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ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 347-351
 

A prospective randomized trial comparing capecitabine-based chemoradiotherapy with 5-FU-based chemoradiotherapy in neoadjuvant setting in locally advanced carcinoma rectum


Department of Radiation Oncology, Regional Cancer Centre, IGMC, Shimla, Himachal Pradesh, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. K Singh
Department of Radiation Oncology, Regional Cancer Centre, IGMC, Shimla, Himachal Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_174_17

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 » Abstract 

INTRODUCTION: Fluorouracil (FU)based chemoradiotherapy is regarded as a standard perioperative treatment in locally advanced rectal cancer. Capecitabine is an oral fluoropyrimidine that generates 5FU preferentially at the tumor site by exploiting the higher activity of the enzyme thymidine phosphorylase in tumor tissue compared with healthy tissue. As an oral agent, capecitabine can be administered in the outpatient setting, potentially providing FU exposure similar to a lowdose continuous infusion of 5FU. AIMS AND OBJECTIVES: To compare capecitabine with 5FU, with regard to efficacy and toxicity when used in neoadjuvant setting along with radiotherapy for locally advanced carcinoma rectum. MATERIALS AND METHODS: Thirty patients were enrolled, 14 in 5FU and 16 in capecitabine arm. All patients were planned for 45 Gy/25#/5 weeks pelvic radiotherapy followed by a boost of 5.4 Gy/3#/3 days. 5FU was prescribed at a dose of 500 mg/m2 #1–#5 and #21–#25 of RT and capecitabine was given at 1650 mg/m2 on RT days throughout the course of radiotherapy. A magnetic resonance imaging/computerized tomography scan was done at the start of treatment and 1 month after completion of treatment, followed by surgery. Toxicity was assessed weekly during treatment and on the first followup. RESULTS: Response rates and toxicity profile of capecitabinebased cathode ray tube (CRT) was similar to 5FUbased CRT with nonsignificant P values. CONCLUSION: Capecitabine may be used as an alternative in patients who do not tolerate 5FU.


Keywords: 5-fluorouracil, capecitabine, locally advanced carcinoma rectum, neoadjuvant chemoradiotherapy


How to cite this article:
Singh K, Gupta M K, Seam R K, Gupta M. A prospective randomized trial comparing capecitabine-based chemoradiotherapy with 5-FU-based chemoradiotherapy in neoadjuvant setting in locally advanced carcinoma rectum. Indian J Cancer 2017;54:347-51

How to cite this URL:
Singh K, Gupta M K, Seam R K, Gupta M. A prospective randomized trial comparing capecitabine-based chemoradiotherapy with 5-FU-based chemoradiotherapy in neoadjuvant setting in locally advanced carcinoma rectum. Indian J Cancer [serial online] 2017 [cited 2020 Mar 29];54:347-51. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/347/219554



 » Introduction Top


Rectum is the most frequent site for intestinal cancer, with 40,000 cases annually, equally divided by gender.[1] The relative frequency of gastrointestinal malignancies in Himachal Pradesh is 11.6% with that of rectal cancer being 1.68% (institutional data).

Neoadjuvant chemoradiotherapy followed by surgery followed by adjuvant chemotherapy has become the mainstay of treatment in Stages II and III rectal cancer. 5-Fluorouracil (5-FU) is used both in neoadjuvant and adjuvant setting along with radiation O'Connell et al. showed that infusion of 5-FU throughout the entire course of radiotherapy prolonged both overall and disease-free survival and significantly decreased the rate of development of distant metastases compared with bolus 5-FU.[2] However, this schedule requires indwelling catheters and ambulatory pumps and is more difficult to administer on an outpatient basis.

Capecitabine is an oral fluoropyrimidine that generates 5-FU preferentially at the tumor site by exploiting the higher activity of the enzyme thymidine phosphorylase in tumor tissue compared with healthy tissue.[3],[4]

As an oral agent that mimics continuous infusion 5-FU, capecitabine has the potential to replace intravenous 5-FU and simplify chemoradiation for rectal cancer. Hence, the aim of the study was to compare the efficacy and toxicity of capecitabine versus I/V 5-FU in the preoperative setting in locally advanced rectal cancer.


 » Materials and Methods Top


This study was conducted in Department of Radiotherapy, Regional Cancer Centre IGMC, Shimla from July 2013 to June 2014.

This study was a two-arm, two cohort study, in which 5-FU and capecitabine-based chemoradiotherapy were compared in neoadjuvant setting in locally advanced rectal cancer. Enrolled patients were randomized to control and study arm. Patients were enrolled in this study if they: (1) were of age >18 years, (2) had histologically proven rectal cancer, and (3) had Stage II and III disease.

Pretreatment workup included a complete history and physical examination, complete hemogram, blood biochemistry, chest X-ray (PA), colonoscopy and biopsy, histology and grade of the tumor, magnetic resonance imaging (MRI) of abdomen and pelvis, and contrast enhanced computed tomography abdomen and pelvis if MRI was not done.

Exclusion criteria included prior treatment of rectal cancer, women who were pregnant, breastfeeding or unwilling to use effective contraception, patients with an associated medical condition or comorbid illness that impaired compliance.

Randomization

Patients were randomized to two groups the study and control group using stratified randomization based on age, gender, stage, and Karnofsky performance score (KPS). Patients in the study arm received tablet capecitabine in a dose of 1650 mg/m 2 in two divided doses along with radiation therapy, 5 days/week, the mean dose received was 2425.6 mg/day. Patients in the control arm received injection 5-FU 500 mg/m 2 in a 6–8 h infusion along with fraction 1–5 and 21–25 of radiation therapy, the mean dose received was 667.8 mg/day. Patients in both arms received whole pelvis radiation of 45 Gy/in 25# over 5 weeks, given 5 days/week delivered with Theratron 780E and Equinox. This was followed by another 5.4 Gy/in 3# boost to the gross tumor volume. Radiation toxicity was recorded weekly. Patients were reassessed clinically and radiologically after 6–8 weeks of completion of treatment. Skin, hematological, and gastrointestinal toxicities were graded as per the Radiation Therapy Oncology Group criteria. The World Health Organization grading criteria were used for the grading of hand-foot syndrome.

The data obtained from the two arms was analyzed by Pearson Chi-square test to determine the statistical significance between the two treatment arms.

A total of 30 patients were enrolled in the study. Sixteen in the study arm, i.e., capecitabine arm and 14 in the control or 5-FU arm. All patients were given radiotherapy as described along with the drug as per the arm under which they were treated.

The patient characteristics and disease characteristics in the two arms were comparable with nonsignificant P values [Table 1].
Table 1: Patient characteristics

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RECIST 1.0 was used for response evaluation. The RECIST criteria define objective response as follows complete response (CR)-disappearance of all target lesions, confirmed at >4 weeks; partial response (PR), >30% decrease from baseline, confirmed at >4 weeks; progressive disease (PD), >20% increase, or appearance of new lesions; and stable disease (SD) when neither PR nor PD criteria are met. For nontarget lesions, CR was defined as disappearance of all nontarget lesions and normalization of tumor markers, confirmed at >4 weeks; PD-unequivocal progression of nontarget lesions or appearance of new lesions; non-PD, persistence of one or more nontarget lesions or tumor markers above normal limits radiologically at 1 month.

In patients who underwent surgery the response was also assessed pathologically, and in those who could not undergo surgery due to any reason and had completed treatment, the response was assessed clinically and radiologically.


 » Results Top


The response could not be evaluated in three patients. Out of three patients, one patient in each arm died during treatment. In the capecitabine arm, the patient died due to gastrointestinal toxicity. In 5-FU arm, one patient died due to treatment-related acute gastrointestinal obstruction. One patient in 5-FU arm left treatment after 1 week of starting treatment. Thus, there were 27 evaluable patients.

At the first follow-up, one patient in study arm (6.6%) achieved CR, while four patients in control arm (33.3%) achieved CR (P = 0.101). Seven out of 15 (46.6%) evaluable patients in capecitabine arm and 4 out of 10 (40%) evaluable patients in 5-FU arm had PR (P = 0.0.195). Three patients in 5-FU arm (25%) and five patients in capecitabine arm (33.3%) had SD (P = 0.0.543).

Finally, 3 (20%) patients in capecitabine arm had PD while none of the patients in control arm had PD (P = 0.0.087). Thus, the two arms were found to be comparable with respect to treatment response.

Of the total 27 patients who completed chemoradiotherapy, 11 patients did not undergo surgery. One patient in 5-FU (8.3%) and five in capecitabine arm (33.3%) refused surgery (P = 0.09) following resolution of disease-related symptoms after Chemoradiotherapy (CRT). Five patients were found inoperable (two in 5-FU and three in capecitabine arm, P = 0.87). Thus, only 16 out of 30 (53%) patients underwent surgery which was a small percentage of the total.

Of the 16 patients who underwent surgery, five had sphincter saving surgery three were in the capecitabine arm (37.5%), and two were in 5-FU arm (25%) (P = 1.00). Of the five patients who underwent low anterior resection two had disease in the lower one-third (both in capecitabine arm), and three had disease in the upper one-third (two in 5-FU and one in capecitabine arm). All the patients who underwent abdominoperineal resection had disease in the lower one-third.

At a median follow-up of 15 months, since the completion of treatment, 5 (31.25%) patients in capecitabine arm, 6 (42.85%) patients in 5-FU arm were free of disease (P = 0.514). Five (31.25%) patients in capecitabine arm and 2 (14.28) patients in 5-FU arm had distant recurrence (P = 0.273). None of the patients in capecitabine arm had local recurrence while 1 (7%) patient in 5-FU arm had a local recurrence (P = 0.276). Three (18.75%) patients in capecitabine arm and 2 (14.28%) patients in 5-FU arm were dead (P = 0.743), of these two patients (one in each arm) died due to complications of surgery.

Of the eight patients who completed chemoradiotherapy but did not undergo surgery, 3 (37.5%) were free of disease at median follow-up. This was an interesting finding, as 37.5% of patients who completed chemoradiotherapy but did not undergo surgery were free of disease at median follow-up and 50% of patients who underwent chemoradiotherapy and also surgery were free of disease at median follow-up (P = 0.675). Patients who did not undergo surgery were mainly elderly who either refused surgery or were not fit for surgery. Two elderly patients who were completely relieved of their symptoms following chemoradiotherapy died after surgery due to surgery-related complications (nonhealing of surgical wound and sepsis). The sample is very small to draw any robust conclusions, however, these findings indicate that chemoradiotherapy followed by observation may be a treatment option for elderly patients in whom surgery may lead to added morbidity and mortality without contributing to improvement in the quality of life. Larger studies are, however, needed to validate this point and surgery continues to remain the mainstay of treatment in patients with rectal cancer.

Toxicity assessment

Two patients in the capecitabine arm, i.e. 9.3% and in 1 (8.3%) patient in 5-FU arm (P = 0.805) had Grade 3–4 hematological toxicity. Thus, the two groups had comparable hematological toxicity. Four (18.75%) patients in capecitabine arm and 7 (50%) patients in 5-FU arm had Grade 3–4 gastrointestinal toxicity, while one patient in each group died during the treatment course (P = 0.299). None of the patients in either arm had Grade 4 skin toxicity. Grade 3 toxicity was seen in three (20%) of patients in capecitabine arm and in 1 (8.3%) of patients in 5-FU arm in our study (P = 0.7623). Hand-foot syndrome was seen in only one of the patients in the study arm and in none of the patients in control arm which was nonsignificant. Five (33.3%) patients in capecitabine arm and 3 (21.4%) patients in 5-FU arm had Grade 3–4 proctitis (overall P = was 0.962). The posttreatment KPS was comparable between the two groups with none of the P values statistically significant.


 » Discussion Top


Based on the current high level of evidence, the gold standard for treatment of Stages II and III rectal cancer consists of neoadjuvant chemoradiotherapy before transmesorectal excision, followed by postoperative chemotherapy.[5]

5-FU along with leucovorin-based CRT is currently the standard of care in locally advanced rectal cancer. Due to the short half-life of 5-FU, the drug needs to be administered as a continuous infusion during radiation therapy to achieve adequate blood levels required for tumor cell kill. Thus, leading to a need of treatment in an inpatient setting. Capecitabine is an oral drug, that is converted to 5-FU in the tumor cell, thymidine phosphorylase being the key enzyme in its conversion to 5-FU in tumor cells. Radiation exposure leads to upregulation of this enzyme in tumor cells, thus causing increased production of 5-FU in tumor cells in comparison to normal cells. Compared with continuous infusions of 5-FU, oral capecitabine is convenient for patients and health-care professionals, overcoming infusion-related side effects of 5-FU such as thrombosis, thrombophlebitis, and embolism.

Thus, with this background, this trial was conducted at the Department of Radiotherapy and Oncology, Regional Cancer Centre, IGMC, Shimla, to establish the noninferiority of capecitabine-based CRT in comparison to 5-FU based CRT in neoadjuvant setting in patients with locally advanced rectal cancer.

A total of thirty patients were enrolled, of these three patients were not evaluable for a response as two patients, one in each arm died, and one patient in 5-FU arm was lost to follow-up. Thus, total evaluable patients for response assessment were 27, 12 in 5-FU arm and 15 in capecitabine arm. All the patients were matched in both the arms with respect to patient characteristics and disease characteristics except for endophytic type of tumor which was significantly more in the 5-FU arm. Of the 27 patients who completed treatment, 26 patients completed treatment within the stipulated time, while 1 patient in the 5-FU arm had a delay of 1 week due to noncompliance.

Surgery was performed 4–6 weeks after completion of treatment, in a total of 16 (45.45%) patients. Therefore, the response could be assessed pathologically in only 16 patients. Of the patients who did not undergo surgery, 6 (20%) refused surgery, 5 (16.62%) were found inoperable, 3 (10%) died, and 1 (3.3%) was lost to follow-up. In patients who did not undergo surgery, the response was assessed clinically and radiologically using RECIST 1.0 criteria, 4–6 weeks after completion of treatment.

The response rates at first follow-up were as follows: one patient in study arm (6.6%) achieved a complete pathological response, while four patients in control arm (33.3%) achieved complete pathological response (P = 0.101). Seven out of 15 (46.6%) evaluable patients in capecitabine arm and 4 out of 10 (40%) evaluable patients in 5-FU arm had PR (P = 0.0.195). Three patients in 5-FU arm (25%) and 5 patients in capecitabine arm (33.3%) had SD (P = 0.0.543). Finally, 3 (20%) patients in capecitabine arm had PD while none of the patients in control arm had PD (P = 0.0.087). Thus, the difference in outcome was not statistically significant.

In the NSABP R-04[6] study, the pathological CR obtained with 5-FU in a dose of 225 mg/m 2 given on radiotherapy days (postamendment) was 17.8% and the pathological CR obtained with capecitabine in a dose of 1650 mg/m 2 on radiotherapy days was 20.7%. In a study by Hofheinz et al.[7] Pathological complete remission (ypT0N0) was more frequent in the capecitabine group, being achieved by ten (14%) of 73 patients in the capecitabine group versus four (5%) of 74 in the 5-FU group (P = 0.09). In this study, a trend toward better response rates was seen in the 5-FU arm, i.e., pathological CR rate of 33.3% compared with 6.6% pathological CR in capecitabine arm, however, this could be because more number of patients in the capecitabine arm refused surgery after resolution of disease-related symptoms as compared to 5-FU arm (i.e., 33.3% versus 8.3%). In these patients who did not undergo surgery, response was assessed radiologically and clinically, which are both inferior to response assessment pathologically, as postradiotherapy fibrosis can be mistaken for residual disease. Thus, lesser pathological CR in capecitabine arm could be due to lesser number of patients undergoing surgery. The overall response rate was 66.6% in 5-FU arm compared with 53.3% in capecitabine arm (P = 0.759). However, none of the results were statistically significant.

The second endpoint of the study was toxicity assessment. The most common observed toxicity was gastrointestinal toxicity, with Grade 3–4 toxicity seen in 50% of patients in the 5-FU arm and approximately 18.75% patients in the capecitabine arm (P = 0.299), there was one death each in the 5-FU and capecitabine arm due to gastrointestinal toxicity. There was a trend towards higher gastrointestinal toxicity in the 5-FU arm although the difference between the two arms was not statistically significant. Grade 3–4 hematological toxicity was seen in two patients in the capecitabine arm, i.e. 9.3% and in 1 (8.3%) patient in 5-FU arm (P = 0.805). Grade 3–4 proctitis was seen in 5 (33%) patients in the capecitabine arm and 3 (21.4%) patients in the 5-FU arm in our study, with no statistically significant difference (P = 0.962). Grade 3 radiation dermatitis was seen in 3 (20%) of patients in capecitabine arm and in 1 (8.3%) of patients in 5-FU arm in our study (P = 0.762), no Grade 4 radiation dermatitis was seen. Grade 3–4 hand-foot syndrome was seen in none of the patients in our study. All the toxicities were comparable between the two arms with insignificant P values.

In the study by Hofheinz et al.[7] the Grade 3–4 gastrointestinal toxicity was observed in 8.6% of patients in capecitabine arm and 2% of patients in 5-FU arm which was statistically significant (P = 0.07). Grade 3–4 hematological toxicity was seen in 1.5% of patients in the capecitabine arm and 9.7% patients in the 5-FU arm which was statistically significant (P = 0.04). Any grade proctitis was seen in 15.7% of patients in the capecitabine arm and 5.1% patients in the 5-FU arm, with a significant P < 0.001. Any grade radiation dermatitis was seen in 14.7% patients in the capecitabine arm and 17.9% patients in the 5-FU arm which was statistically insignificant (P = 0.39).

In the NSABP R-04,[6] the Grade 3–4 gastrointestinal toxicity was 6.9% in both the arms which was comparable. Grade 3–4 radiation dermatitis was seen in 2.5% patients in either arm which was again comparable. There was no Grade 4 hand-foot syndrome observed, Grade 3 Hand-foot syndrome was seen in 0.3%patients in both the arms which was also comparable. In general, the toxicities observed in our study were more than the reference studies, i.e., the NSABP R-04[6] and the study by Hofheinz et al.[7] This could be due to the use of more conformal radiotherapy techniques in these studies, thus leading to lesser radiation toxicity. Furthermore, the toxicity can be attributed to the comparatively poorer general condition of our patients and nontolerance to similar drug doses as used in the above-mentioned studies. However, the toxicities between the two arms in our study were comparable.

Sphincter-sparing surgery was performed in our study in 37.5% of patients in capecitabine arm, who underwent surgery and in 25% of the patients in the 5-FU arm. Thus, there was a trend toward an increased rate of sphincter preservation in the capecitabine arm compared with 5-FU arm; however, the difference was not statistically significant. In the study by Hofheinz et al. published in 2012 the low anterior resection was performed in 78% of patients in the 5-FU arm and in 73% of patients in capecitabine arm. In the NSABP R-04[6] trial, the sphincter saving surgery was done in 59.4% of patients in 5-FU arm and in 59.3% patients in the capecitabine arm, with a nonsignificant P value. This decreased rate of sphincter preservation in our study could be because in the above studies conformal techniques of radiation delivery were used for initial planning and boost, which could have led to better tumor coverage and surgical down staging compared to the conventional radiotherapy technique used in our study. Furthermore, in our study, more than 80% patients had Stage III disease compared to <50% in NSABP R-04[6] and approximately 60% in the study by Hofheinz et al.[7]

Thus, in our study, the response rates and toxicities of 5-FU and capecitabine-based chemoradiotherapy were compared in the neoadjuvant setting in locally advanced rectal cancer. A trend toward better response rates with 5-FU-based CRT was observed, however, the difference was statistically insignificant. Better sphincter preservation rate was seen in the capecitabine arm compared with 5-FU arm, but with an insignificant P value. The gastrointestinal toxicity was higher in the 5-FU arm, but the difference was again statistically insignificant. Other toxicities between the two groups were found to be comparable.

Another important observation was the nonprogression of disease in 37.5% of patients who did not undergo surgery compared to 50% in those who underwent surgery along with chemoradiotherapy. However, this being a small study, no conclusive results can be drawn from this finding, however, chemoradiotherapy alone may be further evaluated as an option of treatment in elderly patients with comorbidities and nonfitness for surgery.


 » Conclusion Top


Based on our result, we can recommend that capecitabine-based neoadjuvant chemoradiotherapy in locally advanced rectal cancer has similar efficacy and toxicity as 5-FU-based chemoradiotherapy, with added advantage of convenience for both patients as well as the treating physician. The hospitalization required for 5-FU continuous infusion can be avoided with oral capecitabine, thus, reducing the overall cost of treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
Rubin P, Hansen JT. Rectum. TNM Staging Atlas with Oncoanatomy. 2nd ed., Ch. 32. Philadelphia: Lippincott Williams and Wilkins; 2013.  Back to cited text no. 1
    
2.
O'Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994;331:502-7.  Back to cited text no. 2
    
3.
Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998;34:1274-81.  Back to cited text no. 3
    
4.
Schüller J, Cassidy J, Dumont E, Roos B, Durston S, Banken L, et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 2000;45:291-7.  Back to cited text no. 4
    
5.
Valentini V, Aristei C, Glimelius B, Minsky BD, Beets-Tan R, Borras JM, et al. Multidisciplinary rectal cancer management: 2nd European Rectal Cancer Consensus Conference (EURECA-CC2). Radiother Oncol 2009;92:148-63.  Back to cited text no. 5
    
6.
O'Connell MJ, Colangelo LH, Beart RW, Petrelli NJ, Allegra CJ, Sharif S, et al. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: Surgical end points from national surgical adjuvant breast and bowel project trial R-04. J Clin Oncol 2014;32:1927-47.  Back to cited text no. 6
    
7.
Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, et al. Chemoradiotherapy with capecitabine versus fl uorouracil for locally advanced rectal cancer: A randomised, multicentre, noninferiority, phase 3 trial. Lancet Oncol 2012;13:579-88.  Back to cited text no. 7
    



 
 
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