|Year : 2016 | Volume
| Issue : 4 | Page : 518-523
Preoperative long-course chemoradiation for localized rectal cancer: A retrospective comparison of response and outcome between 5-fluorouracil/leucovorin versus capecitabine
B Kunheri, B Gurram, R Madhavan, D Makuny
Department of Radiotherapy, Amrita School of Medicine, Amrita Viswavidyapeetham University, Kochi, Kerala, India
|Date of Web Publication||21-Apr-2017|
Department of Radiotherapy, Amrita School of Medicine, Amrita Viswavidyapeetham University, Kochi, Kerala
Source of Support: None, Conflict of Interest: None
BACKGROUND: Preoperative concurrent chemoradiation therapy (CRT) with either capecitabine or 5-florouracil/leucovorin (5 FU/LV) is the standard of care in locally advanced rectal cancer (LARC). Literature comparing the toxicity and response of these two regimens in Indian patients is sparse. Our objective was to compare the pathological response (PR) and clinical outcome of capecitabine versus 5 FU/LV in CRT for LARC. MATERIALS AND METHODS: Sixty patients with LARC treated with preoperative CRT with capecitabine or 5FU/LV from January 2009 to May 2014 were analyzed. Ryan's tumor regression grading was used for PR assessment and tumor downstaging was defined as a reduction in the T and N stages by at least one level. Toxicity was assessed with RTOG acute toxicity assessment criteria and CTCAE 4.0 version. Statistical analysis was done using IBM SPSS 20 software. Percentage of patients with respect to response rates and toxicities was computed in each of the treatment groups. To test the statistical significance of the difference in PR rates and toxicities between the two groups, Chi-square test was used. Kaplan–Meier estimate of survival rate was computed for each group. To test the statistical significance of the difference in survival rate, the log-rank test was applied. RESULTS AND CONCLUSION: The two groups (5 FU/LV vs. capecitabine) were comparable with respect to pathological complete response (20% vs. 24%), pathological downstaging (76% vs. 69%), sphincter preservation rates, and acute complication rates. Both regimens were well tolerated. Overall survival and disease-free survival also did not show a statistically significant difference between the two groups (P values 0.720 and 0.255, respectively). In summary, our analysis showed the equivalence of both regimens in the preoperative CRT setting.
Keywords: 5-florouracil/leucovorin, capecitabine, chemoradiation therapy, locally advanced rectal cancer
|How to cite this article:|
Kunheri B, Gurram B, Madhavan R, Makuny D. Preoperative long-course chemoradiation for localized rectal cancer: A retrospective comparison of response and outcome between 5-fluorouracil/leucovorin versus capecitabine. Indian J Cancer 2016;53:518-23
|How to cite this URL:|
Kunheri B, Gurram B, Madhavan R, Makuny D. Preoperative long-course chemoradiation for localized rectal cancer: A retrospective comparison of response and outcome between 5-fluorouracil/leucovorin versus capecitabine. Indian J Cancer [serial online] 2016 [cited 2019 Aug 21];53:518-23. Available from: http://www.indianjcancer.com/text.asp?2016/53/4/518/204777
| » Introduction|| |
Colorectal malignancies are the third most common cancer in males and the second most common cancer in females with an overall incidence of 1.2 million new cases per year in the world. Early stages as in other sites, single modality treatment with surgery alone gives reasonable cure rates, but in the setting of locally advanced rectal cancers (LARCs), recurrence rates following surgical resection alone were nearly 50%. Combined modality treatment comprising of surgery, chemotherapy and radiation is the standard of care for LARC ever since the National institute of health consensus statement in 1990. With this tri-modality treatment, the 5-year overall survival (OS) for LARC was 60%–75%, reducing the overall mortality by 29% compared to surgery alone. The strategy of neoadjuvant chemoradiotherapy (CRT) has certain advantages over adjuvant treatment such as: treating the micro-metastasis, better efficacy with intact vasculature, potential sphincter preservation with less small bowel toxicity, and tumor downstaging. Advantages were proved in two phase III trials, the German trial CAO/ARO/AIO 94 and the NSABP-R03 in terms of better sphincter preservation, pelvic control, and less toxicities., Since then, preoperative CRT with 5-fluorouracil (5-FU) and leucovorin (LV) has been the standard of care in the LARC. Capecitabine, an orally administered fluoropyrimidines carbamate, a prodrug of 5-FU, was developed for prolonged and continuous antitumor activity of 5-FU which mimics continuous infusion. Conversion to 5-FU involves three steps with thymidine phosphorylase (TP) used in the final step. Drug not only exhibits tumor selective activity, as TP is high in tumor cells, but also has a synergistic effect with radiation treatment (RT), which was confirmed by Sawada et al. that RT upregulates TP levels in the tumor.,
There are few phase II studies which compared 5-FU/LV and capecitabine in CRT setting, and the recent German randomized trial by Hofheinz et al. proved the noninferiority of capecitabine compared to 5-FU/LV in neoadjuvant CRT setting. Literature regarding its tolerability and equivalence in CRT setting is sparse from our continent. Therefore, in this study, we have planned to evaluate and compare the response and outcomes of patients with LARC who received neoadjuvant CRT with either 5-FU/LV or capecitabine in our center.
The primary objective was to evaluate and compare the pathological response (PR) and clinical outcomes of LARC patients treated with neoadjuvant chemoradiation with either 5FU/LV or capecitabine.
The secondary objective was to evaluate and compare acute toxicity and compliance to treatment between the two groups.
| » Materials and Methods|| |
This retrospective study compared the PR and outcome in biopsy-proven LARC patients treated with preoperative concurrent chemoradiation with either 5-FU/LV or capecitabine during January 2009–May 2014. A total of 30 patients with LARC were treated with concurrent capecitabine and radiation during the study period. Age- and gender-matched cohort of 30 patients were selected from 5-FU/(LV) group during the same period.
All patients with biopsy-proven LARC (clinically bulky T2, T3, T4, and node-positive) who received neoadjuvant concurrent chemoradiation with capecitabine during January 2009–May 2014 were eligible. Age- and gender-matched cohort of the same number of patients who received neoadjuvant concurrent chemoradiation with 5-FU/LV during the same period was taken for comparison. Data collection was done from electronic medical records and RT files, and various parameters were recorded with a specifically designed proforma.
Before preoperative CRT, all patients underwent evaluation, which consisted history, complete physical examination, colonoscopy with biopsy, and pathology slide review in case of outside biopsy. Local imaging was with computerized tomography, to assess the extent of the primary and nodal involvement. A complete hemogram, liver function tests, renal function tests, and CEA were also done. Following workup, all patients were staged according to the AJCC staging (currently followed is 2010 and there is no significant difference between the previous version and the present version of AJCC). All T3, T4, or Bulky T2 and node-positive patients were considered for preoperative CRT treatment. Patients were treated with using 3D conformal radiotherapy with either concurrent 5-FU/LV or capecitabine.
Patients who did not want intravenous chemotherapy and could afford capecitabine were given concurrent capecitabine. Preoperative RT dose delivered was 46–50 Gy in 23–25 fractions in 5 weeks.
Chemotherapy protocol followed was 5FU/LV: two cycles of IV bolus 5FU (425 mg/m 2/day) and LV (20 mg/m 2/day) for 5 days during the first and last weeks of RT. The capecitabine dose was of 825 mg/m 2/day given in two divided doses, per oral for 5 days a week throughout the course of radiation. During CTRT, weekly review was done and acute toxicity was assessed with RTOG acute toxicity assessment criteria and CTCAE 4.0 version. 97
Approximately 6–8 weeks after completion of chemoradiation treatment, patients underwent definitive surgery. Surgical management was abdominoperineal resection or low anterior resection (LAR) with total mesorectal excision. Sphincter-sparing approach was considered whenever possible.
For response assessment, Ryan's tumor regression grading (TRG) was used [Table 1].
Primary tumor and node downstaging were defined as reductions in T and N stages by at least one level.
OS was defined as time from diagnosis to death resulting from any cause. Patients who were alive were classified as censored observation at the time of the last follow-up for OS.
Disease-free survival (DFS) was defined as the time of diagnosis to locoregional failure, systemic failure, or death resulting from any cause, which ever occurred first. Patients who were alive without failure were classified as censored observations at the time of the last follow-up for DFS.
Statistical analysis was done using IBM SPSS 20 software. Percentage of patients with respect to response rates and toxicities was computed in each of the treatment groups. To test the statistical significance of the difference in pathological tumor response rates and toxicities between the two groups, Chi-square test was done. Kaplan–Meier estimate of survival rate was computed for each group. To test the statistical significance of the difference in survival rate, the log-rank test was applied. To test the impact of various clinical parameters on survival, univariate and multivariate analysis was done.
| » Results|| |
A total number of 60 patients with LARC (30 patients in the 5-FU/LV group and 30 in the capecitabine group), who received neoadjuvant long-course chemoradiation between January 2009 and May 2014, were analyzed. Patient, tumor, and treatment characteristics are given in [Table 2] and [Table 3]. PR assessment was possible only in 59 patients as one patient did not undergo surgery due to neutropenic sepsis and subsequent poor general condition. Grade 3 and 4 neutropenia developed in three patients, two in 5 FU/LV arm and one in capecitabine arm. Only two patients had hand-foot syndrome and both were in the capecitabine group. The overall rate of downstaging was 69% in the capecitabine group and 76% in the 5-FU/LV group (P = 0.5), and complete pathological response (pCR) was 24% in the capecitabine group and 20% in the 5-FU/LV group (P = 0.7). PR and toxicity comparison is given in [Table 4] and [Table 5].
A total of 12 patients had recurrences in the entire cohort. Among them, 4 patients were in capecitabine group and 8 patients in the 5-FU/LV group. In the capecitabine group, all were distant metastasis except for 1 patient who had both local and distant recurrence. Three of the four patients with recurrence died due to disease, and the fourth patient is undergoing chemotherapy. In the 5-FU group, 8 patients had recurrence: local only – 2 patients, local + regional – 1 patient, local + distant – 1 patient, distant only – 4 patients.
In the capecitabine group, the mean OS calculated was 48.5 months with 95% confidence interval (41.4–55.7 months). All events had occurred within the first 3 years, and the OS remained the same thereafter. In the 5FU/LV group, the mean OS calculated was 44.4 months with 95% confidence interval (38–50.7 months). All events had occurred within the first 2 years, and the OS remained the same thereafter [Figure 1]. Four patients in the capecitabine arm died, and of which, three were disease-related. In the 5 FU/LV arm, 6 patients died, 4 were disease-related, and 2 due to unrelated causes.
DFS also remained the same between two groups and the 3-year DFS was 78.9% for capecitabine and 63.7% for 5 FU/LV group (P = 0.2) [Figure 2].
Univariate analysis was done to check the impact of different variables on survival, and the factors found to be significant are listed in [Table 6]. Multivariate analysis was performed to find the cumulative correlation of these factors with OS and DFS. Factors found significant in the multivariate analysis where hematological toxicity was associated with poorer OS (P = 0.002). Pathological downstaging was associated with a better OS (P = 0.001), Ryan's TRG: response versus no response was associated with a better OS and DFS (P = 0.003 and P = 0.007).
| » Discussion|| |
The proven efficacy of capecitabine over intravenous 5-FU/LV in the treatment of colon cancer has led to the development of a number of studies evaluating the use of capecitabine in concurrent CRT schedules for patients with LARC. The definitive demonstration that the efficacy of capecitabine with RT is similar to 5-FU with RT has been provided by the NSABP-R-04 and the German noninferiority trial., Capecitabine is expensive compared to 5-FU/LV, and hence, majority of our patients preferred 5-FU/LV. Since data comparing preoperative CRT with 5-FU/LV versus capecitabine in LARC were limited from India, we retrospectively compared the pathological tumor downstaging, pathologic tumor regression, sphincter preservation rates, clinical outcomes, and acute toxicities between the two groups. The overall rate of downstaging was 69% in the capecitabine group and 76% in the 5-FU/LV group (P = 0.5), and pCR was 24% in the capecitabine group and 20% in the 5-FU/LV group (P = 0.7); however, this difference did not reach statistical significance. A phase II trial from M. D. Anderson reported tumor downstaging after CI 5-FU as 62% and pCR rates as 27%. In a meta-analysis of 71 trials with a total of 4732 patients by Sanghera et al., they found similar pCR rates with capecitabine and infusional fluorouracil (17% vs. 20%). In a recent German phase III noninferiority trial comparing 5-FU/LV and capecitabine by Hofheinz et al., pCR rate was 14% and 5% in capecitabine and 5-FU/LV groups, respectively. In our study also, pCR was slightly better in the capecitabine group compared to 5-FU/LV group though statistically not significant. PR was also assessed using RTG grade. TRG is used to quantify the pathological downstaging in many preoperative CRT trial and its prognostic significance was shown in a retrospective review by Dhadda et al. In our analysis, the pCR was 24% in capecitabine group and 20% in 5-FU/LV group (P = 0.7). None of the studies which compared preoperative CRT with 5-FU/LV and capecitabine used Ryan's grading for PR assessment. Tumor downstaging and pCR after neoadjuvant CRT is closely related to sphincter preservation in patients with low-lying rectal cancer. In our patients with low rectal tumors, sphincter preservation rates were higher in the capecitabine group (21%) than in the bolus 5-FU arm (11%), but P value was not significant (P = 1.00). However, sphincter preservation in low rectal tumors is affected by several other factors such as tumor distance from anal verge, clinical stage, and surgical expertise in performing ultra-low LAR. In our study, a total of 4 patients in the capecitabine group and 8 patients in the 5-FU group had recurrent disease. Locoregional recurrences were less in the capecitabine group (one) when compared to the 5-FU/LV group (four).
An attempt has been made to compare the outcome in terms of OS and DFS between the two groups. There was no statistically significant difference in OS (P = 0.720). One-, two-, and three-year OS for the capecitabine group was 93%, 87.5%, and 78%, respectively, and in the 5FU group, it was 90%, 82%, and 76%, respectively. Observations were similar to the German phase III noninferiority trial1, in which 5-year OS between capecitabine and 5-FU was 76% versus 67%. The 2-year DFS was better in capecitabine group, 78.7%, when compared to 71.9% in the 5FU/LV group but it was not statistically significant (P = 0.2).
Two-year OS for patients with any pathological downstaging versus no downstaging was 93% versus 58% (P = 0.001), pathological node-negative versus node-positive was 94% versus 57% and Ryan's TRG-3 (no response) versus response (0, 1, 2) was 57% versus 92% (P = 0.003). Pathological node positivity and no PR were significantly associated with reduced DFS. Kim et al. also reported pathologic node positivity as the most important factor affecting survival.
Even though preoperative CRT is associated with improved outcome, tolerance of the same with different concurrent chemo agents has been an issue. An attempt has been made to compare the documented acute toxicities and compliance to treatment in our patients. Except for one in capecitabine group, all patients completed their scheduled course of radiation without breaks. Eighty percent in capecitabine group and 96.7% in 5-FU/LV group completed their scheduled course of concurrent chemotherapy; the difference was not significant (P = 0.103). The proportion of patients who received adjuvant chemotherapy after resection in both groups is similar (89.7% in the capecitabine group and 83.3% in the 5-FU group). Majority of chemo interruptions during CRT were due to grade 3 or 4 toxicities such as hematological, lower gastrointestinal toxicity, or anorectal pain. In the German noninferiority phase III trial, substantial proportion of patients in the neoadjuvant cohort did not continue chemotherapy after resection of the primary tumor, adjuvant chemotherapy of four cycles was received by 44% of patients in 5-FU group and 52% in the capecitabine group.
Onset of acute toxicity in 40% of our patients in both groups was during the 2nd week of RT irrespective of the chemotherapy schedule. The incidence of hematological toxicities of any grade was 23% in 5-FU group and 16% in capecitabine group (P = 0.5). The most common hematological toxicity was grade 2 neutropenia. Grade 3 and 4 neutropenia occurred in a total of 3 patients (1 in capecitabine group and 2 in 5-FU/LV group). The patient with grade 4 neutropenia in capecitabine group expired due to sepsis immediately after CRT. In the German noninferiority trial by Hofheinz et al., the most common hematological toxicity was leukopenia which was significantly higher in the 5-FU group (P = 0.04) probably due to continuous infusion 5-FU. The most common nonhematological toxicity in our study was lower gastrointestinal toxicity, 27% in bolus 5-FU/LV group and 30% in capecitabine group. The second most common toxicity was radiation dermatitis 33% in the 5-FU/LV group and 30% in the capecitabine group. Hand-foot syndrome was documented only in 2 capecitabine patients. Statistically, there was no difference in any toxicity between both the treatment groups except for perineal pain which was significantly higher with oral capecitabine (33% versus 6.7%, P = 0.024). Forty-seven percent of tumors in the capecitabine group were located <5 cm from the anal verge compared to 30% in the 5-FU group; this naturally implies that fields would be larger in the former group, contributing to increased perineal toxicity in those patients. In most of the published literature, side effect profiles of the two drugs differed with a greater incidence of hand-foot syndrome, proctitis, diarrhea, and fatigue in the capecitabine arm, and more alopecia and leukopenia in the 5-FU arm.
Outcomes of cancer therapy are traditionally being evaluated using objective response and survival criteria. There is, however, increasing emphasis on assessment of the quality of life (QoL), convenience, and patient preference. A study by Twelves et al. assessing QoL and patients preference between 5-FU and capecitabine in metastatic colorectal cancers revealed a significant patient preference for oral treatment due to convenience and home-based administration. QoL data were available only for 34 patients, and hence, we did not attempt to compare the QoL.
Limitations of the study
This study, being retrospective, was subject to the limitations of that study design with its inherent bias and had a small sample size.
| » Conclusion|| |
A few important conclusions from the observations and analysis of our study are: pathological complete response using Ryan's grading (pCR 20% in 5 FU/LV and 24% in capecitabine arm) was minimally higher in capecitabine group, whereas pathological T and N tumor downstaging (76% in 5-FU/LV and 69% capecitabine group) was slightly better in the 5-FU/LV group with no statistical significance.
In low rectal tumors, there was a slightly higher sphincter preservation rate in capecitabine group, but the difference was not significant. Acute complication rates were comparable and both regimens were well tolerated. Only 2 patients had hand-foot syndrome, and both were in the capecitabine group. Most common hematological toxicity was grade 2 neutropenia. Grade 3 and 4 neutropenia occurred in a total of 3 patients (1 in capecitabine group and 2 in 5-FU/LV group).
OS and DFS also did not show a statistically significant difference between the two groups with a P value of 0.720 and 0.255, respectively. Factors which were significantly associated with OS on both univariate and multivariate analysis were Ryan's TRG, pathological downstaging, and hematological toxicity; whereas Ryan's TRG alone was significantly associated with DFS. Survival comparison between 5FU/LV and capecitabine with these subgroups was not done because of the small sample size and limited follow-up time. In summary, our analysis showed the equivalence of both regimens in the preoperative chemoradiation setting.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]