Incidence of Head and neck cancers (HNCs) is increasing, with an estimated worldwide incidence of more than 500,000 new cases each year (1). Squamous-cell carcinoma of the head and neck is predominantly a loco-regional disease. The primary treatment modalities are surgery and radiotherapy with or without chemotherapy.(2) Head and neck cancer can be cured by chemoradiation in 35-45% of locally advanced cancers, however due to the heterogeneity in intrinsic cellular radiosensitivity such as tumour hypoxia,tumour-cell proliferation etc. variation in the total dose is needed to control the tumour (2-4).

Accelerated repopulation of clonogenic tumour cells is one of the causes of treatment resistance. Clinically and biologically it has been well documented that prolonging the treatment time will reduces the chances of tumour control (5, 6). On the other hand benefit of shortening overall treatment time in terms of loco regional control and distant metastases has been seen in several clinical studies (7,8). A shorter treatment time is possible either by applying a higher dose per fraction or by increasing weekly number of fractions. Increasing dose per fraction will disproportionately increase the incidence of late complications (10). Accelerated fractionation is also possible by increasing weekly number of fractions without increasing dose per fractionation. Accelerated fractionation has already been tested by DAHANCA and IAEA trial (12, 13). Both the trials showed the benefit of this accelerated fractionation in term of local control and disease free survival with acceptable toxicity. Drawback of these trials is that they have compared different protocols of Radiotherapy alone and not chemoradiation which has the best possible reported outcomes and is currently the standard of care. K. Kian Ang et al. in their study compared accelerated chemoradiation with five days conventional chemoradiation and showed 3 year overall survival of 70.3% vs 64.3% (14). MACHNC update 2009 has shown an absolute benefit of 6.5% at 5 year with addition of chemotherapy to radiation (9). Recent Network metanalysis showed that adding altered fractionation to chemoradiotherapy would lower the relative risk of death by 8% (HR between Accelerated Chemoradiation and Chemoradiation: 0.92 [0.77, 1.11]) (11). On the basis of this we have designed a Randomized clinical trial to compare Accelerated Chemoradiation(6fr/week) with Conventional Chemoradiation(5fr/week).

References

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3. Overgaard J, Horsman MR. Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitizers. Semin Radiat Oncol 1996; 6: 10–21.

4. Peters LJ, Ang KK. The role of altered fractionation in head and neck cancers. Semin Radiat Oncol 1992; 2: 180–94.

5. Withers HR, Taylor JM, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 1988; 27: 131–46.

6. Overgaard J, Vendelbo Johansen L, Hjelm-Hansen M, Andersen AP. Comparison of conventional and split-course radiotherapy as primary treatment in carcinoma of the larynx. Acta Oncol 1988; 27: 147–52

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8. Bernier J, Bentzen SM. Altered fractionation and combined radiochemotherapy approaches: pioneering new opportunities in head andneck oncology. Eur J Cancer 2003; 39: 560–71.

9. Pignon J, Maître A, Maillard E, Bourhis J, on behalf of the MACH-NCCollaborative Group Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiotherapy and Oncology 92 (2009) 4–14.

10. Thames, H.D., Bentzen, S.M., Turesson, I, Overgaard, M. & van der Bogaert, W. Fractionation parameters for human tissues and tumors. Int. J. Rad. Biol. 1989: 56: 01-710.

11. Blanchard P, Hill C, Guihenneuc-Jouyaux C, Baey C, Bourhis J, Pignon J,Mixed treatment comparison meta-analysis of altered fractionated radiotherapy and chemotherapy in head and neck cancer on behalf of the MACH-NC and MARCH Collaborative Groups. Journal of Clinical Epidemiology – 2011;64:985-92.

12. Overgaard J, Mohanti BK, Begum N, Ali R, Agarwal JP, Kuddu M, Bhasker S, Tatsuzaki H, Grau C.Five versus six fractions of radiotherapy per week for squamous-cell carcinoma of the head and neck (IAEA-ACC study): a randomised, multicentre trial.Lancet Oncol. 2010 ;11(6):553-60.

13. Overgaard J, Hansen H, Specht L, Overgaard M, Grau C, Andersen E, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6&7 randomised controlled trial The Lancet 2003;362:933-40.

14. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, et al.,Human papillomavirus and survival of patients with oropharyngeal cancer. NEJM 2010;363(1):24-35.