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Clin. Pract. 2018 152 549-560 549 ISSN 2044-9038 A clinical study of adjuvant chemotherapy in younger and elder rectal cancer patientsA Abbreviations CT: Chemotherapy CC: Colon Cancer CI: Confdence Interval CRC: Colorectal Cancer CRT: Chemo-Radiation DSF: Disease Free Survival DRFS: Distant Recurrence Free Survival HR: Hazard Ratio RC: Rectal Cancer RT: Radiotherapy TME: Total Mesorectal Excision TNM: T umor Node Metastasis Introduction Colorectal cancer CRC is one of the leading causes of cancer-related death in both genders worldwide. In Sweden there are around 5500 new cases each year where 2000 of these cases are rectal cancers RC. For many years colon and rectal cancer have been considered as one disease and many oncological studies have evaluated these two together. In recent years it has been shown that colon and rectal cancers have diferent biological behavior despite being seemingly identical tumors 1. Colon and rectal cancers have diferences in the lymphatic drainage and the location of the large blood vessels. RC also has more local recurrences and fewer distant metastases compared to colon cancer CC 1. Even gene expression profle difers signifcantly in CC and RC 23. Te aim of postoperative adjuvant chemotherapy CT is to eliminate circulating tumor cells to reduce the risk of recurrence and improve patient’s survival. In previous studies on CC patients it was shown that 5 fuorouracil 5- Fu based adjuvant CT was related to improved survival compared to patients without adjuvant treatment 4 and that capecitabine administered orally was equally efective compared to bolus 5-Fu/leukovorin 5. Further the addition of oxaliplatin to capecitabine improved the disease free survival DFS 6. In RC patients the role of postoperative CT is still not yet clear. Some studies have found a positive relationship between survival and adjuvant CT 78 while others showed no survival beneft 9. Due to increased life expectancy the number of elderly patients is increasing today and the Maja Zemmler 12 Maria Albertsson 12 Annica Holmqvist 12 1 Department of Clinical and Experimental Medicine Linköping University Linköping Sweden 2 Department of Oncology County Council of Östergötland Linköping Sweden Author for correspondence: annika.holmqvist regionostergotland.se The role of postoperative chemotherapy CT is still unclear and the evidence for recommendations of adjuvant therapy in rectal cancer RC is sparse. The aim of this study was to investigate the outcome and tolerability of postoperative adjuvant CT in a clinical study of patients with RC ≥ 69 or 69 years. Two hundred and thirty one patients with stage II-IV rectal adenocarcinoma from the South East Health Care Region of Sweden were included in this retrospective nested case control study. The patients received radiotherapy RT or chemo- radiation CRT followed by surgery. Seventy-six patients were subjected to postoperative adjuvant CT. In all patients and in patients ≥ 69 years patients with capecitabine had an improved overall survival OS and cancer specifc survival CSS compared to patients without adjuvant CT p0.01 p0.02 p0.03 p0.05 independent of sex age TNM stage diferentiation grade and preoperative RT p0.003 HR 0.29 p0.002 HR 0.13 p0.006 HR 0.26 p0.007 HR 0.13 95 CI but not in patients 69 years p0.05. In patients ≥ 69 years treatment with capectiabine/oxaliplatin were related to worse CSS compared to patients with capectiabine alone p0.02. Fifty seven percent of the patients with capectiabine/oxaliplatin and 17 with capecitabine alone had to stop the treatment due to severe side efects. Adjuvant capecitabine is related to better OS and CSS in RC patient’s ≥ 69 years. Oxaliplatin containing regimen should be administered with caution especially in elderly patients. Keywords: adjuvant chemotherapy elderly patients rectal cancer survival younger patients RESEARCH

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10.4172/clinical-practice.1000392 RESEARCH median age at diagnosis has now reached the age of 70 years. It has been shown that patients more than 70 years old are underrepresented in clinical trials although age itself should not be considered as a contraindication to diferent therapies 10. Te researchers concerns have been that elderly patients’ body has diferent physiology which can lead to decreased CT clearance and risk for side efects. Tey also have other diseases and multiple medications which may interact with CT. Today it is difcult to defne which patients should be considered as elderly only based on their chronological age. It is also difcult to compare the data from diferent CT trials since most of the clinical trials only enroll younger patients and data for older patients are extrapolated 1011. It has been suggested that combined CT for elderly patients should be used with caution due to increased risk of severe toxicity 1213. Recently it was shown that elderly patients with adjuvant 5-Fu was related to a better survival compared to patients with surgery alone 14. Te addition of adjuvant oxaliplatin to 5-Fu in elderly patients has not been recommended due to increased toxicity and no beneft regarding survival 13. Te aim of this study was to analyse the diferences in treatment response side efects and compliance between patients with RC with adjuvant CT and patients without adjuvant treatment by also considering younger 69 years and elder patients ≥ 69 years. Patients and methods „ Data A retrospective medical review was performed on all patients n390 diagnosed between 2004-2012 with rectal adenocarcinoma from the Southeast Swedish Health Care Region. Out of the 390 patients 111 patients wit h stage I disease were excluded from further analyses since none of these patients received adjuvant CT. Also patients with poor performance status who did not went through primary surgery n28 patients who received a palliative sigmoidostomy due to advanced disease at diagnosis n3 and 17 patients in the group without adjuvant CT who had microscopically not radical surgery R1 were excluded. Further statistical analyses are based on the remanining 231 patients with stage II-IV disease as shown in TABLE 1. Out of the 231 patients 76 33 were subjected to postoperative adjuvant CT. Te mean follow up duration was 56 months for overall survival OS 56 months for cancer specifc survival CSS range 0-133 and 44 months for disease free survival DFS range 0-131. Te mean age of the patients was 69 range 25-90 and the mean time from operation to start CT was 54 days range 23-115 mean 7.7 weeks. Te cut-of point for further analyses was selected as 69 years since the mean age of the patients in this study was 69 years. Descriptive data such as sex age histological examination tumor location pathological and radiological stage time of diagnosis date of surgery information about CT and RT were obtained from patients’ oncological and surgical records. All information abou t the side efects of cancer treatment CT dose reduction and regimens change were taken from the patients’ oncological fles. „ Treatment Te preoperative treatment consisted mostly of RT given with 25 Gy in 5 fractions. Te surgery was perfor med with the median of 10 days range 1-13 after RT. Fifty-seven percent n43 of the patients with adjuvant CT n76 received short term RT before surgery as shown in TABLE 1. For advanced RC T4 tumors a long-term RT was given with concomitant CT with 504 Gy in 28 fractions and the patients were operated with a median of 39 days range 20-75 after RT. Tirty percent n23 of the patients with adjuvant CT received long RT ± CT before surgery as shown in TABLE 1. Patients were planned to receive a total of 8 treatments 21 days of each cycle of postoperative adjuvant CT. During the CT treatment patients were monitored every 3 weeks with interviews and blood sample for signs of acute toxic efects. Forty-two percent n32 of the adjuvant CT consisted of capecitabine 1000 mg/m 2 × 2 or the combination of capecitabine 850 mg/m 2 × 2/oxaliplatin 130 mg/m 2 38 n29. Of the patients ≥ 69 years 73 n16 received capecitabine 23 n5 capecitabine/ oxaliplatin and 4 n1 had other treatments. In the group of patients with the age of 69 years 30 n16 received capecitabine 44 n24 capecitabine/oxaliplatin and 26 n14 other treatments. In total 19 n15 Clin. Pract. 2018 152 550 Annica Holmqvist

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A clinical study of adjuvant chemotherapy in younger and elder rectal cancer patients 10.4172/clinical-practice.1000392 551 Clin. Pract. 2018 152 RESEARCH Table 1. Patients and characteristics of the 231 patients with RC without and with adjuvant CT. Variables No adjuvant CT n155 Adjuvant CT n76 All patients n231 p-value Sex 0.94 Female 64 41 31 41 95 41 Male 91 59 45 59 136 59 Age 69 years 59 38 54 71 113 49 0.0001 ≥ 69 years 96 62 22 29 118 51 TNM IIA-IIB 80 51 14 18 94 41 0.0001 IIIA 6 4 5 7 11 5 IIIB 23 15 25 33 48 21 IIIC 14 9 21 28 35 15 IV 32 21 11 14 43 18 Diferentiation grade Good 6 4 1 2 7 3 0.09 Moderate 103 66 42 55 145 63 Poor 46 30 33 43 79 34 Mucinous No 137 88 64 84 201 87 0.37 Yes 18 12 12 16 30 13 Vacular invasion No 129 83 47 62 176 76 0.0003 Yes 26 17 29 38 55 24 Perineural growth No 141 91 52 68 193 84 0.0001 Yes 14 9 24 32 38 16 Distant recurrence No 103 66 41 54 144 62 0.07 Yes 52 34 35 46 87 38 Local recurrence No 145 94 67 88 212 92 0.16 Yes 10 6 9 12 19 8 Neoadjuvant CT No 130 84 55 72 185 80 0.04 Yes 25 16 21 28 46 20 Type of preoperative RT No preoperative RT 43 28 10 13 53 23 0.05 Short RT 5 × 5 Gy 72 46 43 57 115 50 Long RT ± CT 40 26 23 30 63 27 Surgery Rectum amputation 56 36 30 39 86 37 0.57 TME 92 59 45 59 137 60 TEM 3 2 0 3 1 Proctocolectomy 4 3 1 1 5 2 Resection margin Tumour free 155 100 64 84 219 95 0.0001 Tumour 0 0 12 16 12 5 Distant to anal verge cm 808 764 793 RCrectal cancer RTradiotherapy CTchemotherapy TMEtotal mesorectal excision TEMtransanal endoscopic microsurgery of the patients with adjuvant CT received other treatments therefore further survival analyses are based on these 2 treatment regimes. Te study protocol was approved by the regional ethical committee in Linköping Sweden reference number: 2014/79-31 according to the World Medical Associations Declaration of Helsinki 1964 and the Amendment of Tokyo in 1975. All the patients in this study had signed a written consent just before they went through the surgery. „ Statistics Chi-square method was used to analyze

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10.4172/clinical-practice.1000392 RESEARCH the diferences between patients with or without adjuvant CT in relation to clinical and histological factors. Cox’s proportional hazard model was used to estimate the relationship between adjuvant CT and survival including both univariate and multivariate analyses. Survival curves were computed according to the Kaplan-Meier method. Te tests were two- sided and p-value of p0.05 was considered statistically signifcant. Results „ Adjuvant CT in relation to survival At frst we investigated the relationship between adjuvant CT OS and CSS in the whole group of patients n231 and in patients 69 years and ≥ 69 years respectively. Next the subgroup of patients with stage II-III tumors were studied. In the whole group of patients patients with adjuvant CT had a better OS compared to the patients without adjuvant CT p0.002 FIGURE 1A the signifcance still remained even after adjustment for sex age TNM stage diferentiation grade and preoperative RT p0.03 HR 0.57 95 CI 0.40-0.95. A trend towards signifcance was seen in patients ≥ 69 years p0.06 FIGURE 1B. No signifcant diferences was found in the subgroup of patients 69 years p0.39 FIGURE 1C. No signifcant diferences in CSS was found between patients with adjuvant CT and patients without adjuvant CT in the whole group of patients or in the subgroups of patients aged 69 or ≥ 69 years p0.15 p0.64 p0.26. In stage II-III tumors there were no signifcant diferences in the whole group of patients or in patients aged 69 or ≥ 69 years for both OS and CSS p0.05. „ Adjuvant capecitabine in relation to survival We further compare the survival between patients with capecitabine and the patients without adjuvant CT. In all patients and in patients ≥ 69 years patients with capecitabine had a signifcantly better OS compared to patients without adjuvant CT p0.01 p0.02 FIGURE 2A and 2B independent of sex age for the whole group TNM stage diferentiation grade and preoperative RT p 0.003 HR 0.29 95 CI 0.13-0.67 p0.002 HR 0.13 95 CI 0.04-0.49. Tere was no signifcance in the group of patients 69 years p0.31 FIGURE 2C. Te same signifcant diference was found for the CSS where patients with adjuvant capecitabine had a better CSS compared to patients without adjuvant CT in all patients and in patients ≥ 69 years p0.03 p0.05 after adjustment for sex age for the whole group TNM stage diferentiation grade and preoperative RT p0.006 HR 0.26 95 CI 0.10-0.68 p0.007 HR 0.13 95 CI 0.03- 0.57 FIGURE 2D and 2E but not in patients with the age of 69 years p0.30 FIGURE 2F. Te distribution of the TNM stage for patients’ ≥ 69 years old with and without adjuvant CT and with capecitabine alone are shown in TABLE 2. Tere were no signifcant diferences found in OS or CSS in patients with stage II-III tumors in the whole group of patients or the subgroup of patients 69 years or ≥ 69 years old p0.05. „ Adjuvant capecitabine/oxaliplatin in relation to survival Further the survival in patients with adjuvant capecitabine/oxaliplatin was compared with patient without adjuvant CT. No signifcant relationships were found in OS and CSS between patients with or without adjuvant capecitabine/oxaliplatin in all patients p0.42 p0.98 or in patients aged ≥ 69 years p0.37 p0.18 or 69 years p0.49 p0.74. In stage II-III tumors the CSS was signifcantly reduced in patients ≥ 69 years with capecitabine/oxaliplatin compared to patients without adjuvant CT p0.04 and the signifcance remained even after adjustment for sex diferentiation grade and preoperative RT p0.03 HR 3.72 95 CI 1.10-12.60. No signifcant diferences were found in all patients or in the subgroup of patients 69 years p0.11 p0.22. Te TNM stage for patients’ ≥ 69 years old with capecitabine/oxaliplatin are shown in TABLE 2. „ Comparison between adjuvant capecitabine and capecitabine/ oxaliplatin in relation to survival Te OS and CSS were further compared between patients with capecitabine and capecitabine/oxaliplatin. Patients ≥ 69 years with capecitabine had a signifcantly better CSS compared to patients with capecitabine/ oxaliplatin p0.02 no multivariate analysis was Clin. Pract. 2018 152 552 Annica Holmqvist

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A clinical study of adjuvant chemotherapy in younger and elder rectal cancer patients 10.4172/clinical-practice.1000392 553 Clin. Pract. 2018 152 RESEARCH OS OS OS ≥69 FIGURE 1. The overall survival OS in patients with adjuvant chemotherapy CT and patients without adjuvant CT A in all patients in patients B ≥ 69 years and C 69 years

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10.4172/clinical-practice.1000392 RESEARCH g n i v i v r u S n o i t r o p o r P e v i t a l u m u C OS OS CSS CSS ≥ OS ≥ CSS FIGURE 2. The overall survival OS in patients with capecitabine and patients without adjuvant CT A in all patients B in patients ≥ 69 years and C 69 years. The cancer specifc survival CSS in patients with capecitabine and without adjuvant CT D in all patients E in patients ≥ 69 years and F 69 years Table 2. TNM stage in patients ≥ 69 years old with or without adjuvant CT and in patients ≥ 69 with capecitabine and capecitabine/oxaliplatin Age ≥ 69 years No adjuvant CT n Adjuvant CT n Capecitabine n Capecitabine /oxaliplatin n TNM stage IIA-IIB IIIA IIIB IIIC IV Total 55 57 2 2 12 13 9 9 18 19 96 100 3 13 1 5 7 32 10 45 1 5 22 100 5 17 3 10 13 43 6 20 3 10 30 100 1 20 0 1 20 3 60 0 5 100 possible due to few cases FIGURE 3A and 3B. In the whole group of patients a trend towards signifcance was seen p0.08 FIGURE 3A but not in patients 69 years old p0.48 FIGURE Clin. Pract. 2018 152 554 Annica Holmqvist

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A clinical study of adjuvant chemotherapy in younger and elder rectal cancer patients 10.4172/clinical-practice.1000392 555 Clin. Pract. 2018 152 RESEARCH 3C. For the OS no statistical signifcance was found in all patients in patients 69 and ≥ 69 years p0.05. In stage II-III tumours a signifcantly better OS and CSS was seen in patients ≥ 69 years with capecitabine compared to capecitabine/ oxaliplatin p0.04 p0.02 no multivariate analyze was possible due to few ca ses. „ Side efects/compliance in RC patients with adjuvant CT Next the side efects in RC patients with adjuvant CT were analyzed. Te most common side efect was neurotoxicity in the whole group of patients 32 and in the subgroups of patients aged 69 33 and ≥69 29 TABLE 3. No signifcant diferences were found in the number of side efects between the groups of patients aged 69 and ≥69 years p0.78 TABLE 3. Te patient’s compliance in relation to adjuvant CT was furt her investigated. Of the 76 patients with adjuvant CT 28 37 CSS CSS CSS ≥69 FIGURE 3. The cancer specifc survival CSS in patients with capecitabine/oxaliplatin and in patients with capecitabine alone A in the whole group B in patients ≥ 69 years and C 69 years old.

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10.4172/clinical-practice.1000392 RESEARCH patients completed all the treatments without dose reduction. Twenty-six 34 patients had to stop the treatment due to severe side efects TABLE 3. „ Side efects/compliance in RC patients with adjuvant capecitabine and capecitabine/oxaliplatin Further the side efects in RC patients with adjuvant capecitabine and capecitabine/ oxaliplatin were investigated. Compared to capecitabine alone patients with capecitabine/ oxaliplatin had a higher frequency of neurotoxicity 73 vs. 17 diarrhea 63 vs. 37 and neutropenia/pancytopenia 80 vs. 0. Capecitabine had a higher rate of hand foot syndrome compared to capecitabine/ oxaliplatin 89 vs. 11 TABLE 4. Fifty seven percent n17 of the patients with capectiabine/oxaliplatin and 17 n5 with capecitabine alone had to stop the treatment due to severe side efects. Sixty fve percent n17 of the patients who had to stop the treatment due to severe side efects received capecitabine/ oxaliplatin and 19 n5 single capecitabine. Of the patients with no dose modifcation 62 n16 received capecitabine and 23 n6 capecitabine/oxaliplatin TABLE 4. Table 3. Side efects and compliance of adjuvant CT in patients with RC in relation to age. Patients with adjuvant CT n76 69 years n ≥ 69 years n All patients n p-value Side efects No 19 35 7 32 26 34 0. 78 Yes 35 65 15 68 50 66 Type of side efects Neurotoxicity 15 33 5 29 20 32 Diarrhea 3 7 6 35 9 14 Hand foot syndrome 7 15 1 6 8 13 Neutropenia 7 15 1 6 8 13 Vomiting 3 7 0 3 5 Allergic reaction 3 7 0 3 5 High performance status WHO 2 2 4 1 6 3 5 Kidney toxicity 2 4 0 2 3 Pancytopenia 1 2 1 6 2 3 Thrombocytopenia 1 2 1 6 2 3 Liver toxicity 1 2 1 6 2 3 Skin infection 1 2 0 1 1 Total 46 100 17 100 63 100 Compliance n 76 69 years n ≥ 69 years n All patients n p-value No dose modifcation 20 37 8 36 28 37 Dose reduction 15 28 7 32 22 29 0.58 Dose interruption 19 35 7 32 26 34 Total 54 100 22 100 76 100 Some patients had more than one side efect at the same time CTchemotherapy RCrectal cancer Table 4. Side efects and compliance in patients with RC 69 or ≥ 69 years old with adjuvant capecitabine and capecitabine/oxaliplatin. Type of adjuvant CT Capecitabine n Capecitabine/ oxaliplatin n Other treatments n Total n Age years Side efects 69 ≥ 69 69 ≥ 69 69 ≥ 69 Neurotoxicity 16 2 11 10 56 3 17 4 22 0 18 100 Hand foot syndrome 2 22 6 67 1 11 0 0 0 9 100 Diarrhea 2 25 1 12 5 63 0 0 0 8 100 Neutropenia/pancytopenia 0 0 5 55 2 25 2 25 0 9 100 Age years Compliance 69 ≥ 69 69 ≥ 69 69 ≥ 69 No dose modifcation 11 73 5 33 5 19 1 25 4 29 2 100 Dose reduction 3 20 6 40 6 23 1 25 6 42 0 Interruption 1 7 4 27 15 58 2 50 4 29 0 15 100 15 100 6 100 4 100 14 100 2 100 CTchemotherapy RCrectal cancer Clin. Pract. 2018 152 556 Annica Holmqvist

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A clinical study of adjuvant chemotherapy in younger and elder rectal cancer patients 10.4172/clinical-practice.1000392 557 Clin. Pract. 2018 152 RESEARCH Discussion In this study we showed that 5-Fu based postoperative CT was related to improved OS patients with RC with preoperative RT or CRT. Our results are in line with two previous meta- analyses of patients with RC treated with either preoperative RT or CRT. In these studies it was shown that 5-Fu based postoperative CT was associated with improved survival compared to the patients who went through surgery alone 78. Even though these two large meta-analyses showed signifcantly positive results the role of postoperative CT in RC patients is still not yet clear. In the meta-analysis by 7 only 5 out 21 trials showed signifcantly positive results for patients with adjuvant CT compared to patients without CT. Many studies were conducted on a Japanese population treated with Uracil-T egafur and the postoperative adjuvant CT was only found benefcial in older studies not employing TME surgery 7. In the meta-analysis by 8 patients were signifcantly younger than average and the follow up time was less than 5 years which were suggested to afect the beneft of OS 8. Te weaknesses of our study are that it is a small study based on a retrospective material and the material is taken from patients with real life experience with no randomization. Our result is in line with the previous large meta-analyses but since this material is relatively small it is difcult to draw any frm conclusions. Te cornerstone of adjuvant CT in RC is fuoropyrymidine containing agents such a 5-Fu administrated either by continuous intravenous infusion or by bolus. It was shown in CC studies that patients with adjuvant 5-Fu and levamisole had a better survival compared to patients with surgery alone 4 and that the use of capecitabine administered orally was equally efective compared to bolus 5-Fu/leucovorin 5. Te main adjuvant treatment today in CRC patients is capecitabine as monotherapy or capecitabine in combination with oxaliplatin. In our study where only patients with RC were included 42 of the patients received capecitabine and 38 the combination of capecitabine/oxaliplatin as adjuvant CT. Since most of the adjuvant CT consisted of capecitabine or the combination of capecitabine/oxaliplatin we further wanted to investigate the survival relationships between patients with capecitabine or capecitabine/ oxaliplatin and patients without adjuvant CT. Here we showed that both the OS and CSS were signifcantly increased in the whole group of patients with adjuvant capecitabine compared to patients without adjuvant treatment. Te signifcance still remained even after adjusting for sex age diferentiation preoperative RT and neoadjuvant CT. Interestingly the same signifcant relationship was found in patient’s ≥ 69 years where capacitabine improved the OS and CSS independent of sex diferentiation preoperative RT and neoadjuvant CT. No signifcant diference was found in patients less than 69 years. In previous reports it has been shown that patients above 70 years have been underrepresented in clinical trials 11. Te reason for that decision has been that elderly patients’ body has diferent physiology with increased fat content and chronic organ insufciency and that elderly patients more often have other diseases and multiple medications which may interact with the CT. A recent study on CC patients showed that the survival beneft with adjuvant 5-Fu did not diminish with patients’ age 14 and that patients with stage III CRC with the age of ≥ 75 years had a survival beneft with 5-Fu based regimes 13. Te previous studies on elderly patients have included patients with either CC or CRC. As far as we know this is the frst study on a pure RC material that shows that postoperative adjuvant capecitabine is related to improved OS and CSS in patients with RC ≥ 69 years. Unfortunately there were no signifcant diferences in the subgroup analyses of stage II- III tumors which might be caused by too few cases in this material. A larger randomized study of patients with RC and adjuvant CT would be benefcial to further investigate this relationship. Te addition of oxaliplatin to 5-Fu based regimes has been shown to prolong the DFS and improve the OS in CRC patients with stage II-III tumors 615. Here in this study there were no signifcant diferences in OS or CSS between patients with adjuvant capecitabine/ oxaliplatin and patients without adjuvant CT in the whole group of p atients and in subgroups of patients more or less than 69 years old. Interestingly in stage II-III tumors the CSS survival was signifcantly reduced in patients ≥ 69 years with capecitabine/oxaliplatin compared to patients without adjuvant CT and the signifcance still remained even after adjustment for sex diferentiation preoperative RT and neoadjuvant CT. No signifcant relationship was found in the subgroup of pat ients aged

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10.4172/clinical-practice.1000392 RESEARCH 69 years. Tis result makes us suggest that the addition of oxaliplatin to 5-Fu based regimes does not improve the outcome especially in elderly patients with RC. Few have analyzed the diferences in survival between capecitabine and capectabine/ oxaliplatin in elderly CRC patients. One previous study on elderly CC patients showed that the addition of oxaliplatin to 5-Fu was equally efcient compared to 5-Fu as monotherapy 13. Here we showed that patients ≥ 69 years had a signifcantly better CSS with capecitabine alone compared to capecitabine in combination with oxaliplatin. Te same result were found in the subgroup of stage II-III tumors where a signifcantly better OS and CSS was seen in patients ≥ 69 years with capecitabine compared to capecitabine/oxaliplatin. Unfortunately no multivariate analysis was able to perform due to few cases. Tis result together with our previous fndings strengthens the theory that capectabine alone is a good adjuvant treatment for patients ≥ 69 years old. However more studies on a larger cohort of patients are needed to confrm this relationship. We also showed that only 37 of the patients 69 and 36 the patient’s ≥ 69 years were able to complete all CT cycles without dose reduction or treatment interruption. Tirty-four percent 34 of the patients had to interrupt the adjuvant treatment due to severe side efects CTCA2. Our results shows a slight higher frequency of side efects compared to previous studies where 41-42 of the patients with RC with preoperative RT/ CRT managed to complete all the adjuvant CT cycles 9. Te reason for that could be that the patient’s performance status was higher in our study compared to the previous trials WHO 0-1 where a more selected group of patients with a better performance status received the treatment. In the patients with capecitabine/oxaliplatin only 43 of the patients with capecitabine/ oxaliplatin managed to complete the treatment without dose reduction or interruption. Tis result is in line with one previous study where 48 completed six cycles of treatment 16. Even though it is few patients it is worth to note that 57 of the patients in our study had to interrupt the treatment with capecitabine/ oxaliplatin. In patients with capecitabine 17 had to stop the treatment due to severe side efects and 33 were able to complete the treatment after dose modifcation. Te same results were found by others where 17 of the patients with capecitabine had to interrupt the treatment due to severe side efects and 43 needed a dose modifcation 5. We also showed that 63 of the patients with treatment interruption received capecitabine/oxaliplatin and 19 single capecitabine. Of the patients with no dose modifcation 57 received capecitabine and 21 capecitabine/ oxaliplatin Oxaliplatin based regimes gives a high frequency of treatment interruptions due to severe side efects compared to single capectiabine. Finally the side efects were studied in patients with adjuvant CT. Te most common side efect in the whole group of patients was neurotoxicity 32 diarrhea 14 hand foot syndrome 13 and neutropenia 13. In the patients with capecitabine/oxaliplatin compared to patients with capecitabine a higher frequency of neurotoxicity 73 vs. 17 diarrhea 63 vs. 37 and neutropenia/ pancytopenia 80 vs. 0 was seen. Our result shows that treatment with oxaliplatin in combination with capectiabine has a higher frequency of severe side efects compared to treatment with capecitabine alone. Conclusions Capecitabine as a monotherapy given postoperatively contribute to better OS and CSS in RC patients’ ≥69 years. Considering the high prevalence of side efects and no survival beneft the oxaliplatin containing regimen should be administered with caution especially for elderly patients. In order to confrm these relationships more studies on a larger cohort of patients are needed. Acknowledgements Te authors would like to thank Professor Xiao-Feng Sun Department of Oncology Linköping Sweden for her great support during this project. Tis study was supported by grants from the foundation of Oncological Clinical Research in Linköping the Swedish Clin. Pract. 2018 152 558 Annica Holmqvist

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A clinical study of adjuvant chemotherapy in younger and elder rectal cancer patients 10.4172/clinical-practice.1000392 559 Clin. Pract. 2018 152 RESEARCH Cancer Foundation Swedish Research Council and the Health Research Council in the South- East of Sweden. Competing interests Te authors declare no conficts of interest or funding sources that could be perceived as a confict of interest.

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10.4172/clinical-practice.1000392 RESEARCH REFERENCES Tamas K Walenkamp AM de Vries EG et al. Rectal and colon cancer: Not just a diferent anatomic site. Cancer T reat. Rev. 418 671-679 2015. Fransen K Klintenas M Osterstrom A et al. Mutation analysis of the BRAF ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis. 254 527-533 2004. Birkenkamp-Demtroder K Olesen SH Sorensen FB et al. Diferential gene expression in colon cancer of the caecum versus the sigmoid and rectosigmoid. Gut. 543 374-384 2005. Moertel CG Fleming TR Macdonald JS et al. Levamisole and fuorouracil for adjuvant therapy of resected colon carcinoma. N. Engl. J. Med. 3226 352- 358 1990. Twelves C Wong A Nowacki MP et al. Capecitabine as adjuvant treatment for stage III colon cancer. N. Engl. J. Med. 35226 2696-2704 2005. Haller DG Tabernero J Maroun J et al. Capecitabine plus oxaliplatin compared with fuorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J. Clin. Oncol. 2911 1465-1471 2011. Petersen SH Harling H Kirkeby LT et al. Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst. Rev. 3 CD004078 2012. Petrelli F Coinu A Lonati V Barni S. A systematic review and meta-analysis of adjuvant chemotherapy after neoadjuvant treatment and surgery for rectal cancer. Int. J. Colorectal Dis. 304 447-457 2015. Bosset JF Calais G Mineur L et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 152 184-190 2014. Hutchins LF Unger JM Crowley JJ et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N. Engl. J. Med. 34127 2061- 2067 1999. Zulman DM Sussman JB Chen X et al. Examining the evidence: a systematic review of the inclusion and analysis of older adults in randomized controlled trials. J. Gen. Intern. Med. 267 783-790 2011. Kim JH. Chemotherapy for colorectal cancer in the elderly. World J. Gastroenterol. 2117 5158-5166 2015. Sanof HK Carpenter WR Sturmer T et al. Efect of adjuvant chemotherapy on survival of patients with stage III colon cancer diagnosed after age 75 years. J. Clin. Oncol. 3021 2624-2634 2012. Iwashyna TJ Lamont EB. Efectiveness of adjuvant fuorouracil in clinical practice: a population-based cohort study of elderly patients with stage III colon cancer. J. Clin. Oncol. 2019 3992-3998 2002. Andre T Boni C Navarro M et al. Improved overall survival with oxaliplatin fuorouracil and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J. Clin. Oncol. 2719 3109-3116 2009. Glynne-Jones R Counsell N Quirke P et al. Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin XELOX versus control. Ann. Oncol. 257 1356- 13562 2014. Clin. Pract. 2018 152 560 Annica Holmqvist

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