第18回国際癌学会連合(2002，オスロ)

学会場のオスロのオスロフィヨルドとアーケシュフース城：フィヨルド巡りボートより

Oslo,　Norway- June 30 - July 5, 2002

Phase III study of prophylactic Hange-Shashinto treatment of diarrhea following cisplatin and irinotecan combination chemotherapy for non-small cell lung cancer

T.SAWA, T.YOSHIDA, M.SAWADA, T.ISHIGURO, M.KAWADA, T.IKOMA, Y.OHNO, K.GOTO, H.FUJIWARA Division of Pulmonary Medicine, Gifu Municipal Hospital,Gifu, Japan
Department of 2nd Internal Medicine, Gifu University, Gifu, Japan

Rationale
Cisplatin (CDDP) + Irinotecan (CPT-11) combination chemotherapy is one of the most effective regimen for stage IV (advanced) non-small cell lung cancer (Fukuoka, 1999), while myelosupression and diarrhea are main adverse effects, and these adverse effects limit dose intensity and course schedule. As well, control of diarrhea is important to maintain good performance status and QOL. Hange-Shashinto, a Japanese herbal medicine containing baicalin, is reported to be useful to prevent diarrhea induced by Irinotecan in various malignant tumors (Sakata, 1994). However, there is no further report that Hange-Shashinto prevent diarrhea by popular regimen of Cisplatin and Irinotecan combination chemotherapy in non-small lung cancer.

Purpose
To evaluate the efficacy of prophylactic Hange-Shashinto and symptomatic loperamide combination treatment on Irinotecan induced diarrhea, comparative study was carried out in 62 patients with advanced or relapsed non-small cell lung cancer treated with CDDP +CPT-11.

Eligibility Criteria
1. Pathological or cytological diagnosis for non-small cell lung cancer.
2. Possible to treat with more than 2 cycles of CDDP+CPT-11
combination chemotherapy.
a) Adult patients < 75 years old, Performance status (ECOG): 0-2
b) Major organ function (bone marrow, liver, renal, cardiac and
respiratory function)
c) Nothing of diarrhea, myelosupression, serious infections.
d) Satisfy the required conditions for Irinotecan (excluding clause).
1) Ileus or intestinal paresis
2) Interstitial pneumonia or lung fibrosis
3) Massive pleural effusion or peritoneal effusion
4) Visual jaundice
5) Hypersensitivity to Irinotecan
3. Four weeks interval in the patients with previous chemotherapy.
4. Possible to administrate oral Kampo-medicine
(oral hange-shashinto herbal medicine).
5. Informed consent from patient in person.

Method
Patients were treated with more than 2 cycles of CDDP (80mg/m<SUP>2</SUP>, day 1) + CPT-11(60mg/m<SUP>2</SUP>, day 1, 8, 15). Patients were assigned alternatively to two groups supported with prophylactic Hange-Shashinto and with only loperamide. In the prophylactic Hange-Shashinto group, 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.

Results
The result was as follows.
1) In two groups,there were no difference in background of the patients.
2) Severity of diarrhea was significantly (p<0.05) improved in the group with prophylactic Hange-Shashinto compared with the control group. In the prophylactic Hange-Shashinto group, additional loperamide medication was significantly reduced.
3) As adverse effect of Hange-Shashinto, constipation less than grade 2 was observed in 42% cases.
4) Anti-tumor response showed overall response rate at 42% in prophylactic Hange-Shashinto group and at 39% in control group. In prophylactic Hange-Shashinto group, dose intensity was superior significantly (p<0.01 in CDDP, p<0.05 in CPT-11).

Discussion
Dose limiting factor of CDDP+CPT-11 combination chemotherapy is reported to be neutropenia / leucopenia and diarrhea (Masuda, 1995). It is easy to control neutropenia / leucopenia using G-CSF, while diarrhea is difficult to control and serious diarrhea as near fatal adverse effect has been reported because of individual variation. Irinotecan is metabolized to form active SN-38, which is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 enzyme. Genetic polymorphisms of the UGT1A1 would affect an interindividual variation of the toxicity by irinotecan via the alternation of bioavailability of SN-38. It is reported that determination of the UGT1A1 genotypes might be clinically useful for predicting severe toxicity by irinotecan in cancer patients (Ando, 2000). Nowadays we can detect individual with high-incidence of diarrhea by the UGT1A1 genotypes. In these patients, we should aggressively control diarrhea by symptomatic treatment with loperamide and prophylactic treatment with Hange-Shashinto, as so called "tailor made medicine".

Conclusion
To evaluate the efficacy of prophylactic Hange-Shashinto and symptomatic loperamide combination treatment on Irinotecan induced diarrhea, comparative study was carried out in 62　patients. It is concluded that symptomatic treatment with loperamide and prophylactic treatment with Hange-Shashinto is useful to prevent diarrhea induced by CDDP+CPT-11 combination chemotherapy.

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