iran. E-mail: m-babaei@ sina.tums.ac.ir
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.155098 PMID: *** Quick Response Code:
Journal of Cancer Research and Therapeutics - January-March 2015 - Volume 11 - Issue 1
Majdaeen, et al.: Concomitant chemoradiotherapy in head and neck cancer
methods has not been approved in some clinical studies because of their intensification effects on healthy tissues and also high treatment failure in patients with advanced head and neck cancers.[6] Besides the quality of the recommended therapies, the overall duration of treatment protocols is also an important factor that influence treatment outcomes in these patients.[7] Extending the duration of therapy in these patients is an important cause of treatment failure that is associated with increased long‑term complications.[8] In the present study, we evaluated treatment tolerance and side effects of 6 days a week accelerated radiation therapy using concomitant boost methods with chemotherapy and celecoxib in locally advanced head and neck cancer. METHODS This study was a phase I clinical trial on patients suffered locally advanced head and neck squamous cell carcinoma referred to Radiotherapy and Oncology Department of Imam Khomeini Hospital. Inclusion criteria were age ranged 18–60 years, no history of surgery, neoadjuvant chemotherapy, suitable cell blood count and renal function test for chemotherapy, Karnofsky scale index higher than 70, and documented pathological features of carcinoma. Baseline assessments including medical history, full physical examination, bone scan in cases with bone pain were done. Accelerated radiotherapy was performed with the total dose of 70 Gy. Boost was scheduled for all patients using three‑dimensional method and by determining organ at risk including spine, temporomandibular joint, optic nerve, chiasma, salivary glands. Thus, the patients’ treatment included 2 Gy daily for 5 weeks. The patients also received cisplatin (100 mg/m2) every 3 weeks and also celecoxib (100 mg) every 6 h during radiotherapy. Dysphagia was graded according to the World Health Organization as grade 0: Without mucosal changes, grade I: Sore throat, and erythema, grade II: Erythema, ulcers, ability to swallow solid food, grade III: Ulcer, ability to swallow food, liquid, and grade IV: Impaired swallowing. Mucositis was also classified as follows: Grades 0 and I: Mild mucositis, grades II and III: Moderate mucositis and grade IV: Severe mucositis. The study information was recorded in an SPSS statistical file. Results were reported as mean ± standard deviation for the quantitative variables and percentages for the categorical variables. The groups were compared using the Student’s t‑test for the continuous variables and the Chi‑square test (or Fisher’s exact test if required) for the categorical variables. Trend of the changes in study parameters was assessed by the repeated measure ANOVA test. P < 0.05 were considered statistically significant. All the statistical analyses were performed using SPSS version 16.0 (SPSS Inc., Chicago, IL, USA) for windows. RESULTS Thirty patients were enrolled with the average age of 51.47 ± 11.49 years (ranged 29–69 years) that 83% were
male. The most common type of carcinoma was laryngeal cancer (43.3%), followed by nasopharyngeal carcinoma (33.3%) and hypo pharyngeal cancer (16.7%). Stage II was not reported in none of them. 73.3% had stage III and others had stage IV. One‑third of patients were staged N0, 40% staged N1, 20% staged N2, and others staged N3. Regarding tumor grading, 16.7% were graded as I, 33.3% were graded as II, 20.0% were graded as III, and others were graded as IV. The incidence of acute mucositis at the end of the 1st week was 33.3% that was gradually increased until the end of the 5th week (93.3%) and then had a decreasing trend within the 6th week (70.0%) [Figure 1]. In the 1st week of treatment, none of the patients developed severe mucositis. At the end of the 6th week, 23.1% of patients were diagnosed with severe mucositis [Table 1]. The incidence of acute dysphagia was estimated 23.3% at the end of the 1st week, but it was gradually increased to 80.0% until the end of the 4th week. However, the incidence of this complication was reduced within the 5th and 6th week and reached 60% at completion of treatment [Figure 2]. Severe dysphagia was observed in only one patient during the 4th and 5th week that the condition improved within 6 weeks [Table 2]. Weight loss was seen in our patients during treatment. Mean weight of patients at the 1st week was 63.8 kg and reached 57.3 kg at the end of treatment. Changes in the levels of white blood cells in a 6 weeks treatment period were variable, but the trend was not significant. In general, the levels of these parameters ranged between 5176 (in 6th week) and 9360 (in 2nd week) [Figure 3]. Changes in serum hemoglobin levels had a decreasing trend
Figure 1: Changes in the incidence of severe mucositis in patients treated within 6 weeks
Table 1: Severity of mucositis within 6 weeks Treatment (week) 1st 2nd 3rd 4th 5th 6th
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Mild mucositis (%) 9 (34.6) 14 (53.8) 14 (53.8) 7 (26.9) 4 (15.4) 4 (15.4)
Moderate mucositis (%) 0 (0) 3 (11.5) 9 (34.6) 15 (57.7) 17 (65.4) 16 (61.5)
Severe mucositis (%) 0 1 (3.3) 3 (11.5) 4 (15.4) 5 (19.2) 6 (23.1) 25
Majdaeen, et al.: Concomitant chemoradiotherapy in head and neck cancer
during the 6 weeks of treatment so that the mean hemoglobin level was reduced from 13.9 during the 1st week to 11.9 at the end of the 6th week of treatment [Figure 4]. Furthermore, plasma platelet level was decreased from the 1st week until the end of the 6th week, and this trend was not significant [Figure 5]. Chemotherapy was discontinued in three patients because of hematologic side effects.
Severe dysphagia (%) 0 1 (3.3) 1 (3.3) 1 (3.3) 1 (3.3) 0
improvement of patients’ outcome. Despite agreement between professions in concomitantly performing these two procedures as a standard approaches in head and neck cancers, due to the toxic effects of chemotherapy drugs used in standard treatment, this issue remains controversial between radiation oncologist. While there are clear evidences on the effectiveness of cisplatin‑based chemotherapy regimen, no general agreement on the use of this regimen has been reported.[9] Some phase III trials reported that the use of high‑dose cisplatin and radiotherapy has resulted in considerable improving in these patients.[10‑13] In some studies, common side effects of this chemoradiation regimen such as mucositis, dysphagia, anemia, and renal function impairment have been identified as the main factors for regimen discontinuing as well as for prolongation of treatment.[14] Mucositis is a common acute complication of radiation usually manifested by painful lesions with dysphagia that adversely affect patient’s quality of life and may lead to discontinuation of treatment. This event may be accompanied with different problems such as treatment incompleteness due to patient intolerance that directly influence patients’ treatment response.[15] In the present study,
Figure 2: Changes in the incidence of severe dysphagia in patients treated within 6 weeks
Figure 3: Changes in serum white blood cells level in patients treated within 6 weeks
Figure 4: Changes in serum hemoglobin level in patients treated within 6 weeks
Figure 5: Changes in serum platelet level in patients treated within 6 weeks
DISCUSSION Some phase II to III clinical trials showed that concomitant radiotherapy and chemotherapy resulted in significant Table 2: Severity of dysphagia within 6 weeks Treatment (week) 1st 2nd 3rd 4th 5th 6th
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Mild dysphagia (%) 7 (23.3) 12 (40) 14 (46.7) 18 (60) 17 (56.7) 6 (20)
Moderate dysphagia (%) 0 (0) 0 2 (6.7) 5 (16.7) 5 (16.7) 12 (40)
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Majdaeen, et al.: Concomitant chemoradiotherapy in head and neck cancer
although incidence of mucositis was gradually increased at the end of the 5th week of treatment (to 93.3%), but this trend was significantly reduced at the end of the 6th week and reached 70.0%. In a study by Mojahed et al., grade II mucositis was not reported in patients who received celecoxib at the 2nd week of treatment, while the incidence of mucositis reached 76.0% at the 5th week and was again decreased to 19.0% at the end of the 8th week. Furthermore, grade III mucositis was not detected in none of those who received celecoxib in the 4th week of treatment. In their study, it was finally concluded that the use of celecoxib as a cyclooxygenase‑2 (COX‑2) inhibitor not only can result in reducing incidence of grades III and IV mucositis, but also lead to delaying appearance and progression of grade I mucositis to higher grades.[16] We used COX‑2 inhibitor (celecoxib) because it is a safe and inexpensive drug and may reduce acute toxicities of chemoradiation specially mucositis in head and neck carcinoma.[16] In a study by Abitbol et al., grades III and IV mucositis was observed in 74% and 11%, respectively.[17] In Medina study in 2006, treatment radiochemotherapy protocol containing 5 days a week for 6 weeks led to the occurrence of grade III mucositis in 85% and dysphagia in 50%[18] that was consistent with other observations.[19‑22] In our study, the maximum incidence of mucositis was observed in 5th and 6th weeks of treatment that was consistent with Medina observation.[18] However, higher incidence of this phenomenon was also reported by Staar et al.[23] that was higher than that reported with similar standard protocol[ 20,24,25] or Radiation Therapy Oncology Group protocol.[26] In Fu et al. study in 1995 with standard treatment protocol, the incidence of mucositis was estimated 56%.[27] In another study by Tsao et al., mucositis was occurred in 81%.[28] The incidence of mucositis in Regine et al. study was 69% in grade III and 7% in grade IV states.[29] Vees and Allal reported early mucositis in 80% of patients,[30] and de Arruda et al. detected grades I to III of mucositis in 8%, 54%, and 38%, respectively.[31] In current study, the incidence of acute dysphagia was estimated 23.3% at the end of the 1st week, but it was gradually increased to 80.0% until the end of the 4th week. However, the incidence of this complication was reduced within the 5th and 6th week and reached 60% at completion of treatment, and this event may be due to celecoxib. In Mojahed et al. study, incidence of dysphagia was significantly lower in the celecoxib group than the control group.[16] In another study by Garden et al., acute similar complications in these patients were more severe.[32] in Vivek et al. survey in 2006, 12.5% of patients undergoing chemoradiotherapy suffered dysphagia.[33] In our study, changes in serum level of white blood cells were fluctuating during the 6 weeks of treatment. However, the trend of these changes was not meaningful. Furthermore, despite decreasing trends of serum hemoglobin and platelet levels, these trends were not also significant. In Abitbol et al. survey, decrease in hemoglobin level was observed in 15%, decrease in platelet level was observed in 11%, and decrease
in white blood cell concentration was reported in 22% of treated patients.[17] In chemotherapy, cisplatin has been considered as the gold standard,[34] and additional concurrent chemotherapy may lead to acute toxicity due to radiation.[35,36] In some clinical meta‑analyses, the risk of acute mucositis can be increased by chemotherapy >3 times of radiotherapy alone.[37] It seems that the present studied protocol was accompanied with lower acute toxicity in comparison with the previous studies, and none of the patients faced with a recurrence. According to our study results, despite appearing acute complications in some of the patients who receiving accelerated regimen, this treatment method has a high efficiency compared to other methods. In the studied 6 weeks treatment protocol, in addition to reducing the duration of treatment, the incidence of complications might be decreased in the final weeks of treatment by adding COX‑2 selective inhibitor drugs. Thus, considering treatment protocol including concomitant radiotherapy and chemotherapy 6 days a week is recommended in patients with advanced head and neck cancers. This treatment protocol is tolerable by the patients and has no relapse. For definitive clinical recommendations for clinical radiotherapists and oncologists, future studies should be conducted with a larger sample sizes. REFERENCES 1. Clark J, Busse P, Deschler D. Head and neck cancer. In: Chabner B, Lynch T, Longo D, editors. Harrison’s Manual of Oncology. New York, NY: McGraw Hill; 2008. p. 593‑609. 2. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Head and Neck Cancer. 2014. Available from: http:// www.nccn.org/professionals/physician_gls/. 3. Krstevska V. Radiotherapy and chemotherapy in locally advanced head and neck squamous cell carcinoma. J BUON 2009;14:361‑73. 4. Vokes EE, Weichselbaum RR, Lippman SM, Hong WK. Head and neck cancer. N Engl J Med 1993;328:184‑94. 5. Katori H, Tsukuda M, Taguchi T. Analysis of efficacy and toxicity of chemotherapy with cisplatin, 5‑fluorouracil, methotrexate and leucovorin (PFML) and radiotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck. Cancer Chemother Pharmacol 2007;59:789‑94. 6. Bourhis J, Wibault P, Lusinchi A, Bobin S, Luboinski B, Eschwege F. Status of accelerated fractionation radiotherapy in head and neck squamous cell carcinomas. Curr Opin Oncol 1997;9:262‑6. 7. Jackson SM, Weir LM, Hay JH, Tsang VH, Durham JS. A randomised trial of accelerated versus conventional radiotherapy in head and neck cancer. Radiother Oncol 1997;43:39‑46. 8. Dobrowsky W, Dobrowsky E, Naudé J, Millesi W, Pavelka R, Kautzky M, et al. Conventional vs accelerated fractionation in head and neck cancer. Br J Cancer Suppl 1996;27:S279‑81. 9. Bourhis J, Guigay J, Temam S, Pignon JP. Chemo‑radiotherapy in head and neck cancer. Ann Oncol 2006;17 Suppl 10:X39‑41. 10. Adelstein DJ, Li Y, Adams GL, Wagner H Jr, Kish JA, Ensley JF, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92‑8.
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11. Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091‑8. 12. Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945‑52. 13. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy for high‑risk squamous‑cell carcinoma of the head and neck. N Engl J Med 2004;350:1937‑44. 14. Wilkes JD. Prevention and treatment of oral mucositis following cancer chemotherapy. Semin Oncol 1998;25:538‑51. 15. Shih A, Miaskowski C, Dodd MJ, Stotts NA, MacPhail L. Mechanisms for radiation‑induced oral mucositis and the consequences. Cancer Nurs 2003;26:222‑9. 16. Mojahed MM, Aghili M, Kazemian A, Farshid F, Izadi S. Celecoxib - Chemoradiation therapy for reducing mucositis and other acute side effects in advance head and neck carcinoma. Tehran University Medical Journal 2009;66:797-803. 17. Abitbol A, Abdel‑Wahab M, Lewin A, Troner M, Rodrigues MA, Hamilton‑Nelson KL, et al. Phase II study of tolerance and efficacy of hyperfractionated radiotherapy and 5‑fluorouracil, cisplatin, and paclitaxel (Taxol) in stage III and IV inoperable and/or unresectable head‑and‑neck squamous cell carcinoma: A‑2 protocol. Int J Radiat Oncol Biol Phys 2002;53:942‑7. 18. Medina JA, Rueda A, de Pasos AS, Contreras J, Cobo M, Moreno P, et al. A phase II study of concomitant boost radiation plus concurrent weekly cisplatin for locally advanced unresectable head and neck carcinomas. Radiother Oncol 2006;79:34‑8. 19. Beckmann GK, Hoppe F, Pfreundner L, Flentje MP. Hyperfractionated accelerated radiotherapy in combination with weekly cisplatin for locally advanced head and neck cancer. Head Neck 2005;27:36‑43. 20. Allal AS, Taussky D, Mach N, Becker M, Bieri S, Dulguerov P. Can concomitant‑boost accelerated radiotherapy be adopted as routine treatment for head‑and‑neck cancers? A 10‑year single‑institution experience. Int J Radiat Oncol Biol Phys 2004;58:1431‑6. 21. Harrison LB, Raben A, Pfister DG, Zelefsky M, Strong E, Shah JP, et al. A prospective phase II trial of concomitant chemotherapy and radiotherapy with delayed accelerated fractionation in unresectable tumors of the head and neck. Head Neck 1998;20:497‑503. 22. Widder J, Dobrowsky W, Schmid R, Pokrajac B, Selzer E, Pötter R. Hyperfractionated accelerated radiochemotherapy (HFA‑RCT) with mitomycin C for advanced head and neck cancer. Radiother Oncol 2004;73:173‑7. 23. Staar S, Rudat V, Stuetzer H, Dietz A, Volling P, Schroeder M, et al. Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy – Results of a multicentric randomized German trial in advanced head‑and‑neck cancer. Int J Radiat Oncol Biol Phys 2001;50:1161‑71. 24. Ang KK, Harris J, Garden AS, Trotti A, Jones CU, Carrascosa L, et al. Concomitant boost radiation plus concurrent cisplatin for advanced head and neck carcinomas: Radiation therapy oncology group phase II trial 99‑14. J Clin Oncol 2005;23:3008‑15. 25. Kumar S, Pandey M, Lal P, Rastogi N, Maria Das KJ, Dimri K. Concomitant boost radiotherapy with concurrent weekly cisplatin
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in advanced head and neck cancers: A phase II trial. Radiother Oncol 2005;75:186‑92. 26. Forastiere AA. Cisplatin and radiotherapy in the management of locally advanced head and neck cancer. Int J Radiat Oncol Biol Phys 1993;27:465‑70. 27. Fu KK, Clery M, Ang KK, Byhardt RW, Maor MH, Beitler JJ. Randomized phase I/II trial of two variants of accelerated fractionated radiotherapy regimens for advanced head and neck cancer: Results of RTOG 88‑09. Int J Radiat Oncol Biol Phys 1995;32:589‑97. 28. Tsao AS, Garden AS, Kies MS, Morrison W, Feng L, Lee JJ, et al. Phase I/II study of docetaxel, cisplatin, and concomitant boost radiation for locally advanced squamous cell cancer of the head and neck. J Clin Oncol 2006;24:4163‑9. 29. Regine WF, Valentino J, Arnold SM, Haydon RC, Sloan D, Kenady D, et al. High‑dose intra‑arterial cisplatin boost with hyperfractionated radiation therapy for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 2001;19:3333‑9. 30. Vees H, Allal AS. Carbogen breathing combined with radical radiotherapy in advanced head and neck cancer patients with severe co‑morbidities. Clin Oncol (R Coll Radiol) 2006;18:493‑6. 31. de Arruda FF, Puri DR, Zhung J, Narayana A, Wolden S, Hunt M, et al. Intensity‑modulated radiation therapy for the treatment of oropharyngeal carcinoma: The Memorial Sloan‑Kettering Cancer Center experience. Int J Radiat Oncol Biol Phys 2006;64:363‑73. 32. Garden AS, Harris J, Vokes EE, Forastiere AA, Ridge JA, Jones C, et al. Preliminary results of Radiation Therapy Oncology Group 97‑03: A randomized phase ii trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck. J Clin Oncol 2004;22:2856‑64. 33. Vivek RS, Baludavid M, Mohanram R, Chitra, Amanullah, Vijayalakshmi, et al. Concurrent chemo-irradiation using accelerated concomitant boost radiation therapy in loco-regionally advanced head and neck squamous cell carcinomas. J Cancer Res Ther 2006;2:90‑6. 34. Pignon JP, Bourhis J, Domenge C, Designé 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;355:949‑55. 35. Trotti A, Bellm LA, Epstein JB, Frame D, Fuchs HJ, Gwede CK, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: A systematic literature review. Radiother Oncol 2003;66:253‑62. 36. Henk JM. Controlled trials of synchronous chemotherapy with radiotherapy in head and neck cancer: Overview of radiation morbidity. Clin Oncol (R Coll Radiol) 1997;9:308‑12. 37. El‑Sayed S, Nelson N. Adjuvant and adjunctive chemotherapy in the management of squamous cell carcinoma of the head and neck region. A meta‑analysis of prospective and randomized trials. J Clin Oncol 1996;14:838‑47. Cite this article as: Majdaeen M, Kazemian A, Babaei M, Haddad P, Hashemi FA. Concomitant boost chemoradiotherapy in locally advanced head and neck cancer: Treatment tolerance and acute side effects. J Can Res Ther 2015;11:24-8. Source of Support: Nil, Conflict of Interest: None declared.
Journal of Cancer Research and Therapeutics - January-March 2015 - Volume 11 - Issue 1
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