|Year : 2015 | Volume
| Issue : 1 | Page : 88-93
A randomized controlled pilot study to compare capecitabine-oxaliplatin with 5-FU-leucovorin as neoadjuvant concurrent chemoradiation in locally advanced adenocarcinoma of rectum
Animesh Saha1, Sajal Kumar Ghosh1, Chhaya Roy2, Makhan Lal Saha3, Krishnangshu Bhanja Choudhury2, Koushik Chatterjee1
1 Department of Radiotherapy, Institute of Post Graduate Medical Education and Research, Kolkata, India
2 Department of Radiotherapy, Radha Gobinda Kar Medical College and Hospital, Kolkata, West Bengal, India
3 Department of Surgery, Institute of Post Graduate Medical Education and Research, Kolkata, India
|Date of Web Publication||16-Apr-2015|
Department of Radiotherapy, Institute of Post Graduate Medical Education and Research, 2/1A Kalinath Munsi Lane, Kolkata - 700 036, West Bengal
Source of Support: None, Conflict of Interest: None
Context: Established as an adjuvant chemotherapy, CapeOX has recently been shown to have radiosensitizer property in a phase I and II studies, with appreciable downstaging and tolerable toxicities.
Aims: The study was designed to evaluate whether the capecitabine-oxaliplatin combination was superior to 5-fluorouracil (5-FU)-leucovorin as radiosensitizer for neoadjuvant chemoradiation in downstaging locally advanced rectal adenocarcinoma and to compare the toxicities between the two arms.
Settings and Design: Single institutional, double blinded, prospective, noncrossover, randomized control pilot study.
Subjects and Methods: In arm A (n = 21), patients received capecitabine (1,000 mg/m 2 daily) in twice dailydoseon days 1-14 and 25-38 and oxaliplatin (85mg/m 2 ) intravenous ( IV) over 2 h, on D1 and D29. In arm B (n = 21), patients received leucovorin (20mg/m 2 ) and 5-FU (350mg/m 2 ) from D1-5 and D29-33. Patient in both the arms received concurrent radiation (50.4 Gy in 28 #, in conventional fractionation of 1.8 Gy per fraction). Six to eight weeks after concurrent chemoradiation, patients underwent assessment and surgery with total mesorectal resection. Postoperatively, adjuvant chemotherapy with m-FOLFOX 6 of 4 months was given to all patients.
Statistical Analysis Used: Chi-square test was used to compare categorical variables between the groups.
Results: Objective response rate (ORR) in arm A was 80.95% compared to arm B which had 66.66% (P = 0.3055). Pathological complete response (pCR) rate of arm A was comparable to arm B (23.8vs 14.28%, P value = 0.6944). Surgery with R0 resection was possible in 80.95% cases of arm A compared to 66.66% cases of arm B (P = 0.4827). Grade III toxicities were quite comparable between two treatment arms.
Conclusions: In terms of ORR, pCR rate, R0 resection, and toxicity profile; both the arms were comparable.
Keywords: Capecitabine-oxaliplatin, chemoradiation, neoadjuvant, rectal cancer
|How to cite this article:|
Saha A, Ghosh SK, Roy C, Saha ML, Choudhury KB, Chatterjee K. A randomized controlled pilot study to compare capecitabine-oxaliplatin with 5-FU-leucovorin as neoadjuvant concurrent chemoradiation in locally advanced adenocarcinoma of rectum. J Can Res Ther 2015;11:88-93
|How to cite this URL:|
Saha A, Ghosh SK, Roy C, Saha ML, Choudhury KB, Chatterjee K. A randomized controlled pilot study to compare capecitabine-oxaliplatin with 5-FU-leucovorin as neoadjuvant concurrent chemoradiation in locally advanced adenocarcinoma of rectum. J Can Res Ther [serial online] 2015 [cited 2019 Sep 21];11:88-93. Available from: http://www.cancerjournal.net/text.asp?2015/11/1/88/150341
| > Introduction|| |
Globally, colorectal cancer (CRC) is the fourth most common cancer in males and third leading cause of cancer in females with mortality paralleling incidence.  Unlike the high incidence of rectal cancer in western world, in India, CRC does not figure amongst the 10 most common malignancies. The age-standardized rates of CRC in India have been estimated to be 4.2 and 3.2/100,000 for males and females, respectively.  The 5-year survival is 90% when CRC is diagnosed at an early stage, however, less than 40% cases are diagnosed when the cancer is still localized.  Surgical resection is the only curative treatment. Curative surgery includes total mesorectal excision (TME) as standard procedure for rectal cancer, with other options being abdominoperineal resection (APR), low anterior resection, and local excision. However, following potentially curative resection, local recurrence rate varies between 5 and 40%. , This high recurrence rate is largely due to presentation of rectal cancer in locally advanced stages. Downstaging of rectal carcinoma before TME can contribute to reduction of recurrence rate as well as improve sphincter preservation and survival. Swedish rectal cancer trail showed that preop radiotherapy (25Gy in 5 fractions) improved 5-year local relapse (11 vs 27%) and 5-year overall survival (58 vs 48%) compared to surgery alone for resectable rectal cancers.  French FFCD 9203 study showed that preop chemoradiotherapy increased pCR (4 vs 11%) and LC (83 vs 92%) in T3-4N0 resectable adenocarcinoma rectum. But there was also increase in grade 3-4 toxicity (3 vs 15%) and there was no difference in sphincter saving surgery, event-free survival, or overall survival.  Downstaging can be achieved by use of 5- fluorouracil (5-FU) or 5-FU-leucovorin, or capecitabine (Cape) based neoadjuvant concurrent chemoradiation. The patients arefollowed-up postoperatively with total of 6 months of perioperative treatment with adjuvant chemotherapy of 5-FU +/−leucovorin, capecitabone-oxaliplatin, or FOLFOX regimens. Established as an adjuvant chemotherapy, CapeOX has recently been shownto have radiosensitizer property in a phase I and II studies, with appreciable downstaging and tolerable toxicities. The study was designed to evaluate whether the capecitabine-oxaliplatin combination was superior to 5-FU-leucovorin as radiosensitizer for neoadjuvant chemoradiation in downstaging locally advanced rectal adenocarcinoma to complete pathological response (pCR), objective response rate (ORR), and surgery with R0 resection and to compare the toxicities between the two arms.
| > Subjects and methods|| |
It was a single institutional, double-blinded, prospective, longitudinal, interventional, noncrossover, randomized control pilot study conducted from April, 2011 to March, 2013, for a period of 24 months. Inclusion criteria was: Histologically confirmed primary adenocarcinoma of the rectum; primary growth restricted to within 15 cm from the anal verge; stage T3, T4, and/or N + and M0 (AJCC 2010); absence of complete obstruction; no prior chemotherapy for cancer; no prior pelvic radiotherapy/surgery or major comorbidities; age- 18-70 years; Eastern Cooperative Oncology Group (ECOG) performance status 0-2; adequate hematological, renal, hepatic, and cardiac function; and patient must provide informed consent before trial entry, abiding the rules and regulations of Declaration of Helsinki. Patients were randomized by computer generated randomization procedure. Pretreatment assessmentincluded history taking, clinical Examination (including per-rectalfinding), biopsy from the primary site, contrast-enhanced computed tomography (CECT) of abdomen, CT thorax, colonoscopy, and routine investigation-complete blood count (CBC),
urea/creatinine (renal function test (RFT)/liver function test (LFT). In arm A (n = 21) patients received capecitabine (1,000 mg/m 2 twice daily) on days 1-14 and 25-38 and oxaliplatin (85mg/m 2 ) IV over 2 h, on D1 and D29. In arm B (n = 21) patients received leucovorin (20mg/m 2 ) and 5-FU (350mg/m 2 ) from D1 to 5 and D29 to 33. Radiation was given with Telecobalt-60 machine. Dose prescription of 50.4 Gy in 28 fractions, in conventional fractionation of single fraction of 1.8 Gy per day. The patients were treated in prone position with a full bladder. Conventional treatment planning with (anteroposterior/posteroanterior (AP/PA) portals were used. The superior port edge was placed at the L4/L5 vertebral body. The distal port edge should be 5 cm below distal margin of the tumor. Most low lying rectal tumors was treated at least to the level of dentate line. Anterior and posterior portals will have at least a 1.5cm margin on the pelvic brim. Irradiation was delivered 5 days per week at a dose of 1.8 Gy/day to a total dose of 45 Gy with a boost to the tumor in 3 fractions of 1.8 Gy to a total of 50.4 Gy. The boost dose was delivered by three-field technique (one PA and two lateral field). During treatment, the patients had blood reports of CBC, RFT, LFT, and electrolytes. Clinical assessment for grading of treatment-induced toxicities was done using Common Terminology Criteria for Adverse Events (CTCAE) version 4. Appropriate conservative management using antiemetics, antidiarrheal, antibiotics, blood transfusion, and inj. filgrastim was used in patients so as to avoid treatment interruption or delay resulting from chemoradiation-induced toxicities. Chemotherapy was interruptedin the face of grade III toxicity and resumed with 25% dose reductionif symptoms resolved to grade 0 or I. Chemotherapy dose also reduced to 75% in patients with ECOG performance status was II. Six to eight weeks after concurrent chemoradiation, patients underwent assessment with CECT scan of whole abdomen and responses were assessed using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. After surgical assessment, all operable patients underwentsurgery withtotal mesorectal resection with intention of achieving R0 resection. Postoperatively, adjuvant chemotherapy with m-FOLFO × 6 of 4 months was given to all patients irrespective of pathological response. A post-therapy pathologic complete response (ypCR) was defined as the absence of viable tumor cells in the surgical specimens including the primary tumor area, the whole mesorectal fat, and the resected lymph nodes (ypT0N0), regardless the presence of mucin lakes. Primary endpoint was ORR, that is, complete response plus partial response. Secondary endpoints were surgery with R0 resection, pCR, and acute and late toxicities. After completion of treatment, patients were followed-up 3-monthly for first 2 years, then 6-monthly for next 3 years, and then annually. Posttreatment evaluation included detailed clinical examination and assessment of toxicity using CTCAE version 4. Radiological assessment (including CECT of abdomen and/or CT thorax) was done only if there were signs and symptoms suggestive of recurrence. MEDCALC version 11 software was used for data analysis. Chi-square test or Fisher's exact test was utilized to compare categorical variables between the groups. Statistical significance was assumed at P < 0.05, with all tests being two-tailed.
| > Results|| |
Between April 2011 and March 2012, 46 patients were selected of which 4 patient (2 patient remained inoperable, 1 found to have progressive disease with liver metastases after chemoradiation and treated outside this study protocol, and 1 patient was lost to follow up after chemoradiation) did not complete the protocol treatment. So there were 42 evaluable patients. The pretreatment characteristics were compared by Chi-square analysis test. The accrual in both the arms was comparable. The characteristics of the patients enrolled are listed in [Table 1]. In our study, 57.1% of the patients had pretreatment carcinoembryonic antigen (CEA) >5ng/ml, which is considered as a poor prognostic marker.
ORR (complete response plus partial response) [Figure 1] in arm A was 80.95% compared to arm B which was 66.66% (P-value = 0.3055). pCR rate [Figure 2] of arm A was comparable to arm B (23.8vs 14.28%, P value = 0.6944 was not significant). Surgery with R0 resection [Figure 3] was possible in 80.95% cases of arm A compared to 66.66% cases of arm B, P value = 0.4827, not significant [Table 2].
|Figure 1: Bar diagram showing objective response rate between the two treatment arms|
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|Figure 2: Bar diagram showing pathological complete response (CR) rate between the two treatment arms|
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|Figure 3: Bar diagram showing comparison of percentage of surgery with R0 resection between two treatment arms|
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Grade III hematological (arm A vs arm B = 19.04 vs14.28%), gastrointestinal (19.04 vs 14.28%), genitourinary (4.76 vs 4.76%), and skin toxicity (23.80 vs 19.04) were quite comparable between two treatment arms. 19.04% of patient in study arm and 14.28% patient in control arm had grade III diarrhea, 14.28% patients in study arm and 9.5% patients in control arm had grade II vomiting, and none of the patient had grade III vomiting. 19.04% patients in control arm and 14.28% patients in study arm had grade II mucositis, no patient had grade III mucositis. 14.28% patients incapecitabine and oxaliplatin arm had hand foot syndrome compared to 9.52% patients in the 5-FU-leucovorin arm [Table 3].
| > Discussion|| |
Combined-modality therapy consisting of surgery, radiotherapy, and chemotherapy is the recommended management strategy for patients with stage II and III rectal cancer. The 5-year survival is 90% when CRC is diagnosed at an early stage; however, less than 40% cases are diagnosed when the cancer is still localized.  TME is now the standard technique for primary resectable rectal cancer and has significantly improved local control. , Adam et al., showed in 1994 that the incidence of local recurrence 5 years after resection will rise from 10 to 78% in case of circumferential margin (CRM) involvement.  This concept holds good specially for locally advanced rectal cancer of T3 and T4 lesions with nodal involvement. Pre-and postoperative radiation treatment strategies have been extensively studied with intention for better disease control. Randomized trials have demonstrated that the addition of chemotherapy to preoperative radiotherapy significantly enhances tumor downstaging, pathologic response, and local control over radiation alone. So downstaging before the TME procedure may decrease the incidence of CRM involvement and local recurrence. The recently published 5-year results of the randomized German CAO/ARO/AIO 94 trial of preoperative versus postoperative chemoradiotherapy support a standard preoperative treatment approach.  However, in the Dutch TME trial, no tumor downstaging was detected in the week after 5 × 5 Gy.  A recent Polish trial demonstrated that a radiotherapy schedule of 50.4 Gy combined with chemotherapy (5-FU/leucovorin) followed after 4-6 weeks by surgery resulted in a significant higher percentage of downstaging compared with short-term preoperative radiotherapy of 5 × 5 Gy followed by surgery within 7 days.  So downstaging is dependent on both the total radiotherapy dose and the interval between the end of the radiotherapy and the surgery. With chemoradiation firmly established as the standardized treatment both pre-and postoperatively, the choice of chemotherapy in chemoradiation became a controversial issue. 5-FU and its modulation drugs became the choice of concurrent chemotherapy with potent radiosensitizer effects for gastrointestinal cancer. The EORTC 22921 study and the French FFCD 9203 study employed 5-FU bolus injection modulated with leucovorin. , However, 5-FU administered by continuous infusion or orally (capecitabine/tegafur-uracil (UFT)) may be more effective and less toxic than 5-FU administered by bolus injection. ,, Neoadjuvant 5-FU-leucovorin chemoradiation results in average of 18% pCR with downstaging possible in 59%. 
Capecitabine is an oral prodrug of 5-FU with three-step in vivo enzymatic conversion to tumor-activated fluoropyrimidine carbamate. The final step is mediated by the enzyme thymidine phosphorylase (TP), which is upregulated in tumor tissue compared with adjacent healthy tissue. This theoretically allows a selective activation of the drug and low systemic toxicity.  Capecitabine has proven activity as both adjuvant and first-line treatment for CRC. There is a potential therapeutic advantage to the use of capecitabine in combination with radiation. Exposure of normal tissues to 5-FU within the radiation field is likely to be lower with oral capecitabine compared with intravenous 5-FU. This was demonstrated in a study conducted in 19 CRC patients that compared 5-FU concentrations in primary tumor and adjacent normal tissue, liver metastasis and adjacent normal tissue, and plasma following administration of capecitabine; there was a potential therapeutic advantage to the use of capecitabine in combination with radiation, but with limited toxicities of normal tissues.  The results from two large, randomized phase III trials including over 1,200 patients showed that oral capecitabine was more active than bolus 5-FU/leucovorinin terms of tumor response (26 vs 17%), and produced at least equivalent time to disease progression (TTP) and overall survival, with an improved safety profile.  Efficacy and safety are mirrored in the adjuvant setting, with recently published data from a large phase III trial of 1,987 patients with Dukes' C colon carcinoma showing a significant improvement in relapse-free survival and trends towards superior disease-free and overall survival.  Reviewed by Punt et al., oxaliplatin or irinotecan were used in conjugation with 5-FU and/or leucovorin as effective chemotherapy with improved survival in advanced CRC.  Both in vivo and in vitro, oxaliplatin has been shown to have at least an additive interaction with radiotherapy in the management of digestive tract tumors. ,
In a Phase I-II Multicenter Study of the Dutch Colorectal Cancer Group, the maximum tolerated dose (MTD) and efficacy of oxaliplatin added to capecitabine and radiotherapy (CapeOX-RT) as neoadjuvant therapy were evaluated in 21 patients with T3-4 rectal cancer patients. The patients received escalating doses of oxaliplatin (day 1 and 29) with a fixed dose of capecitabine of 1,000 mg/m 2 twice daily (days 1-14, 25-38) added to RT with 50.4 Gy and surgery after 6-8 weeks. The MTD, determined during phase I, was used in the subsequent phase II, in which R0 resection rate (a negative circumferential resection margin) was the primary end point. In the phase I part, oxaliplatin at 85 mg/m 2 was established as MTD. In phase II, the main toxicity was grade III diarrhea (18%). All patients underwent surgery, and 20 patients had a resectable tumor. An R0 was achieved in 17/21 patients, downstaging to T0-2 in 7/21 and a pCR in 2/21. It was the combination of CapeOX-RT that had an acceptable acute toxicity profile and a high R0 resection rate of 81% in locally advanced rectal cancer. However, the pCR rate was low.  Carlomagno et al.,
reported 43 patients treated with preoperativeRT: 45 Gy/25 fractions with concurrent capecitabine: 825 mg/m 2 per day twice daily on days 1-14 every 3 week/2 cycles oxaliplatin 50 mg/m 2 days 1 and 8 every 3 week and PCR rate was 20.9%.  Fakih et al., reported 25 patients treated withRT: 50.4 Gy/1.8 Gy day with concurrent capecitabine: 725 mg/m 2 /day twice daily (Monday to Friday) and oxaliplatin 50 mg/m2 weekly for 5 weeks. pCR rate was 24%, effective downstaging was possible in 52% of patients, and 20% of patients had Grade 3 diarrhea. 
In our study though ORR (80.95 vs 66.66%, P value = 0.3055); percentage of pCR rate (23.8vs 14.28%, P value = 0.6944); and surgery with RO resection (80.95 vs 66.66%, P-value = 0.4827) were numerically favorable in patients receiving concurrent chemoradiation with capecitabine-oxaliplatin compared to those receiving concurrent chemoradiation with 5-FU-leucovorin, but it was statistically not significant. Grade III hematological (arm A vs arm B = 19.04 vs 14.28%), gastrointestinal (19.04 vs 14.28%), genitourinary (4.76 vs 4.76%), and skin toxicity (23.80 vs 19.04) were quite comparable between two treatment arms. 14.28% patients incapecitabine and oxaliplatin arm had hand foot syndrome compared to 9.52% patients in the 5-FU-leucovorin arm. 19.04% of patients in study arm had grade III diarrhea which is quite comparable to the published literature. ,, CapeOX regimen has already been established as an adjuvant chemotherapy regimen in locally advanced and metastatic CRC, ,, but benefit of adding oxaliplatin to fluoropyrimidine has not been demonstrated in STAR-01.  and recent ACCORD 12/0405-PRODIGE 2 trail.  Till now most of the centers in India use only capecitabine or 5-FU-leucovorin as a radiosensitizer in neoadjuvant chemoradiotherapy for downstaging locally advanced rectal cancer. Due to limited accrual it was not possible to conclude any superiority of capecitabine-oxaliplatin as a radiosensitizer over 5-FU-leucovorin in our study. More accrual of patients in this study and longer median follow-up will give us a clearer picture in terms of response, toxicity, and disease-free survival.
| > Acknowledgement|| |
The authors would like to thank the patients who braved their disease and suffering during the course of this work.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]