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/lp/springer-journals/the-effect-on-the-small-bowel-of-5-fu-and-oxaliplatin-in-combination-bIa88TCLn2
- Publisher
- Springer Journals
- Copyright
- Copyright © 2009 by Gunnlaugsson et al; licensee BioMed Central Ltd.
- Subject
- Medicine & Public Health; Oncology; Radiotherapy
- eISSN
- 1748-717X
- DOI
- 10.1186/1748-717X-4-61
- pmid
- 20003187
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- See Article on Publisher Site
Abstract
Background: In locally advanced rectal cancer, 5-Fluorouracil (5-FU)-based chemoradiation is the standard treatment. The main acute toxicity of this treatment is enteritis. Due to its potential radiosensitizing properties, oxaliplatin has recently been incorporated in many clinical chemoradiation protocols. The aim of this study was to investigate to what extent 5-FU and oxaliplatin influence the radiation (RT) induced small bowel mucosal damage when given in conjunction with single or split dose RT. Methods: Immune competent balb-c mice were treated with varying doses of 5-FU, oxaliplatin (given intraperitoneally) and total body RT, alone or in different combinations in a series of experiments. The small bowel damage was studied by a microcolony survival assay. The treatment effect was evaluated using the inverse of the slope (D ) of the exponential part of the dose- response curve. Results: In two separate experiments the dose-response relations were determined for single doses of RT alone, yielding D values of 2.79 Gy (95% CI: 2.65 - 2.95) and 2.98 Gy (2.66 - 3.39), for doses in the intervals of 5-17 Gy and 5-10 Gy, respectively. Equitoxic low doses (IC5) of the two drugs in combination with RT caused a decrease in jejunal crypt count with significantly lower D : 2.30 Gy (2.10 - 2.56) for RT+5-FU and 2.27 Gy (2.08 - 2.49) for RT+oxaliplatin. Adding both drugs to RT did not further decrease D : 2.28 Gy (1.97 - 2.71) for RT+5-FU+oxaliplatin. A clearly higher crypt survival was noted for split course radiation (3 × 2.5 Gy) compared to a single fraction of 7.5 Gy. The same difference was seen when 5-FU and/or oxaliplatin were added. Conclusion: Combining 5-FU or oxaliplatin with RT lead to an increase in mucosal damage as compared to RT alone in our experimental setting. No additional reduction of jejunal crypt counts was noted when both drugs were combined with single dose RT. The higher crypt survival with split dose radiation indicates a substantial recovery between radiation fractions. This mucosal- sparing effect achieved by fractionation was maintained also when chemotherapy was added. Page 1 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:61 http://www.ro-journal.com/content/4/1/61 of 3 Gy/min. The animals were treated five at a time in a Background Surgery is the cornerstone of curative therapy for colorec- lucite box, specially designed for obtaining a homoge- tal cancer. In locally advanced cases, radiotherapy is used nous total body dose (within ± 5%) and for gentle fixation preoperatively to shrink the tumor in order to facilitate a of the animals. Control animals were sham irradiated. The curative resection. An improved effect has been shown time of radiation was defined as time point 0. The radio- when radiation is combined with the chemotherapeutic therapy was given as a single fraction (0, 2.5, 5, 7.5, 10, agent, 5-fluorouracil (5-FU) [1-3]. This has made 5-FU- 14, or 17 Gy) or as a split dose treatment with 2.5 Gy frac- based chemoradiation a standard treatment for locally tions delivered two or three times with six-hour intervals. advanced rectal cancer. Another drug, oxaliplatin, has Five mice were treated at each radiation dose level. become widely used in adjuvant [4], as well as palliative 5-FU and oxaliplatin [5,6] treatment of colorectal cancer. Several phase II stud- ies indicate good efficacy when oxaliplatin was combined Both drugs were administered intraperitoneally. Single with 5-FU or oral fluoropyrimidines such as capecitabine doses of 5-FU (Mayne Pharma) 0-200 mg/kg and of oxali- and radiotherapy [7-11]. Preclinical studies have demon- platin (Mayne Pharma) 0-10 mg/kg were administered strated that both 5-FU and oxaliplatin have radiosensitiz- alone or in combination with radiotherapy. When com- ing properties on tumor cell lines in vitro [12,13], while bined, 5-FU was injected immediately followed by the the additional effect of oxaliplatin in vivo is more uncer- administration of oxaliplatin one hour prior to radiother- tain [13,14]. apy. Control animals were given saline injection instead of chemotherapy. For each different dose level, five mice The main dose-limiting acute side effect during abdomi- were treated. nal radiation is enteritis. Randomized studies have shown that combined treatment with radiation and 5-FU Microcolony assay increases the risk of diarrhea as compared to radiotherapy A microcolony survival assay [15] was used to analyze alone [2]. There are no published results from rand- crypt survival after treatment. Three days after radiother- omized trials on whether the addition of oxaliplatin fur- apy or chemotherapy, the mice were killed by cervical dis- ther increases gastrointestinal toxicity, but the location and a 10 cm section of the jejunum was collected, combination of 5-FU (or capecitabine), oxaliplatin and stretched and pinned to a cork plate to ease histological radiotherapy has lead to 12-37% grade 3+ enteritis in preparation. Tissues were fixed immediately in 4% forma- phase II trials [7-11]. lin with phosphate buffer and 10 transverse sections of jejunum from each mouse were prepared and stained with The regeneration of the bowel mucosa is dependent on its hematoxylin and eosin (H&E). These transverse sections clonogenic stem cells which are located in the small bowel were analyzed microscopically, and a surviving colony crypts. Therefore, the survival of these clonogens is likely was defined as one demonstrating the presence of ten or to be a decisive factor in the repair of the bowel after cyto- more well-stained cells in the section. The slides were ana- toxic therapy. The pioneering work of Withers and Elkind lyzed by one observer (A.G.) in a blinded fashion. presented in 1970 has given us the opportunity to study this in the mouse intestinal mucosa [15]. Development of Data analysis radiation enteritis is thought to be mediated through a The number of regenerating crypts/circumference was counted for each section from each treated (t) or toxic effect on these mucosal stem cells. The aim of this study was to study the bowel damage caused by radiation, untreated (control, c) animal. The surviving crypt fraction 5-FU or oxaliplatin as well as combinations thereof by was thus t/c and the proportion of crypts destroyed/trans- using a microcolony survival assay and comparing the dif- verse section was 1-t/c. Since ten transverse sections were ference between single and split dose radiotherapy. obtained from each mouse and five mice were used for each treatment dose, each data point was composed of a maximum of 50 observations. A linear regression was Methods Mice done to estimate D , i.e., the inverse of the slope of the Immune competent balb-c mice were used. The mice were exponential part of the survival curve, for radiotherapy treated at the age of six to seven weeks and were housed in alone and for the combinations of 5-FU and/or oxalipla- well-ventilated lucite boxes with food and water ad libi- tin with radiotherapy. The Mann-Whitney test was used to tum. The study was approved by the Malmö-Lund animal compare crypt survival after single versus split-dose radio- ethics committee. therapy. All tests were two-sided and p-values < 0.05 were considered statistically significant. Irradiation Total body irradiation was administered with a 6 MV pho- Experimental design ton beam from a medical linear accelerator at a dose rate Four sets of experiments were performed as follows: Page 2 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:61 http://www.ro-journal.com/content/4/1/61 1. The effect of radiation alone was studied at single doses Increasing doses of oxaliplatin resulted in an essentially ranging from 0 - 17 Gy, with the purpose of describing the linear decrease in the number of surviving crypts in the dose-response relations in our experimental setting and dose range from 6 to 10 mg/kg (Fig. 2B). finding appropriate doses for the combined treatment (step 3). Chemoradiation - single fraction radiation The experiment described above (Fig. 2A-B) showed that 2. The effect of each drug alone, at different doses, was a 5-FU dose of 50 mg/kg and an oxaliplatin dose of 6 mg/ studied to find suitable doses which produced moderate kg each had a modest and equal effect on the intestinal and equal intestinal damage. These doses were then com- crypts, and these doses were chosen for combination with bined with radiation in the next step. radiation. 3. Single radiation fractions, ranging from 0 - 10 Gy, were The addition of 5-FU (Fig. 1C) or oxaliplatin (Fig. 1D) to given alone, or in combination with equitoxic single radiotherapy significantly decreased the number of surviv- doses of 5-FU, oxaliplatin, or both drugs. ing crypts per circumference as compared to radiation for radiation decreased from 2.98 Gy to alone. The D 4. The same single doses of 5-FU and oxaliplatin were 2.30 Gy (p = 0.001) and 2.27 Gy (p = 0.0003) when 5-FU combined with split dose radiation. and oxaliplatin were added respectively. Results The combination of both oxaliplatin and 5-FU with radi- A total of 265 mice were used in the study. Nineteen died otherapy did not lead to any further decrease in D as before histological analysis: radiation alone (n = 4), 5-FU compared to the addition of each drug alone (Fig. 1E-F). alone (n = 1), oxaliplatin alone (n = 6), radiation + 5-FU Split-dose radiotherapy (n = 2), radiation + oxaliplatin (n = 3), radiation + 5-FU + oxaliplatin (n = 2) and 5-FU + oxaliplatin (n = 1) and thus Splitting the radiation dose into two or three fractions 246 mice were available for crypt analysis. A total of 2206 lead to significantly more surviving crypts per circumfer- transverse sections (mean 45 sections per data point) were ence as compared to the same total dose given in one frac- available for analysis. tion (Table 1), with the largest difference noted for 3 × 2.5 Gy compared to 7.5 Gy as a single treatment. Also when Radiotherapy adding chemotherapy, there were clearly more surviving The first radiation series with doses of 0, 5, 7.5, 10, 14 and crypts with fractionated radiation compared to chemo- 17 Gy is visualized in Fig. 1A. The surviving crypts per cir- therapy plus the same radiation dose given as a single cumference decreased with increasing radiation doses dose. showing a dose-response relationship. D was calculated using data points for doses from 5 - 17 Gy where the dose- Discussion effect curve was considered exponential. In this first exper- This is to our knowledge the first study on chemoradia- iment we found a D of 2.79 Gy (95% CI: 2.65 - 2.95). The tion-induced bowel mucosal damage in mice including highest radiation doses of 14 - 17 Gy caused a near com- oxaliplatin. A dose relationship was confirmed between plete eradication of jejunal crypts (Fig. 1A). When plan- radiation dose and crypt survival (Fig. 1A-B). Adding 5-FU ning the chemoradiation experiment, we assumed that or oxaliplatin lead to a significant increase in jejunal crypt radiation doses of 14-17 Gy plus chemotherapy also damage, in terms of decreased D , compared to radiation would lead to zero crypt count, and the highest radiation alone (Fig. 1C-D). The co-administration of both drugs doses were therefore omitted in the studies of combined did not further increase radiation induced mucosal dam- treatment. The result from the radiation alone experiment age (Fig. 1E). Fractionated radiation caused less mucosal with doses in the 0-10 Gy range is depicted in Fig. 1B, damage than the same total dose given as a single fraction. demonstrating a D of 2.98 Gy (95% CI: 2.66 - 3.39). This damage-sparing effect by fractionating the radiation was retained also when chemotherapy was added (Table Chemotherapy 1). 5-FU administration decreased the surviving fraction of crypts per circumference up to a dose of 150 mg/kg (Fig. The initial part of our study aimed at determining the 2A), followed by a further, slight increase in the mean mucosal injury caused by radiation alone. In the two crypt level at the highest 5-FU dose (200 mg/kg). In order series using radiation doses up to 17 Gy and 10 Gy, we to rule out a methodological error as an explanation for found D values of 2.79 and 2.98, respectively, which is this finding, these two 5-FU doses were reevaluated in a higher than usually reported in the literature (typically in separate experiment, which confirmed our original result, the range 1-1.5 [16,17]). In those studies D was calcu- although again with large error bars at this dose level. lated at radiation doses ranging from around 9 - 14 Gy Page 3 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:61 http://www.ro-journal.com/content/4/1/61 A. B. RT RT D =2.79 (2.65-2.95) D =2.98 (2.66-3.39) 0 0 10 10 1 1 0 2 4 6 8 101214 1618 0 2 4 6 8 1012 14 1618 Dose (Gy) Dose (Gy) C. D. 1000 1000 RT + oxa RT + 5FU 100 100 D =2.30 (2.10-2.56) D =2.27 (2.08-2.49) 0 0 10 10 1 1 0 2 4 6 8 1012141618 02468 10 12 14 16 18 Dose (Gy) Dose (Gy) E. F. 1000 1000 RT RT + 5FU + oxa RT + 5FU RT + oxa RT + 5FU + oxa D =2.28 (1.97-2.71) 0 2 4 6 8 1012141618 0246 8 10 12 14 16 18 Dose (Gy) Dose (Gy) Figure 1 The number of surviving crypts per circumference and D with 95% confidence interval after A st The number of surviving crypts per circumference and D with 95% confidence interval after A. Radiotherapy (1 nd experiment, 0-17 Gy), B. Radiotherapy (2 experiment, 0-10 Gy), C. 5-FU + radiotherapy (0-10 Gy), D. Oxaliplatin + radio- therapy (0-10 Gy) and E. 5-FU + oxaliplatin + radiotherapy (0-10 Gy). F. Survival curves for all treatment combinations above with separate data points removed for clarity. Each data point represents the mean in each group and the error bars 1 SD. Oxaliplatin dose: 6 mg/kg, 5-FU dose: 50 mg/kg. Page 4 of 7 (page number not for citation purposes) Crypts per circumference Crypts per circumference Cr ypts per cir cumfer ence Crypts per circumference Cr ypts per circumfer ence Crypts per circumference Radiation Oncology 2009, 4:61 http://www.ro-journal.com/content/4/1/61 ery may be the slightly shorter time span from treatment A. 1.20 to analysis compared to other similar studies [20]. 5-FU 1.00 Regarding oxaliplatin, no previous studies have been pub- lished on its effect on jejunal clonogenic crypt survival, 0.80 neither alone nor in combination with radiotherapy. The oxaliplatin doses tested, from 4 to 10 mg/kg, have previ- 0.60 ously been used in combination with radiotherapy in 0.40 xenografted mice and have shown antitumoral effect and limited general toxicity [14]. Our study showed a slight to 0.20 moderate drop in jejunal crypt surviving fraction within that dose range (Fig. 2B), when administering oxaliplatin 0.00 0 50 100 150 200 alone. 5-FU (mg/kg) B. In the chemoradiation experiments we used chemother- 1.20 Oxaliplatin apy doses that caused a low degree of mucosal damage on 1.00 their own. This principle is often applied also in the clini- cal setting. Despite these low doses we saw a significant 0.80 reduction of the D values by adding either of the two drugs to radiation compared to radiation alone, which 0.60 indicates that both 5-FU and oxaliplatin may potentiate radiation-induced mucosal damage. However, there was 0.40 no additional jejunal injury when both drugs were added 0.20 to radiation. 0.00 02 46 8 10 When treating patients with colorectal cancer, radiation Oxaliplatin (mg/kg) doses higher than 5 Gy per fraction are usually not used, especially not in combination with chemotherapy. To bet- Th tion of chemotherapy dose Figure 2 e surviving fraction of crypts per circumference as a func- ter mimic the clinical situation, we investigated the effect The surviving fraction of crypts per circumference as of fractionated radiation. Compared with 5 and 7.5 Gy as a function of chemotherapy dose. A. 5-Fluorouracil (5- FU), B. Oxaliplatin. Each data point stands for the mean of a single dose, 2 and 3 × 2.5 Gy resulted in considerably each group and error bars represent +/- 1 SD. less jejunal damage (Table 1), indicating a substantial cel- lular recovery during the 6 h time span between radiation fractions. The fact that there was no significant reduction [17], compared to 5 Gy and higher in the present study. of crypt survival when chemotherapy was added to split Using only data points from 7.5 or 10 Gy and higher did dose radiation, indicates that neither 5-FU nor oxaliplatin not significantly decrease the D in our study (data not seem to abolish the mucosal-sparing effect achieved by shown). One possible explanation for the inter-study dis- fractionating the radiation. To elucidate this further a crepancies could be variations in inherent radiosensitivity larger study with graded fraction doses is needed where between different mouse strains [18]. Since radiation alpha/beta values for these treatments can be calculated. doses of 14 to 17 Gy lead to a near complete eradication of jejunal crypts, we chose to use only doses up to 10 Gy How do these results correlate to the clinical experience? in the combined chemoradiation experiments. Besides, 5-FU is known to cause mucositis, which can involve the the aim of our study was not to determine the absolute D intestines and cause enteritis. Depending on the schedule values but rather to investigate the relative impact on jeju- of administration, the frequencies of grade 3-4 diarrhea nal damage by adding 5-FU and oxaliplatin to radiation. were 3% and 7% for infusional and bolus regimens, respectively, in a randomized trial [21]. 5-FU has been subjected to several previous studies using murine models. The doses chosen for our experiments For oxaliplatin as single treatment, a grade 3-4 diarrhea have shown antitumoral efficacy with reasonable toxicity frequency of 6% has been reported [22]. For radiotherapy, in these studies [19]. We found that doses above 100 mg/ the relationship between toxicity and radiation dose is kg resulted in surviving fractions between 20 and 40% well known with the grade of diarrhea also correlated with (Fig. 2A), which indicates a stronger cytotoxic effect than the irradiated volume of the small bowel [23,24]. Addi- previous studies using the microcolony assay for 5-FU tion of 5-FU to radiotherapy has been shown in two ran- [20]. One explanation for this lower clonogenic cell recov- domized trials to increase the risk of enteritis [2,3]. Thus Page 5 of 7 (page number not for citation purposes) Surviving fraction Surviving fraction Radiation Oncology 2009, 4:61 http://www.ro-journal.com/content/4/1/61 Table 1: Comparison of single versus split dose irradiation with multiple chemotherapy doses, more radiation fractions or or without concomitant chemotherapy different mouse strains would have led to a further when combining both drugs with radio- decrease in D Treatment Crypt count (95% CI) p-value 0 therapy. The basis for this clonogenic assay is that the regeneration of the bowel mucosa is dependent on its clo- 5 Gy 101 (99-103) < 0.0001 nogenic stem cells. Therefore, the survival of these clono- 2 × 2.5 Gy 114 (111-116) gens is likely to be a decisive factor in the repair of the bowel after cytotoxic therapy. However, it is possible that 5 Gy + 5-FU 80 (66-95) < 0.0001 other factors, such as inflammation and bacterial distur- bances, also may add to chemoradiation-induced enteritis 2 × 2.5 Gy + 5-FU 102 (94-111) in the clinical situation. 5 Gy + oxa 101 (94-108) 0.5 Conclusion In conclusion, the addition of 5-FU or oxaliplatin to radi- 2 × 2.5 Gy + oxa 102 (91-112) otherapy lead to a similar decrease in jejunal crypt survival for both drugs. Adding the drugs together with radiation 5 Gy + 5-FU + oxa 88 (77-98) 0.007 did not further increase the mucosal damage in this exper- imental setting. 2 × 2.5 Gy + 5-FU + oxa 93 (75-111) Competing interests 7.5 Gy 54 (29-80) < 0.0001 The authors declare that they have no competing interests. 3 × 2.5 Gy 99 (93-107) Authors' contributions All authors have contributed to the study design, data 7.5 Gy + 5-FU 39 (20-58) < 0.0001 analysis, manuscript drafting and revising and given final 3 × 2.5 Gy + 5-FU 95 (81-110) approval of the version to be published. 7.5 Gy + oxa 23 (15-31) < 0.0001 Acknowledgements This work was supported by grants from the Foundations of Lund's Health 3 × 2.5 Gy + oxa 91 (84-99) District Organization and the Medical Faculty of Lund University, Sweden and from the Cancer Research Foundation in Northern Sweden, University of Umeå, Sweden. 7.5 Gy + 5-FU + oxa 29 (0-57) < 0.0001 Special thanks to Margaretha Olsson and Christina Boll for all help with 3 × 2.5 Gy + 5-FU + oxa 97 (91-103) breeding and treating the animals and jejunal sample preparation. 5-FU dose = 50 mg/kg, oxaliplatin dose = 6 mg/kg References Abbreviations: oxa = oxaliplatin 1. 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"BioMed Central will be the most significant development for 20. Moore JV: Clonogenic response of cells of murine intestinal disseminating the results of biomedical researc h in our lifetime." crypts to 12 cytotoxic drugs. Cancer Chemother Pharmacol 1985, Sir Paul Nurse, Cancer Research UK 15:11-15. 21. de Gramont A, Bosset JF, Milan C, Rougier P, Bouche O, Etienne PL, Your research papers will be: Morvan F, Louvet C, Guillot T, Francois E, Bedenne L: Randomized available free of charge to the entire biomedical community trial comparing monthly low-dose leucovorin and fluorour- acil bolus with bimonthly high-dose leucovorin and fluorour- peer reviewed and published immediately upon acceptance acil bolus plus continuous infusion for advanced colorectal cited in PubMed and archived on PubMed Central cancer: a French intergroup study. J Clin Oncol 1997, 15:808-815. yours — you keep the copyright 22. Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ram- BioMedcentral anathan RK, Hart LL, Gupta S, Garay CA, Burger BG, Le Bail N, Haller Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 7 of 7 (page number not for citation purposes)
Journal
Radiation Oncology – Springer Journals
Published: Dec 9, 2009