Aim of work: This study aimed to evaluate the resectability rate, rate of conservative surgery, toxicity, local control, and disease free survival for oxaliplatin and capecitabine based chemoradiation compared to standard 5-FU based chemoradiation in locally advanced cancer rectum. Patients and methods: 65 patients were eligible; 33 patients received oxaliplatin and capecitabine based chemoradiation (arm I) and 32 patients received 5-FU based chemoradiation (arm II). Results: The overall response rate in arms I and II were 78.7% and 87.5% respectively. Conservative surgery was done in 81.81% and 53.13% of patients with arms I and II, pathologic complete response (pCR) rate was significantly better in arm I than arm II (30.3% vs. 21.9%, P < 0.01). 3-year recurrence rates were 54.5% and 56.2% in arms I, II respectively ; the median disease free survival (DFS) were 30 months and 15 months in arms I and II respectively. Grade III anemia, grade IV diarrhea and severe proctitis were developed in a significantly large number of patients with arm I ; in addition deep venous thrombosis (DVT) was developed in 15.15% of patients with arm I but none in arm II. Conclusion: The addition of oxaliplatin to the preoperative chemo radiation increased the response rate mainly pCR rate which was considered a target goal in the neoadjuvant treatment, but it was not recommended because of higher toxicity and no significant effect on DFS in different response groups of arm I when compared to arm II, but longer follow up may be needed to evaluate the overall survival.
Globally, colorectal cancer is the third most common form of cancer after lung and breast cancers. In 2014, the estimated new cases and deaths from rectal carcinoma in the United States [
In Egypt, reports showed that colorectal cancer was detected in 11% - 15% of patients who underwent colonoscopy and diagnosed in 29% - 31% of patients aged ≤ 40 years [
Preoperative concurrent chemo radiation is routinely performed for locally advanced rectal cancer; (T3-T4 and/or N+) to achieve down staging of the tumor and soto increase its resectability rate. Other benefits of preoperative chemo radiation are to increase the probability of a sphincter-saving procedure, reduce the risk of local recurrence, and thereby, improve the survival [
A number of well randomized controlled trials had been made to evaluate the impact of oxaliplatin when added to 5-FU or capecitabine based chemo radiation on different response rates especially pCR rate and on the toxicity pattern in patients with cT3-4 and/or N+ rectal adenocarcinoma. In the STAR-01 trial 747 patients were randomized to preoperative chemo radiation with 50.4 Gy + CI 5-FU with or without weekly oxaliplatin [
In the ACCORD 12/0405 PRODIGIE trial, patients were randomized to preoperative chemo radiation with radiotherapy dose of 50 Gy concurrently with capecitabine and oxaliplatin (CAPOX) andradiotherapy dose of 45 Gy concurrently with capecitabine [
The NSABP R-04 trial which was a 4 arms trial (2 × 2 comparison) of continuous infusion 5-FU based chemo radiation vs. capecitabine based preoperative chemo radiation (50.4 Gy) with or without oxaliplatin [
However; the German CAO/ARO/AIO-04 [
As 3 of 4 randomized trials revealed an increase in the acute toxicity with no real benefit in the pCR rate so the current preoperative chemoradiation regimensdon’t include oxaliplatin.
We aimed to evaluate the resectability rate, rate of conservative surgery, toxicity profile, local control, and disease-free survival for oxaliplatin and capecitabine-based chemoradiation in comparison to standard 5 FU-based chemoradiation in locally advanced cancer rectum.
This study was a randomized controlled two arm trialand was conducted from June 2012 to September 2013 at Clinical Oncology, Surgical, and Diagnostic Radiology departments of Assiut University Hospital and clinical pathology and surgical oncology departments of south Egypt cancer institute, to compare capecitabine and oxaliplatin based chemoradiation to 5-fluorouracil based chemoradiation as regard treatment outcomes and toxicity patterns for patients with locally advanced cancer rectum.
All patients met the following eligibility criteria:
・ Age > 18 years;
・ Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2;
・ Histologically proven rectal adenocarcinoma TNM staging: T3-T4, Nx M0, any T any N + M0 disease;
・ Adequate bone marrow functions with total leucocytic count > 3000/mm3, platelet count > 100,000/mm3, hemoglobin level > 11 gm/dL, normal hepatic and renal functions (LFTs, RFTs);
・ Patients with temporary colostomy were allowed;
・ No previous chemotherapy or pelvic irradiation;
・ Pregnant or lactating females weren’t included;
・ Written consent from all eligible patients was taken.
All eligible patients underwent the followings:
・ History, physical examination, digital rectal examination;
・ Complete blood picture (CBC), blood chemistries (RFTs, LFTs, electrolytes), carcinoembryonic antigen (CEA);
・ Pelvic magnetic resonance imaging (MRI), multisclice computed tomography (MSCT) chest and abdomen;
・ Colonoscopy to exclude other primaries;
・ Proctoscopy and biopsy.
Protocol of concurrent chemo-radiation:
Patients were randomly assigned either to receive arm I of capecitabine and oxaliplatin based chemoradiation or arm II of standard 5 FU-based chemoradiation.
Arm I: oxaliplatin 45 mg/m2 was given weekly over 2 h infusion and 2 h just before radiation setting. capecitabine 825 mg/m2/dose given twice daily (total = 1650 mg/m2 daily), the 1st daily dose was given 2 h before radiation setting, five days per week, and chemotherapy continued throughout the radiotherapy course.
Arm II: 5-FU 225 mg/m2 was given over 24 hours infusion for 5 days/week during radiotherapy (RT).
The treatment was given by 3D conformal RT for both arms in two phases. Clinical target volume (CTV) for phase I included the tumor, presacral lymph nodes (LN), perirectal LN, external and internal iliac LNs, and inguinal LN for tumors extending below the dentate line, while CTV for phase II included the tumor +3 cm safety margin. The dose for phase I; 45 Gy/25 fractions/5 weeks, and for phase II; 5.4 Gy/3 fractions/half a week. We limited the dose to the small bowel to 45 - 50 Gy, and the femoral head and neck to 42 Gy.
During the treatment: repeated CBC and renal function were done, follow up of improvement of symptoms and monitoring of development of toxicity occurred during progress of therapy were done, and the toxicities were recorded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3 (NCI CTCAEs). Assessment of the response was done within 6 weeks after therapy mainly by imaging; high resolution pelvic MRI 1.5 tesla, MSCT chest and abdomen with contrast using 64 row slices scanner from the root of the neck to pelvic floor. Assessment was done based on response evaluation criteria in solid tumors (RECIST) 1 criteria with scan thickness of ≤5 mm,
Evaluation of target lesions:
Complete Response (CR): disappearance of all target lesions, any pathological LN must have a short axis of <10 mm in diameter whether target or nontarget LNs.
Partial Response (PR): at least 30% reduction in the sum of diameters of target lesions, in comparison to baseline sum diameters.
Progressive Disease (PD): at least 20% increase in the sum of diameters of target lesions; any new lesion is considered PD.
Stable Disease (SD): neither PD nor PR based on the reference of the smallest sum diameters.
Residual Disease was defined based on depth of invasion, distance from anal verge, number of enlarged LNs, site of the primary tumor, mesorectal infiltration. Trans-rectal U/S was done in some cases to evaluate the depth of invasion before surgery. Evaluation of the response also was done through repeated measurement of CEA, CBC, blood chemistries.
Surgery was done 6 weeks later after the end of chemo-radiation and based on the results of clinical, imaging, and laboratory evaluations of the response, in some cases temporary colostomy was done to relieve the obstruction before chemo-radiation, sphinecteric saving surgeries included trans-anal excision, low anterior resection, and coloanal anastomosis, and radical abdominoperineal resection.
The response was evaluated as mentioned based on RECIST 1 criteria, Disease free survival (DFS) was determined from the time of diagnosis to the time of locoregional relapse (the use of DFS rather than overall survival (OS) has become more frequent in adjuvant cancer trials) [
The present study was done at Assiut University Hospital and South Egypt Cancer Institute, and was approved by the ethical committee of institutional review board of Assiut faculty of medicine. 65 patients were accrued from June 2012 to September 2013, 33 patients were included in arm I and 32 patients in arm II.
The mean age for arm I and II were 42.48, 40.16 respectively, male to female ratio were 1.2:1, 0.68:1 for arms I and II respectively. 30% of patients were of ECOG PS 1 in arm I but 53. 1% of patients were in PS 2 in arm II (
The main presenting symptom was bleeding per rectum and encountered in 66.7%, and 68.8% of patients in arm I and II respectively (22 patients in each arm), abdominal pain was reported in 51.5% of patients in arm I (17 patients) and 18.7% (6 patients) of arm II, altered bowel habits in 45% of patients (15 patients) in arm I and 9.4% of patients of arm II (3 patients), and intestinal obstruction was presented in 9% and 9.4% of patients with arm I and II respectively (3 patients in each arm).
The most common adenocarcinoma subtype in arms I and II were conventional type reported in 70% (23 patients) and 81.25% (26 patients) respectively. Tumors arose from mid-rectum were most common in arm I while tumors arose from lower rectum were most common in arm II (
At presentation; CEA was elevated in 63.63% (21 patients), 34.4% (11 patients) of arms I and II respectively.
Conservative surgery was done in 81.81% (27 patients) of patients with arm I, while it was done in 53.13% (17 patients) of patients with arm II, and the results were significant for arm I (P < 0.001) (
The most common pattern of response based on post chemoradiation MRI; in arm I was complete response and developed in 54.5% (18 patients), but it was partial response in 50% (16 patients) of arm II. The overall response rate in arms I and II were 78.7% and 87.5% respectively and the response was significantly better for arm I (P < 0.01) (
The rates of pathological complete response after surgery as defined by Ryan staging of pathological response were 30.3% and 21.9% in arms I and II respectively which was significantly better in arm I than arm II (P < 0.01).
51.85% of patients (14 patients) with arm I who developed CR were underwent SP, while 52.9% (9 patients) of arm II with CR were underwent SP (the percentage was higher in arm II but the actual number was higher in arm I) the results were also significantly better for arm I than arm II (P < 0.01) (
3-year local control rate was 45.5% in arm I (15/33 patients) and it was slightly higher than arm II which was 43.8% (14/32 patients).
Over a period of follow up of more than 40 months for the entire cohort, local recurrence was detected in 18 patients in each arm, so the 3-year recurrence rates were 54.5% and 56.2% in arms I, II respectively.
The mean DFS ± SE were 26.28 ± 1.93 and 17.03 ± 1.98 in arms I and II respectively, while the median DFS in arm I was 30 months (
There was a significant relation between the response and DFS in arms I and II (P < 0.01 arm I and P < 0.000 in arm II) but no significant difference between DFS of both arms in any response group (
Toxicities among patients treated with arm I were significantly higher than toxicities among patients treated with arm II as severe proctitis developed in 9.1% of patients (3 patients), grade III anemia developed in 6.1% of patients (2 patients), grade IV diarrhea was developed in one patient (in arm I). Deep venous thrombosis (DVT) was developed in 15.15% of patients with arm I (5 patients) but none developed DVT in arm II (
Data | Arm I | Arm II |
---|---|---|
N % | N % | |
Age (mean ± SD) Min - max | 42.48 ± 16.3 (17 - 80) | 40.16 ± 10.33 (20 - 60) |
Sex Male Female | 18 54.5% 15 45.5% | 13 40.6% 19 59.4% |
ECOG PS 0 1 2 3 | 9 27.3% 10 30.3% 8 24.2% 6 18.2% | 2 6.25% 11 34.4% 17 53.1% 2 6.25% |
Adenocarcinoma -Conventional type -Mucinous type -Signet ring type | 23 70% 5 15% 5 15% | 26 81.25% 4 12.4% 2 6.2% |
Grading G1 G2 G3 G4 | 15 45.4% 9 27.3% 9 27.3% 0 0% | 7 21.9% 14 43.8% 3 9.4% 8 25% |
T stage T2 T3 T4 | 10 30.3% 14 42.42% 9 27.27% | 2 6.2% 15 46.9% 15 46.9% |
N stage N0 N+ | 15 45.45% 18 54.54% | 15 46.9% 17 53.1% |
Tumor localization from anal verge Lower rectum Mid-rectum Upper rectum | 12 36.36% 16 48.48% 5 15.15% | 23 71.9% 4 12.5% 5 15.6% |
N = node, T = tumor, G = grade.
Surgery | Arm I total = 33 No % | Arm II total = 32 No % | P value |
---|---|---|---|
Conservative (APR) | 27 81.81% 6 18.18% | 17 53.13% 15 46.87% | P < 0.001*** |
APR = abdominoperineal resection, *** = highly significant.
Response | Arm I No % | Arm II No % | P Value |
---|---|---|---|
-CR -PR -SD -Pathologic CR | 18 54.5% 8 24.2% 7 21.3% 10 30.3% | 12 37.5% 16 50% 4 12.5% 7 21.9% | P < 0.01* |
* = significant, CR = complete response, PR = partial response, SD = stable disease.
Response | Rate of sphincter preservation (SP) | ||
---|---|---|---|
Arm I Arm II No % No % | P value | ||
CR PR SD | 14 51.85% 6 22.22% 7 25.93% | 9 52.9% 7 41.2% 1 5.9% | P < 0.01* |
* = significant, CR = complete response, PR = partial response, SD = stable disease.
Item response | DFS Arm I | DFS Arm II | P value |
---|---|---|---|
CR PR SD | 29.16 ± 2.52 23.04 ± 3.84 16.32 ± 3.06 | 24.41 ± 9.37 22.75 ± 8.62 0.0 | P = 0.376 n.s P = 0.382 n.s -- |
P value | <0.01* | P < 0.000*** |
DFS = disease-free survival, n.s = nonsignificant, * = significant, *** = highly significant, CR = complete response, PR = partial response, SD = stable disease.
Toxicity | Arm I | Arm II | P value |
---|---|---|---|
Acute proctitis -Mild -Moderate -Severe ・ Anemia -G1 -G2 -G3 | 18 54.54% 12 36.36% 3 9.1% 6 18.18% 9 27.27% 2 6.1% | 721.9% 825.0% 0 0% 1031.25% 13.1% 0 0% | <0.000*** <0.001*** |
・ Diarrhea -G1 -G2 -G3 -G4 ・ Neutropenia ・ Hand & Foot syndrome ・ DVT | 10 30.3% 7 21.21% 1 3.03% 1 3.03% 5 15.15% 7 21.21% 5 15.15% | 515.62% 515.62% 1 3.0% 0 0% 13.1% 26.2% 0 0% | <0.02* <0.04* <0.04* 0.271 n.s |
---|
G = grade, n.s = non significant, * = significant, *** = highly significant, DVT = deep venous thrombosis.
5-flourouracil is currently the standard cytotoxic agent for preoperative chemo radiotherapy, however; considering the disadvantages of continuous infusion, a number of studies evaluatedother cytotoxic agents. These are mainly oral agents like capecitabine, and these studies concludedthat no significant difference in treatment outcomes and more favorable toxicity when compared to CI 5-FU. Preoperative chemoradiation with concurrent capecitabine is considered astandard treatment for locally advanced rectal adenocarcinoma [
Oxaliplatin is used for preoperative concurrent chemo radiation because of its radiosensitizing properties detected in preclinical studies [
In the German CAO/ARO/AIO-04 trial [
In our study, the results were comparable to the German trial, the percentage of patients achieved pCR was significantly higher in arm I than arm II to an extent sufficiently translated into significantly higher percentage of patients underwent conservative surgery (81.18% vs. 53.13% P < 0.01), but in contrast to the German trial; grade 3 and 4 toxicities were significantly higher in those receiving oxaliplatin.
The response to neoadjuvant chemo radiotherapy is a strong predictor of DFS [
This relation between the response and DFS was also evident in our trial as patients achieved CR was associated with significantly better DFS in both arms (P < 0.01, P < 0.000 in arms I and II respectively), but no significant difference between DFS in different response groups of both arms and no significant differences in DFS of both arms which wasn’t comparable to updated results of the German CAO/ARO/AIO-04 randomized phase III trial which concluded that the addition of oxaliplatin to 5-FU based neoadjuvant chemoradiation with adjuvant chemotherapy in locally advanced cancer rectum significantly improved 3-year DFS (P = 0.03) [
In RadiOxCape trial; Machiels et al concluded that the concurrent chemoradiation with RT dose 50 Gy and capecitabine plus oxaliplatin was associated with 30% incidence of diarrhea, 14% for pCR rate and better down staging [
Borschitz et al. [
The side effects of preoperative chemoradiation for cancer rectum may affect patients’ quality of life and in our study; oxaliplatin and capecitabine based chemoradiation was associated with significantly higher toxicity that was comparable to different literatures and previous studies. DVT occurred in 15.15% of patients in oxaliplatin group and this toxicity is a rare one and not mentioned in many trials, but it may be attributed to long postoperative recovery period in some patients, previous risk factors like diabetes, obesity, previous DVT, chronic liver disease.
There are a number of weak points in our study including the small number of patients to which attributed the difference between our results and international studies, and our patients came from only two institutions so the results were not generalized.
The addition of oxaliplatin to the preoperative chemoradiation increases the response rate especially pCR rate which was considered a target goal in the neoadjuvant treatment, but it was not recommended because of higher toxicity, and it added no significant effect on DFS in different response groups of both arms when compared to CI 5-FU based chemoradiation, but longer follow up may be needed to evaluate the overall survival.
The authors declare no conflicts of interest regarding the publication of this paper.
Rayan, A., Hasan, H.A., Zahran, A.M., Soliman, A. and Rezk, K. (2018) Capecitabine and Oxaliplatin versus 5-Fluorouracil in the Neoadjuvant Chemoradiation for Patients with Locally Advanced Rectal Carcinoma: A Comparative Study. Journal of Cancer Therapy, 9, 767-779. https://doi.org/10.4236/jct.2018.910063