Further advances have been limited by the observation that any additional increase in tumour control appears often to be balanced by an increase in acute and late normal tissue toxicity. The current national trial in the UK (ARISTOTLE) is examining the selleck kinase inhibitor utility of the incorporation of irinotecan into pre-operative CRT in MRI defined unresectable/borderline resectable rectal cancer (www.controlled-trials.com/ISRCTN09351447). Similar phase II trials with oxaliplatin appeared encouraging (36,37). However, preliminary results from
randomized phase III trials, evaluating the addition of oxaliplatin to preoperative fluoropyrimidines-based CRT, have not shown a significant impact on Inhibitors,research,lifescience,medical early pathological response (STAR-01, ACCORD 12/0405-Prodige 2, NSABP R-04) with the exception of the German CAO/ARO/AIO-04 study. In addition, the PETACC-6 trial randomized patients between preoperative RT (50.4 Gray in 25 fractions) with capecitabine Inhibitors,research,lifescience,medical alone the same radiation schedule with capecitabine + oxaliplatin (50 mg/m2). Results have not yet been reported (Table 2). Table 2 Short
Inhibitors,research,lifescience,medical term outcomes from randomised phase III studies integrating oxaliplatin as radiosensitizer Efforts to improve the outcome from chemoradiotherapy further have focussed on adding biological agents to avoid overlapping toxicities. A landmark randomised phase III study in patients with locally advanced head and neck cancer showed that cetuximab in combination with radical Inhibitors,research,lifescience,medical radiotherapy significantly improved overall survival (41) compared to radiation alone. Many mechanisms have been postulated (42), including inhibition of repopulation during the latter phase of radiotherapy. Accelerated treatments improve outcome only in head and neck cancers, which have high EGFR expression (43). Yet, this benefit from cetuximab has not been extended to chemoradiation. In the Radiation Therapy Oncology Group (RTOG) 0522 trial patients
with locally advanced head and neck showed a 2-year progression-free survival (PFS) of 63.4% with cetuximab versus 64.3% with cisplatin-based Inhibitors,research,lifescience,medical chemoradiation alone, and overall survival improved slightly but not significantly with cetuximab (44). Hence, with our next increasing knowledge of molecular pathways in cancer, can we identify sufficient potential targets that may be manipulated to enhance the radiation response selectively in rectal cancers compared to normal tissues such as small bowel and the sphincter complex? We found 13 papers documenting combinations of chemoradiotherapy with cetuximab, 2 with panitumumab and 15 with bevacizumab. Cetuximab-containing neoadjuvant chemoradiation has not been shown to improve tumor response/ pathologic complete responses in locally advanced rectal cancer patients in recent phase I/II trials (Tables 3,,4).4). The data with panitumumab and small molecules is even sparser (Table 5).