信州医誌，57⑹：247〜253，2009

Combination Chemotherapy with Low‑dose 5‑FU, Cisplatin, andGemcitabine for Gemcitabine‑Refractory Pancreatic Cancer
Norikazu ARAKURA ＊, Osamu HASEBE , Yasuhide OCHI
Hideaki HAMANO , Eiji TANAKA and Shigeyuki KAWA
1） Department of Gastroenterology, Shinshu University School of Medicine
2） Department of Gastroenterology, Nagano Municipal Hospital
3） Center for Health, Safety and Environmental Management, Shinshu University

Background : No single agent or combination therapy for advanced pancreatic cancer has been reportedsuperior to single‑agent GEM ,and an eﬀective second‑line chemotherapyoption is needed for patients who areresistant to ﬁrst‑line GEM therapy.
Methods: We analyzed six patients who had disease progression following ﬁrst‑line gemcitabine therapy.
Patients received second‑line chemotherapy with low dose cisplatin, 5‑ﬂuorouracul or S‑1, and gemcitabine
every 21 days.
Results: Two patients showed a partial response (33.3%) and two showed stable disease. Four patients(66.6%)showed a prolonged survival time with partial responses or stable disease.M edian survival times were
7 and 11 months from the start of second‑line therapy and the start of ﬁrst‑line gemcitabine therapy,respectively. In addition, all patients reported relief from pain and had a favorable performance status. The
major toxicities of leucopenia, stomatitis, and diarrhea were found in one patient each.
Conclusion : This second‑line chemotherapy regimen is an eﬀective option for patients with gemcitabine‑resistant pancreatic cancer. Shinshu Med J 57 : 247 ―253, 2009
(Received for publication May 27, 2009 ;accepted in revised form September 10, 2009)
Key words:second‑line chemotherapy, pancreatic cancer, 5‑FU, Cisplatin, Gemcitabine

Introduction

after the start of therapy, so almost all patientsneed second‑line therapy. Combination chemother-Since the ﬁrst report of successful gemcitabine

apy using each anti‑cancer agent that has been(GEM) treatment for the advanced pancreatic can-reported to be at least somewhat eﬀective as acer in 1997 , single‑agent GEM has been widely

single agent has shown promise

used as a standard regimen for unresectable disease.

Japanese case reports as abstracts,which suggested

Because no single agent or combination therapyhasthat a low‑dose combination of cisplatin,5‑ﬂuorour-been reported superior to single‑agent GEM , theacil (5‑FU), S‑1 and gemcitabine was eﬀective insearch for strategies that are more eﬀective con-advanced pancreatic cancer resistant to ﬁrst‑linetinues. In addition, an eﬀective second‑line chemo-

gemcitabine therapy (Shimizu A,et al.The Journal

therapy option is needed for those patients who areof Japan Society for Cancer Therapy 38:763,2003,

resistant to ﬁrst‑line GEM therapy. In general, theand Hasebe O, et al. Suizou 20:308, 2005). Accord-eﬀects of ﬁrst‑line GEM expire three to ﬁve months

ingly, we investigated the eﬃcacy of combination. We found 2

chemotherapy including low‑dose cisplatin , 5‑Corresponding author:Norikazu Arakura
Department of Gastroenterology, Shinshu University

FU , S‑1 , and low‑dose GEM as a second‑line

School of Medicine, 3‑1‑1, Asahi, M atsumoto‑city,chemotherapy for patients with GEM ‑resistant

Nagano‑prefecture, 390‑8621, Japanpancreatic cancer.

No. 6, 2009247

Arakura・ Hasebe・ Ochi et al.

M aterials and M ethods

with the following protocol: cisplatin 10 mg/day/‑deoxy‑5‑ﬂuorouridinebody(days 1 and 8),S‑1 or 5ʼ
‑DFUR) 4 cap/day/body (days 1‑14), and GEM(5ʼ

Patients
Between January 2003 and December 2006, 30

200 mg/day/body(days 1 and 8)every 21 days.Full

patients with pancreatic cancer were treated withdoses were given to patients with grade 0‑2 tox-ﬁrst‑line GEM in our hospital and in aﬃliatedicities; however, for patients with grade 3‑4 tox-hospitals. We analyzed six of these patients whoicities or probable PD, chemotherapy was stopped.

met the following criteria :⑴ resistant to ﬁrst‑line

End points

GEM therapy, ⑵ no history of surgical treatment,

The primary end points were therapeutic⑶ no chemotherapeutic history other than GEM ,response and survival. Tumor size was assessed byand ⑷ Eastern Cooperative Oncology Groupabdominal computed tomography(CT)according to(ECOG) performance status (PS) of 0‑3. The other

the Japan Society for Cancer Therapy Criteria ,24 patients were excluded from the present study

which are similar to the World Health Organization

because of poor condition (15 patients) and thecriteria.Therapeutic response was also assessed byapplication for other regimen (9 patients). Accord-

the Response Evaluation Criteria in Solid Tumors

ing to the World Health Organization criteria,(RECIST) . Brieﬂy, complete response (CR) wasprogressive disease (PD)is deﬁned by the failure todeﬁned as the complete disappearance of all mea-

respond to ﬁrst‑line GEM chemotherapy.Of the six

surable and assessable lesions for at least four

patients,three were men and three were women,theweeks;partial response(PR)was deﬁned as a＞50%

mean age of the group was 55.3 years (range,43‑72

reduction in the sum of the values of the greatestyears), and the mean duration of their ﬁrst‑line

perpendicular diameters of all measurable lesions

GEM therapy was 6.7 months (range,2‑15 months;

for at least 4 weeks;stable disease(SD)was deﬁned

Table 1).

as a＜50% reduction or a＜25% increase in the sum

Second‑line chemotherapy regimenof the values of the greatest perpendicular diame-

The second‑line chemotherapy regimen was con-ters of all measurable lesions for at least 4 weeks;

structed based on the two previous case reports

progressive disease (PD) was deﬁned as a＞25%

mentioned above. The regimen comprised cisplatinincrease or the appearance of new lesions. PS was

5 mg/day/body (days 1‑5 and 8‑12), 5‑FU 500 mg/

scored from 0‑4 according to ECOG criteria. Pain

day/body (days 1‑5 and 8‑12), and GEM 200 mg/

was graded from 0 (none)to 4 (very strong),and theday/body (days 1 and 8) in two 21‑day courses.

eﬀect of chemotherapy on pain was evaluated.

Patients were hospitalized during the ﬁrst two

Overall survival was measured from the initiation

courses to ensure that they could tolerate this regi-of ﬁrst‑line GEM and from the initiation of second‑men and for nightlychronomodulation.The patientsline chemotherapy until death or last follow‑up

were then discharged and treated as outpatients

visit. Physical examination, complete blood cell

Table 1 Patient and tumor characteristics at enrollment
Primary Protocoland Duration ofﬁrst‑lineGEMsite(mg/body or mg/m ,months)

Pt.

AgeGender

153

MPb2345655
4353
72
56

FM
FFMPhPh
PhPhPt1000 mg/body , 81000 mg/body , 151000 mg/body , 131000 mg/body , 51000 mg/body , 21000 mg/body , 2

Response toﬁrst‑line GEM

PS

Pain

LiverMets.

PR1SD
PRSDPDPD

122
1
3＋＋ ＋＋＋＋＋＋−−＋＋＋＋＋ ＋＋＋＋＋−−−＋＋ ＋＋＋＋＋＋ ＋＋＋＋＋−Ascites

Lymph node positive.
248

信州医誌 Vol. 57

Combination chemotherapy for GEM ‑refractory pancreatic cancercounts, blood tests, and urinalysis were assessed atmonths) when measured from the start of second‑

least biweekly. Chest radiography, CT, and mea-line chemotherapy and 15.5 months (range, 5‑33

surements of serum carcino‑embrionic antigen

months)when measured from the start of ﬁrst‑line(CEA)and carbohydrate antigen 19 ‑9 (CA19 ‑9)werechemotherapy.

performed once a month.

Four months after the initiation of second‑line

Statistical Analysis

therapy, 5 patients (83%)reported relief from pain

Statistical analysis of changes in pain, PS, andand 1 (17%) reported no change; the diﬀerences

CA19 ‑9 was performed using the Wilcoxon Signed

were signiﬁcant (Table 3). Performance status wasRank Test.

improved or maintained in all patients but thechanges were not signiﬁcant (Table 3).Serum CA19‑

Results

9 decreased in 5 patients (86%)during three months

Patient characteristics at enrollment are present-of second‑line therapy, but the change was not

ed in Table 1. Three patients had PRs to ﬁrst‑line

signiﬁcant (Table 3). Serum CA19 ‑9 increased inGEM , 1 had SD, and 2 had PD. Five patients com-three patients (43%) or was maintained in threeplained of moderate or severe pain, 5 patients hadpatients (43%)after four months.

liver metastasis, and 2 patients had ascites due toAscites related to peritonitis carcinomatosa wasperitonitis carcinomatosa.

found in two patients and improved in both with

The objective tumor responses to second‑line

combination chemotherapy (100%). Serial image

chemotherapy are shown in Table 2. Two patientsﬁndings of a representative case (patient 3) are

had an objective PR and the overall response rate

shown in Figure 1;those prior to ﬁrst‑line GEM are

was 33.3%. Two patients had SD. The medianshown in ﬁgure 1A and 1D, those prior to second‑

survival times (MST)were 6.5 months (range, 3‑23line low‑dose combination therapy(15 months after

Table 2 Eﬀects of second‑line combination chemotherapy
Survival time since
Adverseinitiation of ﬁrst‑lineeﬀect
therapy (months)

Duration of combination
therapy(months)

Response2318PRSD

Grade 2
Grade 23133

alive
alive34

Cisplatin, GEM , 5‑FU → S‑1
Cisplatin, GEM , 5‑FU → S‑1Cisplatin, GEM , 5‑FU → S‑1
Cisplatin, GEM , 5‑FU → S‑1

76PRSD

Grade 3
Grade 2

2011deathdeath

56Cisplatin, GEM , 5‑FU → S‑1
Cisplatin, GEM , 5‑FU → S‑1

43

PD
PD

Grade 2
Grade 3

65

death
death

Pt.

Regimen

12OutcomeTable 3 Eﬀects of second‑line GEM combination chemotherapy
Pain

Performance Status

CA19 ‑9 (U/ml)

Pt

Response

At therapy
start

At 4 months

At therapy
start

At 4 months

At therapy
start

At 4 months

12345PRSDPRSDPD

23022010101211201212105
84248
4094
3801004254
15189312950

6PD31325822863

P ＝0.031
No. 6, 2009

P ＝0.375

P ＝0.156249

Arakura・ Hasebe・ Ochi et al.

Fig. 1Ａ Ｂ
Ｃ Ｄ
Ｅ Ｆ

Ａ：Abdominal CT of patient 3 prior to ﬁrst‑line GEM showing the pancreas head region.
Ｂ：Abdominal CT of patient 3 prior to second‑line low‑dose combination therapy(15 months after the start ofﬁrst‑line GEM ), showing the pancreas head region.
Ｃ：Abdominal CT of patient 3 seven months after the initiation of second‑line low‑dose combination therapy,
showing the pancreas head region.
Ｄ：Abdominal CT of patient 3 prior to the initiation ofﬁrst‑line GEM showing the umbilical portion ofthe liver.
Ｅ：Abdominal CT of patient 3 prior to the initiation of second‑line low‑dose combination therapy(15 months
after the start of ﬁrst‑line GEM), showing the umbilical portion of the liver.
Ｆ：Abdominal CT of patient 3 seven months after the initiation of second‑line low‑dose combination therapy
showing the umbilical portion of the liver.

250

信州医誌 Vol. 57

Combination chemotherapy for GEM ‑refractory pancreatic cancer

the start of ﬁrst‑line GEM )in Figure 1B and 1E,andmetabolite, 5‑FdUMP, by reducing the levels of its

those of seven months after the initiation of second‑

physiological competitor through ribonucleotide

line low‑dose combination therapy in Figure 1C andreductase inhibition .Fluorouracil enhances the cell

1F.Two patients with PRs after second‑line chemo-uptake of GEM in the GEM plus 5‑FU combination

therapy had experienced PRs after ﬁrst‑line GEM .

regimen . In recent reports, S‑1, a pro‑drug ofOf two patients with SD after second‑line chemo-

ﬂuorouracil, produced a favorable response rate oftherapy, 1 had experienced PR and 1 had experi-

37.5% and an MST of 8.8 months in the treatment

enced SD after ﬁrst‑line GEM therapy. Adverseof for treating advanced pancreatic cancer . The

events related to second‑line therapy are listed in

combination of GEM plus S‑1 showed even more

Table 4. Three patients developed three diﬀerent

promising results . Improvements in response

grade‑3/4 toxicities:leucopenia,stomatitis or diar-rates and MST were also reported for the combina-rhea.

tion of GEM and cisplatin, although there were noAt last follow‑up (18 and 23 months since thesigniﬁcant diﬀerences as compared to GEM monoth-

beginning of second‑line therapy), second‑line

erapy . The combination of GEM, cisplatin, andchemotherapy was ongoing in two patients who

ﬂuorouracil produced a response rate of 19 % and anshowed no evidence of disease progression.

M ST of 9 months . Most of the reports discussed
here have concerned ﬁrst‑line therapy for local orDiscussion

disseminated advanced pancreatic cancer;however,M any chemotherapy regimens for advanced pan-they may provide guidance for developing eﬀective

creatic cancer have been proposed since the intro-

second‑line therapies for GEM ‑resistant disease,duction of GEM in 1997 in hopes of exceeding theand we planned our second‑line chemotherapy regi-eﬃcacy of single‑agent GEM ; however, little evi-men based on these results.

dence showing superior eﬀect has been demonstrat-Here, we showed that second‑line chemotherapy

ed. One exception is the combination of GEM andusing low‑dose ﬂuoropyrimidine, cisplatin, anderlotinib, which prolonged M ST to 6.4 months as

GEM for GEM ‑resistant disease resulted in a 33%

compared to 5.9 months with GEM alone,but severe

PR rate (2/6), and that 67% (4/6) of patients hadinterstitial pneumonia was associated with thisPRs or SD. The eﬃcacy of this low‑dose combina-regimen .In a study comparing the combination oftion regimen was previously shown by two case

GEM and 5‑FU with single‑agent GEM,the combi-reports as abstracts (Shimizu A, et al. The Journal

nation regimen prolonged MST as compared toof Japan Society for Cancer Therapy 38:763,2003,

single agent GEM ;however, the prolongation wasand Hasebe O, et al. Suizou 20: 308, 2005). Thisnot statistically signiﬁcant . Gemcitabine isregimen produced a MST of 11 months as measured

believed to enhance the eﬀect of the 5‑FUfrom the initiation of ﬁrst‑line GEM. Previous

Table 4 Combination therapy‑associated toxicities
Grade 1n (%)

Grade 2n (%)

Grade 3n (%)

Grade 4n (%)

Leucopenia
Anemia3 (50%)
3 (50%)

1 (17%)
2 (34%)

1 (17%)000

Thrombocytopenia
Nausea/Vomiting
Diarrhea
Stomatitis

2 (34%)
2 (34%)
1 (17%)
02 (34%)
1 (17%)
00001 (17%)
00001 (17%)

Toxicity was graded according to the National Cancer InstituteCommon Toxicity Criteria, version 2.0.
No. 6, 2009251

Arakura・ Hasebe・ Ochi et al.

reports showed that MST of ﬁrst‑line GEM wasthat the speciﬁc dosages and combinations or thearound 5‑7 months. Accordingly, this second‑administration of any single agent were crucial toline regimen induced favorable response rates.

the observed responses.There is no time to test theHowever, we could not conclude that this regimen

eﬃcacyof various agents during second‑line chemo-

showed marked prolongation of survival time,therapy for advanced pancreatic cancer;therefore,

because comparison of survival time between thethe use of multiple low‑dose agents, as in thisﬁrst‑line therapyof previous reports and thesecond‑regimen, might prove the most eﬀective strategy.

line therapyof the present studyis diﬃcult.Patients

There are some limitations to this study.Firstly,

receiving this regimen had maintained or improved

the study was retrospective, and secondly, thePS, suggesting that this therapy had a positive

patients were relatively young and able to tolerateeﬀect on quality of life. It is diﬃcult to continue

this combination regimen well. We should conﬁrmintensive treatment when severe adverse events are

the eﬃcacyof this regimen in an older patient groupassociated with second‑line chemotherapy. Most

in a prospective manner.

toxicities associated with this low‑dose regimen

Conclusions

were lower, which was acceptable and manageable
for outpatient treatment. We recommend this low

In conclusion, this combination regimen provides

dose combination regimen for candidates for second‑an eﬀective alternative second‑line regimen forline therapy of pancreatic cancer resistant to ﬁrst‑

patients with advanced GEM ‑refractory pancreaticline gemcitabine therapy.

cancer.The roles of each drug in this regimen need

Of the 4 patients with PR or SD, 4 had experi-to be clariﬁed in a large, prospective trial.

enced PR or SD with ﬁrst‑line GEM therapy. Two

Acknowledgement

patients with PRs to second‑line chemotherapy had
also attained PRs on ﬁrst‑line GEM therapy.There-We thank Dr. Toshinari Kumaki of Nagano

fore, this combination second‑line regimen isM atsushiro General Hospital, Dr. Naoyuki Furuya

eﬀective in patients who experienced favorableof Hotaka Hospital and Dr Yayoi Ozaki of Depart-

responses to ﬁrst‑line GEM . The eﬃcacy of thisment of Gastroenterology, Shinshu University

regimen would be better tested as a ﬁrst‑line ther-

School of M edicine for their helpful and critical

apy. The mechanisms behind the eﬀectiveness ofadvice.

this second‑line regimen are not clear.It is possible
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