The boost was given either with external beam (15Gy) or Ir192 implant (25Gy). Clinical response was measured at 2 months after completion of the boost. The Selleck INK1197 combined modality arm consisted of the same RT schedule with 2 cycles of chemotherapy; bolus MMC (12-10mg/m2) and continuous venous infusion 5FU (1000-750mg/m2/day for 4 days) commencing at the start of RT. An update was recently reported with a median follow up of 13 years. The hazard ratio for local Inhibitors,research,lifescience,medical regional relapse (HR=0.46, P<0.001), disease

free survival (HR=0.70, P<0.001), anal cancer mortality (HR=0.61, P<0.001), and colostomy free survival (HR=0.76, P=0.004) all favored the combined modality arm. The hazard ratio for overall survival was 0.86 and not statistically significant Inhibitors,research,lifescience,medical (P=0.12). There was an increase in non-anal cancer deaths in the first 5 years in the combined modality arm which almost disappeared

at 10 years. Also there were more deaths due to second malignancy in the combined modality arm (P=0.03). Again acute toxicity was higher in the concurrent arm but there were no differences in late toxicity (28). Figure 1 Acute cutaneous toxicity from chemoradiotherapy for a clinical T4 bulky, locally advanced anal canal carcinoma. The EORTC (European Organization for Research and Treatment of Cancer) confirmed the results in a similar study comparing concomitant RT with 5FU and MMC versus RT alone (29). The locoregional Inhibitors,research,lifescience,medical control rate was improved by almost one-fifth and the colostomy free rate improved by one-third in the combined Inhibitors,research,lifescience,medical modality arm at 5 yrs. Both results were statistically significant. There was no difference between the two arms

in overall survival. Again acute toxicity was worse in the combined modality arm (29). The importance of MMC in the treatment of anal cancer was confirmed in the RTOG 87-04 (Radiation Therapy Oncology Group) trial which randomized patients to RT with MMC and 5FU versus RT and 5FU alone (30). RT total doses ranged from 45 to 54Gy. This trial showed that the MMC arm had superior colostomy free survival (71%vs 59%), disease free survival (73% vs. 51%), and fewer post treatment positive biopsies (7.7% vs. 15%) already at 4years. All were statistically Inhibitors,research,lifescience,medical significant. Grade 4 and 5 acute toxicity were greater in the MMC arm (23% versus 7%) (30). MMC is known to be toxic and the question was tested if a potentially less toxic agent, cisplatin, could be substituted. Specifically, the hemolytic uremic syndrome and thrombocytopenia are not uncommon life-threatening toxicities that result from use of MMC (31), (32). RTOG 98-11 tested concurrent MMC and 5FU versus induction cisplatin and 5FU followed by concurrent RT and cisplatin and 5FU. RT total doses ranged from 45-59 Gy. At five years the cisplatin arm had statistically significant inferior colostomy rate of 19% versus 10%. Other end points measured such as disease free survival, overall survival, local regional recurrence, and distant metastasis were not statistically different.