long-term effect of 5-fluorouracil enhanced by intermittent administration of polysaccharide k after...

7/30/2019 Long-Term Effect of 5-Fluorouracil Enhanced by Intermittent Administration of Polysaccharide K After Curative Res

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Accepted: 21 July 2003Published online: 12 September 2003 Springer-Verlag 2003

S. BabaDepartment of Surgery 2,Hamamatsu University School of Medicine,3600 Handa-cho, 431-3192 Hamamatsu,

Japan

M. MaiCancer Research Institute,Kanazawa University,13-1 Takara-machi,920-0934 Kanazawa, Japan

J.-i. SakamotoDepartment of Surgery,Aichi Prefectural Hospital,18 Kuriyado, Kake-machi,444-0011 Okazaki, Japan

Y. OhashiDepartment of Health Science,Faculty of Medicine,

University of Tokyo,7-3-1 Hongo, Bunkyo-ku,113-0033 Tokyo, Japan

after curative resection. Patients andmethods: Employing the minimiza-tion method using three factors

(lymph node metastases, preopera-tive serum CEA level, and institu-tion), 446 patients were allocated in-to groups P and C. Group P receivedimmunochemotherapy, oral PSK(3 g per day) followed by oral5-FU (200 mg/body per day), whilegroup C received only intermittentchemotherapy, oral 5-FU (200 mgper day) followed by 4-week rest.Both groups received ten courses.

Results: Survival for cancer deathwas significantly higher in group P

than in group C, but there was nodifference in 7-year disease-freesurvival or overall survival had.Conclusion: Repeated alternatingadministration with PSK followedby 5-FU can improve survival forcancer death.

Keywords 5-Fluorouracil Polysaccharide K Colon cancer Immunochemotherapy Intermittentadministration

Int J Colorectal Dis (2004) 19:157164DOI 10.1007/s00384-003-0532-x O R I G I N A L A R T I C L E

Katsuki ItoHiroaki NakazatoAkihiko KoikeHiroshi TakagiShigetoyo SajiShozo BabaMasayoshi MaiJun-ichi SakamotoYasuo Ohashi

Long-term effect of 5-fluorouracil enhanced

by intermittent administration

of polysaccharide K after curative resectionof colon cancer

A randomized controlled trial for 7-year follow-up

Introduction

The death rate from malignant neoplasms has been thehighest among all causes of death in Japan since itpassed that of cerebrovascular disease in 1981. The totalnumber of deaths due to cancer has reached over280,000 annually. Lung and gastric cancer have the high-est mortality rates, followed by liver and colon cancer[1]. Based on the fact that the incidence of colon cancer

is increasing (over 22,000 in deaths), in clear contrastwith the decrease in gastric cancer, it appears that the or-der of morbidity rates by cancer site in Japan come tomore closely resemble the pattern in Western countriesin the near future: lung, colon, and breast cancer, respec-tively. To counter the rising trend in colon cancer noveltherapeutic strategies for colon cancer are needed.

For patients with lymph node metastasis after curativeresection of colon cancer, the possibility of recurrence

The authors represent the Study Group ofImmunochemotherapy with PSK for ColonCancer

K. Ito () H. TakagiDepartment of Surgery 2,Nagoya University School of Medicine,65 Tsurumai-cho, Showa-ku,466-8550 Nagoya, Japane-mail: [email protected].: +81-52-7442442Fax: +81-52-7442444

H. NakazatoYokoyama Gastrointestinal Hospital,3-11-20, Chiyoda, Naka-ku,460-0012 Nagoya, Japan

A. KoikeDepartment of Surgery 1,Aichi Medical University,21 Karimata, Yazako, Nagakute-cho,Aichi-gun, 480-1195 Aichi, Japan

S. SajiDepartment of Surgery 2,Gifu University School of Medicine,40 Tsukasa-machi, 500-8705 Gifu, Japan

Abstract Background and aims:The efficacy of a biological responsemodifier polysaccharide K in adju-vant immunochemotherapy wasevaluated in primary colon cancerpatients with macroscopic Dukes C


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due to residual cancer cells or tumor spill during surgerymust be considered. As postoperative treatment, chemo-therapy and immunotherapy have been as frequently ap-plied as radiation therapy in patients with colon cancer.More recently, immunochemotherapy, which is com-bined treatment with immunotherapy and chemotherapywith the intent to take advantage of the effects of each

and intensify antitumor effect, is making progress world-wide. In fact host immune damage due to prolongedadministration of chemotherapeutic agents can be mini-mized by concomitant use of immunotherapy especiallywith polysaccharide K (PSK) or levamisole.

The protein-bound PSK extracted from mycelia ofCoriolus versicolor strain CM-101, belonging to thebasidiomycetes [2], is a recognized biological responsemodifier (BRM). It is composed of proteins and polysac-charides. Its major glycoside portion is -1,4-glucan, andit has an average molecular weight of approximately100 kDa. PSK is a potent inducer of gene expression forseveral interleukins, tumor necrosis factor, and monocyte

chemotactic and activating factors. The antitumor activi-ty of PSK is thought to be based on its regulation of hostimmune response, and the drug is widely prescribed fororal ingestion [3]. This nonspecific immunopotentiatorhas the ability to inhibit the immunosuppression of can-cer patients and is widely used in Japan for this purpose.PSK has been confirmed to be more effective in thetreatment of gastric cancer when intermittently adminis-tered followed by alternating chemotherapy [4]. How-ever, the immunochemotherapeutic efficacy of PSK plusantitumor agents on colorectal cancer remains unclear.

With 93 cooperating institutions, all are the centerhospitals of the local area, the Study Group of Colon

Cancer with Immunochemotherapy was organized toevaluate the efficacy of alternating PSK followed by 5-fluorouracil (5-FU) in patients with curative resection ofprimary colon cancer, and it conducted randomized con-trolled trials from 1991 to 1998. All operations were car-ried out by the registered surgeons to the Japan SurgicalSociety, and their technical abilities were approved bythe society. All operations were performed along theguidelines of the operative procedures, including lymphnodes dissection, detailed in the Japanese Classificationof Colorectal Carcinoma [5]. In addition to analyzingoverall survival (OS), disease-free survival (DFS) andsurvival for cancer-related death (SCD, as an original

analysis), a stratified analysis of cases of macroscopicDukes C has been planned. The study protocol specifiesthat covariate analysis be considered together with thedetermination of subgroups after blind review. The pre-vious review of 5-year follow-up results was presented atthe 35th ASCO meeting in 1999 [6]. Since this reviewshowed promising outcomes, extended follow-up data upto 7 years were investigated in the present study to as-sess the long-term effect on the clinical course of thisimmunochemotherapy.

Materials and methods

Organization

Colon cancer patients who had undergone curative resection andhad developed macroscopic lymph node metastasis were randomlyassigned to receive postoperative administration of both PSK and5-FU, or 5-FU alone as a control, at one of 93 institutions in the

Chubu region of Japan between February 1991 and March 1993.The characteristics of the all patients were shown in Table 1. Theprotocol was approved by the institutional review board of eachhospital, and informed consent was obtained from all the patientsor their relatives.

Eligibility

The patients were assessed to be eligible when all the followingconditions were met: matched: primary colon cancer with curativeresection and positive macroscopic lymph node metastases (mac-roscopic Dukes C); under 75 years of age with PS 0 or 1; no seri-ous complications; no preoperative treatment (radiation therapy,chemotherapy, immunotherapy) for cancer; no previous history ofcancer; acceptable preoperative laboratory data (white blood cell

count 3,000/mm3

, platelet count 100,000/mm3

, glutamic-oxalo-acetic transaminase and glutamic-pyruvic transaminase 100 IU);preoperative records of serum carcinoembryonic antigen (CEA)level (below 5 ng/dl or not) and purified protein derivative (PPD)skin test reactions (smaller than 10 mm or not). A total of 441 pa-tients were judged to be eligible according to the criteria of eligi-bility.

Stratification and randomization procedures

A chart of the randomization following registration is shown inFig. 1. All the patients received a 48-h constant intravenous infu-sion of 5-FU (Kyowa Hakko Kogyo, Tokyo, Japan) at the doseof 2 1,000 mg1 m2 per 24 h [7] on postoperative days 12, 8,9, 15, 16, 22, and 23 (if possible); that is, weekly for 34 weeks

as pretreatment. The dose was supposed to be very safe and ef-fective with a low level of adverse effects and to be associatedwith prolonged survival time in patients with absolutely noncur-ative gastric and colorectal cancer [5, 8, 9]. In the expectationof postoperative weight reduction, weight was remeasured todetermine individually the amount of 5-FU after the secondadministration. At the point when the 5-FU infusion courseswere completed the patients were stratified according to fourfactors: degree of histopathological lymph node metastases [5](N0, N1, N2, N3); preoperative serum CEA level [10] (5 ng/ml,5 ng/ml


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Table 1 Patient characteristics

Group P (n=220) Group C (n=221) P

n % n %

Sex 0.88 (2)

Male 123 55.9 121 54.8

Female 97 44.1 100 45.2Age (years) 0.77 (U)

49 28 12.7 35 15.85059 66 30.0 50 22.66069 85 38.6 107 48.47075 41 18.6 29 13.1

Mean 60.4 60.0 0.60 (t)

Performance status (PS) 0.11 (2), 0.09 (Fi)

0 186 84.5 199 90.01 34 15.5 22 10.0

Tumor location 0.27 (2)

Cecum 29 13.2 18 8.1Ascending colon 42 19.1 44 19.9Transverse colon 18 8.2 29 13.1Descending colon 16 7.3 16 7.2Sigmoid 115 52.3 114 51.6

Curability 0.26 (2)

Absolute 197 89.5 188 85.1Relative 23 10.5 33 14.9

PPD (balancing factor) 1.00 (2)

10 mm 126 57.3 127 57.5


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(200 mg/body per day) as one course. Group C received a 4-weekrest and 4-week oral 5-FU chemotherapy (200 mg/body per day)as one course so that intermittent 5-FU was administered at 4-week intervals. A total of ten courses were given to both groups(Fig. 2).

Follow-up procedure

Follow-up observation was based on the following factors: physi-cal examination, hematological tests, blood biochemistry, check ofcompliance to oral treatment, assessment of postoperative compli-cations and toxicity, initial recurrence, and outcome. Follow-upvisits were requested once a month until 18 months and thereafterevery 36 months up to 7 years. Abdominal computed tomogra-phy (CT) or echogram, chest radiography, and CEA/CA19-9 mea-surements were performed every 6 months during the follow-upperiod. In addition, either a barium enema or colonoscopic exami-nation was performed every year. If recurrence was detected, thepatient was not required to continue the allocated regimen but wasgiven individually appropriate treatment. If a patient experiencedtoxic effects, the assigned treatment was suspended until remis-sion.

Statistical considerations

In the coprimary endpoints of the study, OS, DFS, and SCD, thestarting point was defined to be the day of operation. In calculat-ing OS and DFS all deaths were treated as events in OS, whereasrecurrences or deaths from all causes were treated as events inDFS. For SCD cancer death and noncancer death were defined asan event and a censored case, respectively.

Noncancer death was classified as death from another diseasecompletely or an accident unassociated with cancer-related dis-ease. All the events of recurrence and deaths were calculated fromthe date of operation. Patients who were judged to be ineligiblebased on the information before randomization were excludedfrom the primary analysis, and all the other patients were includedin the analysis according to the intention-to-treat principle.

The required sample size was calculated to be 224 in each

group, which would ensure the power of the primary log-rank testto be 80% with 0.05 type 1 error (one-sided) [12], based on the ex-pectation that PSK would reduce the hazard rate of mortality totwo thirds and on the assumption that the 7-year OS rate in thecontrol group would be 60%. The expected number of deaths(events) was 155 in total.

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Fig. 1 Registration and randomization procedure. The eligiblecases were allocated into groups P or C by dynamic randomizationconsidering the degree of histological lymph node metastases, pre-operative CEA level, PPD skin test reaction, and institution

Fig. 2 Modality of therapy. Pa-tients were excluded from cen-tral registration who could notbegin pretreatment of 5-FUwithin 7 postoperative days, orcould not receive the treatmentfor more than 2 weeks

Protocol management

Oral PSK (Krestin, Kureha Chemical, Tokyo, Japan) at a dose of3 g/body per day was administered to group P from the 29th post-operative day for 4 weeks followed by 4-week oral 5-FU treatment


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All statistical analyses were carried out using SAS version6.12. The OS, DFS, and SCD rates were calculated by the Kaplan-Meier method. The stratified log-rank test adjusted by the threefactors was used for a comparison between groups P and C, andthe similar stratified Cox regression was used for estimating riskreductions. Exclusion of PPD skin test reactions and inclusion ofPS status from primary analysis were decided based on a blind re-view which showed the PPD skin test reaction had no influence onendpoint whereas PS had a strong effect. All P values were two-sided. Additionally, the logarithmic hazard ratio was estimated foreach subgroup of prognostic factors from the adjusted log-ranktest, based on which the interaction test between each factor andtreatment effect was performed.

Results

There were 37 cancer-related deaths (16.82%) in group Pand 49 (22.17%) in group C. The major causes of twentynoncancer deaths were: myocardial infarction (n=2), ce-rebral infarction (n=1), cerebral hemorrhage (n=1), dia-betic nephropathy (n=1), respiratory insufficiency (n=1),

burn death (n=1), and suicide (n=1).The 7-year DFS of group P was statistically similar tothat of group C (74.1% vs. 71.0%), and the P values cal-culated using the log-rank test were 0.48 (crude) and 0.10(adjusted by the three factors), respectively (Fig. 3). The7-year OS rates showed slight but not significant differ-ences between groups P and C (79.6% vs. 75.6%, crude:P=0.38; adjusted: P=0.081). For 7-year SCD, however,group P was statistically higher than group C (83.4% vs.78.5%, crude: P=0.17; adjusted: P=0.019, Fig. 4).

Subgroup analysis of logarithmic hazard rates re-vealed that the interaction due to PS was markedly sig-nificant in SCD (Fig. 5) and was also seen in OS andDFS (P


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tic toxic effect was identified for PSK even after meticu-

lous review of all individual medical records by the in-vestigator in charge.

Discussion

The effectiveness of 5-FU has been reported as adjuvantchemotherapy for curatively resected colorectal carcino-ma [13, 14]. In Japan there is as yet no standard chemo-therapy regimen as there is in the United States. There-fore as a control group we selected the 5-FU, as a drugof adjuvant chemotherapy. Simultaneous administrationof immunochemotherapy with PSK and 5-FU in patients

with colon cancer has been reported, and immunochemo-therapeutic advantages were confirmed in both OS andDFS [15]. The 5-year OS and DSF of adjuvant chemo-therapy for curatively resected colon cancer of Dukes Cpatients of 5-FU vs. surgery alone were 72.8%, 55.2%vs. 61.0%, 54.5%, respectively, with statistical signifi-cance in both group [13]. Similar outcomes are suggest-ed from studies on adjuvant immunochemotherapy usingpyrimidine fluoride drugs and PSK [13, 16]. One study,however, failed to show a statistically significant differ-ence in 6-year OS and another demonstrated significant-ly higher 5-year OS and DFS in all cases but failed toshow significant results when the patients were stratified

into subgroups of colon and rectum cancer. Furthermore,concomitant administration of 5-FU and levamisole, an-other BRM such as PSK in colon cancer patients withDukes C showed significant efficacy [17] as an adjuvanttherapy. However, the immunotherapeutic effect of le-vamisole has been controversial in recent studies [18].

Currie et al. [19] experimentally investigated the ef-fectiveness of immunochemotherapy in various regimensincluding concomitant or alternating administration, andlong afterward Kondo et al. [20] hypothesized that alter-

nating administration of a chemotherapeutic agent (car-

bazilquinone) and BRM would further optimize the anti-tumor effect in comparison with concomitant administra-tion, considering the pharmacodynamic competing ac-tion between the two types of agents. Chemotherapeuticagents would suppress immune response system, whileBRM would regulate or modulate the host immune re-sponse. Their results from a preclinical animal study in-dicated for the first time the superiority of repeating cy-cles of immunotherapy and chemotherapy.

Adopting the modality of alternating therapy withPSK and chemotherapeutic agents including carbazilqui-none, 5-DFUR (Futraful), and 5-FU as a postoperativeadjuvant immunochemotherapy in patients with macro-

scopic curative resection of gastric and colorectal cancer,a series of studies showed significant differences be-tween alternating administration groups (chemotherapeu-tic agent followed by PSK) and groups receiving inter-mittent chemotherapy alone, not only in individual stud-ies but also in meta-analysis [4, 21, 22, 23].

The present 7-year follow-up study suggests that anintensified effect in terms of prolonged survival in SCDcould be induced by repeated alternating administrationwith PSK followed by 5-FU. The regimen of oral admin-istration would also help maintain the patients quality oflife. The alternating therapy does not appear to lose itseffectiveness with time, at least as far as can be deter-

mined from a comparison of the outcome between our 5-year [6] and 7-year follow-up studies. That is, the 7-yearSCD clearly exceeded the 5-year SCD that was adjustedby two balancing factors (lymph node metastases, preop-erative CEA level) and PS (P=0.019 vs. P=0.026).

Furthermore, a positive interaction was revealed be-tween PS 0 and 1 in the analysis of logarithmic hazardratio, suggesting that patients with PS 1 would be moresensitive to the immunomodulating effect of PSK thanpatients with PS 0. The orally administered dose of PSK,

Table 2 Adverse effects: num-ber and ratio (patients/year) Group P Group C P (

2)

Number Ratio Number Ratio

Hemoglobin 46 10.70 56 13.08 0.104White blood cells 84 19.53 99 23.13 0.232Platelet 12 2.79 10 2.34 0.742Glutamic oxaloacetic transaminase 44 10.23 51 11.92 0.630

Glutamic pyruvic transaminase 51 11.86 54 12.62 1.000Alkaline leukocyte phosphatase 47 10.93 55 12.85 0.157Creatinine 3 0.70 3 0.70 0.351Oral cavity disorders 1 0.23 5 1.17 0.269Loss of appetite 16 3.72 28 6.54 0.214Nausea-vomiting 13 3.02 22 5.14 0.185Diarrhea 14 3.26 23 5.37 0.450Obstipation 37 8.60 29 6.78 0.612Pain 31 7.21 26 6.07 0.548Skin disorders 6 1.40 4 0.93 0.579Others 47 10.93 65 15.19 0.010


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3.0 g/body per day, was the same as used conventionally[12, 24]. There may be, however, potential advantagewith a greater amount of PSK in patients diagnosed asPS 1. Regarding the correlation between preoperative se-rum immunosuppressive acidic protein (IAP) level andthe sensitivity to postoperative BRM therapy, the surviv-al rate in the low IAP group (cutoff value 580 g/ml)

was reported to be significantly higher than in the highIAP group in curatively resected gastric cancer patients[25]. Moreover, significantly longer survival outcomeswere observed in the subgroup receiving immunochemo-therapy than that receiving chemotherapy alone amongthe low IAP group, while in the high IAP group no sig-nificant tendency was observed between the immunoche-motherapy and chemotherapy subgroups. Taking theseobservations into account, it will be necessary to investi-gate in future studies whether there is a correlation be-tween PS and the degree of preoperative IAP level sincethe survival rates between the PS 0/1 and IAP low/highsubgroups might exhibit similar tendencies.

Numerous studies have investigated the immunothera-peutic actions of PSK through the pathways augmentinghost immunity. Their modes of action can be defined as

radical trapping [2], modulation of cytokine production [2,26, 27, 28] and effector cell functions [2]. Other reportshave indicated that they also stimulate dendritic or Langer-hans cells [29], activate killer T-cells or human natural kill-er cells [30, 31] and provoke secretion of cytokines [26].

However, much is unknown mechanistically about theimmunotherapeutic pathways of PSK interacting with

chemotherapeutic agents. The efficacy of alternating im-munochemotherapy with PSK followed by other chemo-therapeutic agents should be investigated to clarify theimmunoactivation characteristics of PSK. Further appli-cation of the alternating therapy with other BRM mayalso be beneficial for prolongation of survival.

Conclusion

The repeated alternating administration with PSK fol-lowed by 5-FU would be suggested to enhance antitumoreffect, resulting in a superior survival for cancer-related

death compared with 5-FU alone.Acknowledgements We thank Ms. Atsuko Tanaka for the assis-tance in the preparation of the manuscript.

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long-term effect of 5-fluorouracil enhanced by intermittent administration of polysaccharide k after...

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