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© 2003 American Society for Clinical Oncology Phase I/II Trial of Capecitabine, Oxaliplatin, and Radiation for Rectal Cancer
From the Departments of Radiation Therapy and Surgery and Institute of Pathology, University of Erlangen, Erlangen; and Department of Internal Medicine and Hematology/Oncology, University of Halle-Wittenberg, Halle, Germany. Address reprint requests to Claus Rödel, MD, Department of Radiotherapy, University of Erlangen, Universitätsstr 27, 91054 Erlangen, Germany; email: claus.roedel{at}strahlen.med.uni-erlangen.de.
Purpose: The purpose of this study was to establish the feasibility and efficacy of preoperative radiotherapy (RT) with concurrent capecitabine and oxaliplatin (XELOX-RT) in patients with rectal cancer. Patients and Methods: Thirty-two patients with locally advanced (T3/T4) or low-lying rectal cancer received preoperative RT (total dose, 50.4 Gy). Capecitabine was administered concurrently at 825 mg/m2 bid on days 1 to 14 and 22 to 35, with oxaliplatin starting at 50 mg/m2 on days 1, 8, 22, and 29 with planned escalation steps of 10 mg/m2. End points of the phase II study included downstaging, histopathologic tumor regression, resectability of T4 disease, and sphincter preservation in patients with low-lying tumors.
Results: Dose-limiting grade 3 gastrointestinal toxicity was observed in two of six patients treated with 60 mg/m2 of oxaliplatin. Thus, 50 mg/m2 was the recommended dose for the phase II study. Toxicities observed at this dose level were generally mild, with only two cases of short-lived grade 3 diarrhea. Myelosuppression, mainly leukopenia, was restricted to grade 2 in 19% of patients. T-category downstaging was achieved in 17 (55%) of 31 operated patients, and 68% of patients had negative lymph nodes. Pathologic complete response was found in 19% of the resected specimens. Radical surgery with free margins could be performed in 79% of patients with T4 disease, and 36% of patients with tumors Conclusion: Preoperative XELOX-RT is a feasible and well tolerated treatment. This regimen is proposed for phase III evaluation comparing standard fluorouracil-based therapy with XELOX chemoradiotherapy.
ADVANCES IN surgery together with pre- or postoperative radiotherapy (RT) have markedly improved local control in patients with rectal cancer. Now that local relapse rates above 10% to 15% are no longer acceptable, the current aim is to enhance systemic control and improve quality of life by more conservative surgery. Although the use of preoperative chemotherapy and RT schedules for resectable rectal cancer remains a controversial issue, ongoing randomized trials suggest that preoperative chemoradiation is clearly indicated when maximal tumor shrinkage is required before surgery, that is, in locally advanced T4 disease and low-lying tumors when sphincter preservation is attempted.1,2 The high risk for developing distant disease, particularly in subgroups of rectal cancer with extended lymph node involvement, provides further support for the use of systemically more active chemotherapy. Although attempts to improve the efficacy of fluorouracil (FU)-based chemoradiation by incorporation of semustine3 or FU modulation through the addition of leucovorin or levamisole have failed to demonstrate any significant benefit,4 continuous infusion of FU during RT has been shown to be superior to bolus FU in terms of disease-free and overall survival.5 Capecitabine is an oral fluoropyrimidine that mimics the pharmacokinetics of continuous FU infusion and is preferentially converted to the active FU metabolite within tumor cells by exploiting the higher activity of the enzyme thymidine phosphorylase in tumor tissue compared with normal tissue.6 This tumor-selective activation of capecitabine might be improved further when combined with RT, which upregulates thymidine phosphorylase in tumor cells but not in healthy tissue.7 Two phase I studies have been conducted to determine the maximum-tolerated dose (MTD) of capecitabine in combination with RT in patients with rectal cancer.8,9 Capecitabine plus RT demonstrated promising activity in the first study, including one pathologic complete remission (pCR) and nine partial responses in the 10 patients treated in the neoadjuvant setting.8 Furthermore, no grade 3 or 4 toxicities occurred in patients treated at the recommended dose (continuous capecitabine, 825 mg/m2 twice daily, in combination with RT). In a second study, the MTD of capecitabine was reached at a dose level of 1,000 mg/m2 twice daily on Monday to Friday throughout the course of preoperative RT for patients with locally advanced rectal cancer.9 Oxaliplatin is also a reasonable candidate for inclusion into neoadjuvant downsizing regimens because of its rapid cytoreductive capacity and its relative lack of acute dose-limiting side effects when added to FU or capecitabine. Two randomized phase III trials have demonstrated the superiority of combined oxaliplatin and FU/leucovorin compared with FU/leucovorin alone in metastatic colorectal disease.10,11 As a preoperative regimen for initially unresectable liver metastases, the combination of oxaliplatin and FU/leucovorin resulted in tumor downsizing in 59% of patients and in a complete resection rate of 38%.12 Moreover, recent in vitro and in vivo preclinical and clinical studies have demonstrated oxaliplatin to be a potent radiosensitizing agent.13 Available data from phase I and II trials with capecitabine and oxaliplatin in metastatic colorectal disease established a 21-day treatment cycle of oral capecitabine, 1,000 to 1,250 mg/m2 bid on days 1 to 14, in combination with oxaliplatin, 130 mg/m2 administered on day 1.14,15 The aim of our phase I study was to determine the MTD of oxaliplatin when administered with capecitabine 825 mg/m2 bid on days 1 to 14 and 22 to 35 of preoperative RT. To exploit the radiosensitizing properties of oxaliplatin, this latter drug was administered weekly (on days 1, 8, 22, and 29) during the fortnightly capecitabine schedule. In a subsequent phase II trial, we investigated the efficacy and safety of preoperative RT with concurrent capecitabine and oxaliplatin (XELOX-RT) in terms of resectability of T4 rectal cancer, rate of sphincter-sparing surgery, and the histopathologically determined response rates achieved by this intensified chemoradiation regimen.
We performed this study according to the principles of the Declaration of Helsinki (amended in Edinburgh, Scotland, October 2000). The institutional review board approved the protocol in October 2001 (protocol no. 2528, Erlangen University Hospital Ethics Committee). Each patient gave written informed consent before being recruited.
Eligibility Criteria Patients were excluded if they had prior RT to the pelvic region or previous cytotoxic chemotherapy or if they had other synchronous cancers. Patients suffering from the following conditions were also ineligible: inflammatory bowel disease, malabsorption syndrome, ischemic heart disease, peripheral neuropathy, and psychiatric disorders or psychologic disabilities thought to adversely affect treatment compliance. In addition, pregnant or lactating patients and women with childbearing potential who lacked effective contraception were excluded.
Pretreatment Evaluation
RT
Chemotherapy
The following recommendations for chemotherapy dose reductions were applied. In patients who experienced grade 3 toxicity, according to National Cancer Institute common toxicity criteria,17 capecitabine and oxaliplatin treatment was interrupted, and appropriate symptomatic and prophylactic treatment was administered. When the toxicity resolved to grade 0 or 1, treatment was continued at 75% of the original dose at the first appearance of the respective toxicity and at 50% of the starting dose at the second appearance. In patients who experienced grade 2 hand-foot syndrome, capecitabine was reduced to 50% of the original dose, and it was stopped in patients who had grade 3 toxicity until this side effect resolved to grade  2. Capecitabine was then restarted at 50% of the original dose. In patients who developed grade 2 and 3 sensory neuropathy, oxaliplatin was withheld until recovery to grade 1 and then restarted at 75% of the original dose (after grade 2) and 50% of the dose (after grade 3). If the total WBC count was 3.0 x 109/L, 2.5 x 109/L, or 2.0 x 109/L at the beginning of the second chemotherapy cycle, oxaliplatin and capecitabine doses were reduced to 75%, 50%, and 0%, respectively, of the starting doses.
We did not modify the RT schedule for grade
Surgery
Histopathologic Assessment of Response to Chemoradiotherapy
Study Design, Definitions, and End Points
DLTs were defined as the occurrence of one or more of the following: grade 4 neutropenia, grade 4 hyperbilirubinemia, grade 4 nausea/vomiting, grade 3 neutropenic fever, grade 3 thrombocytopenia, hemorrhage, anemia, severe infection requiring hospitalization, grade 3 shift in liver transaminases, grade 3 stomatitis, grade 3 diarrhea or grade 3 hand-foot syndrome (neither resolving to grade
A total of 32 patients were accrued onto the study between July 2001 and September 2002. Baseline patient and tumor characteristics are listed in Table 1  . The median distance of the lower pole of the primary tumor to the dentate line was 2.8 cm for all patients; in 22 patients, this distance was 2 cm.
Dose Escalation and DLTs Three patients were treated at the lowest dose level of oxaliplatin (50 mg/m2/d) with no DLTs observed. When the oxaliplatin dose was escalated to 60 mg/m2, a 55-year-old female with recurrent disease presented with profuse grade 3 diarrhea and grade 2 vomiting associated with dehydration and asthenia during the second cycle of chemotherapy on day 30. In this patient, further chemotherapy was omitted and RT stopped at 41.4 Gy. She recovered after hospitalization and parenteral support without further complications within 2 weeks. For this reason, a total of six patients were included at the 60 mg/m2 oxaliplatin dose level. In the third week of XELOX-RT, a 60-year-old female with a primary T4 tumor developed grade 3 diarrhea together with fever (38.5°C), an increase of laboratory infection parameters (C-reactive protein), and radiographic signs of a paralytic ileus, requiring parenteral support and intravenous antibiotics. In this patient, the second cycle of chemotherapy was omitted, but RT was continued to a total dose of 45 Gy. Thus, two of six patients at the second oxaliplatin dose level experienced DLTs. Consequently, oxaliplatin dose escalation was stopped at 60 mg/m2, and six additional patients were treated at the lower dose level (50 mg/m2). No National Cancer Institute common toxicity criteria grade 3 toxicity was observed in these patients, and therefore, all subsequent patients were treated with this recommended oxaliplatin dose during the phase II study.
Toxicity and Compliance With the Regimen
Hematologic toxicity did not exceed grade 2 leukopenia. At the 60-mg/m2 oxaliplatin dose level, WBC counts at the start of the second cycle of chemotherapy were 2.6 x 109/L in one patient and 2.3 x 109/L in another patient, and consequently, the doses of both chemotherapeutic agents were reduced to 75% and 50% of the starting dose, respectively. For all other patients, the leukocyte nadir (median, 3.4 x 109/L; range, 2.6 to 4.2 x 109/L) only occurred during the last week or within 1 week after completion of XELOX-RT. No dose adjustments, blood transfusions, or granulocyte colony-stimulating factors were necessary. Apart from the two patients with DLTs mentioned previously, all patients received the full course of RT, with a total dose of 50.4 Gy. Thus, with concomitant oxaliplatin at a dose of 50 mg/m2, compliance with RT and chemotherapy was 100% and 89%, respectively (one patient with angina pectoris did not receive capecitabine for the second cycle; and in two patients with grade 3 diarrhea, capecitabine was withheld for 3 days and then restarted at 75% of the original dose).
Efficacy
Table 3
Surgical Morbidity Twelve patients (39%) experienced postoperative complications. Five patients (16%) had a delay in wound healing because of infection or dehiscence, none of whom required additional surgery. Two patients (6%) with radiographic signs of anastomotic leakage were treated conservatively. One patient (3%) with an anastomotic leakage developed a presacral abscess that required percutaneous drainage; one internal postoperative hemorrhage was controlled by surgical re-operation. Other surgical morbidity included bowel (n = 2) and bladder dysfunction (n = 1). No intra- or postoperative deaths occurred.
If the goal of preoperative chemoradiation is to maximize tumor shrinkage before surgery and to improve systemic control, chemotherapy schedules should be as dense as possible (ie, applied concomitantly and as often as possible during RT), to maximize local effectiveness by radiation sensitization, and as intense as possible, to eradicate microscopic distant disease. Freyer et al19 have recently published results from a phase I study of RT plus oxaliplatin and FU/leucovorin that demonstrate the feasibility of such an intensified chemotherapy regimen when given concomitantly with RT. For historical reasons, chemotherapy was administered only in the first and fifth week of RT in this study; using escalating doses of oxaliplatin (80, 100, or 130 mg/m2 on days 1 and 29), FU (350 mg/m2 on days 1 to 5 and 29 to 33), and leucovorin (100 mg/m2 on days 1 to 5 and 29 to 33), the MTD was not reached. Dunst et al8 have demonstrated, in a phase I trial, the feasibility and good tolerability of continuous capecitabine chemotherapy during a conventional RT period of approximately 6 weeks. The DLT in this study was grade 3 hand-foot syndrome at a capecitabine dose of 1,000 mg/m2 bid; consequently, the recommended dose of capecitabine in this setting was 825 mg/m2 bid. Our study is the first report of a combination of capecitabine and oxaliplatin given concomitantly with preoperative RT, apart from a 7-day break during the third week of RT, which was included on the basis of available data from phase I and II trials with oxaliplatin and capecitabine in metastatic colorectal disease.14,15 The objective of the phase I part of our study was to determine the DLTs of escalated oxaliplatin doses when combined with fixed doses of capecitabine and preoperative RT. According to the strict safety criteria of our study, gastrointestinal DLT occurred at an oxaliplatin dose level of 60 mg/m2 administered on days 1, 8, 22, and 29. Therefore, the recommended oxaliplatin dose for the phase II trial was 50 mg/m2, yielding a cumulative dose of 200 mg/m2. This cumulative dose of oxaliplatin is somewhat lower than the cumulative dose reached in the phase I study by Freyer et al19 in which oxaliplatin was administered on days 1 and 29 only. It is possible that the radiosensitizing properties of oxaliplatin might cause more acute gastrointestinal side effects when administered at lower but more frequent doses than in the established first- and fifth-week schedule of RT. It is noteworthy that other immediate toxicities, especially hand-foot syndrome and sensory neuropathy, were minimal in this trial because of the short duration of oxaliplatin and capecitabine treatment, which is also reflected in the 89% compliance rate during the phase II part of our study. Moreover, gastrointestinal DLT only occurred in two patients with largely extended pelvic disease that necessitated more extended pelvic RT fields to cover a diffuse pelvic relapse in one patient and a primary T4 tumor in the other. The surgical morbidity of this new regimen seems acceptable, with no deaths occurring during the 60 days after surgery, one patient requiring re-operation for hemorrhage, and 16% of patients having delay in wound healing. These figures are in line with our prior experiences of preoperative RT and concomitant FU chemotherapy in T4 rectal cancer.20 Interestingly, Aschele et al21 have recently reported the feasibility of an even more intense preoperative chemoradiation regimen in which oxaliplatin is administered at a dose of 60 mg/m2 weekly for six cycles together with FU 225 mg/m2/d as a continuous infusion during the whole course of RT (50.4 Gy/28 fractions). In this trial, no grade 4 toxicity was observed, although five (13%) of 39 patients experienced grade 3 diarrhea and 25 patients (64%) complained of grade 1/2 neurotoxicity.
The primary end points of the phase II part of our trial were the histopathologic resection rate, the pCR rate, and the pathologic downstaging rate, with the ultimate goal of being to enable curative surgery in T4 disease and sphincter preservation in low-lying tumors. Tumor downstaging with respect to the T category was achieved in 17 (55%) of 31 operated patients, and 68% of patients had negative lymph nodes. Radical surgery with negative margins (R0) could be performed in 85% of patients with clinical T4 disease. XELOX-RT led to significant tumor shrinkage and enabled sphincter-saving surgery in 36% of patients with tumors located Given the fact that, within a multimodality concept, any component, including staging procedures and individual surgeon’s preferences, might have a considerable impact on these different end points, direct comparison between studies using different chemotherapy schedules is difficult. Therefore, to further evaluate the impact of our intensified XELOX-RT regimen, we used a standardized pathologic assessment and regression grading system to evaluate the biologic response of the tumor. Complete regression was found in 19% of the resected specimens. We compared these figures to the preoperative chemoradiation arm of the CAO/ARO/AIO-94 German Rectal Cancer Trial, which randomly assigned patients with resectable rectal cancer to receive standard adjuvant versus neoadjuvant chemoradiation.2,22 Apart from the chemotherapy regimen (in CAO/ARO/AIO-94: FU 1,000 mg/m2 for 5 days during the first and fifth week of RT) and the stages entered (more locally advanced T4 rectal cancer in the XELOX-RT study), surgery, RT, and pathologic work-up were identical in both studies. Complete regression in the CAO/ARO/AIO-94 protocol was limited to 9% of 277 assessable patients. Notwithstanding the limitations of a nonrandomized comparison, the doubling of the pCR rate observed in our study might indicate a substantially enhanced tumor-cell eradication by the intensified XELOX-RT regimen. Combined FU-based chemoradiation remains the standard postoperative therapy for patients with stage II and III rectal cancer in the United States and in Germany.23,24 The basic issue of timing of chemoradiation (preoperative v postoperative) is currently being addressed in the prospective trial of the German Rectal Cancer Group (CAO/AIO/ARO-94). Preliminary data from this trial indicate a reduction in acute toxicity and a higher rate of sphincter-sparing surgery in the preoperative chemoradiation arm.2,22 Final results with respect to local and distant failure are expected to be published in mid 2003. If the results indicate that preoperative chemoradiation is superior to adjuvant chemoradiation, the standard treatment recommendations may need to be reconsidered. Our future plans are to compare the best arm of the CAO/ARO/AIO-94 protocol with an intensified chemoradiation regimen using capecitabine plus oxaliplatin. The treatment schedule developed in this phase I/II trial may then be incorporated into subsequent trials.
Supported in part by a grant from Hoffmann-La Roche AG, Grenzach-Wyhlen, Germany, and Sanofi-Synthelabo GmbH, Berlin, Germany.
1. Bosset JF, Pavy JJ, Bolla M, et al: Four arms phase III clinical trial for T3-T4 resectable rectal cancer comparing preoperative pelvic irradiation to preoperative irradiation combined with fluorouracil and leucovorin, with or without postoperative adjuvant chemotherapy. EORTC Radiotherapy Cooperative Group. Protocol no. 22921. Brussels, Belgium, EORTC Datacenter, October 1992 2. Sauer R, Fietkau R, Wittekind C, et al: Adjuvant versus neoadjuvant radiochemotherapy for locally advanced rectal cancer: A progress report of a phase-III randomized trial (protocol CAO/ARO/AIO-94). Strahlenther Onkol 177:173–181, 2001[CrossRef][Medline]
3. Gastrointestinal Tumor Study Group: Radiation therapy and fluorouracil with or without semustine for the treatment of patients with surgical adjuvant adenocarcinoma of the rectum. J Clin Oncol 10:549–557, 1992
4. Tepper JE, O’Connell M, Niedzwiecki D, et al: Adjuvant therapy in rectal cancer: Analysis of stage, sex, and local control—Final report of Intergroup 0114. J Clin Oncol 20:1744–1750, 2002
5. O’Connell MJ, Martenson JA, Wieand HS, et al: Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 331:502–507, 1994 6. Schüller J, Cassidy J, Dumont E, et al: Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 45:291–297, 2000[CrossRef][Medline]
7. Sawada N, Ishikawa T, Sekiguchi F, et al: X-ray irradiation induces thymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) in human cancer xenografts. Clin Cancer Res 5:2948–2953, 1999
8. Dunst J, Reese T, Sutter T, et al: Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer. J Clin Oncol 20:3983–3991, 2002
9. Zalcberg J, Ngan S, Michael M, et al: Observed toxicities in a phase I study of preoperative radiotherapy combined with capecitabine for locally advanced, potentially resectable rectal cancer. Ann Oncol 13:81, 2002 (abstr)
10. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947, 2000
11. Giacchetti S, Perpoint B, Zidani R, et al: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18:136–147, 2000
12. Giacchetti S, Itzhaki M, Gruia G, et al: Long-term survival of patients with unresectable colorectal liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 10:663–669, 1999 13. Cividalli A, Ceciarelli F, Livdi E, et al: Radiosensitization by oxaliplatin in a mouse adenocarcinoma: Influence of treatment schedule. Int J Radiat Oncol Biol Phys 52:1092–1098, 2002[CrossRef][Medline]
14. Diaz-Rubio E, Evans TR, Tabernero J, et al: Capecitabine (Xeloda) in combination with oxaliplatin: A phase I, dose-escalation study in patients with advanced or metastatic solid tumors. Ann Oncol 13:558–565, 2002
15. Borner MM, Dietrich D, Stupp R, et al: Phase II study of capecitabine and oxaliplatin in first- and second-line treatment of advanced or metastatic colorectal cancer. J Clin Oncol 20:1759–1766, 2002 16. Green FL, Balch CM, Fleming ID, et al (eds): AJCC Cancer Staging Manual: TNM Classification of Malignant Tumors (ed 6). New York, NY, Springer, 2002 17. Trotti A, Byhardt R, Stetz J, et al: Common toxicity criteria: Version 2.0—An improved reference for grading the acute effects of cancer treatment: Impact on radiotherapy. Int J Radiat Oncol Biol Phys 47:13–47, 2000[CrossRef][Medline] 18. Dworak O, Keilholz L, Hoffmann A: Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 12:19–23, 1997[CrossRef][Medline]
19. Freyer G, Bossard N, Romestaing P, et al: Addition of oxaliplatin to continuous fluorouracil, l-folinic acid, and concomitant radiotherapy in rectal cancer: The Lyon R 97-03 phase I trial. J Clin Oncol 19:2433–2438, 2001 20. Rödel C, Grabenbauer GG, Schick C, et al: Preoperative radiation with concurrent 5-fluorouracil for locally advanced T4-primary rectal cancer. Strahlenther Onkol 176:161–167, 2000[CrossRef][Medline] 21. Aschele C, Friso ML, Pucciarelli S, et al: A phase I–II study of weekly oxaliplatin (OXA), 5-fluorouracil (FU) continuous infusion (CI) and preoperative radiotherapy (RT) in locally advanced rectal cancer (LARC). Onkologie 25:25, 2002 (abstr 527)[Medline] 22. Sauer R, Rödel C, Fietkau R, et al: Phase III trial: Adjuvant versus neoadjuvant radiochemotherapy for locally advanced rectal cancer. Strahlenther Onkol 178:12, 2002 (abstr V6-Z)
23. NIH Consensus Conference: Adjuvant therapy for patients with colon and rectal cancer. JAMA 264:1444–1450, 1990 24. Junginger T, Hossfeld DK, Sauer R, et al: Adjuvante Therapie bei Kolon-und Rektumkarzinom. Dtsch Ärztebl 96:A698–700, 1999 Submitted February 21, 2003; accepted May 16, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2.5 x 109/L, platelet count 
