第2回国際肺癌学会，1996，ギリシャ：クレタ島：アンギオニコラスにて
LOPERAMIDE AND HANGE-SHASHINTO COMBINATION TREATMENT ON DIARRHEA FOLLOWING
CISPLATIN AND IRINOTECAN COMBINATION CHEMOTHERAPY FOR NON-SMALL CELL LUNG
CANCER
T.SAWA, T.YOSHIDA, Y.OHNO, M.TOYODA, N.YASUDA*, K.GOTO*, H.FUJIWARA*
Division of Pulmonary Medicine, Gifu Municipal Hospital, and 2nd Internal
Medicine, Gifu University*, Gifu, 500, Japan
SUMMARY
Hange-Shashinto, a Japanese herbal medicine containing baicalin, is suggested
to be useful to control diarrhea induced by Irinotecan (CPT-11). To evaluate
the efficacy of loperamide and Hange-Shashinto combination treatment on
diarrhea, a pilot cross-over study in 9 patients and a phase II study in
20 patients with advanced non-small cell lung cancer treated with Cisplatin
(CDDP) +CPT-11 were carried out. Patients were treated with 2-4 cycles of
CDDP (80mg/m2, day 1) + CPT-11(60mg/m2, day 1, 8, 15). 6g/day of oral Hange-Shashinto
was administered preventively through the chemotherapy. In the case of diarrhea
more than grade 2, 2mg of oral loperamide was administered. Diarrhea was
classified into ECOG grade and evaluated with score of grade by days. 1)
In the pilot cross-over study, severity of diarrhea was significantly (p<0.05)
improved in the cycle with Hange-Shashinto compared with the control cycle.
2) In the phase II study, loperamide and Hange-Shashinto combination treatment
showed good efficacy on the diarrhea. 3) Adverse effect of loperamide and
Hange-Shashinto was constipation with 10 cases less than grade 2. 4) Antitumor
response, in 20 evaluable cases, showed an overall response rate at 50%
with 10 PR cases, 6 NC cases and 4 PD cases.
It is concluded that symptomatic treatment with loperamide and prophylactic
treatment with Hange-Shashinto is useful to diarrhea induced by CDDP+CPT-11
combination chemotherapy.
INTRODUCTION
Cisplatin (CDDP) and irinotecan (CPT-11), a semisynthetic camptothecin derivative,
are both active against non-small cell lung cancer (NSCLC) as single agents.
Preclinical studies have shown that CPT-11 and its major active metabolite,
SN-38, are synergistic with CDDP. In a clinical trial of combination chemotherapy
with CDDP+CPT-11, good response rate of 54% was obtained in NSCLC patients,
and dose-limiting toxicities were leukopenia and diarrhea (Masuda et al.,
1992). Although leukopenia could be eliminated by G-CSF support, effective
supportive therapy for diarrhea induced by CPT-11 has not been established.
Hange-Shashinto, a Japanese herbal medicine containing baicalin, is suggested
to be useful to prevent diarrhea induced by single administration of CPT-11(Sakata
et al., 1994). In addition, loperamide has been used to control diarrhea
as a symptomatic treatment. To evaluate the efficacy of loperamide and Hange-Shashinto
combination treatment on diarrhea, a pilot cross-over study and a phase
II study in patients with NSCLC treated with CDDP+CPT-11 were performed.
PATIENTS AND METHODS
9 patients were enrolled in the pilot cross-over study and 20 patients in
the phase II study. All the patients met the following criteria: 1) a histologic
diagnosis of NSCLC; 2) no chemotherapy or radiotherapy, within 4 weeks before
entry; 3) age < 75 years; 4) performance status of 0-2 on the ECOG scale;
5) adequate bone marrow, hepatic and renal function; 6) written informed
consent. Patients were treated with 2-4 cycles of CDDP (80mg/m2, day 1)
+ CPT-11(60mg/m2, day 1, 8, 15) every 4 weeks. CPT-11 treatment was prolonged
to next week if grade 2 or worse leukopenia or diarrhea was noted on day
8 and 15. Patients with grade 3 and 4 leukopenia were supported with 75μg/day
of granulocyte colony-stimulating factor (G-CSF) until leukocyte counts
were over 10000/mm3. In the cross-over study, 6g/day of oral Hange-Shashinto
was administered preventively through the chemotherapy of second cycle.
In the phase II study, that was administered through all cycles. In the
case of diarrhea of more than grade 2, 2mg/day of oral loperamide was administered
until the diarrhea improved to less than grade 2. Diarrhea was classified
into 5 grades (0-4) according to the ECOG criteria and evaluated with grade
and total score of grades by days.
RESULTS AND CONCLUSIONS
1) In the pilot cross-over study, all of the 9 patients (age range; 54-75
years old, histologic diagnosis; 7 patients of adenocarcinoma and 2 of squamous
cell carcinoma, performance status; 5 of PS 1 and 4 of PS 2, clinical stage;
1 of stage IIIA, 1 of stage IIIB and 7 of stage IV) completed 2 cycles of
chemotherapy. Grade and total score of diarrhea were significantly (p<0.05
and p<0.01 respectively) improved in the cycle with Hange-Shashinto compared
with the control cycle .
2) In the phase II study, 20 patients (age range; 31-74 years old, histologic
diagnosis; 15 patients of adenocarcinoma, 4 of squamous cell carcinoma and
1 of adenosquamous carcinoma, performance status; 1 of PS 0, 16 of PS 1
and 4 of PS 2, clinical stage; 6 of stage IIIA, 3 of stage IIIB and 11 of
stage IV) were eligible. 5 patients were treated with more than 3 cycles
of chemotherapy, 11 patients with 2 cycles. In 4 patients, chemotherapy
was finished after one cycle because of progressive disease in 2 cases,
cisplatin induced ileus in 1 case and severe leukopenia (grade 4) in 1 case.
Loperamide and Hange-Shashinto combination treatment showed good efficacy
on the diarrhea . There was no difference in incidence of severe diarrhea
( >grade 2) between the first cycle and the second cycle. In day 2 and
day 7-17 of the first cycle and all cycles, incidence of diarrhea was high
and grade of diarrhea was severe. Limiting toxicity of dose intensity was
leukopenia and 11 patients were supported with G-CSF. Mean values of the
dose intensity of CDDP and CPT-11 were 17.7 and 40.1 mg/week respectively.
3) Adverse effect of loperamide and Hange-Shashinto was constipation with
10 cases of less than grade 2. Although 3 patients complained of odor with
Hange-Shashinto, it was tolerable to complete the regimen.
4) Antitumor response, in 20 evaluable cases, showed an overall response
rate of 50% in 10 PR cases, 6 NC cases and 4 PD cases.
It is concluded that symptomatic treatment with loperamide and prophylactic
treatment with Hange-Shashinto is useful in diarrhea induced by CDDP+CPT-11
combination chemotherapy. The mechanisms by which this treatment alleviate
the diarrhea induced by CPT-11 is thought to be the following. CPT-11 is
transformed to SN-38 by carboxylesterase and converted to SN-38-glucuronide
by glucuronyltransferase in the liver. SN-38-glucuronide which is excreted
in the bile is re-transformed to SN-38 by β-glucuronidase in the intestinal
microflora. SN-38 is considered to damage the intestinal epithelium and
cause the delayed diarrhea (Asumi et al., 1991). Baicalin which is contained
in Hange-Shashinto is reported to be a strong β-glucuronidase inhibitor
and prevent the delayed diarrhea induced by CPT-11 in animals (Narita et
al., 1993 and Takasuna et al., 1995). Loperamide and Hange-Shashinto combination
treatment will be beneficial in clinical use because loperamide controls
acute diarrhea and Hange-Shashinto prevents delayed diarrhea.
第2回国際肺癌学会，1996，ギリシャ：クレタ島：アンギオニコラスにて