1 2 4 4 6 7 8 9 9 10 11 12 13 14 16 17 18 20 We investigated the combination of capecitabine and oxaliplatin given concomitantly with radiotherapy in patients with locally advanced rectal cancer. The optimal dose of oxaliplatin was first established in a phase I study, and in the following phase II study the efficacy of this regimen was tested. PATIENTS AND METHODS Objectives The objective of the phase I study was to determine the maximum tolerated dose (MTD) of oxaliplatin in combination with a fixed dose of capecitabine and radiotherapy, and the objective of the phase II study was to determine the R0 resection rate and pathological complete response rate (pCR). Eligibility Criteria 9 9 TREATMENT Radiotherapy All patients received radiation delivered by an isocentric three- or four-field technique, using a linear accelerator of at least 10 MV. The patients were treated in either supine or prone position with a full bladder. The radiation field extended superiorly to the L5/S1 junction and covered inferiorly the obturator foramina. The minimal inferior border extended 4–5 cm below the tumor. In case the tumor was located in the lower third of the rectum, the perineum was encompassed in the treatment field. The width of the AP-PA portals had to cover the lateral pelvic inlet with a margin of 1.5 cm. The entire sacrum was included with a dorsal margin of 1.5 cm. Anteriorly, the lateral fields had to encompass the tumor as determined by barium enema (optional) and pelvic CT scan. If there was clinical evidence of involvement of the bladder, the prostate, the cervix or the uterine body, not only the internal iliac nodes but also the external iliac nodes were included in the radiation field. Computerized dosimetry was routinely performed. Irradiation was delivered 5 days per week at a dose of 1.8 Gy/day to a total dose of 45 Gy with a boost to the tumor in 3 fractions of 1.8 Gy to a total of 50.4 Gy. Chemotherapy 2 2 Surgery 2 21 Pathology 7 Statistics Twenty patients were to be included at the MTD to detect with a power of 80% a R0 resectability rate of >80% (with a 95% CI of 56–94%). Monitoring and Management During Treatment 22 9 RESULTS Patients Characteristics 1 TABLE 1. Patient characteristics (n = 22) Characteristics No. Median age (years) 58 Range (years) 45–70 Men/Women 12/10 Performance status   0 3   1 19 Distance of tumor to anal verge (cm)   0–5 11   5–10 7   10–15 3   Unknown 1 T status a 17 b 5 a b Toxicity 2 2 2 TABLE 2. Toxicity in the study population (n = 22) Study Phase I Phase II Dose oxaliplatin (number of patients) 2 2 (22) Toxicity grade (NCI CTCV2.0) Toxicity grade (NCI CTCV2.0) Toxicity grade (NCI CTCV2.0) 3 4 3 4 3 4 Leukopenia – – – – – – Neutropenia – – – – – – Thrombopenia – – – – – – Anemia – – – – – – Diarrhea – – 1 – 4 – Abdominal pain – – – – – – Nausea 1 – – – – – Mucositis – – – – – – Neurotoxicity – – – – – – Surgery TME surgery was performed after a median of 47 days (range 4–8 weeks range in days) following the completion of chemoradiation. Mean hospitalization time was 14 days (range 9–95; 70% < 21 days). The main surgical complications were: major bleeding (1), rectal perforation (1), ureter lesion (1). Postsurgery treatment related complications were seen in 12 patients with mild wound infections (6), wound dehiscences (2), (sub)ileus (4), rhabdomyolysis (1), and in one patient a life-threatening multiorgan failure after a perforation in an abcess located near the anus praeter. Rhabdomyolysis is an unusual complication. In this patient it was probably caused by the operation procedure and not by this specific procedure as there were no other postoperative complications. Three patients (15%) needed reoperation for perforation (1) and pelvic abscesses (2). The 60-day mortality rate was nil. Efficacy Twenty-one patients with a T3–T4 tumor based on CT or MRI underwent surgery with 10 abdominoperineal resections (APRs) and 10 low anterior resections (LARs); in one patient the tumor was not resectable. A R0 resection was achieved in 17 patients (81%, 95% CI 58–95%). A pCR was observed in 2 patients (10%, 95% CI 1–30%), and in one patient (5%) the surgical specimen only showed minimal microscopic disease. The postradiotherapeutic pathologic staging yielded in seven patients (33%; 95% CI 15–57%) a downstaging to pT0–T2. After a median follow-up of 14 months, four patients have died due to metastatic disease and one patient has experienced a local recurrence. Quality of Life p DISCUSSION 11 13 23 2 2 3 TABLE 3. Locally advanced rectal cancer, recent neoadjuvant studies with fluoropyrimidines and oxaliplatin in combination with radiotherapy Study Design (phase) Stage N EBRT (Gy) CT R0 (%) pCR (%) Toxicity grade 3–4 (%) Total Diarrhea Myelotoxic Preoperative radiotherapy vs. chemoradiotherapy (with 5 FU) 11 23 III T3/T4  1011 45 – – 5 a 17– 1– 45 5FU pre – 14 54– 34– 9– 13 III T3/T4 762 45 – 90 4 3 – – 45 5FU pre 91 12 15 – – 9 III T3/T4 316 5 × 5 – 87 1 3 – – 50.4 5FU pre 96 17 18 – – Preoperative CRT with capecitabine 30 II T3/T4/N+ 45 50.4  Cap 3 – 31 17 4 – 31 32 II T3/T4/N+ 98 50.4 + 5.4 Cap 1 – 4 22 4 10 33 II T3+, low T3, N2 77 54 b 99 24 4 deaths   16 II T3/T4 (T2 10%) 46 50.4  5FU vs Cap 2 – 17  4  43 – 30  2  Preoperative CRT with 5 FU based chemotherapy and oxaliplatin 34 II T3 30 50 Tomox – 30 13 3 10 26 II T2/T3/T4 40 50.4 FU + Ox 1 – 15 18 5 3 35 II T3–4 32 50.4 Capox 4 79 19 16 8 0 36 II T3/T4 22 50.4 FU + Ox 2 – 14 – 27 14 25 I/II T3/T4/N+ 25 50.4 FU + Ox 3 89 28 24 16 4 32 I/II Unresectable 94 45 Capox 2 78 28 13 10 – 24 II T3/T4/N+ 40 45 Capox 1 83 14 – 30 – Hospers (2006) This study I/II T3/T4 22 50.4 Capox 81 10 – 18 – 2 Capox 1: Cap 825 2× daily, Monday–Friday, oxali 50 weekly Tomox: raltitrexed 3, oxali 130, day 1, 19, 38 2 Capox 2: Cap 650 2× daily, 7 days, oxali 130 per 2 weeks FU + Ox 1: 5FU 350 daily, Oxali 130 weekly, week 1 and 5 2 Capox 3: Cap 825 2× daily, 7 days, oxali 60 per 2 weeks FU + Ox 2: 5FU 375/4 days, Oxali 25/4 days, week 1 and 5  Capox 4: Cap 825 2× daily, 2 × 14 days, oxali 50, day 1, 8, 22, 29 FU + Ox 3: 5FU 225 daily, Oxali 60 weekly a b 2 24 26 3 27 28 29 2 In conclusion, this multicenter study demonstrated a neoadjuvant regimen with Capox-RT with an acceptable acute toxicity profile. Randomized phase III studies with in the standard arm 5FU will be necessary to show the true benefit of this approach. In such prospective studies, the standardization of the staging technique (i.e., the distance of the tumor to the endopelvic fascia), TME surgery, radiotherapy, and pathology should minimize the influence of these factors on the outcome.