Phase I trial of cetuximab in combination with capecitabine, weekly irinotecan, and radiotherapy as neoadjuvant therapy for rectal cancer

doi:10.1016/j.ijrobp.2006.07.005

International Journal of Radiation OncologyBiologyPhysics

Volume 66, Issue 5, 1 December 2006, Pages 1384-1390

https://doi.org/10.1016/j.ijrobp.2006.07.005 Get rights and content

Purpose: To establish the feasibility and efficacy of chemotherapy with capecitabine, weekly irinotecan, cetuximab, and pelvic radiotherapy for patients with locally advanced rectal cancer.

Methods and materials: Twenty patients with rectal cancer (clinical Stage uT3-T4 or N+) received a standard dosing regimen of cetuximab (400 mg/m² on Day 1 and 250 mg/m² on Days 8, 15, 22, and 29) and escalating doses of irinotecan and capecitabine according to phase I methods: dose level I, irinotecan 40 mg/m² on Days 1, 8, 15, 22, and 29 and capecitabine 800 mg/m² on Days 1–38; dose level II, irinotecan 40 mg/m² and capecitabine 1000 mg/m²; and dose level III, irinotecan 50 mg/m² and capecitabine 1000 mg/m². Radiotherapy was given to a dose of 50.4 Gy (45 Gy plus 5.4 Gy). Resection was scheduled 4–5 weeks after termination of chemoradiotherapy.

Results: On dose level I, no dose-limiting toxicities occurred; however, Grade 3 diarrhea affected 1 of 6 patients on dose level II. Of 5 patients treated at dose level III, 2 exhibited dose-limiting toxicity (diarrhea in 2 and nausea/vomiting in 1). Therefore, dose level II was determined as the recommended dose for future studies. A total of 10 patients were treated on dose level II and received a mean relative dose intensity of 100% of cetuximab, 94% of irinotecan, and 95% of capecitabine. All patients underwent surgery. Five patients had a pathologically complete remission and six had microfoci of residual tumor only.

Conclusion: Preoperative chemoradiotherapy with cetuximab, capecitabine, and weekly irinotecan is feasible and well tolerated. The preliminary efficacy is very promising. Larger phase II trials are ongoing.

Introduction

Advances in surgery, including total mesorectal excision, have significantly improved the prognosis of patients with rectal cancer. Nevertheless, despite optimized surgery, preoperative radiotherapy (RT) can further reduce local recurrence rates (1). The German Rectal Cancer Trial (CAO/AIO/ARO-94) established the neoadjuvant approach as the new standard of care, given its superiority with respect to local failure rates and toxicity (2). Moreover, the European Organization for Research and Treatment of Cancer 22921 and Fédératon Francophone de Cancérologie Digestive (FFCD) 9203 trials recently demonstrated that adding 5-fluorouracil (5-FU) to preoperative RT diminishes the rate of local relapse (3, 4).

Although local recurrence appears to be now less of a problem, distant metastasis remains the most common form of treatment failure. In the CAO/AIO/ARO-94 trial, the rate of distant metastases was not influenced by the timing of chemoradiotherapy (2). This raises the question of whether early administration of systemically effective doses of chemotherapy might improve the long-term outcome. Adding modulators such as folinic acid (FA) or levamisole to 5-FU–based chemoradiotherapy did not improve the treatment results (5) nor did the additional use of older cytostatics (e.g., semustine [6]) or prolongation of chemotherapy (7).

It is hoped that the addition of newer drugs to 5-FU–based chemoradiotherapy will lead to optimized results. The feasibility of combinations of 5-FU or its pro-drug capecitabine (Xeloda, Hoffmann-La Roche, Basel, Switzerland) with irinotecan (Campto, Pfizer, Karlsruhe, Germany) during chemoradiotherapy has been demonstrated (8, 9, 10, 11, 12, 13, 14, 15). Irinotecan has radiosensitizing properties (16, 17) and is a standard of care in the first-line treatment of metastatic colorectal cancer (18, 19, 20). In a phase I trial, we established a chemoradiotherapy regimen of capecitabine and irinotecan with conventional RT (CapIri-RT) for the neoadjuvant treatment of rectal cancer (14). The tolerability was good, and promising pathologic complete remission (pCR) rates were observed. These preliminary results were confirmed by a larger phase II study (15). Summarizing the data from the phase II trials (8, 9, 10, 11, 12, 13, 14, 15), the pCR rate achieved by irinotecan/5-FU–based combinations appeared to be at least twice as great as 5-FU–based chemoradiotherapy (about 8% in trials with quality-controlled pathologic evaluations [2]). The pCR rate has been identified as a prognostic factor for patients undergoing neoadjuvant radiochemotherapy for rectal cancer (21, 22). It might therefore serve as a surrogate marker for the efficacy of treatment regimens.

Cetuximab (Erbitux, Merck KGaA, Darmstadt, Germany), an antibody against the epidermal growth factor receptor (EGFR) has been introduced in the treatment of chemotherapy-refractory colorectal cancer (23). Moreover, when added to first-line chemotherapy, the preliminary efficacy parameters were very promising (24).

Overexpression of EGFR is regarded as a negative prognostic factor and is associated with resistance to radiotherapy (25, 26). Therefore, EGFR has emerged as a promising target in radiotherapy. In head-and-neck cancer, the addition of cetuximab to RT resulted in superior outcomes with respect to locoregional failure and survival (27). In retrospective analyses, patients with EGFR-expressing rectal cancer undergoing neoadjuvant RT had significantly lower disease-free survival and lower chance of achieving pCR (28).

In all, a strong rationale exists for combining cetuximab with neoadjuvant chemoradiotherapy for rectal cancer. Currently, published data on such a combination regimen are lacking. We started the present phase I trial to define a suitable dosing regimen for CapIri-RT in combination with cetuximab.

Section snippets

Methods and materials

The institutional review board reviewed and approved the protocol, and the study was performed in accordance with the Declaration of Helsinki. All patients provided written informed consent.

Results

We entered 20 patients into this single-center trial between December 2004 and July 2005. The patient characteristics are listed in Table 1. All patients had newly diagnosed rectal adenocarcinoma. The median distance from the lower border of the primary to the anal verge was 7 cm.

Discussion

Combined modality treatment with 5-FU and pelvic RT, as well as surgery, are the cornerstones of treatment of locally advanced rectal cancer. Preoperative 5-FU–based chemoradiotherapy resulted in an improved local control rate and a significantly lower rate of toxicity compared with postoperative treatment (2). Nevertheless, no differences in the rates of distant metastases were observed. This highlights the need for more effective perioperative systemic treatment.

With regard to the

Conclusion

A safe dosing regimen for cetuximab combined with the CapIri-RT regimen was established. Promising response rates were observed, and surgical morbidity was not different from that of our experience with CapIri-RT. A strong rationale exists to study cetuximab combined with chemoradiotherapy in rectal cancer further.

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Clinical investigationRectumPhase I trial of cetuximab in combination with capecitabine, weekly irinotecan, and radiotherapy as neoadjuvant therapy for rectal cancer

Introduction

Section snippets

Methods and materials

Results

Discussion

Conclusion

Int J Radiat Oncol Biol Phys

Radiother Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer

N Engl J Med

Preoperative versus postoperative chemoradiotherapy for rectal cancer

N Engl J Med

Preoperative radiation (Preop RT) in rectal cancer: Effect and timing of additional chemotherapy (CT)5-Year results of the EORTC 22921 trial

Proc Am Soc Clin Oncol

Preoperative (preop) radiotherapy (RT) +/- 5-FU/folinic acid (FA) in T3-4 rectal cancers: Results of the FFCD 9203 trial

Proc Am Soc Clin Oncol

Adjuvant therapy in rectal cancer: Analysis of stage, sex, and local control—Final report of Intergroup 0114

J Clin Oncol

Improving adjuvant therapy by combining protracted infusion fluorouracil with radiation therapy after curative surgery

N Engl J Med

Adjuvant radio-chemotherapy with 5-fluorouracil and folinic acid in stage II and III rectal cancer: 12 vs. 6 months of therapy

Onkologie

Randomized phase II study of neoadjuvant combined-modality chemoradiation for distal rectal cancer: Radiation Therapy Oncology Group Trial 0012

J Clin Oncol

Irinotecan, 5-FU and radiotherapy in locally advanced inoperable rectal cancer

Proc Am Soc Clin Oncol

Continuous infusion of 5-FU and weekly irinotecan with concurrent radiotherapy as neoadjuvant treatment for locally advanced or recurrent rectal cancer

Br J Cancer

Concurrent chemoradiation with capecitabine and weekly irinotecan as preoperative treatment for rectal cancer: Results from a phase I/II study

Br J Cancer

Phase I study of capecitabine plus weekly irinotecan (CAPIRI) plus radiotherapy as preoperative downstaging treatment for locally advanced rectal cancer (LARC)

Proc Am Soc Clin Oncol

Phase I trial of capecitabine and weekly irinotecan in combination with radiotherapy for neoadjuvant therapy of rectal cancer

J Clin Oncol

Phase II trial of capecitabine and irinotecan in combination with concurrent radiotherapy for neoadjuvant treatment of locally advanced rectal cancer

Proc Am Soc Clin Oncol

Irinotecan in preoperative combined-modality therapy for locally advanced rectal cancer

Oncology (Huntingt)

Clinical investigation
Rectum
Phase I trial of cetuximab in combination with capecitabine, weekly irinotecan, and radiotherapy as neoadjuvant therapy for rectal cancer