Heating
Enclosure heating Heating units
Heating & Ventilation

Function

Small heating units for enclosures are important accessories for guaranteeing operational safety of control and distribution units. They are mainly used to prevent formation of condensation or to maintain a minimum temperature inside the enclosure, that is, a few degrees above the temperature of the surrounding air.

HGK047 HG040

Operating principle
Small heating units are fitted with PTC heating resistances (positive temperature coefficient semi-conductors). The self-regulating and self-limiting semi-conductor heating elements maintain a constant temperature on the heating surface of the small heating units. The aluminium casing transmits heat to the surrounding air by natural radiation. Special extruded sections ensure the heat is fully radiated.

Advantages

Energy saving Dynamic heating-up Self-regulating Temperature-limiting Quick snap-on fixing No maintenance Long endurance Compact housing
Heating requirements calculation
Using P= A= T = k= the formula: P = A x T x k power supplied by the resistance (W) external free surface of the enclosure (m2) difference in temperature between the internal temperature after heating, and the external temperature, in K. thermal radiation coefficient: sheet steel: 5.5 W/m 2K polyester: 3.5 W/m2K

Standards

VDE 0700 IEC 60 335-1 UL on request

Applications

Switch cabinets, instrument cases, display panels, control desks, automatic bank machines, car park control systems, etc.
Approximation rule: recommended value 100 w/m3 of enclosure volume. For an outdoor installation, the calorific power should be doubled. Several small heating units are better than a single large heating unit.

Fitting

Push-fit onto DIN 35 mm rail (EN 50 022). Installation preferably at the bottom of the cabinet, at about 40 mm from the equipment itself.

GE Power Controls

Heating units HGK047-HG040 Technical data
Nominal voltage Power Heating element Heating body Protection class Protection level Connection 140-250 V AC/DC (max. 265 V) 10 to 150 W self-regulating PTC resistance anodised aluminium sections II, test voltage 4000 V/3 sec IP54 Series HGK047: silicon cable 2 x 0.75 m2 length 300 mm Series HG040: with terminals 0.5 - 2.5 mm2 Series HGK047: 25 x 60 mm Series HG040: 70 x 60 mm

Dimensions (H x D)

Order codes
W(1) HGKI max. (A) 0.8 1.0 1.5 H (mm) 70 Wt. (kg) 0.10 0.11 0.12 Ref. No. 818107 Pack. 1
0.5 1.0 1.0 1.5 1.8 2.4 4.5
0.3 0.3 0.3 0.5 0.5 0.5 0.8

818102

(1) At ambient temperature 20C
Heating unit HGL046 with fan Technical data
Nominal voltage Power Heating element Heating body Surface temperature Protection class Protection level Connection Fitting Fan 220/280V 50-60Hz 250 and 400W traditional heating element with built-in thermostat anodised aluminium sections 75C I IP20 three-pole terminal strip 2.5 mm2 on DIN 35 mm rail rate: 35 m3/h without counter-pressure ball bearing service: 30000 hrs at 20C
With forced ventilation with an axial fan. Prevents formation of dangerous levels of condensation, and maintains a constant temperature inside the enclosure.
W HGL400 BxD 80 x x 80 H (mm) Wt. (kg) 0.95 1.30 Ref. No. Pack. 1 1
Heating units HV031 and HVL031 (with fan) Technical data
Nominal voltage Power Heating element Heating body Connection Surface temperature with fan Fitting Protection class Fan rate (without counterpressure) Dimensions (H x W x D) Weight 220/230V 50-60Hz 100 - 150 - 200 - 300 - 400W traditional heating element with built-in thermostat anodised aluminium sections five-pole terminal strip 2.5 mm2 45C at a distance of 50 mm on DIN rail I 35 m3/h (100 - 150W) 108 m3/h (200 - 300 - 400W) 80 x 112 x 22 mm (100 - 150W) 119 x 151 x 22 mm (200 - 300 - 400W) 240 g (100 - 150W) 490 g (200 - 300 - 400W)
HV031: Heating element, extra compact, flatter, only 22mm thick. HVL031: HV031 heating element with an axial fan to give optimal heat radiation. Fresh air drawn in from outside is heated and dried. If the fan fails, thermal power drops automatically to prevent overheating.

Power HV031 100W 150W 200W 300W 400W Ref. No. 818163 Pack. 1
Telecommunications systems, control panels, display panels, control desks, bank cash machines, car park control systems.

HVL031 with fan

100W 150W 200W 300W 400W

818165

Semi conductor fan heater Technical data
Nominal voltage Power Current at make Heating element Temperature regulation Optical indicator Casing Protection class Protection level Connection Fitting Axial fan Compact heater with integrated ventilation CR 027 350/550W 230V. Heating capacity adjusts to ambient temperature. Safely cut-out in case of fan failure. Adjustable temperature range. Dimensions Weight Approval 220/230V 50-60Hz 350 / 550W 7.5 A - 350W / 230V 8.5 A - 550W / 230V PTC resistor - self regulating Adjustment range 0 - 60C Thermostat control lamp Plastic, light grey II (double insulated) IP pole terminal connector, 2.5 mm2 on DIN 35 mm rail 45 m3/h, ball bearing service life 50,000 h at 25C 128 x 100 x 165 mm (HxWxD) 1.1 kg UL file E 204590

Ref. No. CR Pack. 1

Temperature regulators Function
FZK 011, KTO and KTS elements regulate and control the temperature inside the enclosure by means of small heating elements, fans, heat exchangers and refrigeration units.

KTO / KTS

FZK 011
The electronic temperature regulator and humidity controller ETF 012 controls the temperature and humidity level of the air independently of each other by switching resistive and inductive loads (e.g. small heating units and refrigeration units).

Technical data

Type Range of adjustment: Temperature Hysteresis Contact type Power(1) FZK 011 KTO KTS
10C - 60C 0.5K Inverter: single pole NC 10A (4) 250V AC NO 5A (2) 250V AC resistive load 100 g 67 x 50 x 38
0C - 60C 7K NG 6A (1) 250V AC resistive load 36 g 60 x 33 x 35 red button: heating
0C - 60C 7K NO 6A (1) 250V AC resistive load 36 g 60 x 33 x 35 blue button: cooling, fan, alarm signal IP30
Weight Dimensions (H x W x D) Application diagram Protection level Connection Fitting Case Interference protection
IP30 2.5 mm2 screw connector push fit on DIN 35mm rail (EN 50022) plastic UL 94 VO N according to VDE 0875
(1) Values in brackets = inductive load cos = 0,80

Application diagram*

Ref. No. FZK 011 KTO KTS 818081 Pack. 1
Humidity controller Technical data
Range of adjustment: Temperature Hysteresis Humidity Response time Power supply voltage Contact type Power(1) 0C - 60C 2K 50 %-90 % 160 sec. 230V/50-60Hz relay outputinverter contact 8A (4) 250V AC 0.5A 100V DC 8A 12V DC 5A 35V DC LED 140 g 50 x 67 x 43 IP20 2.5 mm2 screw connector push fit on DIN 35mm rail (EN 50022) plastic UL 94 VO N according to VDE 0875

Application diagram

ETF 012
On/off indicator Weight Dimensions (H x W x D) Protection level Connection Fitting Case Interference protection

Ref. No. ETF Pack. 1

Mechanical hygrostat Technical data
Adjustment range Switching accuracy Voltage Switching capacity, max. load resistive load inductive load cos phi 0.8 inductive load L/R = 3 ms switching capacity, min.load contact type Connection Casing Mounting Protection level Dimensions Weight 35-95% relative humidity 3% 250V AC 5 A 250V 0.2 A AC 250V 1 A DC 50V - DC 75V 100 mA DC/AC 20V change over contact terminals in casing 3 x 2.5 mm2 Plastic, light grey on DIN 35 mm rail IP 20 67x50x38 mm (HxWxD) 60 g
The electromechanical hygrostat is designed to controle enclosure heaters so that the dew point is raised when a critical relative humidity of 65% is exceeded. In this way condensation and corrosion are effectively prevented.

MFR 012

Ref. No. MFR Pack. 1

Ventilation

Enclosure ventilation Filter fan selection
hot The air flow (volume flow rate) of the filter fan depends on the total thermal loss and the temperature difference t between the permissible interior temperature and the ambient temperature. The following formula applies here: 3.1 P (W) V (m3/h) = x 1.15 T (K) 3/h) - P = thermal loss in watts (W) V = required air flow (m T = interior/ambient temperature difference in Kelvin (K) 3.1 = constant numerical value of miscellaneous ventilation data 1.15 = 15% margin Air flows (m3/h) for thermal losses up to 3000 watts and temperature differences (DT) of 5.25 (K) can be taken from the selection chart. It is recommended that a 15% margin be added to allow for contaminated filter mats or extreme conditions. The air flows specified for the individual filter fans were measured in accordance with DIN 24163. At an air density of 1.2 kg/3, the tolerance is 5%.
The electrical operating elements built into a control enclosure, such as power converters, transformers, inductance coils, contactors, relays, etc., emit dissipation heat into the surrounding air. If this dissipation heat is not removed, it may cause the temperature inside the enclosure to exceed the temperature permissible for electrical equipment. This poses a hazard to, in particular, electronic components. The heat must therefore be removed to avoid malfunction and, ultimately, idle time. Natural aeration (by domes, gills, etc.) is not recommended, as the risk of contamination is very high and, in addition, the degree of protection of the enclosure cannot be maintained. In such cases, forced aeration with appropriate built-in filters is the answer. In this system, the cooler ambient air is sucked by a fan into the lower part of the control enclosure, simultaneously filtered, and then blown into the body of the enclosure. Here the air absorbs the dissipated heat and is then removed via an exhaust filter located in the upper part of the enclosure. An overpressure created simultaneously in the enclosure prevents dust particles penetrating any openings in the housing. Removing warm air by suction is not recommended, as the partial vacuum created within the enclosure would neutralise the dustprotective effect.

Filter material

DIN-tested VILEDON P15/350S, P15/500S or T3/290S filter mats (to DIN 24185) are used in the filter fans and exhaust filters. The material is thermally bonded. Behaviour in fire corresponds to DIN 53438, class F1. The P15/350S filter mat collects dust particles of a minimum size of 10 m at a separation efficiency of 85%, while the P15/500S filter mat collects dust particles of a minimum size of 5 m at a separation efficiency of 94%. If the dust particles are extremely fine, the supplementary, denser T3/290S filter mat may be used. This collects dust particles of a minimum size of 0.5 m at a separation efficiency of 96% (please note the reduced air flow). Soiled filter mats can be cleaned by rinsing out with water, by beating, or by blowing through with compressed air (do not wring out!).

Housing

Housings are made of heat-resistant ABS plastic (-35C to +85C), self-extinguishing to UL 94 VO, tracking resistance to 3kA. Colour RAL 7032 pebble grey. Other colours available upon request.

Degree of protection

The R+H-filter fans conform to relevant VDE Regulations. Contact-voltage proof to DIN 31001. Resistance to foreign bodies and water to IP54 (DIN 40050) is achieved by combining a horizontal air flow with a gasket, available as an accessory.
Selection of the filter fan and the exhaust filter
Temperature difference T (K)

Thermal loss Pv (W)

Volume (m3/h)

Example

Parameters Thermal loss Temperature difference Selection Screw-type fixing LS 0 K + LG 11 K Snap-on fixing LV 300 + GV 300 500W 25K
Filter fan + exhaust filter Filter fan free blowing with filter mat P15/500S
Filter fans and exhaust filters Filter fans
Type LSK For screw-type fixing
matching LS 10 K LS 0 K LS 1 K LS 2 K LS 25 K LS 3 K LS 3 K / 380V Ref. No. 818047 Pack. 1

Type LSK

Type LV For snap-on fixing
matching LV 200 LV 300 LV 400 LV 500 LV 700 Ref. No. 818181 Pack. 1

Type LV

Advantages of type LV Quick mounting Low profile Interchangeable filter fan simply snaps into the cut-out maximum protrusion of cover is 6.5 mm filter fan LV200 fits into the cut-out type LS 10 K filter fan LV400/LV500 fits into the cut-out type LS 25K

Exhaust filters

Type LG Filter fans

matching

matching LG 10 K LG 11 K LG 12 K LG 12 K LG 25 K LG 13 K LG 13 K

Ref. No. 818054 Pack. 1

Series LG: Fit filter fans type LS K with the same cut-out pattern as the fan.
Series GV: Fit filter fan type LV with the same snap-on fixing.
LV 200 LV 300 LV 400 LV 500 LV 1 GV 200 GV 300 GV 400 GV 400 GV 1

Type GV

Filter fans and exhaust filters are delivered as standard with filter mat type P15/500S. 115V AC and 24V DC versions available on request.

Dimensional drawings

Page J.54

Spare filter mat

To fit LV 200, GV 200 LV 300, GV 300 LV 400, LV 500, GV 400 LV 700, GV 700 LS 10 K, LG 10 K LS 0 K, LG 11 K LS 1 K, LS 2 K, LG 12 K LS 25 K, LG 25 K LS 3 K, LG 13 K Filter mat P15/500S AM200P AM300P AM400P AM700P AM01P AM11P AM12P AM25P AM13P Ref. No. 818024 Filter mat T3/290S AM300T AM400T AM700T AM11T AM12T AM25T AM13T Ref. No. 818025 Dimens. 112 x x x x x x x x x 330
Filter mat P15/500S T3/290S
Separation efficiency 94% 96%
Filter class DIN 24185 EU 4 standard EU 4 fine mat

Gaskets - IP54

To fit LV 200, GV 200 LV 300, GV 300 LV 400, LV 500, GV 400 LV 700, GV 700 LS 10 K, LG 10 K LS 0 K, LG 11 K LS 1 K, LS 2 K, LG 12 K LS 25 K, LG 25 K LS 3 K, LG 13 K Type D 200 D 300 D 400 D 700 D 10 D 11 D 12 D 25 D 13 Ref. No. 818026
Screw-type fixing - surface Filter fan type Standard filter mat P15/500S (94% sep. efficiency) Free air flow (m3/h) In combination with exhaust filter Air flow (m3/h) With fine mat T3/290 S (96% separat. efficiency) Free air flow (m3/h) In combination with exhaust filter Air flow (m3/h) Power input 230V AC - 50/60Hz (W) Current 230V AC - 50/60Hz (A) In service Noise level dB (A) Service life (hour) Speed (rpm) Temperature -10C to +55C Connection by cable Connection by terminal block Max. thickness wall Approvals CSA/UL VDE Turn motor to 180 degrees to change from blowing to suction (reduced air flow) Suction version can be ordered as variant Screw-type fixing Snap-on fixing 115V AC on request 24V DC on request 380V AC on request Options Spare filter mat P15/500S Fine mat T3/290 S (96% separation efficiency) Gasket IP54 LS 10 K 50 LG 10 K 0.11 100% 2650/3100
LS 0 K 105 LG 11 K 0.11 100% 2650/3100
LS 1 K 110 LG 12 K 0.11 100% 2650/3100
LS 2 K 165 LG 12 K 115 48/47 0.3 100% 2760/3030

1-5 mm

AM 01 P D 10

AM 11 P AM 11 T D 11

AM 12 P AM 12 T D 12
mounting LS 25 K 215 LG 25 K 120 48/47 0.3 100% 2760/3030
Snap-on fixing - flush mounting LS 3 K 580 LG 13 K 320 115/155 0.51/0.68 100% 2550/2750 -10C to +50C
LV GV 18 0.11 100% 2650/3100
LV GV 48/47 0.3 100% 2760/3030
LV GV 50/61 0.24/0.27 100% 2740/3120
LV GV 115/155 0.51/0.68 100% 2550/2750 -10C to +50C

J Soc Colon Rectal Surgeon (Taiwan) December 2008

Original Article

Efficacy and Safety of Two Different Regimens of Irinotecan for Metastatic Colorectal Cancer: Experience in a Southern Taiwan Medical Center
Chin-Fan Chen1,3 Yung-Sung Yeh1 Fang-Ming Chen1,2 Hon-Man Chen1,2 Che-Jen Huang1,2 Jan-Sing Hsieh1,2 Jaw-Yuan Wang1,2
Department of Surgery, Kaohsiung Medical University Hospital 2 Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 3 Department of Surgery, Pingtung Hospital, Department of Health, Executive Yuan, Ping-Tung, Taiwan
Key Words Irinotecan; Metastatic colorectal cancer; Toxicity; Efficacy
Purpose. This retrospective study evaluates the two different regimens of irinotecan/5-fluorouracil(5-FU)/leucovorin(LV) chemotherapy, comparing the toxicities and the efficacy achieved in Taiwanese patients with metastatic colorectal cancer (mCRC). Methods. Sixty-three patients with mCRC receiving irinotecan-based chemotherapy between January 2002 and December 2007 in Kaohsiung Medical University Hospital were analyzed retrospectively. The patients were divided into two arms according to the different regimens. In arm A (IFL): 30 patients received intravenous (IV) irinotecan (125 mg/m2 as a 120-min IV infusion) and LV (20 mg/m2), and then 5-FU (500 mg/m2 as an IV bolus infusion), weekly for 4 weeks, repeated every 6 weeks. In arm B (FOLFIRI), 33 patients received irinotecan (180 mg/m2 as a 120-min IV infusion), and LV (400 mg/m2 IV over 2 hours), and then 5-FU (400 mg/m2 as an IV bolus infusion followed by 2400 mg/m2 IV infusion over a 46-hours period), repeated every 2 weeks. The characteristics of each patient, the adverse effects and responses after chemotherapy were recorded. Results. The overall response rate (all partial responses) was 21.4% (6/28) for IFL group and 45.5% (15/33) for FOLFIRI group, with overall disease control rate (partial response plus stable disease) of 53.6% in IFL group and 66.7% in FOLFIRI group. The median time to progression was 5.5 months in IFL group and 6.5 months in FOLFIRI group. There was no statistically significant difference of overall response and progression free survival between the two arms. Of all toxicities recorded, grade 1 allergic reaction was found with the incidence of 10.0% (3/30) for IFL group and 3.0% (1/33) for FOLFIRI group. The incidence of grade 3/4 neutropenia/leukopenia encountered was 10.0% (3/30)/3.3% (1/30) for IFL group and 15.2% (5/33)/ 9.1% (3/33) for FOLFIRI group. Gastrointestinal adverse effects (nausea, vomiting, or diarrhea) were slightly more common in the FOLFIRI group than in the IFL group, however, these were reversible and manageable. Conclusions. Both FOLFIRI and IFL regimen are comparably safe and well-tolerated regimens. We suggested that both regimens could be considered as front-line regimen of irinotecan-based chemotherapy for Taiwanese patients with mCRC. [J Soc Colon Rectal Surgeon (Taiwan) 2008;19:97-108]
Received: May 2, 2008. Accepted: October 29, 2008. Correspondence to: Dr. Jaw-Yuan Wang, Department of Surgery, Kaohsiung Medical University Hospital, No. 100 Tzyou 1st Road, Kaohsiung 807, Taiwan. Tel: +886-7-3122-805; Fax: +886-7-3114-679; E-mail: cy614112@ms14.hinet.net 97

98 Chin-Fan Chen, et al.

olorectal cancer (CRC) is one of the most common malignancies in Taiwan. The incidence of colorectal cancer in Taiwan is 35.06/100,000 in 2004, and more than 8000 new cases of CRC are diagnosed each year in our country. Furthermore, more than 4000 Taiwanese died of CRC in 2006.1 For the past 3 to 4 decades, therapeutic options of chemotherapy for patients with CRC have been based almost exclusively on 5-fluorouracil (5-FU), which acts as the thymidylate synthase inhibitor and results in interruption of synthesis of DNA.2 Leucovorin (LV), a reduced folate that increases the affinity of fluorouracil for thymidylate synthase, is commonly administered with 5-FU for a better therapeutic effect. However, because of their limited response obtained for patients with advanced colorectal cancer, other therapeutic agents with different mechanisms were obtained later. Irinotecan, a potent inhibitor of topoisomerase I which is involved in the unwinding of DNA during replication, has demonstrated its antitumor activity against metastatic colorectal cancer (mCRC) after the failure of fluorouracil.3 The mechanism of irinotecan and its activity against fluorouracil-resistant colorectal cancer were the rationale for combining this with fluorouracil and leucovorin for mCRC. The toxicity profiles and the efficacy of different schedules of irinotecan/5-FU/LV have been obtained by many clinical trials conducted in Western countries. However, these data were mainly from Caucasians, and they may be different for Taiwanese. Herein, we report our clinical experience with two different schedules of irinotecan/5-FU/LV among our patients with mCRC. We focused on the adverse events encountered and the response achieved in these patients.

Materials and Methods

We conducted a retrospective analysis of patients with mCRC from December 2001 to December 2007, at the Department of Surgery, Kaohsiung Medical University Hospital. Sixty three patients were divided into two arms according to the use of different regimens. In arm A (IFL), thirty patients received intravenous (IV) irinotecan (125 mg/m2 as a 120-min IV in-
fusion) and LV (20 mg/m2), and then 5-FU (500 mg/m2 as an IV bolus infusion), weekly for 4 weeks, repeated every 6 weeks. In arm B (FOLFIRI), thirty three patients received irinotecan (180 mg/m2 as a 120-min IV infusion), and LV (400 mg/m2 IV infusion over 2 hours), and 5-FU (400 mg/m2 as an IV bolus infusion followed by 2400 mg/m2 IV infusion over a 46-hour period), repeated every 2 weeks. One cycle corresponded to 6 weeks for arm A and 2 weeks for arm B. All patients underwent initial staging work-up included history and physical examination, routine biochemistry, blood cell count, serum carcinoembryonic antigen (CEA) level determination, chest X-ray and abdominal computed tomographic (CT) scan. Magnetic resonance image (MRI), bone scan, or positron emission tomography (PET) would be necessary if specific site of metastases was suspected. Our primary objectives were to assess the toxicities and the efficacy of these two regimens of irinotecan-combination chemotherapy. Safety assessment and laboratory tests were performed biweekly. The severity of adverse effects was evaluated according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 2.0 (http://ctep.cancer.gov/reporting/ctc.html; accessed in February 2008). Courses of chemotherapy were continued in the presence of an absolute neutrophil count 1500/ml and platelet count 100,000/ml. For patients with grade 2 or more severe hematologic toxicities, treatment was postponed for one or two weeks until recovery. Otherwise, any grade 3 or 4 adverse events resulted in an approximately 20% dose reduction of irinotecan and bolus 5-FU for the subsequent cycles. Both regimens were continued until one of the following occurred: progressive disease, unacceptable adverse effects, the patient refused further treatment with any irinotecan-combination chemotherapy, or the patient was lost to follow-up. The clinical records of each patient were retrospectively reviewed. The characteristics of the patients being recorded include age, gender, ECOG performance status, location of the primary cancer, involvement of other organs, metastatic sites, history of operations for CRC, serum carcinoembryonic antigen (CEA) level, the prior adjuvant chemotherapy, other regimens being used before the irinotecan-combina-

Vol. 19, No. 4

Two Different Irinotecan-based Regimens for Metastatic Colorectal Cancer
tion chemotherapy, the schedule of irinotecan-combination chemotherapy, the dosage and the observed toxicities encountered after the chemotherapy. The term first-line chemotherapy in this study was defined as the first chemotherapy regimen being used in the patient after identification of his/her mCRC lesion. The second-line chemotherapy was defined as the regimen for treating the mCRC lesion that has not responded after the first-line chemotherapy. Finally , the third-line chemotherapy was defined as the regimen for treating the mCRC lesion that has not responded after the second-line chemotherapy. Besides, we also evaluated the response of each patients achieved after the chemotherapy. The response was assessed radiologically with CT scans and the best response was recorded. The time for the first response assessment was usually after the second cycle in patients who received IFL regimen and after the fourth cycle in patients who received FOLFIRI regimen. Response reassessments with CT were typically performed 2-4 months after the first assessment. Responses were classified according to the Response Evaluation Criteria in Solid Tumors (RECIST).4 A complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as a reference point the baseline sums longest diameter. A progressive disease was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as a reference the smallest sum of longest diameters recorded before the patient started to receive treatment. And it could also be defined if identification of one or more new lesions. A stable disease was defined as neither having sufficient shrinkage to qualify for a partial response nor a sufficient increase to qualify for progressive disease. Moreover, we reported the best response which was defined as the best one recorded by the investigators, since the confirmatory image evidence of response obtained after 2-4 cycles of the chemotherapy was not consistently available.
age for the Social Sciences version 12.0 software (SPSS Inc., Chicago, IL, USA). The Chi-squared test was used to compare toxicities and response in the two arms. A probability of less than 0.05 was considered statistically significant.

Results

A total of sixty-three patients with mCRC were analyzed retrospectively and their characteristics have
Table 1. Characteristics of the patients N IFL (%)N FOLFIRI (%) N = 30 N=33 Age, median (years, range) Gender Male Female 58.73 (38-81) 62.63 (37-79) 019 (63.3) 011 (36.7) 019 (57.6) 014 (42.4) 19 (57.6) 13 (39.4) 1 (3.0) 2 (6.1) 3 (9.1) 3 (9.1) 04 (12.1) 12 (36.4) 09 (27.3) 0 (0) (45.5) 18 (54.5) 19 (57.6) 14 (42.4) 09 (27.3) 06 (18.2) 04 (12.1) 3 (9.1) 1 (3.0) 0 (0) (0) (3.0) 1 (3.0)

Table 2. Toxicities of patients receiving irinotecan-based chemotherapy N IFL (%) N FOLFIRI (%) N = 30 N = 33 Allergic reaction Grade 1 Anorexia Grade 1 Grade 2 Grade 3 Constipation Grade 1 Grade 2 Grade 3 Diarrhea Grade 1 Grade 2 Grade 3 Nausea Grade 1 Grade 2 Grade 3 Vomiting Grade 1 Grade 2 Grade 3 Grade 4 Stomatitis Grade 1 Grade 2 Neutropenia Grade 1 Grade 2 Grade 3 Grade 4 Leukopenia Grade 1 Grade 2 Grade 3 Grade 4 Paresthesia Grade 1 Grade 2 Hand-Foot Syndrome 3 (10.0) 4 (13.3) 1 (3.3) 1 (3.3) 2 (6.7) 1 (3.3) 1 (3.3) 8 (26.7) 4 (13.3) 2 (6.7) 1 (3.3) 4 (13.3) 1 (3.3) 0 (0) 08 (26.7) 2 (6.7) 1 (3.3) 4 (13.3) 0 (0) 00 (0) 00 (0) 00 (0) 03 (10.0) -0 (0) 02 (6.7) 1 (3.3) -0 (0) 01 (3.3) 1 (3.3) 0 (0) (3.0) 0.(6.1) 0-5 (15.2) 0 (0) 0.(3.0) 0 (0)0 (0)0.(9.1) (12.1) 2 (6.1) 0.4 (12.1) 10 (30.3) 1 (3.0) 0.(9.1) (27.3) (12.1) 0 (0)-0.7 (21.2) 2 (6.1) 0.(3.0) (15.2) (12.1) 1 (3.0) 0.(6.1) 1 (3.0) 3 (9.1) 0 (0)0.(3.1) 1 (3.1) 1 (3.0) P 0.340
testinal adverse events being recorded include anorexia, stomatitis, nausea, vomiting, constipation and diarrhea. All gastrointestinal adverse events did not differ significantly between the two arms (Table 2, p > 0.05). Most of these adverse events could be released
by antiemetic agents, prokinetics, stool softeners, antidiarrheal agents, and adequate intravenous hydration, in addition to one patient receiving IFL chemotherapy who discontinued her treatment because of not being able to tolerate grade 4 vomiting. Besides, the incidence of hand-foot syndrome was equivalent in both arms (3%). Neutropenia and leukopenia were noted to be more common in FOLFIRI group (11/33, 33.3% and 6/33, 18.2%) than in IFL group (3/30, 10.0% and 3/30, 10.0%) (Neutropenia, p < 0.05). The main grade 3/4 adverse events encountered in these patients were vomiting (10% in arm A versus 12.1% in arm B), diarrhea (6.7% in arm A versus 6.1% in arm B), neutropenia (10.0% in arm A versus 15.1% in arm B) and leukopenia (3.3% in arm A versus 9.1% in arm B). Granulocyte colony stimulating factors (G-CSF) were administered to the patient with the above severe
neutropenic and leukopenic condition. Patients were subsequently withdrawn from the study due mainly to disease progression (73.3% in arm A versus 50% in arm B). Compared to three patients interrupting their IFL chemotherapy because of grade 3/4 neutropenia and sepsis, no patient in FOLFIRI group discontinued their chemotherapy because of intolerable hemtologic toxicity. As we mentioned above, one patient who received IFL regimen died from sepsis secondary to grade 4 neutropenia after the chemotherapy, whereas another two patients discontinued their treatment by the same reason and their septic condition improved later after the management. The objective responses of patients were summarized in Table 3, Table 4 and Fig. 1. Two patients who received only one and two cycles of IFL regimen and withdrew the chemotherapy later due to intolerable

Table 3. Best objective responses in metastatic colorectal cancer patients receiving IFL and FOLFIRI regimen IFL Regimen Sites of metastases (patients no./%) No. (%) Local Peritoneum Liver only Lung only Recurrence only only 6 (21.4) 1 (3.6) Distant LNs 1 (3.6) Multiple (n > 1) 16 (57.1) nth-Line Chemotherapy 1st 14 (50.0) 2nd 13 (46.4) 3rd 1 (3.6) 1 0
Evaluated 28 patients Complete 0 (0)0 response Partial 6 (21.4) response Stable 9 (32.2) disease Progressive 13 (46.4) disease FOLFIRI Regimen
Sites of metastases (patients no./%) No. (%) Local Peritoneum Liver only Lung only Recurrence only only 8 (24.2) 1 (3.0) Distant LNs 3 (9.1) Multiple (n > 1) 18 (54.5) 3 7
nth-Line Chemotherapy 1st 10 (30.3) 2nd 20 (60.6) 3rd 3 (9.1) 1 1
Evaluated 33 patients Complete 0 (0)0 response Partial 15 (45.5) response Stable 7 (21.2) disease Progressive 11 (33.3) disease
Note: Values in the bracketing are percentages of patients in each group.
102 Chin-Fan Chen, et al.
Table 4. Comparison of Response Between IFL and FOLFIRI Regimens First-Line Chemotherapy IFL CR + PR SD + PD FOLFIRI P 0.092 Second-Line Chemotherapy IFL FOLFIRI P 0.456 Third-Line Chemotherapy IFL FOLFIRI P 1.000
CR = complete response PR = partial response SD = stable disease PD = progressive disease Overall Response Rate = Complete Response Rate + Partial Response Rate
(7/33) of patients receiving the FOLFIRI regimen. The overall disease control rate (PR+SD) was 53.6% in arm A and 66.7% in arm B. The median time to progression was 5.5 months in arm A and 6.5 months in arm B, and no statistically significant difference was noted after analysis. (Fig. 1, p = 0.140) Of all the patients with progressive disease after the FOLFIRI chemotherapy, most (54.5%) had synchronous metastatic lesions at the time of initial diagnosis of CRC. Besides this, extrahepatic metastatic lesions and/or local recurrence lesion identified before initiation of the chemotherapy were noted in most patients (76.9% in arm A, 72.7% in arm B) with progressive disease.
Fig. 1. Analysis of progression-free survival (PFS) of the metastatic colorectal cancer patients treated with FOLFIRI and IFL regimen. The PFS of two groups was not statistically significant (P = 0.1409).

Discussion

Irinotecan has demonstrated its clinical efficacy and tolerability in multiple randomized or non-randomized studies, no matter as a single agent or with either bolus or infusional 5-FU/LV.5-6 The primary objective of this retrospective study was to compare the efficacy and safety of two different therapeutic regimens in which irinotecan was combined with bolus and/or infusional 5-FU/LV for the treatment of advanced colorectal cancer. In the study, these two combinations of irinotecan/5-FU/LV were well-tolerated, and the toxic effects were reversible and manageable except for one patient who died from sepsis secondary to grade 4 neutropenia after IFL chemotherapy. The incidence of grade 3 or higher non-hematologic adverse effects showed little difference in the two arms. Besides, they could be managed easily by the medications and never caused interruption of the chemotherapy in our study.

toxicity in arm A were excluded from the assessment of responses. Therefore, 28 patients in arm A and all 33 patients in arm B were able to be evaluated for treatment response. Among these patients, overall response rates were 21.4% (arm A) and 45.5% (arm B). Of all patients in this retrospective study, however, no complete response was achieved. In contrast to the poor response achieved in arm A, the response rate reached 60% (6/10) and 40% (8/20) among those who received FOLFIRI regimen as the first-line and second-line chemotherapy respectively. However, comparison of the response showed no statistically significant difference between the two arms, either in first-line or second-line chemotherapy (Table 5, firstline p = 0.092 , second-line p = 0.456). The incidence of stable disease (SD) was achieved in 32.2% (9/28) of patients receiving the IFL regimen and 21.2%
The toxicity profiles for the two regimens, especially the lower incidence of grade 3/4 diarrhea (6.7% in arm A, 6.1% in arm B), might be notable in comparison with other reports (18%-28% in patients receiving IFL regimen, 12-17% in patients receiving FOLFIRI regimen) conducted in Western counries.5-14 However, the lower incidence of grade 3 or more severe diarrhea in our study compared with those conducted in Western countries was similar with the result of other studies conducted in East-Asian countries (0-4% of patients receiving IFL, 2.2-9.3% of patients receiving FOLFIRI).15-19 In addition to diarrhea, the incidence of grade 3/4 vomiting was almost identical in both regimens in our study. Unlikely the significantly higher incidence of severe diarrhea noted in Caucasians than in East Asians after the irinotecancombination chemotherapy, the incidence of grade 3/4 vomiting was much more similar (8-14% in IFL, 8.8-13% in FOLFIRI), suggesting less significant difference between East-Asians and Caucasians in regard to severe vomiting.7-15,18 On the other hand, grade 3 or more severe neutropenia was observed in 10% (IFL) and 15.1% (FOLFIRI) of the patients in our study, in whom the incidence was considered to be lower than the reported incidence in patients receiving the same regimen. (30-54% in IFL, 20-43.1% in FOLFIRI).7-14,20 In comparison with the study reported in other Asian countries, however, the incidence of grade 3/4 neutropenia in our study was still lower than that reported in Japanese studies.15,17 Moreover, in contrast to the results of Caucasians, the incidence of grade 3/4 neutropenia in our study (FOLFIRI, 15.1%) was lower than the result of Zhangs study conducted in China (24.1%), but higher than the results of others (5.6% in Luos study, 6.8% in Lees study).16,18-19 It is an interesting issue about the difference in frequency of toxicities between the different ethnic people. The factors responsible for this wide interpatient variability include both genetic and non-genetic causes. Considering its complex disposition, irinotecan is found to be metabolized in vivo to form active SN-38, which is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 enzyme.21 With more understanding about the pharmacokinetics of SN-38 and pharmacogenetics of

UGT1A1 protein, recent studies had demonstrated that the frequency and severity of diarrhea and neutropenia-the two main adverse events encountered in patients with irinotecan chemotherapy, is dependent on the schedule of the treatment as well as on the effectiveness of SN-38 detoxification by UGT1A1 enzyme and other UGT family of enzymes.22-23 Moreover, genetic polymorphisms in the various UGT1A isoforms have been shown to influence the severity of irinotecan-induced gastrointestinal and hematologic toxicities in cancer patients of different ethnic origins. Toffoli et al. and al. both mentioned that UGT1A1*28 is associated with decreased UGT1A1 activity, and this might impair the process of SN-38 detoxication and cause more frequent occurrence of the severe toxicities in patients with this allele.24-25 This polymorphism (UGT1A1*28) is characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter, (TA)7TAA, instead of (TA)6TAA.21 As the studies showed that patients with UGT1A1 (TA) 7 allele were more likely to experience severe neutropenia and diarrhea following irinotecan chemotherapy, Liu et al. also demonstrated that this allele was significantly more common in Caucasians than in Asians.26-27 This might be one of the reasons for the higher frequency of grade 3/4 of diarrhea and neutropenia in Caucasians than in Asians. More studies are still needed, however, to confirm the possible mechanisms which result in the variation of toxicity between the patients of different ethnic groups. In comparison of the response rate achieved after chemotherapy, there were better overall response rates (ORR) and disease control rates (DCR) in patients who underwent the FOLFIRI regimen (FOLFIRI versus IFL, ORR 45.5% vs 21.4%, DCR 66.7% vs 53.6%). This was compatible with the conclusion of one randomized controlled trial by Fuchs et al. that FOLFIRI regimen offered superior antitumor activity to IFL regimen.9 In our study, there is no statistical difference of ORR between the two arms either in first- line or second-line chemotherapy (Table 5, p > 0.05), so is the progression free survival. (Fig. 1, p > 0.05) However, there are still 3 patients in arm B with no clinical evidence of progression of mCRC after FOLFIRI chemotherapy until December 2007, in
104 Chin-Fan Chen, et al.

Table 5. Comparison of common Grade III/IV toxicities of IFL and FOLFIRI Regimens between Caucasians, Asians and Results in our study IFL Caucasians Diarrhea 23% (Saltz, 2001) 18% (Bouzid, 2003) 28% (Goldberg, 2004) Asians 0% (Fujishima, 2004) 4% (Takayuki, 2007) Our Study 6.7% Caucasians FOLFIRI Asians 2.2 % (Lee, 2005) 2.4% (Zhang, 2006) 9.3% (Luo, 2007) Our Study 6.1%

Nausea/ Vomiting

10% (Saltz, 2001) 6%/8% (Bouzid, 2003) 16%/14% (Goldberg,2004)
0% (Fujishima, 2004) 7% (Takayuki, 2007)
Neutropenia 54% (Saltz, 2001) 30% (Bouzid, 2003) 40% (Goldberg, 2004)
66% (Fujishima, 2004) 50% (Takayuki, 2007)
14% (Douillard, 2003) 14% (Tournigand, 2004) 17% (Souglakos, 2006) 13.9% (Fuchs, 2007) 12% (Falcone, 2007) 3.3%/10% 13% (Douillard, 2003) 13%/10% (Tournigand, 2004) 13% (Souglakos, 2006) 8.8% (Fuchs, 2007) 10% (neutropenia) 25% (Douillard, 3.3% (leukopenia) 2003) 24% (Tournigand, 2004) 20% (Souglakos, 2006) 43.1% (Fuchs, 2007) 28% (Falcone, 2007)
2.2 % (Lee, 2005) 8.4% (Zhang, 2006) 9.3% (Luo, 2007)

3.0%/12.1%

6.8% (Lee, 2005, 15.1% (neutropenia) leukopenia) 9.1% (leukopenia) 24.1% (Zhang, 2006) 5.6% (Luo, 2007)
NCI-CTI, National Cancer Institute Common Toxicity Criteria
comparison with none of the patients in arm A without progression of mCRC after IFL chemotherapy. This means the possibility of better progression free survival in arm B in this study if these patients keep follow-up in our clinic. Further evaluation in a larger patient population is needed because the number of patients in this study was relatively small. In contrast to the more similar response rate of FOLFIRI chemotherapy between our study (45.5%) and other studies (ORR of FOLFIRI: 36.6-56% in Caucasians, 42.6-47.8% in Asians), the overall response rate and disease control rate of IFL chemotherapy in this study, however, are lower than that of other studies conducted in Western countries (ORR: IFL 34.6-50%) and Asian countries (ORR: IFL 38.9-48%, Table 6).7-19,28-29 One of the potential rea-
sons is the majority of patients with cancer involvement of multiple organs (metastases one organ, and/or local recurrent lesions) before they underwent the chemotherapy. Another possible reason is that an unexpectedly high proportion of the patients in this study had synchronous metastases (13 patients in arm A, 15 patients in arm B) at the time of diagnosis of CRC, and the majority of these patients got a progressive course and poorer prognosis after initiation of the chemotherapy (6 of 13 patients in arm A, 6 of 15 patients in arm B with progressive course). Moreover, it seems that patients with poor physical activity were more likely to have poor prognosis after treatment. Three of the 5 patients with ECOG performance score 2 in this study suffered from progressive course after the chemotherapy, whereas two other patients were

Table 6. Comparison of Overall Response Rate of IFL and FOLFIRI Regimens between Caucasians, Asians and Results in our study Caucasians IFL 50% (Saltz et al., 2001) 40% (Bouzid et al., 2003) 34.6% (Barcel R et al., 2006) 36.8% (Gluzman A et al., 2007) 56% (Tournigand et al., 2004) 36.6% (Souglakos et al., 2006) 47.2% (Fuchs et al., 2007) 41% (Falcone et al., 2007) 44.7% (Gluzman A et al., 2007) Asians 38.9% (Fujishima et al., 2004) 48% (Takayuki et al., 2007) Our Study 21.4%

FOLFIRI

47.8% (Lee et al., 2005) 12.5% (Zhang et al., 2006) 42.6% (Luo et al., 2007)
Overall Response Rate = Complete Response Rate + Partial Response Rate
excluded from the assessment of response because of interruption of the chemotherapy by the intolerable toxicity. Tournigand et al. had demonstrated in their prospective randomized study that performance status of the patients as one of the independent prognostic factors after FOLFIRI chemotherapy, and it is compatible with our finding.11 At present, first-line FOLFIRI have become one of the standards of treatment for mCRC patients since its superior overall survival; disease free survival and tolerable toxicities compared with other irinotecan regimens.10,15,21,29 In conclusion, both two different therapeutic combinations of irinotecan/5-FU/LV in this retrospective study were active and well-tolerated treatments for Taiwanese patients with mCRC. For the majority of patients, toxic effects encountered after the chemotherapy were reversible and manageable. After analyzing the efficacy of both regimens, there is a trend for an increased response rate and disease control rate in the patients receiving FOLFIRI chemotherapy. In consideration of no statistically significant difference of overall response and progression free survival between the two arms in this study, herein, we suggest that both FOLFIRI and IFL regimen could be considered as front-line regimen of irinotecan-based chemotherapy for Taiwanese patients with advanced colorectal cancer.

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