1 Clinique des Pathologies Tumorales du Colon et du Rectum, Centre du Cancer, Université Catholique de Louvain, Brussels; 2 Service d'Oncologie et de Radiothérapie, Hôpital St-Joseph, Gilly; 3 Service de Gastroentérologie, Clinique St-Pierre, Ottignies; 4 Service d'Oncologie, Cliniques Universitaires de Mont-Godinne (UCL) and Clinique St-Elisabeth, Namur; 5 Service de Radiothérapie, Clinique St-Elisabeth, Namur; 6 Service d'Oncologie, Clinique Notre-Dame, Charleroi; 7 Service de Gastroentérologie, Clinique Saint-Jean, Brussels; 8 Service de Radiothérapie, Hôpital de Jolimont, Haine-St-Paul; 9 Service de Radiothérapie, 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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Patients and methods: Forty patients with rectal cancer (T3T4 and/or N+) received radiotherapy (1.8 Gy, 5 days a week over 5 weeks, total dose 45 Gy, 3D conformational technique) in combination with intravenous oxaliplatin 50 mg/m2 once weekly for 5 weeks and oral capecitabine 825 mg/m2 twice daily on each day of radiation. Surgery was performed 68 weeks after completion of radiotherapy. The main end points were safety and efficacy as assessed by the pathological complete response (pCR).
Results: The most frequent grade 3/4 adverse event was diarrhea, occurring in 30% of patients. pCR was found in five (14%) patients. According to Dworak's classification, good regression was found in six (18%) additional patients.
Conclusions: Combination of preoperative radiotherapy with capecitabine and oxaliplatin is feasible for downstaging rectal cancer.
Key words: capecitabine, oxaliplatin, preoperative, radiotherapy, rectal cancer
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Introduction |
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Studies are now trying to increase the local control rate as well as survival by improving radiation sensitization and by identifying the optimal chemoradiation regimens. Capecitabine and oxaliplatin are both highly active in colorectal cancer and have radiosensitizing properties. Therefore, these drugs would be expected to improve effectiveness of preoperative radiotherapy in terms of local control and 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 [14]. Therefore, capecitabine may represent a more effective, better tolerated and more convenient alternative to 5-FU as a combination partner for oxaliplatin. A dose-finding study suggested that capecitabine in combination with radiotherapy is safe and active [15
].
Oxaliplatin is a third-generation platinum compound that has shown synergy with fluoropyrimidines in colorectal cancer. Results from the MOSAIC adjuvant study have shown that the addition of oxaliplatin to infusional 5-FU/leucovorin (LV) (FOLFOX-4) improves the disease-free survival of patients with stage II or III colon cancer [16]. FOLFOX-4 as first-line treatment in metastatic colorectal cancer improves response rates and time to disease progression compared with 5-FU/LV alone [17
, 18
]. In a large phase II trial of 96 previously untreated patients, treatment with oxaliplatin (130 mg/m2 intravenously on day 1) plus capecitabine (1000 mg/m2 twice daily on days 114) every 3 weeks led to objective tumor responses in 55% of patients, including two complete and 51 partial responses [19
]. This regimen was convenient to administer and had a safety profile very similar to FOLFOX-4.
Addition of oxaliplatin to continuous 5-FU or capecitabine and concomitant radiotherapy in rectal cancer has been shown to be feasible and active in phase I and II studies [20]. In the study by Rödel et al. [21
], chemoradiation with oxaliplatin and capecitabine was shown to be feasible, effective and well tolerated. A phase I/II study (SOCRATES, Synchronous Oxaliplatin, Capecitabine, Radiotherapy and Elective Surgery) is ongoing to determine the maximum tolerated dose of continuous oral capecitabine administered twice daily in combination with oxaliplatin plus standard pelvic radiotherapy in patients with primary unresectable locally advanced rectal cancer studies [22
].
To further explore the combination of capecitabine and oxaliplatin, we investigated a preoperative chemoradiation regimen including capecitabine and oxaliplatin in patients with rectal cancer. The main end points were safety and efficacy as assessed by the pathological complete response (pCR) rate.
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Patients and methods |
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Exclusion criteria were: prior pelvic irradiation; active second malignancy during the previous 5 years (except non-melanomatous skin cancer or in situ cervical carcinoma); pregnancy and lack of contraception; presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; prior or concurrent evidence of peripheral neuropathy, inflammatory bowel disease, malabsorption syndrome, synchronous colic and rectal tumors, and other uncontrolled severe disease precluding administration of chemotherapy and radiation. Distant metastases were not an exclusion criteria but inclusion of these patients was not recommended since no chemotherapy was allowed between the end of radiotherapy and surgery. The study was approved by the independent ethics committee of each participating center and conducted in accordance with the Declaration of Helsinki (October 2000).
Pretreatment evaluation
Pretreatment examinations had to be performed within 4 weeks before starting treatment and included complete history and physical examination including digital rectal examination, rectoscopy with tumor biopsy, transrectal ultrasound, colonoscopy, chest computed tomography (CT), abdominal and pelvic CT, electrocardiogram, and complete laboratory tests (electrolytes, liver function, creatinine, blood urea nitrogen, creatinine kinase enzyme, complete blood count, dosage of carcinoembryonic antigen, and pregnancy test if indicated). Pelvic MRI was optional.
Radiotherapy
Megavoltage equipment was used with 8 MV as minimal energy. According to the EORTC 22921 protocol, we delivered 45 Gy in 25 fractions (1.8 Gy daily from Monday through Friday, days 133) (Figure 1). Conformational 3D radiotherapy was used for all patients based on a contrast CT scan of the pelvis. CT was performed in the treatment position (strictly), with 5-mm thick slices and a 5-mm spacing between images. The rectum was not opacified with barium in order to avoid contour artifacts. No attempt was made to delineate a gross tumor volume (GTV) as the CT scan does not provide sufficient contrast in the soft tissues for an accurate definition of the tumor size and extension. Only a clinical target volume (CTV) was delineated, encompassing the entire mesorectum, identified after careful exchange with the radiologist, surgeon and anatomist of the Université Catholique de Louvain. Pararectal nodes were also included, together with the presacral and promontory nodes (limit S1/S2), and the internal iliac nodes up to the venous bifurcation. External iliac nodes were not included as they have not been a site for recurrence in our experience. On the contrary, internal pudendal nodes were included in the CTV as it has been a demonstrated site of recurrence in three patients during the previous years, before the trial was designed. The planning target volume (PTV) was an isotropic expansion of the CTV (10 mm). It spared the lower centimeter of the anal canal (which is typically 2.5 cm long). Its shape was typically of an inverted triangle in AP/PA direction and an S shape laterally. A dummy run was organized between radiation oncologists in order to homogenize the learning curve. Organs at risk were also contoured: bladder (with intravenous contrast), small bowel (with oral contrast) and femoral heads. The small bowel was contoured on all CT slices where it could be visualized, which was highly variable among patients. Maximum, mean and median doses were calculated on the relative small bowel dosevolume histogram (DVH). The absolute volume of small bowel irradiated at any dose level was thereafter converted from the relative DVH.
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Surgery and follow-up
Patients underwent radical resection of rectal cancer within 68 weeks after completion of chemoradiation. There was no restriction of the technique used by the surgeons but total mesorectal excision was recommended and performed in all cases. The principles for a covering stoma during surgery were left at the discretion of the surgeon but were the classic ones: malnutrition (loss of >20% of the initial weight), intraoperative features (ischemia, hematoma, bleeding) and liver metastases. Adjuvant chemotherapy with 5-FU/LV was recommended in patients with nodal involvement at surgery. After surgery, all patients were followed every 3 months.
Histopathological assessment of response to chemoradiation
In case of persistence of macroscopic residual tumor, standard pathological examination was performed 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 and 2 cm periphery was examined for residual tumor and deepest invasion in the bowel wall. All lymph nodes were included according to standard procedures and the circumferential resection margin was measured according to Quirke et al. [23]. All the slides of the surgical specimens were reviewed centrally by two different pathologists (C. Sempoux and S. Aydin). The pathologists had to agree for all cases. pCR was defined as the complete disappearance of all tumor cells. In addition, semi-quantitative evaluation of histological regression was performed according to rectal cancer regression grading established by Dworak and colleagues: 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) [24
]. Wheeler's grade was also used: grade 1, sterilization or only microscopic foci of adenocarcinoma remaining with marked fibrosis; grade 2, marked fibrosis but macroscopic disease; grade 3, little or no fibrosis with abundant macroscopic disease [25
].
Study end points
The aims of this study were to determine the histopathological response rate after surgery, and to evaluate the feasibility of this preoperative regimen by determining its safety assessed by National Cancer Institute Common Toxicity Criteria (version 2.0) and the surgical complication rate.
Statistical analysis
The different parameters of each individual patient were entered into a database and analyzed using SPSS statistical software (multivariate logistic regression) to identify variables that might influence the occurrence of adverse events. The multivariate logistic regression included the following variables: age, small intestine irradiated volume (V), mean dose (Gy) per fraction (dose/F) on the irradiated intestine volume, and the value obtained by the product of V multiplied by dose/F. The significance levels were determined by means of the likelihood ratio test.
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Results |
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The relative dose intensities of oxaliplatin and capecitabine in the intention-to-treat population were 85% and 84%, respectively. The main reason for reducing chemotherapy doses was diarrhea, occurring during the fourth or fifth week of treatment. Any decision to delay or interrupt radiotherapy was left to the discretion of the local investigators. Radiation was stopped in two patients owing to diarrhea and suspicion of ileitis (total dose received 37.8 and 39.6 Gy, respectively). Chemoradiation was interrupted during 1 and 4 weeks in two additional patients because of diarrhea; treatment was restarted and the patients received their full dose of radiation.
We tried to identify the parameters associated with grade 3/4 diarrhea. The following variables were studied: age (median 63 years; range 3280), small intestine irradiated volume (V) (median volume 1223 ml; range 03704), mean dose (Gy) per fraction (dose/F) on the irradiated intestine volume (median 0.3 Gy; range 013.3), and the value obtained by the product of V multiplied by dose/F (median 468; range 01328). In the multivariate logistic regression analysis, the only parameter that correlated significantly with grade 3/4 diarrhea was increasing age (P < 0.01). A trend towards a higher rate of diarrhea was observed for the value obtained by the product of the total volume (ml) of small intestine that was irradiated multiplied by the mean dose received (Gy) per fraction on the irradiated small intestine (P = 0.13).
Efficacy
Efficacy was assessed by pathological examination of operative specimens. One patient was excluded from this analysis owing to the discovery of a neuroendocrine tumor on the surgical specimen. Three additional patients were not evaluable for pathological response because they did not undergo surgery (two disease progression and one death). Thirty-six patients were therefore evaluable for pathologic assessment of tumor and nodes (Tables 2 and 3). Pathologic TNM classification showed downstaging compared with preoperative transrectal ultrasound staging in some patients. In addition, pCR was found in five patients (14%).
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Surgery and surgical morbidity
Surgery was performed in all patients except two who had disease progression (appearance of peritoneal carcinomatosis) during chemoradiation. The median time spent in hospital for surgery was 15 days (range 838). Twelve patients had an abdominoperineal resection with a permanent colostomy. A low anterior resection with colorectal or coloanal anastomosis was performed for the other patients. One patient had a right hepatectomy for a unique metastasis at the same time as rectal surgery. In patients with anterior resection, no definitive stoma was needed. Sphincter control was subjectively judged acceptable by each of these patients.
The following post-surgical morbidities were noted: anastomotic fistula (n = 4), pelvic abscess (n = 2), delay in perineal healing (n = 2), cutaneous necrosis (n = 1), ureteral stenosis (n = 1), hemoperitoneum (n = 1) and suture dehiscence (n = 1). A second surgical procedure was necessary in five patients (one suture dehiscence, one hemoperitoneum, one pelvic abscess, and two plastic surgery for cutaneous necrosis and delay in healing). One of the two patients with a pelvic abscess finally developed renal insufficiency, ureteral breach, abdominal collection and peritonitis. He died of these complications 6 months after surgery.
Follow-up
Although the median follow-up is still short (14 months; range 920), no additional long-term complications have been recorded to date. As mentioned earlier, two patients had disease progression with peritoneal carcinomatosis between diagnosis and surgery. Among the 36 patients who are evaluable after chemoradiation and rectal surgery, no local relapses have been observed. Two patients developed distant metastases at 6 and 10 months, respectively.
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Discussion |
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While postoperative chemoradiation is currently used in the USA, preoperative chemoradiation is more often used in Europe. Randomized trials showed that preoperative chemoradiation reduces local recurrence rate and, in selected cases, may allow resection of the primary tumor with a high rate of sphincter preservation [9, 10
]. Randomized trials are ongoing to assess the potential advantage of preoperative chemoradiation (5-FU 350 mg/m2 intravenous bolus plus LV 20 mg/m2/day on days 15 during the first and fifth weeks of radiotherapy) over preoperative radiotherapy alone (EORTC 22921 and Fédération Française de Cancérologie Digestive 9203 trials) [12
]. In recent years, new and/or more efficient chemotherapeutic agents have been developed to treat patients with metastatic colorectal cancer. The use of the following agents in chemoradiation regimens is under intense investigation: capecitabine, oxaliplatin, irinotecan, UFT (uracil and tegafur) and raltitrexed [15
, 21
, 22
, 26
36
].
A recommended preoperative chemoradiation regimen for rectal cancer is capecitabine 825 mg/m2 twice daily on days 114 and 2235 plus oxaliplatin 50 mg/m2 on days 1, 8, 22 and 29 given concurrently with radiotherapy (total dose 50.4 Gy) [21]. We used a weekly schedule of oxaliplatin to reduce the toxic effect of this drug and try to maximize its radiosensitizing properties. In the first step of the study, we did not observe any grade 3/4 adverse events and so we proceeded to the planned accrual. The most frequent adverse event was diarrhea, generally occurring in the fourth or fifth week of chemoradiation. Diarrhea was usually easy to manage with dose interruption and, if necessary, dose reduction with rehydration and supportive care as appropriate. However, diarrhea seemed to occur more frequently than with previously described chemoradiation regimens including oxaliplatin. In other studies, the rate of grade 3/4 diarrhea ranged from 6% to 33% when oxaliplatin was combined with capecitabine or 5-FU (Table 4). Rödel et al. [21
] found a 33% (two of six patients) rate of grade 3 diarrhea when oxaliplatin (60 mg/m2 on days 1, 8, 22 and 29) was given in combination with capecitabine (825 mg/m2 twice daily on days 114 and 2235) and radiation therapy (total dose 50.4 Gy). They subsequently decreased the oxaliplatin dose to 50 mg/m2.
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Two patients died during the follow-up period without any disease progression. One developed systemic candidemia during radiation after an episode of diarrhea and the other had a peritonitis complicating a pelvic abscess. Although speculative, we could not definitively determine whether the addition of capecitabine and oxaliplatin to the radiation therapy contributed to these deaths. So, we believe that additional studies are needed to confirm the safety of this new chemotherapy regimen. In this context, the results of the Capecitabine Oxaliplatin Radiotherapy and Excision (CORE) study as well as other appropriately designed and powered clinical trials are awaited with interest before moving on to a phase III trial with this chemoradiation regimen.
A significant correlation between response to preoperative chemoradiation and improved outcome has been suggested by some series [3840
]. In the large phase III trials (EORTC 22921 and FFCD 9203) comparing preoperative chemoradiation with bolus 5-FU (weeks 1 and 5) over radiation alone, better pathological response was observed in the combined modality arm (EORTC, 14% versus 5.3% pT0; FFCD, 10.2% versus 3.2% pCR) [41
, 42
]. Although using different regimens than us, pCR reported with oxaliplatin-based preoperative chemoradiation regimens ranged between 14% and 37% (Table 4). While pathological response is a good end point to evaluate the efficacy of preoperative regimens, results are clearly dependent on the pretreatment status of the patients, pathologic technique, the definition of viable cells and the motivation of the pathologist to find residual tumor cells. This may explain some discrepancy between published results from different phase II trials. In this context, we think that randomized phase III trials with a central pathology review will be necessary to prove that one chemoradiation regimen is better than another in terms of pathological response.
In conclusion, combining preoperative radiotherapy with capecitabine and oxaliplatin is active in downstaging rectal cancer. Additional studies are being undertaken to refine the dose intensities and enhance the safety profile of capecitabine/oxaliplatin chemoradiation regimens.
Received for publication April 16, 2005. Revision received August 1, 2005. Accepted for publication August 2, 2005.
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