This review shows that a significant proportion of patients in curative-intent clinical trials experience toxicities that result in dose modifications-dose reduction , dose delays or missed doses-despite strict selection criteria and intense monitoring .
Toxicities of systemic cancer therapies are often less frequently observed in clinical trials than in clinical practice , due to the careful selection of patients with fewer comorbidities .
Although guidelines exist for the estimation of chemotherapy dose , clinical factors like age , comorbid illness and extremes of body habitus are not considered in the method of dose calculation , which can result in significant toxicity .
Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial.
BACKGROUND Chemoradiation became the st and ard of care for anal cancer after the ACT I trial . However , only two-thirds of patients achieved local control , with 5-year survival of 50 % ; therefore , better treatments are needed . We investigated whether replacing mitomycin with cisplatin in chemoradiation improves response , and whether maintenance chemotherapy after chemoradiation improves survival . METHODS In this 2 × 2 factorial trial , we enrolled patients with histologically confirmed squamous-cell carcinoma of the anus without metastatic disease from 59 centres in the UK . Patients were r and omly assigned to one of four groups , to receive either mitomycin ( 12 mg/m(2 ) on day 1 ) or cisplatin ( 60 mg/m(2 ) on days 1 and 29 ) , with fluorouracil ( 1000 mg/m(2 ) per day on days 1 - 4 and 29 - 32 ) and radiotherapy ( 50.4 Gy in 28 daily fractions ) ; with or without two courses of maintenance chemotherapy ( fluorouracil and cisplatin at weeks 11 and 14 ) . The r and om allocation was generated by computer and patients assigned by telephone . R and omisation was done by minimisation and stratified by tumour site , T and N stage , sex , age , and renal function . Neither patients nor investigators were masked to assignment . Primary endpoints were complete response at 26 weeks and acute toxic effects ( for chemoradiation ) , and progression-free survival ( for maintenance ) . The primary analyses were done by intention to treat . This study is registered at controlled-trials.com , number 26715889 . FINDINGS We enrolled 940 patients : 472 were assigned to mitomycin , of whom 246 were assigned to no maintenance , 226 to maintenance ; 468 were assigned to cisplatin , of whom 246 were assigned to no maintenance , 222 to maintenance . Median follow-up was 5.1 years ( IQR 3.9 - 6.9 ) . 391 of 432 ( 90.5 % ) patients in the mitomycin group versus 386 of 431 ( 89.6 % ) in the cisplatin group had a complete response at 26 weeks ( difference -0.9 % , 95 % CI -4.9 to 3.1 ; p=0.64 ) . Overall , toxic effects were similar in each group ( 334/472 [ 71 % ] for mitomycin vs 337/468 [ 72 % ] for cisplatin ) . The most common grade 3 - 4 toxic effects were skin ( 228/472 [ 48 % ] vs 222/468 [ 47 % ] ) , pain ( 122/472 [ 26 % ] vs 135/468 [ 29 % ] ) , haematological ( 124/472 [ 26 % ] vs 73/468 [ 16 % ] ) , and gastrointestinal ( 75/472 [ 16 % ] vs 85/468 [ 18 % ] ) . 3-year progression-free survival was 74 % ( 95 % CI 69 - 77 ; maintenance ) versus 73 % ( 95 % CI 68 - 77 ; no maintenance ; hazard ratio 0.95 , 95 % CI 0.75 - 1.21 ; p=0.70 ) . INTERPRETATION The results of our trial -- the largest in anal cancer to date --show that fluorouracil and mitomycin with 50.4 Gy radiotherapy in 28 daily fractions should remain st and ard practice in the UK . FUNDING Cancer Research UK
This review shows that a significant proportion of patients in curative-intent clinical trials experience toxicities that result in dose modifications-dose reduction , dose delays or missed doses-despite strict selection criteria and intense monitoring .
Toxicities of systemic cancer therapies are often less frequently observed in clinical trials than in clinical practice , due to the careful selection of patients with fewer comorbidities .
Although guidelines exist for the estimation of chemotherapy dose , clinical factors like age , comorbid illness and extremes of body habitus are not considered in the method of dose calculation , which can result in significant toxicity .