Annals of Oncology Advance Access published online on January 5, 2007
Annals of Oncology, doi:10.1093/annonc/mdl460
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© 2007 European Society for Medical Oncology
Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer
1 Clinique des Pathologies Tumorales du Côlon et du Rectum, Centre du Cancer, Université catholique de Louvain, Cliniques universitaires Saint-Luc, Brussels
2 Service de Gastroentérologie et d'Oncologie, Clinique St-Pierre, Ottignies
3 Digestive Oncology Unit, Katholieke Universiteit Leuven/University Hospital Gasthuisberg, Leuven
4 Service d'Oncologie, Cliniques universitaires de Mont-Godinne (UCL) and Clinique St-Elisabeth, Namur
5 Service d'Oncologie, Clinique Notre-Dame, Charleroi
6 Digestive Oncology Unit, UZ Gent, Belgium
7 Service d'Oncologie et de Radiothérapie, Hôpital St-Joseph, Gilly
8 Radiation Oncology, Katholieke Universiteit Leuven/University Hospital Gasthuisberg Leuven, Gasthuisberg, Leuven
9 Service de Radiothérapie, Clinique St-Elisabeth, Namur
10 Service de Radiothérapie, Université catholique de Louvain, Cliniques universitaires Saint-Luc, Brussels, Belgium
* Correspondence to: Dr J.-P. Machiels, Medical Oncology Unit, Université catholique de Louvain, Cliniques universitaires Saint-Luc, 10, avenue Hippocrate, 1200 Brussels, Belgium. Tel: 32-2-764-54-85; Fax: 32-2-764-54-28; E-mail: jean-pascal.machiels{at}onco.ucl.ac.be
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Abstract |
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Background: To assess the safety and preliminary efficacy of concurrent radiotherapy, capecitabine, and cetuximab in the preoperative treatment of patients with rectal cancer.
Patients and methods: Forty patients with rectal cancer (T3–T4, and/or N+, endorectal ultrasound) received preoperative radiotherapy (1.8 Gy, 5 days/week for 5 weeks, total dose 45 Gy, three-dimensional conformal technique) in combination with cetuximab [initial dose 400 mg/m2 intravenous given 1 week before the beginning of radiation followed by 250 mg/m2/week for 5 weeks] and capecitabine for the duration of radiotherapy (650 mg/m2 orally twice daily, first dose level; 825 mg/m2 twice daily, second dose level).
Results: Four and six patients were treated at the first and second dose level of capecitabine, respectively. No dose-limiting toxicity occurred. Thirty additional patients were treated with capecitabine at 825 mg/m2 twice daily. The most frequent grade 1/2 side-effects were acneiform rash (87%), diarrhea (65%), and fatigue (57%). Grade 3 diarrhea was found in 15%. Three grade 4 toxic effects were recorded: one myocardial infarction, one pulmonary embolism, and one pulmonary infection with sepsis. Two patients (5%) had a pathological complete response.
Conclusions: Preoperative radiotherapy in combination with capecitabine and cetuximab is feasible with some patients achieving pathological downstaging.
capecitabine, cetuximab, preoperative, radiotherapy, rectal cancer
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introduction |
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Because of a significant risk of locoregional failure, pelvic radiation is routinely used in patients with stage II or III rectal cancer [1–10]. Both pre- and postoperative radiotherapy decrease local relapse [1–6]. Moreover, postoperative 5-fluorouracil (5-FU)-based chemoradiation improves disease-free survival (DFS) and overall survival (OS) [7–9]. Preoperative chemoradiation, given for a period of 5–6 weeks followed by delayed surgery allows tumor downstaging and resection of the primary tumor with sphincter function preservation in patients with distal rectal cancer [11]. The German Rectal Cancer Study Group reported that preoperative chemoradiation improves local control and sphincter preservation and is associated with reduced toxicity but does not improve survival compared with postoperative therapy [12]. Prospective trials that investigated the potential advantage of preoperative 5-FU-based chemoradiation over radiotherapy alone show that the addition of chemotherapy to preoperative radiation increases downsizing and pathological downstaging [13, 14]. Following these studies, preoperative chemoradiation for locally advanced rectal cancer patients is now considered as the standard treatment in many centers.
Nowadays, studies are investigating the role of radiation-sensitizing agents and the combination of radiotherapy with targeted agents in an attempt to improve local control and DFS. Capecitabine and cetuximab are both highly active in metastatic colorectal cancer and have radiosensitizing properties [15, 16]. Therefore, these drugs can be expected to improve the effectiveness of preoperative radiotherapy in terms of local control and possibly also in the prevention of distant metastases. Capecitabine is an effective oral fluoropyrimidine that exploits the high intratumoral activity of thymidine phosphorylase to generate 5-FU, preferentially within tumor tissue [17]. Previous studies have shown that capecitabine in combination with radiotherapy is safe and effective [18]. Cetuximab is a chimeric immunoglobulin G1 monoclonal antibody that binds to epidermal growth factor receptor (EGFR) with high specificity and with a higher affinity than either epidermal growth factor or transforming growth factor-
[19, 20]. Cetuximab has been shown to be effective in the treatment of metastatic colorectal cancer as both monotherapy and in combination with chemotherapy [21, 22].
Cetuximab can be safely administered with conventional or hyperfractionated radiotherapy in patients with head and neck cancer [23, 24]. Moreover, cetuximab has been shown to improve survival in combination with curative-intent radiotherapy in patients with locally advanced head and neck carcinoma [25]. The addition of cetuximab to the preoperative chemoradiation treatment of patients with locally advanced rectal cancer could also improve their outcome.
We report the results of a phase I/II study combining capecitabine, cetuximab, and radiotherapy in the preoperative treatment of patients with rectal cancer.
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eligibility criteria
To be eligible, patients had a histologically proven rectal adenocarcinoma stage T3–T4 and/or N1–N2 by transrectal ultrasound. Other inclusion criteria were as follows: age >18 years; Eastern Cooperative Oncology Group (ECOG) performance status of two or less; signed informed consent; and acceptable liver, renal, and hematological parameters: granulocytes >1500/mm3, platelets >100 000/mm3, bilirubin
1x upper limit of normal (ULN), aspartate aminotransferase/alanine aminotransferase 2.5x ULN, creatinine 1.5 mg/dl or creatinine clearance at least 60 ml/min. Exclusion criteria were as follows: prior pelvic irradiation; any other malignancy during the previous 5 years (except nonmelanoma skin cancer or in situ cervical carcinoma); presence of distant metastases; pregnancy or lack of contraception in women with childbearing potential; presence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; and prior or concurrent evidence of inflammatory bowel disease, malabsorption syndrome, synchronous colic and rectal tumors, and other uncontrolled severe disease precluding administration of chemotherapy and radiation. All patients signed an informed consent. The study was approved by the Independent Ethics Committee and Belgian Health authority in accordance with European Regulations and conducted in accordance with the Declaration of Helsinki (October 2000).
pretreatment evaluation
Pretreatment examinations were carried out within 4 weeks before the start of treatment and included complete history, physical examination, digital rectal examination, rectoscopy, tumor biopsy, transrectal ultrasound, colonoscopy, chest computed tomography (CT), abdominal and pelvic CT, electrocardiogram, and complete laboratory tests. Pelvic magnetic resonance imaging was optional.
study objectives
The aims of this study were as follows: (i) to determine the recommended dose of capecitabine in combination with cetuximab and radiotherapy in the preoperative treatment of rectal cancer, (ii) to evaluate the feasibility of this preoperative regimen based on the National Cancer Institute Common Toxicity Criteria (NCI CTC, version 2.0) and the surgical complication rate, and (iii) to determine the histopathological response rate. After the inclusion of the first 20 patients, the protocol was amended to allow inclusion of a total of 40 patients (April 2005).
radiotherapy
Megavoltage equipment was used with 6–8 mV as minimal energy. According to the European Organization for Research and Treatment of Cancer (EORTC 22921) protocol, we delivered 45 Gy in 25 fractions (1.8 Gy daily from Monday through Friday, days 1–33) (Figure 1). Three-dimensional conformal radiotherapy was used for all patients based on a contrast CT scan of the pelvis. This planning CT was carried out in the treatment position, with 3- to 5-mm-thick slices. The clinical target volume (CTV) included the entire mesorectum, as identified by the radiologist and surgeon. Internal iliac nodes were included up to the venous bifurcation, together with the presacral nodes (limit S1/S2) [26]. The planning target volume (PTV) was an isotropic expansion of the CTV (10 mm). Maximum, mean, and median dose to the PTV were calculated.
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chemotherapy and cetuximab administration: study design
A loading dose (400 mg/m2) of cetuximab was given intravenously 1 week before the start of radiation (day –6) and then weekly (dose: 250 mg/m2) throughout radiotherapy on days 1, 8, 15, 22, and 29 (Figure 1). Radiotherapy was carried out within 2 h of cetuximab infusion.
Capecitabine was taken orally twice daily, continuously (weekends included) for the duration of radiotherapy (days 1–33). Patients were asked to take capecitabine within 30 min after breakfast and dinner, 
12 h apart.
We used the recommended doses of cetuximab and radiotherapy, known from previous studies in head and neck cancer patients. For safety reasons and because this combination has never been tested before, we decided to treat a few patients at a lower dosage of capecitabine and to escalate its dosage. The first dose level of capecitabine was 650 mg/m2, the second dose level 825 mg/m2 (twice daily, every day). Standard rules for dose escalation used were as follows: at least three patients were enrolled per dose level and dose escalation was stopped if dose-limiting toxic effects (DLTs) occurred in two or more patients. It was planned to do the following: (i) to include only three patients at the first dose level if no DLT was recorded, (ii) to extend the first dose-level group to six patients if one out of the first three patients experienced DLTs, and (iii) to include a minimum of six patients at the second dose level. If less than two of the six patients with 825 mg/m2 (twice daily) experienced DLTs, this dose level would be considered as the recommended dose of capecitabine. No further dose escalation with capecitabine was allowed since 825 mg/m2 twice daily is the recommended dose of this drug in combination with radiotherapy [16]. If 650 mg/m2 capecitabine (twice daily, every day) was found to be too toxic, capecitabine dose had to be reduced to 500 mg/m2 (twice daily, every day) in another six patients. DLTs were defined according to the criteria observed by Dunst et al. [18].
The relative dose intensity for cetuximab, capecitabine, and radiation was calculated as the dose intensity divided by the planned dose intensity, multiplied by 100. All the patients were included in this analysis, even the ones who experienced toxicity with treatment interruption.
surgery and follow-up
Patients underwent radical resection within 6–8 weeks after completion of chemoradiation. Total mesorectal excision was carried out in all cases. Decision for a covering stoma during surgery was left to the surgeon's discretion. Administration of adjuvant chemotherapy was left to the treating physician's discretion. After surgery, all patients were followed up every 3 months.
histopathological assessment of response to chemoradiation
In case of residual macroscopic tumor, standard pathological examination was carried out with three to five sections to investigate the deepest invasion in the bowel wall. If no macroscopic tumor was present and only a small ulcer was observed, the ulcer with a 2-cm margin was examined for residual tumor and deepest invasion in the bowel wall. All lymph nodes were examined according to standard procedures and the circumferential resection margin was measured according to Quirke et al. [27]. All the sections of the surgical specimens were reviewed centrally by two different pathologists (SC and AS). Pathological complete response (pCR) was defined as the complete disappearance of all tumor cells. In addition, semiquantitative evaluation of histological regression was carried out according to rectal cancer regression grading established by Dworak et al. [28]: grade 0, no regression; grade 1, minimal regression (dominant tumor mass with obvious fibrosis or vasculopathy or both); grade 2, moderate regression (predominantly fibrotic changes with few tumor cells or groups); grade 3, good regression (very few tumor cells in fibrotic tissue with or without mucous substance); and grade 4, total regression (no tumor cells, only fibrotic mass). The grading system of Wheeler et al. [29] was also used: grade 1, sterilization or only microscopic foci of adenocarcinoma remaining with marked fibrosis; grade 2, marked fibrosis but macroscopic disease; and grade 3, little or no fibrosis with abundant macroscopic disease.
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patient characteristics
Forty patients were enrolled during a period of 18 months in seven Belgian centers. Patient characteristics are summarized in Table 1. Median age was 61 years (range: 34–78) with an ECOG performance status of zero or one. The most frequent endorectal ultrasound staging was uT3N0/N+. The majority (87%) of the tumors were located in the lower or middle rectum.
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dose escalation and DLTs
Four instead of three patients were treated at the first dose level (650 mg/m2 twice daily) because the two last patients signed the informed consent on the same date. No DLT was recorded in these first four patients and so the dose of capecitabine was escalated to 825 mg/m2 (twice daily) in six patients. Again, no DLT was observed. As a consequence, the protocol allowed further patient accrual at this dose level to a total of 40 patients.
acute adverse events and dose intensity
The safety results are presented for the whole population. Grade 1/2 and grade 3/4 adverse events according to NCI CTC (version 2.0) are shown in Table 2. The most frequent grade 1/2 toxic effects were acneiform rash (87%), diarrhea (65%), and fatigue (57%). These complications did not result in any treatment interruption or dose modification. The most frequent grade 3 adverse event was diarrhea (15%). Two patients had grade 3 diarrhea followed by ileitis and occlusive syndrome confirmed on abdominal CT scan. Chemoradiation was discontinued in both patients and was not resumed (total dose received was 41.4 and 32.4 Gy, respectively). Both patients fully recovered with medical supportive care within a few days. One patient experienced a grade 3 allergic reaction to cetuximab at the first infusion. This patient was treated with capecitabine and radiotherapy without cetuximab. Three grade 4 toxic effects were recorded: one myocardial infarction during chemoradiation treated by percutaneous coronary intervention and stent placement, one pulmonary embolism treated medically, and one fatal pulmonary infection with sepsis. This last serious adverse event occurred 3 weeks after the end of chemoradiation without neutropenia and was not related to the treatment according to the local investigator.
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The relative dose intensities of cetuximab, capecitabine, and radiation in the intention-to-treat population were 93%, 89%, and 90%, respectively.
efficacy
Efficacy was assessed by pathological examination of the surgical specimen. Three patients were not assessable for pathologically documented response (pathological response) because they did not undergo surgery (one disease progression, one death, and one unresectable disease found at surgery). Thirty-seven patients were therefore assessable for pathologic assessment of tumor and nodes (Tables 3 and 4, respectively). Pathological TNM (tumour–node–metastasis) classification showed downstaging in 14/37 patients (38%) compared with preoperative transrectal ultrasound staging. Two patients had a pCR (5%).
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Grade 4, 3, 2, and 1 regression, as defined by Dworak, was found in two (5%), 10 (27%), 21 (57%), and four (11%) patients, respectively. Grade 1, 2, and 3 regression, as defined by Wheeler, was observed in 26 (70%), 10 (27%), and one (3%) patients, respectively. The circumferential resection margin was negative (defined as >2 mm between the tumor and the mesorectal fascia) in 27 patients (73%).
surgery and surgical morbidity
Surgery was carried out in all but one patient who developed overt lung and liver metastases during chemoradiation. This patient did not undergo surgery and received additional chemotherapy. Palliative surgery was carried out in two other patients: tumor was found not resectable at surgery in one patient and presence of peritoneal carcinomatosis was discovered in the other patient also during surgery. All other patients had a complete macroscopic resection of their tumor. Median hospital stay for surgery was 13 days (range: 7–32 days). Nine patients had an abdominoperineal resection with a permanent colostomy. A low anterior resection with colorectal or coloanal anastomosis was carried out for the other patients. In patients with anterior resection, no definitive stoma was needed. All patients considered their sphincter function as acceptable.
The following postsurgical morbidities were observed: pelvic abscess or collection (n = 5), suture dehiscence (n = 2), cutaneous infection (n = 1), small intestine occlusion (n = 1), hemoperitoneum (n = 1), reconstructed J-pouch reservoir necrosis (n = 1), and urethral breach (n = 1). A second surgical procedure was necessary in five patients (two suture dehiscence, one J-pouch reservoir necrosis, one pelvic abscess, and one small intestinal occlusion). In addition, one patient had a pulmonary embolism treated medically.
follow-up
Although the median follow-up of 9 months is still short (range: 1–20 months), no additional long-term complications have been recorded to date.
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discussion |
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The recommended dose of capecitabine concurrent with radiotherapy for the preoperative treatment of rectal adenocarcinoma is 825 mg/m2 twice daily. Our study demonstrates that this dose can be safely administered when cetuximab is added to this regimen and results in tumor downstaging in some patients.
The safety profile of capecitabine and cetuximab was found to be favorable and treatment-related toxicity manageable in most patients. Diarrhea (15%) was the most frequent grade 3 toxicity and seems to be slightly more frequent than in other trials using capecitabine and radiotherapy without cetuximab (<5%) [18, 30, 31]. One patient died of pulmonary infection but it is unlikely that this event was related to the neo-adjuvant treatment, although we must remain prudent. We observed two grade 4 vascular events: one pulmonary embolism and one myocardial infarction. Recently, addition of gefitinib, another EGFR inhibitor, to capecitabine (650 mg/m2 twice daily) and radiotherapy in patients with localized rectal and pancreatic cancer was found to be associated with significant toxicity, in particular diarrhea and arterial thrombi [32]. Whether EGFR inhibition in combination with radiation therapy and capecitabine increases the risk of these events will have to be carefully examined in future trials. In contrast, acneiform rash (87%) and allergic reaction (2.5%) were attributed to cetuximab but were similar in frequency compared with other studies [22].
In our study, cetuximab did not seem to increase the pCR (5%, confidence interval: 2% to 20%) obtained with capecitabine and radiotherapy, although some patients experienced T/N tumor downstaging as well as tumor regression according to the criteria of Wheeler and/or Dworak [18, 28, 29, 31, 33, 34]. In another very preliminary report, pCR was obtained in 12% of patients treated with a regimen combining 5-FU, cetuximab, and preoperative radiotherapy [35]. In addition, while pathological response is a good end point to evaluate the efficacy of preoperative regimens, results are highly dependent on the pretreatment status of the patient, the processing of the pathological specimen, the definition of viable tumor cells, and the motivation of the pathologist to find residual tumor cells. These limitations make it difficult to compare results of published phase II trials. In this context, we believe that a central review by experienced pathologists, as we carried out in our study, is necessary. Moreover, the impact of the radiation dose on pathological response is unknown: we gave 45 Gy, which is 10% lower than the dose (50.4 Gy) tested in the phase I study of Dunst et al. [18]. So, additional phase II trials with a larger number of patients are needed to better characterize the pCR rate of this novel regimen. Interestingly, combination of cetuximab and capecitabine with irinotecan or oxaliplatin is also under investigation in association with radiation therapy in the preoperative treatment of locally advanced rectal cancer [36, 37].
The addition of 5-FU and leucovorin to preoperative radiation was not associated with an increase in DFS or OS and the distant relapse rate remained high (30%) despite locoregional control being improved by the addition of chemotherapy [38, 39]. Some pathological parameters after preoperative chemoradiation including T and N staging, tumor regression grading, and circumferential resection margin involvement have been correlated with DFS [40, 41]. This indicates that if new multimodal treatment regimens are able to improve the pathological response, the outcome for these patients could be better. In recent years, new and/or more efficient chemotherapeutic agents as well as targeted therapies have been developed to treat patients with metastatic colorectal cancer. The role of these agents is now under intense investigation [42, 43, 44, 45, 46, 47]. Some reports have suggested that EGFR expression resulted in worse prognosis for patients with rectal cancer treated with preoperative radiotherapy and was associated with an increased risk of locoregional relapse [48, 49]. In this context, integration of EGFR inhibitors seems particularly appealing.
In conclusion, preoperative radiotherapy in combination with capecitabine and cetuximab is feasible and well tolerated in rectal cancer patients. Additional studies are being undertaken to better define the efficacy of this new chemoradiation regimen.
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The authors are grateful to Tom Boterberg (Radiation Department, UZ Gent), Draguet (Department of Pathology, Loverval), Cuvelier (Department of Pathology, UZ Gent), Geboes and Ectors (Department of Pathology, Gasthuisberg), and Delos (Department of Pathology, Mont-Godinne, UCL). This work was supported by a grant from the Belgian Foundation Against Cancer (2005). Preliminary results of this work have been presented at the American Society of Clinical Oncology 2006 (poster).
Received for publication October 21, 2006. Revision received November 5, 2006. Accepted for publication November 7, 2006.
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References |
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