The Head and Neck Intergroup conducted a phase III randomised trial to test the benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer. Eligible patients were randomly assigned between arm A (the control), single daily fractionated radiation (70 Gy at 2 Gy/day); arm B, identical radiation therapy with concurrent bolus cisplatin, given on days 1, 22, and 43; and arm C, a split course of single daily fractionated radiation and three cycles of concurrent infusional fluorouracil and bolus cisplatin chemotherapy, 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle. Surgical resection was encouraged if possible after the second chemotherapy cycle on arm C and, if necessary, as salvage therapy on all three treatment arms. Survival data were compared between each experimental arm and the control arm using a one-sided log-rank test.
It was concluded that the addition of concurrent high-dose, single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival, although it also increases toxicity. The loss of efficacy resulting from split-course radiation was not offset by either multiagent chemotherapy or the possibility of midcourse surgery.r
There is controversy regarding the optimal schedule of cisplatin. Recent retrospective datar showed no difference, but a prospective study demonstrated inferiority of lower dose weekly treatment.r There is a direct dose response relationship demonstrated and it is likely that the delivered cumulative dose is the most critical variable.r Overall there is evidence that the total cumulative dose of cisplatin is important. There appears to be a threshold for efficacy at 200 mg/m2, thus maximum doses of cisplatin should be aimed for, with the intention of achieving at least 200 mg/m2.
Kaplan-Meier curve showing estimated progression-free survival according to the dosing schedule of cisplatinr
© Medicine, 2018
Kaplan-Meier curve showing estimated overall survival according to the dosing schedule of cisplatinr
© Medicine, 2018
Kaplan-Meier of overall survivalr
© Journal of Clinical Oncology 2003
|Projected 3 year survival
|Median survival (months)
NR: not reported
Grade 3 or worse toxicity occurred with 52% of arm 1 (RT alone) compared with 89% of arm 2 (RT plus cisplatin) (p <0.0001).
Grade 3 to 5
Radiation therapy alone
Radiation therapy plus cisplatin