determination of operation time in colorectal diseases: preoperative chemotherapy application

Journal of Surgical Research 124, 209–215 (2005)

Determination of Operation Time in Colorectal Diseases:Preoperative Chemotherapy Application

Mustafa Sahin, Mehmet Erikoglu,1 Sükrü Özer, Ahmet Tekin, Serkan Boz, Murat Gölcük,Mustafa C. Avunduk, and Mehmet Aköz

Meram Medical Faculty, Selcuk University, Konya, Turkey

Submitted for publication June 4, 2004

doi:10.1016/j.jss.2004.09.021

Background. Our aim was to determine the time ittakes for wound healing to return to normal in caseswhere patients have undergone preoperativechemotherapy.

Materials and methods. Eighty-four Wistar-albinorats were included in the study. Twelve of them wereplaced in the control group (Group I), with no furtherdrug administration. Another 12 rats were placed in asham group (Group II) and were peritoneally injectedwith 1 cc of isotonic saline solution 5 days a month, fora period of 6 months. The remaining 60 rats wereplaced in five chemotherapy groups (Groups III–VII)and were administered 20 mg/kg 5-fluorouracilthrough peritoneal injection, 5 days a month for aperiod of 6 months. At the end of the sixth cure, 12 ratsfrom the control (Group I), sham (Group II), and che-motherapy groups (Group III) were operated on, andan intestinal transsection was applied to the rectosig-moid junction, followed by one-by-one anastomosis us-ing 5/0 vicryl. Other groups (Groups IV–VI) with che-motherapy treatment were operated on at 1-weekintervals and subjected to the same procedure. Thesubjects were reoperated on on the eleventh day. Afull-layer 4 � 4 cm piece was removed from the abdom-inal wall containing the previous incision line at themiddle, for tensile strength pressure measurements.In addition, a 4 cm colon segment was removed forbursting pressure measurements. Plasma albumin andtissue hydroxyproline levels were measured, and fi-broblast numbers were counted in the sections pre-pared from the abdominal wall.

Results. The control and sham groups were found tobe similar to each other with respect to all parametersmeasured (P > 0.05). Significant reductions were ob-

1 To whom correspondence and reprint requests should be addressedat Selcuk University Meram Medical Faculty General Surgery, 42080
Akyokus, Konya, Turkey. E-mail: [email protected].
209

served in all parameters in the early chemotherapygroups compared with the control and sham groups(P <0.05). All parameters measured in Groups V, VI,and VII were found to be similar to those in the controland sham groups (P <0.05).

Conclusion. Wound healing is impaired in rats withchemotherapy, but following the second week afterthe chemotherapy, disrupted parameters return totheir normal levels. © 2005 Elsevier Inc. All rights reserved.

Key Words: primary chemotherapy; neoadjuvantchemotherapy; bursting pressure; tensile strengthpressure; fibroblastic activity; tissue hydroxyproline;colorectal cancer.

INTRODUCTION

Colorectal cancers are the most common gastrointes-tinal system cancers. Even after curative surgical re-section, local recurrence and distant organ metastasisfrequently continue to be a significant problem in thesecancers. Rich et al. [1] reported local recurrence rates ofrectal cancers as 30.2%, distant organ metastasis as29.5%, and fatalities due to local recurrence and dis-tant organ metastasis as 41.5%.

In advanced colorectal cancers, curative attemptsare not possible and patients must be satisfied withpalliative attempts which are known to increase mor-tality and morbidity as well as to diminish life quality[2, 3].

It has been shown that curative surgical proceduresfollowing preoperative radiotherapy and neoadjuvantchemotherapy separately and in combination reducedlocal recurrence and distant organ metastasis and pro-longed the survey [4, 5]. In addition, these preoperativeprocedures reduce the tumor stage in advanced-stagecolorectal cancers, thus enabling tumor resection and
curative treatment attempts [6–10].
0022-4804/05 $30.00© 2005 Elsevier Inc. All rights reserved.

210 JOURNAL OF SURGICAL RESEARCH: VOL. 124, NO. 2, APRIL 2005

Clinical and experimental work conducted in rela-tion with these applications generally emphasizes com-plications that can develop during the postoperativeperiod [11, 12]. The most significantly stressed aspectin such applications is the disruption of wound healingand consequently the development of anastomosisleakage [12, 13]. It has been shown in clinical andexperimental studies that radiotherapy and chemo-therapy, when applied separately or together, can di-minish wound healing [14, 15]. It is reported that thisadverse effect cannot be diminished by the use ofagents but is corrected over time [13, 16].

Surgical intervention is generally delayed for a pe-riod due to complications that may arise following pre-operative chemotherapy. However, we found no scien-tific data indicating how long this period should be.Nevertheless, senior surgeons argue that approxi-mately 4–6 weeks should be allowed after chemother-apy but this may lead to the progression of the tumor,causing the loss of the stage reduction obtained withchemotherapy.

Our aim in this experimental study was to determinethe period during which wound healing, disrupted fol-lowing preoperative chemotherapy, returns to normallevels, and to determine the optimal operation timefollowing primary chemotherapy.

MATERIALS AND METHODS

The study was carried out in the Experimental Medical Research

TAB

Time Schedu

Day Group I Group II Group III

1–5 No action IP saline IP 5-FU6–26 Interval Interval Interval27–31 No action IP saline IP 5-FU32–52 Interval Interval Interval53–57 No action IP saline IP 5-FU58–78 Interval Interval Interval79–83 No action IP saline IP 5-FU84–104 Interval Interval Interval105–109 No action IP saline IP 5-FU110–130 Interval Interval Interval131–135 No action IP saline IP 5-FU136 Operated Operated Operated142147 Reoperated Reoperated Reoperated149153156160163167174

a IP, intraperitoneal; 5 FU, 5-flourourasil.

and Application Center of Selcuk University. Permission for the

study was obtained from the Ethical Board of Medical Faculty of theUniversity, and international animal ethics rules were observed.

A total of 84 female Winstar Albino rats with weights between 230and 260 g were included in the study. The rats were divided intoseven groups, each containing 12 subjects. They were kept in roomsunder controlled temperature, humidity, and light conditions and fedwith standard rat food (Table 1).

Group I. This was the control group, in which no drugs wereadministered.

Group II. This was the sham group, in which subjects were given1 cc isotonic saline solution during the first 5 days of each month, fora period of 6 months.

Groups III–VII. These were the study groups, in which subjectswere injected with 20 mg/kg 5-fluorouracil into the peritoneal cavityduring the first 5 days of each month, for a period of 6 months.

During the chemotherapy, 0.5 cc blood was sampled from the tailveins of the subjects on the first day of each month and leukocyteswere counted.

The rats in Groups I, II, and III were operated on on the day afterdrug administration was completed, at the end of the sixth month(13th day).

Operative procedure. During the operations, the subjects wereanesthetized with 70 ml/kg Ketamine HCL, and Diklofenak sodiumwas used for postoperative analgesia.

The subjects fasted 1 day before the operation. Following anes-thesia, a 4-cm long laparatomy was made in the midline. A colonictranssection was applied to the rectosigmoid junction and anastomo-sis was performed one-by-one using 5/0 vicryl. The abdominal wallwas closed one-by-one using 2/0 vicryl. The rats were placed intotheir cages and allowed food and drinking water the next day.

The same operative procedures were repeated for Group IV 1 weeklater; on the 142nd day for Group V 2 weeks later (149th day); forGroup VI 3 weeks later (156th day); and for Group VII 4 weeks later(163rd day).

The subjects were reoperated on on the 11th day after their initialoperation. Blood samples (5 cc) were taken by cardiac puncture and

1

f the Studya

roup IV Group V Group VI Group VII

5-FU IP 5-FU IP 5-FU IP 5-FUterval Interval Interval Interval5-FU IP 5-FU IP 5-FU IP 5-FU

terval Interval Interval Interval5-FU IP 5-FU IP 5-FU IP 5-FU




perated

Operatedeoperated

OperatedReoperated

OperatedReoperated

Reoperated

LE

le o

G

IPInIPInIPInIPInIPInIP

O

R

then, a full-thickness layer of 4 � 4 cm was removed from the

211SAHIN ET AL.: OPERATION TIME IN COLORECTAL DISEASES

abdominal wall. Following this procedure, a 4 cm colonic segmentwas removed in a manner to contain 2 cm proximal and distal of thecolon anastomosis.

Tensile-strength pressure (TSP) measurement of the abdominalwall wound. After the sutures in the abdominal wall layer haddesolved, the tensile strength pressure of the incision line was mea-sured taking as a reference the method defined by Peacock [17]. Thelayer removed from the abdominal wall was fixed from one end sothat the incision line was contained in the middle, and stepwiseincreasing weights were hung on the other end. The weight that wasmeasured at the moment when the tissue in the incision line beganto separate was accepted as the tensile strength pressure. The fol-lowing formula was used with TSP given in g/mm2. TSP � BW/AWTx LI, where BW is the breaking weight (in g), AWT is the abdominalwall thickness (in mm), and LI is the length of incision (in mm).

Bursting pressure of the colonic anastomosis line. Bursting pres-sure of the removed colonic segment was measured pneumaticallyusing a sphingomanometer by the method defined by El-Malt et al.[6]. Both ends of the colonic segment containing the anastomosiswere tied up, and a catheter fixed to one end was connected to thesphingomanometer, and the segment was inflated. The pressurepoint at which air bubbles started to emerge from the anastomosisline submerged into water was measured as the bursting pressure.

Measurement of tissue hydroxyproline levels. For the measure-ment of tissue hydroxyproline level, 1 g tissue sample was takenfrom the abdominal wall incision line and was preserved in the deepfreeze at –83°C. Tissue hydroxyproline levels were measured usingthe method defined by Bergman-Loxley [18].

Fibroblast count. Histopathologic examination of the tissues wasmade by a pathologist who was not informed of the groups. Threedifferent sections were taken from each subject and fibroblasts werecounted in a 40x magnification area. The average of these counts wasreported.

Paraffin blocks of the tissue samples taken from the abdominalwall wound and from the colonic anastomosis line were prepared bystaining with hematoxylen-eosin and examined under the light mi-croscope.

TAB

Leukocyte Numbers of th

Day Group I Group II Group III

1 8483 � 958 8562 � 1218 8233 � 91627 7846 � 952 7888 � 1083 6271 � 70853 9008 � 1841 9329 � 1643 5471 � 73379 8382 � 1214 9412 � 1286 4580 � 456

105 8652 � 965 8438 � 794 4365 � 356131 8558 � 1229 8787 � 1516 4084 � 482136 8698 � 1100 9220 � 964 3365 � 296142 —149 —156 —

TAB

Mortality and the

Groups Group I Group II

n 12 12Obstruction in anastomosis line 1 —Anastomotic leakage and peritonitis — —No reason — —Total death 1 —

163 —

Measurement of plasma albumin levels. Plasma albumin levelswere studied from the blood samples of the subjects and measured onan automatic analyzer (Olympus 2700, Japan).

Statistical analyses. The Kruskal Wallis test was used to com-pare the leukocyte values between the groups. Comparisons of in-group changes of leukocyte counts were made using the Wilcoxontest. The One Way Variance Analysis was used in the into groupscomparisons of fibroblast counts, tissue hydroxyproline levels,plasma albumin levels, tensile strength pressure of abdominal wallwound, and bursting pressure of the colonic anastomosis line. Thevalue of P � 0.05 was accepted as significant.

RESULTS

A total of eight rats died before the completion of thestudy, one of which was from Group I and one was fromGroupVI; two died from Groups III, IV, and VII, re-spectively.

One rat from Group I and one from Group VII pre-sented an obstruction in the anastomosis line. In addi-tion, peritonitis due to anastomosis leakage was ob-served in four subjects in Groups III and IV (4/24,16.6%). One rat in Group VI and one other in GroupVII exhibited no pathologies (Table 2).

Leukocyte counts obtained during the drug adminis-tration period are presented in Table 3.

It was observed that leukocyte counts in the controlgroup and sham group did not show any changes dur-ing the procedure (P � 0.05). Leukocyte counts of che-motherapy groups (Groups III, IV, V, VI, and VII)presented significant reductions starting from the firstweek compared with the control and sham groups(P � 0.05).

3

roups (Mean � SD, mm3)

roup IV Group V Group VI Group VII

83 � 1073 8012 � 1250 8042 � 1442 8254 � 117967 � 653 6254 � 562 6292 � 696 6150 � 54979 � 1024 5450 � 911 5308 � 1137 5417 � 113534 � 384 4496 � 382 4824 � 632 4464 � 38634 � 418 4325 � 386 4456 � 388 4287 � 39220 � 380 3682 � 434 3712 � 442 3688 � 296

— — — —44 � 312 — — —

3540 � 312 — —3288 � 321 —

2

eason in Groups

roup III Group IV Group V Group VI Group VII

12 12 12 12 12— — — — 12 2 — — —

— — — 1 12 2 — 1 2

LE

e G

G

836157544441

32

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R

G

3514 � 582


Tissue hydroxyproline levels, plasma albumin levels,tensile strength pressure of the abdominal wall wound,bursting pressure values of colon anastomosis, andfibroblast counts in the abdominal wall and in the colonanastomosis line are given in Table 4.

A significant decrease was observed in the hy-droxyproline levels of the subjects to which chemother-apy was applied and which were operated on on thefirst day and in the first week, in comparison with thecontrol and sham groups (P � 0.05). The hydroxypro-line levels were found to have returned to normal levelsin all groups starting from the second week (P � 0.05).

Plasma albumin levels were found to be similar inthe control and sham groups (P � 0.05). In contrast, asignificant decrease was observed in the subjects fromthe chemotherapy groups which were operated on ondays 1, 7, and 14 (P � 0.05). The decrease was observedto disappear at the end of the second week (P � 0.05).

There was no difference between the control andsham groups with respect to both tensile strength pres-sures of the abdominal wall and bursting pressures ofcolon anastomosis region (P � 0.05). In the chemother-apy groups, tensile strength pressures of abdominalwall and bursting pressures of colon anastomosis werefound to be significantly lower (P � 0.05). This dropwas observed to disappear on day 21 (P � 0.05).

Changes in fibroblast counts in the abdominal wallwound and in the colon anastomosis line did notpresent any significant difference, similar to the otherparameters in the control and sham groups (P � 0.05).However, there were remarkable decreases in fibro-blast counts in all groups with chemotherapy treat-ment (Fig. 1A and B and Fig. 2A and B). The decreasewas significantly different in the groups that were op-erated on days 1, 7, 14, and 21 after chemotherapyadministration (P � 0.05). Statistically significant lev-els were observed to disappear after the fourth week(P � 0.05).

It was determined that parameters other than fibro-blast counts and plasma albumin levels rose to the level

TAB

Parameters Measur

Parameter Group I Group II Grou

Hydroxyproline (�g/mg) 3.2 � 0.2 3.3 � 0.2 2.3 �Plasma albumin (g/dL) 3.6 � 0.5 3.6 � 0.6 2.7 �Abdominal wall tensile

strength pressure(g/mm2) 17.7 � 1.3 17.6 � 1.1 6.1 �

Colonic anastomosisbursting pressure(mmHg) 291 � 14 271 � 19 157 �

Abdominal wallfibroblast count 27.0 � 3.3 26.2 � 2.7 9.3 �

Colonic anastomosis
fibroblast count 31.5 � 3.1 30.8 � 2.4 8.5 � 2
in the control and sham groups starting from the secondweek. The significant difference in fibroblast counts dis-appeared as of the fourth week, while plasma albuminlevels returned to normal levels after the third week.

DISCUSSION

Despite the advanced imaging technologies and scantests available today, the prevalence of advanced stagecolorectal cancer patients still remains high [19]. Sur-gical interventions performed during the early stageare reported to provide a cure in colorectal cancers [20,21]. Curative treatment procedures cannot be appliedin advanced colorectal cancers, while sometimes evensurgical resection or palliative intervention may not bepossible either [3, 21].

Several studies have shown that primary chemo-therapy and/or radiotherapy subsides the tumor stagein advanced stage colorectal cancers and brings thepatient within operable stages, thus reducing the tu-mor recurrence rate in the postoperative period [2, 4, 7,8, 15]. It has also been shown in several studies that,while primary chemotherapy has positive effects suchas subsiding the tumor stage and reducing the recur-rence rates in the postoperative period, it also impairswound healing thus causing increases in postoperativemorbidity and mortality [2, 8, 12, 21]. Research con-ducted on the subject draw attention to anastomosisleaks developing as a result of impaired wound healingassociated with primary chemotherapy and to conse-quently developing peritonitis and increases in mortal-ity [22–24].

Many experimental studies have indicated that che-motherapy applied in the preoperative period preventsmicrometastasis and provides a large tumor-free mar-gine while it retards colonic anastomosis healing [13,14, 23]. In these studies, it was determined that, com-pared to subjects without chemotherapy treatment,those subjects exposed to primary chemotherapy with5-fluorourasil had significantly lower bursting pres-

4

in Groups (X � SD)

II Group IV Group V Group VI Group VII

.2 2.8 � 0.3 3.0 � 0.3 3.0 � 0.4 3.1 � 0.2

.3 2.8 � 0.3 3.2 � 0.4 3.7 � 0.3 3.5 � 0.4

.6 11.6 � 2.2 16.3 � 1.5 17.8 � 1.8 16.7 � 3.3

4 204 � 19 269 � 33 266 � 45 240 � 41

.8 11.3 � 1.8 17.7 � 2.1 22.7 � 2.0 26.6 � 2.9

LE

ed

p I

00

0

1

1

.4 13.3 � 2.4 23.0 � 2.6 29.0 � 4.6 29.3 � 4.2


sures of the colon anastomosis and tensile strengthpressures of the abdominal wall incision line. We alsofound that the groups with chemotherapy treatmenthad a significant decrease in bursting pressures of thecolon anastomosis and tensile strength pressures ofabdominal wall incision line.

Studies conducted on this subject generally argue thatprimary chemotherapy subsides the tumor stage and re-duces tumor recurrence in the postoperative period, withsome complications despite such positive effects. Thesecomplications include, depending on the impairment ofwound healing, anastomosis leakage, intestinal obstruc-tion, infection, lethargy, nausea, diarrhea, erythema, andskin eruption [2, 12, 24]. However, an important part ofthese side effects are the expected effects of chemother-apy. What was important for us in this study was theimpairment of wound healing and complications thatmay develop as a consequence. Kuzu et al. [25] and

FIG. 1. (A) Reduced fibroblasts in the abdominal wall wound ina subject in Group III. (B) Fibroblast count returned to normal levelsin the abdominal wall in a subject in Group VIII. (Color version offigure is available online.)

Weiber et al. [22] reported that the impairment by che-

motherapy of wound healing is an effect which continuesafter the chemotherapy has finished, but that this effectdiminishes with time.

However, the subjects in these studies were operatedon following short-term applied chemotherapies, andwound healing was investigated after days 3 and 7.

We operated on chemotherapy subjects at certainintervals and investigated the time when the effect ofchemotherapy on the wound healing was eliminated.The chemotherapy model we applied is a copy of aclinical application with respect to a time period. 5-FUis still primarily used in the chemotherapeutic combi-nations and is one of the most common chemothera-peutic agents that impairs wound healing [15, 23]. Forthis reason 5- FU has been used in this study. Inaddition, we aimed to investigate the general condi-tions affecting the wound healing instead of the effectof a specific agent in this study. The dosage adjustmentwas carried out according to human doses and is thesame as in previously published studies [15, 23].

FIG. 2. (A) Reduced fibroblasts in the colonic anastomosis line ina subject in Group III. (B) Fibroblast count returned normal levels in
the colonic anastomosis line in a subject in Group VII. (Color version of figure is available online.)


In our study, we determined that all parametersrelated to wound healing were affected adversely in thegroups that were operated on (Groups III and IV) onthe first day and at the end of the first week followingthe chemotherapy (bursting pressure of colon anasto-mosis and tensile strength pressure of abdominal wallwound, tissue hydroxyproline level, plasma albuminlevel, and fibroblast counts in abdominal wall woundand colonic anastomosis line were all found to be sig-nificantly lower compared with the control and shamgroups).

The most important complications due to breaking ofwound healing after chemotherapy are anastomoticleakage and peritonitis, and this was observed only inthe early chemotherapy groups in four (16.4%) rats. Incontrast, subjects operated on at the end of the second,third, and fourth weeks following the chemotherapyshowed that all wound-healing indicator parametersexcept fibroblast counts and plasma albumin level re-turned to their normal limits starting from the secondweek. The similarity between Groups I and II valuesled to the concept that neither saline nor injectionprocedure had an effect on wound healing. It wasthought that only 5 FU is responsible for the impair-ment of wound healing.

Using a different approach, Kuzu et al. [25] mea-sured postoperative third and seventh day wound heal-ing parameters in subjects they operated on followingchemotherapy and showed that these parameters werebetter on the seventh day. Weiber et al. [22], to inves-tigate the effect of 5-FU on wound healing, applied it inpostoperative early and late postoperative periods, andobserved that the rate of anastomosis leakage in theearly groups was higher.

It has long been known that primary chemotherapyimpairs wound healing, as we showed in this study.Studies have indicated that this adverse effect disap-pears following chemotherapy in parallel to the periodelapsed after the chemotherapy. During the planningphase of this study, we aimed to find answers to thequestions of when such chemotherapy-dependent ad-verse effects would disappear and when the most ap-propriate time would be to operate. We did not find anyrecord on when to perform the operation, but Mohiud-din et al. [7] applied surgical resection 6 weeks afterthe completion of radiochemotherapy in patients withadvanced stage rectal cancers. We have not found anyinformation on the surgical intervention time after pri-mary chemotherapy. However, senior surgeons statethat this period is 4–6 weeks, and many clinics observethis.

We found in this study that fibroblast counts in theabdominal wall line and in the colonic anastomosis linereturned to their normal levels 3 and 4 weeks after
chemotherapy. Except for these, all other measured
parameters returned to their normal levels at the endof the second week.

In conclusion, it can be said, based on the findings inthis study, that the adverse effects of chemotherapy onwound healing disappear starting from the secondweek following primary chemotherapy. Because thisstudy was conducted on rats, a decisive comment maynot be made due to differences in human metabolism,but according to the data obtained from this study,similar studies and certain results could be obtainedfrom studies on humans.

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determination of operation time in colorectal diseases: preoperative chemotherapy application

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