Rectal cancer Intensified irinotecan-based neoadjuvant chemoradiotherapy in rectal cancer: Four consecutive designed studies to minimize acute toxicity and to optimize efficacy measured by pathologic complete response q Gunther Klautke a, * , Ute Ku ¨chenmeister a , Thomas Foitzik b , Kaja Ludwig c , Sabine Semrau a , Friedrich Prall d , Ernst Klar b , Rainer Fietkau a a Department of Radiotherapy, and b Department of Surgery, University Hospital, Rostock, Germany, c Department of Surgery, Klinikum Su ¨dstadt, Rostock, Germany, d Department of Pathology, University Hospital, Rostock, Germany Abstract Background. The objective of the present study was to analyse toxicity and efficacy of irinotecan-based neoadjuvant chemoradiotherapy by the help of four consecutively planed and prospectively performed phase II studies. Patients and methods. Patients with locally advanced rectal cancer received radiotherapy and concurrently chemotherapy consisting 5-Fu/capecitabine in a continuous or intermittent application and irinotecan in two different total doses (240 vs. 200 mg/m 2 ). Results. Diarrhea CTC grade III was seen in 35% in continuous application of 5-Fu/capecitabine versus 12.5% in intermittent application (p = 0,008). Complete response according to the irinotecan dose during chemoradiotherapy (240 mg/m 2 vs. 200 mg/m 2 ) was 24% and 0%. Conclusions. Chemoradiotherapy of the last phase II study with intermittent capecitabine (1500 mg/m 2 /day, delivered on days 1–14 and 22–35) and irinotecan (4 · 60 mg/m 2 ) concurrently to radiotherapy is a safe treatment with low toxicity and high efficacy.  c 2007 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 85 (2007) 379–384. Keywords: Rectal cancer; Neoadjuvant chemoradiotherapy; Toxicity; Efficacy; Irinotecan Background The rate of pathologic complete response (pCR) is fre- quently used as a surrogate parameter of the efficacy of neoadjuvant chemoradiotherapy. A correlation between the rate of pCR/tumor regression and survival has been observed, at least in univariate analyses [1–3]. In a multi- variate analysis of phase II and III neoadjuvant chemoradio- therapy trials Hartley et al. [4] found that protracted continuous infusion of 5-fluorouracil (p = 0.01) in combina- tion with a second chemotherapeutic drug (p = 0.001) is associated with higher pCR rates. In this analysis a radiation dose less than 45 Gy was associated with a lower rate of pCR, but a dose escalation above 45 Gy was not correlated with a higher rate of pCR. In contrast to the GRCSG (German rectal cancer study group) study [5], phase I/II trials with longer follow-up periods demonstrated that intensified neoadjuvant radiochemotherapy may lower the rates of both local and distant recurrence [6]. Many oncologists fear that an increase in acute toxicities, especially diarrhea, will be a main problem associated with intensified treatment. The objective of the present study is to analyse acute toxicity and efficacy by the help of four consecutively designed irinotecan-based protocols for intensified neoadju- vant chemoradiotherapy. Some of the individual study results have already been published [7,8]. These results will now be supplemented with data from the longer follow-up period. Patients and methods Study protocols (Fig. 1) and rationale of the study concept All studies were based on the results of the proceeding studies and were consecutively designed. In the first study (July 1999 to December 2001) [7], patients received radiotherapy concurrently with chemo- therapy consisting of a protracted continuous infusion of 5-Fu (250 mg/m 2 ; days 1–43) in combination with irinotecan once weekly (40 mg/m 2 ; days 1, 8, 15, 22, 29 and 36). q The data were presented in a part at the 25th annual meeting of the European Society for Therapeutic Radiology and Oncology, 2006, in Leipzig. Radiotherapy and Oncology 85 (2007) 379–384 www.thegreenjournal.com 0167-8140/$ - see front matter  c 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2007.10.042