Three Weekly Versus Weekly Cisplatin as Radiosensitizer in Head and Neck Cancer: a Decision Dilemma

  • Published : 2016.06.01


Cisplatin-based concurrent chemoradiation plays an undisputed key role as definitive treatment in unresectable patients with locally advanced squamous cell carcinoma head and neck or as an organ preservation strategy. Treatment with 100 mg/m2 3-weekly cisplatin is considered the standard of care but is often associated with several adverse events. The optimum drug schedule of administration remains to be defined and presently, there is insufficient data limiting conclusions about the relative tolerability of one regimen over the other. This review addresses regarding the optimal dose schedule of cisplatin focusing mainly on three-weekly and weekly dose of cisplatin based concurrent chemoradiotherapy in locally advanced head and neck cancer with an emphasis on mucositis, dermatitis, systemic toxicity, compliance, and treatment interruptions. To derive a definitive conclusion, large prospective randomized trials are needed directly comparing standard 3-weekly cisplatin ($100mg/m^2$) with weekly schedule ($30-40mg/m^2$) of concurrent cisplatin based chemoradiotherapy in locally advanced squamous cell carcinoma head and neck.


  1. Adelstein DJ, Li Y, Adams GL, et al (2003). 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, 21, 92-8.
  2. Al-Sarraf MD (2007). The role of concurrent chemo-radiotherapy in patients with head and neck cancers: a review. Gulf J Oncol, 7, 8-16.
  3. Asif R, Chandra K, Chopra V, Bhatt ML (2003). Concurrent cisplatin and radiotherapy in advanced head and neck cancer. Indian J Otolaryngol Head Neck Surg, 55, 94-6.
  4. Bagri PK, Kapoor A, Kalwar A, et al (2014). Comparative analysis of cisplatin-induced nephrotoxicity in head and neck cancer and carcinoma cervix during concurrent chemoradiotherapy. South Asian J Cancer, 3, 217-20.
  5. Bahl M, Siu LL, Pond GR, et al (2004). Tolerability of the Intergroup 0099 (INT 0099) regimen in locally advanced nasopharyngeal cancer with a focus on patients' nutritional status. Int J Radiat Oncol Biol Phys, 60, 1127-36.
  6. Beckmann GK, Hoppe F, Pfreundner L, Flentje MP (2005). Hyperfractionated accelerated radiotherapy in combination with weekly cisplatin for locally advanced head and neck cancer. Head Neck, 27, 36-43.
  7. Bernier J, Domenge C, Ozsahin M, et al (2004). Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med, 350, 1945-52.
  8. Bonner JA, Harari PM, Giralt J, et al (2006). Radiotherapy plus Cetuximab for squamous cell carcinoma of the head and neck. N Engl J Med, 354, 567-78.
  9. Bourhis J, Lapeyre M, Tortochaux J, et al (2006). Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cell head and neck cancer: a GORTEC trial. J Clin Oncol, 24, 2873-8.
  10. Browman GP, Hodson DI, Mackenzie RG, Bestic N, Zuraw L (2001). Cancer care ontario practice guideline initiative head and neck cancer disease site group: choosing a concomitant chemotherapy and radiotherapy regimen for squamous cell head and neck cancer: a systematic review of the published literature with subgroup analysis. Head Neck, 23, 579-89.
  11. Calais G, Alfonsi M, Bardet E, et al (1999). Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst, 91, 2081-6.
  12. Cooper JS, Pajak TF, Forastiere AA, et al (2004). Post-operative concurrent radiotherapy and chemotherapy for high-risk squamous cell carcinoma of the head and neck. N Engl J Med, 350, 1937-44.
  13. De Jongh FE, Van Veen RN, Veltman SJ, et al (2003). Weekly high-dose cisplatin is a feasible treatment option: Analysis on prognostic factors for toxicity in 400 patients. Br J Cancer, 88, 1199-206.
  14. Espeli V, Zucca E, Ghielmini M, et al (2012). Weekly and 3-weekly cisplatin concurrent with intensity-modulated radiotherapy in locally advanced head and neck squamous cell cancer. Oral Oncol, 48, 266-71.
  15. Fayette J, Molin Y, Lavergne E, et al (2015). Radiotherapy potentiation with weekly cisplatin compared to standard every 3 weeks cisplatin chemotherapy for locoregionally advanced head and neck squamous cell carcinoma. Drug Des Devel Ther, 9, 6203-10.
  16. Florea AM, Busselberg D (2011). Cisplatin as an anti-tumour drug: cellular mechanism of activity, drug resistance and induced side effects. Cancers, 3, 1351-71.
  17. Geeta SN, Padmanabhan TK, Samuel J, Pavithran K, Iyer S, Kuriakose MA (2006). Comparison of acute toxicities of two chemotherapy schedules for head and neck cancers. J Cancer Res Ther, 2, 100-4.
  18. Geiger JL, Lazim AF, Walsh FJ, et al (2014). Adjuvant chemoradiation therapy with high-dose versus weekly cisplatin for resected, locally-advanced HPV/p16-positive and negative head and neck squamous cell carcinoma. Oral Oncol, 50, 311-8.
  19. Gladkov OA, Vazhenin AV, Sharabura TM, et al (2007). Effectiveness of different regimens of combined treatment (cisplatin + radiotherapy) for intraoral and oropharyngeal cancer. Vopr Onkol, 53, 575-7.
  20. Glaser MG, Leslie MD, O’Reilly SM, Cheesman AD, Newlands ES (1993). Weekly cisplatinum concomitant with radical RT in the treatment of advanced head and neck cancer. Clin Oncol, 5, 286-9.
  21. Goncalves MS, Silveira AF, Teixeira AR, Hyppolito MA (2013). Mechanisms of cisplatin ototoxicity: theoretical review. J Laryngol Otol, 127, 536-41.
  22. Gupta T, Agarwal JP, Laskar SG, Parikh PM, Cruz AKD, Dinshaw KA (2009). Radical radiotherapy with concurrent weekly cisplatin in loco-regionally advanced squamous cell carcinoma of the head and neck: a single-institution experience. Head Neck Oncol, 1, 17.
  23. Hao D, Ritter MA, Oliver T, Browman GP (2006). Platinumbased concurrent chemoradiotherapy for tumours of the head and neck and the esophagus. Semin Radiat Oncol, 16, 10-9.
  24. Ho KF, Swindell R, Brammer CV (2008). Dose intensity comparison between weekly and 3-weekly cisplatin delivered concurrently with radical radiotherapy for head and neck cancer: a retrospective comparison from New cross hospital, Wolverhampton, UK. Acta Oncol, 47, 1513-8.
  25. Homma A, Inamura N, Oridate N, et al (2011). Concomitant weekly cisplatin and radiotherapy for head and neck cancer. Jpn J Clin Oncol, 41, 980-6.
  26. Huguenin P, Beer KT, Allal A (2004). Concomitant cisplatin significantly improves loco-regional control in advanced head and neck cancers treated with hyperfractionated RT. J Clin Oncol, 22, 4665-73.
  27. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011). Global cancer statistics. Cancer J Clin, 61, 69-90.
  28. Kang MH, Kang JH, Song HN, et al (2015). Concurrent chemoradiation with low-dose weekly cisplatin in locally advanced stage IV head and neck squamous cell carcinoma. Cancer Res Treat, 47, 441-7.
  29. Kiyota N, Tahara M, Okano S, et al (2012). Phase II feasibility trial of adjuvant chemoradiotherapy with 3-weekly cisplatin for Japanese patients with post-operative high-risk squamous cell carcinoma of the head and neck. Jpn J Clin Oncol, 42, 927-33.
  30. Kose F, Besen A, Sumbul T, et al (2011). Weekly cisplatin versus standard three-weekly cisplatin in concurrent chemoradiotherapy of head and neck cancer: the Baskent University Experience. Asian Pac J Cancer Prev, 12, 1185-8.
  31. Krstevska V, Stojkovski I, Ivanovska BZ (2012). Concurrent radiochemotherapy in locally-regionally advanced oropharyngeal squamous cell carcinoma: analysis of treatment results and prognostic factors. Radiat Oncol, 7, 78.
  32. Kulkarni MR (2013). Head and neck cancer burden in India. Int J Head Neck Surg, 4, 29-35.
  33. Lawrence TS, Blackstock AW, McGinn C (2003). The mechanism of action of radiosensitization of conventional chemotherapeutic agents. Semin Radiat Oncol, 13, 13-21.
  34. Maqbool LM, Malik TR, Afroza F, Khan NA, Haq M, Patigaroo AR (2012). Treatment outcome with weekly cisplatin concurrent with radiation therapy in locally advanced head and neck squamous cell carcinoma. JIMSA, 25.
  35. Mitra D, Choudhury K, Rashid MA (2011). Concurrent chemotherapy in advanced head and neck carcinoma - A prospective randomized trial. Bangladesh J Otorhinolaryngol, 17, 88-95.
  36. Mohanty BK, Bahadur S, Lal P, Gairola M, Rath GK (2000). Textbook of Radiation Oncology: Principles and Practice, Eds Rath GK and Mohanty BK. BI Churchill Livingstone, New Delhi, 131-99.
  37. Newlin HE, Amdur RJ, Riggs CE, Morris CG, Kirwan JM, Mendenhall WM (2010). Concomitant weekly cisplatin and altered fractionation radiotherapy in locally advanced head and neck cancer. Cancer, 116, 4533-40.
  38. Osman N, Elamin YY, Rafee S, et al (2014). Weekly cisplatin concurrently with radiotherapy in head and neck squamous cell cancer: a retrospective analysis of a tertiary institute experience. Eur Arch Otorhinolaryngol, 271, 2253-9.
  39. Pajak TF, Laramore GE, Marcial VA, et al (1991). Elapsed treatment days - a critical item for radiotherapy quality control review in head and neck trials: RTOG report. Int J Radiat Oncol Biol Phys, 20, 13-20.
  40. Pala M, Odrazka K, Holeckova P, et al (2012). Definitive radiochemotherapy with weekly cisplatin in patients with head and neck cancer; single institution outcome analysis. J Buon, 17, 471-7.
  41. Pignon JP, Bourhis J, Domenge C, Designe L (2000). Chemotherapy added to locoregional treatment for head and neck squamous cell carcinoma: three meta-analyses of updated individual patient data. MACH-NC Collaborative Group Meta-analysis of chemotherapy on head and neck cancer. Lancet, 355, 949-55.
  42. Pignon JP, Maitre LA, Bourhis J (2007). Meta-Analyses of Chemotherapy in Head and Neck Cancer (MACH-NC): an update. Int J Radiat Oncol Biol Phys, 69,112-4.
  43. Pignon JP, le Maitre A, Maillard E, Bourhis J (2009). Metaanalysis of chemotherapy in head and neck cancer (MACHNC): an update on 93 randomized trials and 17,346 patients. Radiother Oncol, 92, 4-14.
  44. Quon H, Leong T, Haselow R, Leipzig B, Cooper J, Forastiere A (2011). Phase III study of radiation therapy with or without cis-platinum in patients with unresectable squamous or undifferentiated carcinoma of the head and neck: an intergroup trial of the eastern cooperative oncology group (E2382). Int J Radiat Oncol Biol Phys, 8, 719-25.
  45. Rademaker-Lakhai JM, Crul M, Zuur L, et al (2006). Relationship between cisplatin administration and the development of ototoxicity. J Clin Oncol, 24, 918-24.
  46. Rutten H, Pop LA, Janssens GO, et al (2011). Long-term outcome and morbidity after treatment with accelerated radiotherapy and weekly cisplatin for locally advanced head and neck cancer: Results of a multidisciplinary late morbidity clinic. Int J Radiat Oncol Biol Phys, 81, 923-9.
  47. Rosenberg B, Vancamp L, Krigas T (1965). Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Nature, 205, 698-9.
  48. Sambargi UC, Mahesh DR, Pai A, Maligi P, Ramanarayan BK, Sanjay CJ (2012). Recent advances in chemotherapy for head and neck cancers. J Orofac Sci, 4, 15-9.
  49. Steinmann D, Cerny B, Karstens JH, Bremer M (2009). Chemoradiotherapy with weekly cisplatin 40 mg/m2 in 103 head and neck cancer patients: a cumulative dose-effect analysis. Strahlenther Onkol, 185, 682-8.
  50. Traynor AM, Richards GM, Hartig GK, et al (2010). Comprehensive IMRT plus weekly cisplatin for advanced head and neck cancer: The University of Wisconsin Experience. Head Neck, 32, 599-606.
  51. Tsan DL, Lin CY, Kang CJ, et al (2012). The comparison between weekly and three-weekly cisplatin delivered concurrently with radiotherapy for patients with postoperative high-risk squamous cell carcinoma of the oral cavity. Radiat Oncol, 7, 215.
  52. Uygun K, Bilici A, Karagol H, et al (2009). The comparison of weekly and three-weekly cisplatin chemotherapy concurrent with radiotherapy in patients with previously untreated inoperable non-metastatic squamous cell carcinoma of the head and neck. Cancer Chemother Pharmacol, 64, 601-5.
  53. Wee J, Tan EH, Tai BC (2005). Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with american joint committee on cancer / international union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol, 23, 6730-8.
  54. Wendt TG, Grabenbauer GG, Rodel CM, et al (1998). Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicentre study. J Clin Oncol, 16, 1318-24.
  55. Yang LX, Douple EB, Wang HJ (1995). Irradiation enhances cellular uptake of carboplatin. Int J Radiat Oncol Biol Phys, 33, 641-6.
  56. Zenda S, Onozawa Y, Tahara M, et al (2007). Feasibility study of single agent cisplatin and concurrent radiotherapy in Japanese patients with squamous cell carcinoma of the head and neck: preliminary results. Jpn J Clin Oncol, 37, 725-9.

Cited by

  1. Do selective radiation dose escalation and tumour hypoxia status impact the loco-regional tumour control after radio-chemotherapy of head & neck tumours? The ESCALOX protocol vol.12, pp.1, 2017,
  2. Breast cancer subtype and stage are prognostic of time from breast cancer diagnosis to brain metastasis development vol.134, pp.2, 2017,
  3. Once-a-Week Versus Once-Every-3-Weeks Cisplatin Chemoradiation for Locally Advanced Head and Neck Cancer: A Phase III Randomized Noninferiority Trial vol.36, pp.11, 2018,