Clinical Study on Kanglaite Injection Combined with Intervention Chemotherapy in the treatment of Primary Hepatic Carcinoma and Primary Pulmonary Carcinoma

Qian Mingshan*, Liu Zhijiang**

Traditional Chinese Medicine Hospital of Zhejiang Province*, People's Hospital of Zhejiang Province**

Abstract
　

Kanglaite Injection (KLT) was developed from the extract of a traditional Chinese medicinal herb semen coicis through modern scientific process technology by Zhejiang Kanglaite Pharmaceutical Co., Ltd. In 1995 the product was awarded with the "National Category B New Drug" certificate and the permit for production as well. In accordance with the requirement from the New Drug Examination and Approval Office under the Ministry of Public Health, the Phase III clinical trial on KLT interventional treatment of primary hepatic carcinoma and primary pulmonary carcinoma was carried out from February 1996 to May 1997. The objective was to observe its curative effect and adverse reactions in treating primary hepatic carcinoma and primary pulmonary carcinoma so as to determine its effectiveness and safety. The trial was performed on the basis of  “Principles of Clinical Guidance to New Medicine (TCM)” issued by the Pharmaceutical Administration Bureau under the Ministry of Public Health. The trial was led by the Traditional Chinese Medicine Hospital of Zhejiang Province with cooperative units such as the Hospital Attached to Nanjing Medical University and the People's Hospital of Zhejiang Province. The results showed that the effective rate of KLT used in interventional treatment for primary hepatic carcinoma (CR+PR) was 69.23% while effective rate of chemotherapy group was only 38.24%. The effective rate of KLT used in intervention treatment for primary pulmonary carcinoma (CR+PR) was 52.11% while the effective rate of chemotherapy group was only 28.95%. KLT had shown optimum effect in treating  hepatic carcinoma with symptom-sign of "water retention due to hypofunction of spleen or toxic heat" and pulmonary carcinoma with "deficiency of both qi and yin".  KLT could markedly improve major clinical symptoms of primary hepatic carcinoma and primary pulmonary carcinoma. Total symptom improvement rate for hepatic carcinoma was  82.31% and 80.99% for pulmonary carcinoma. In addition patients in KLT treatment group had their survival quality improved, value of CD₄⁺/CD₈⁺ elevated, body immune function enhanced and peripheral blood pictured protected. No damage on liver and kidney functions and no evident toxic and adverse reactions were observed in this trial except slight nausea, fever and dryness of mouth which could get relieved spontaneously. Phlebitis occurred in a few patients which could disappear after symptomatic treatment. Quick artery injection speed would cause oppression in chest and severe cough which could also be remitted by slowing down infusion speed or injecting 1% procaine.

1. Case enrollment and methods

1.1   Diagnostic standard

1.1.1 Diagnostic standard for hepatic carcinoma

(1)  Pathological diagnosis

a) Primary hepatic carcinoma being confirmed by hepatic tissue examination

b) Hepatic-cell carcinoma being confirmed by extra-hepatic histological examination

(2)  Clinical diagnosis

a) AFP positive in CIE or >400ng/ml in radio-immunoassay for more than 4 weeks while pregnancy, gonadial embryonal carcinoma, movable hepatic disease or metastatic hepatic carcinoma could be excluded if without other evidence of hepatic carcinoma.

b) With or without clinical evidence but evidence of space-occupying lesion in liver could be confirmed by imaging examination like B-supersonic and CT while hepatic hemanogioma or metastatic hepatic carcinoma could be excluded. Subject should meet one of the following.

  - AFP> 200ng/ml or γ-GT elevated evidently

  - Imaging evidence of typical primary hepatic carcinoma

  - AFP or γ-GT elevated evidently without jaundice

  - With metastatic lesion in further location or bloody ascites or carcinoma cells detected in ascites

  - Hepatic sclerosis with confirmed positive of hepatitis B 

(3)  Standard of clinical staging

Stage I:  without symptom and physical sign of hepatic carcinoma. Single tubercle (diameter<5cm) could be detected by  

              CT and B-supersonic.

Stade II: with slight symptoms and average physical state, worse than stage I without evidence of stage III

Stage III: with evident cachexia, jaundice, ascties or extrahepatic metastasis

1.1.2 Diagnosis standard for pulmonary carcinoma

According to the diagnostic standard of primary pulmonary carcinoma in Book VI of  “Diagnostic Principles of Common tumors in China” from the Ministry of Public Health, subjects with pathological or cytological evidence of Squamous or adenocarcinoma after receiving examinations of X-ray or bronchoscope (biopsy, brush biopsy, washing), hydrothorax, sputum, pulmonary puncture, lymph puncture biopsy and expectoration, etc. were clinically confirmed with primary pulmonary carcinoma.

(1) Pathological diagnosis

Subjects without the evidently recognized extra-pulmonary focus must meet one of the following items before establishing pathological diagnosis.

a) Subjects whose pulmonary surgical specimen was confirmed by pathological or histological evidence.

b) Subjects who were diagnosed of primary pulmonary carcinoma by histological examination on specimen obtained through pectoral exploration, pulmonary puncture or fiberbrochoscopic examination.

c) Subjects whose biopsy resulted in metastatic focus in neck, infra-auxiliary lymphoglandula, chest wall, pleura as well as subcutaneous nodule histologically  were confirmed with primary pulmonary carcinoma. And pulmonary carcinoma was suspected in lung or bronchi yet other primary carcinoma could be excluded.

(2) Cytological diagnosis

The cytological specimen obtained from sputum, bronchoscopic brush and washing met with cytologically diagnostic standard of pulmonary carcinoma. Upper respiratory tract carcinoma and esophageal carcinoma, however, should be cautiously ruled out.

(3) Clinical diagnosis

The diagnosis could be established provided the patients could meet one of the following.

a) Solitary tubercles or tumor shadow could be seen in chest X-ray with gyrus edge and shape of leave or  fine spicules which could be gradually enlarged within 2-3 months. After short term of active medication tuberculosis or other inflammatory lesion could be excluded.

b) Subjects with segmental pneumonia developed into lobus atelectasis within a short period (2-3 months) or lobus pulmonis developed into full atelectasis within a short period or with growing mass in the root of lung.

c) Subjects with the above pulmonary focus that had metastasis to further location and with symptoms of neighbor organs being invaded or oppressed such as adjacent bone-necrosis, evident enlargement of hilus of lung and/or mediastinal lymphaden, fast developed venacaval oppression, paralysis of homolateral recurrent laryngeal nerve (tuberculosis and pahological change of artery excluded) and invasion in jugular sympathetic ganglion (surgical injury excluded), brachial plexus or phrenic nerve, etc.

(4) Clinical staging

Clinical staging was based on the TNM staging of broncho-pulmonary carcinoma in the Book VI of  “Diagnostic Principles of Common Malignant Tumors in China”  issued by the Ministry of Public Health in 1989.

(5) Classification of physical condition

Classification was based on the Karnofsky scoring system as statistic evaluation standard in diagnosis of tumors in Book IX of “Diagnostic Principles of Common Malignant Tumors in China” issued by the Ministry of Public Health.

1.2 Standard of cases in trial

1.2.1 Standard of enrollment and exclusion of hepatic carcinoma cases

(1) Standard of case enrollment

Subjects clinically diagnosed as primary hepatic carcinoma in Stage I, II and early III with estimated survival period over 3 months and Karnofsky score >=50

(2) Standard of case exclusion (including those unadaptable or rejected)

a) With secondary hepatic carcinoma

b) Accompanied with severe primary disease in heart, blood vessel or kidney, severe hepato-cirrhosis or pathological 

    hyperlipemia

c) Age younger than 18 or older than 70, women in pregnancy or patients allergic to the product

d) Patients failed to meet the enrollment standard or did not follow medication or had difficulty to evaluate therapeutic effect 

    due to insufficient data materials

1.2.2 Standard of enrollment and exclusion of pulmonary carcinoma cases 

(1) Standard of case enrollment

Subjects whose primary pulmonary carcinoma was confirmed by X-ray or CT diagnosis with measurable lesions met one of the following conditions.

a) Confirmed with primary pulmonary carcinoma (squamous, adenocarcinoma or squamo-adenocarcinoma) 

    by cytological and pathological evidences

b) Met TCM clinical syndrome-sign

c) Inoperable stage III-IV or operation-refusal stage II patients with primary pulmonary carcinoma 

d) Karnofsky score >=50, age >18 but <70 with estimated survival period as 3 months

e) Non-treated or inefficacious after chemo or radiotherapy and more than 2 months after chemotherapy

f)  Inpatients only

g) Voluntary to receive treatment

(2) Standard of case exclusion

a) unable to meet the above standard, not following regime, difficult to identify therapeutic effect/safety or losing contact　

b) metastasis in liver, brain or bone (asymtomatic patients excluded)　

c) pulmonary carcinoma case after surgical excision (recurrence  excluded) or under radiotherapy (new lesion excluded)　

d) with severe disease on heart, liver or kidney, abnormal in blood picture,  liver or kidney function

1.3 Clinical trial method

1.3.1 Clinical trial method of hepatic carcinoma group

(1) Group

Subjects were randomly divided into the observation group and control group with envelop method and perspective observation of comparison was made.

(2) Treatment method

a) KLT treatment group

During intervention, catheter was confirmed by angiography to enter hepatic intrinsic artery via femoral artery. 100ml of KLT was slowly injected into the hepatic artery within 30 minutes followed by injection of ADM 50mg + 5-FU 1.0g + DDP 80mg. Then 10ml of iodized oil was injected intravenously. 100ml KLT, once daily for 20 days as a cycle and the second cycle started 6 weeks later (2 cycles in all).

b) Chemotherapy group

ADM 50mg + 5-FU 1.0g + DDP 80mg + iodized oil 10ml was administered. The regimen was repeated 6 weeks later for 

a total of 2 treatment courses.

1.3.2 The clinical trial method of pulmonary carcinoma group

(1) Group

Subjects were randomly divided into the treatment group and the control group by envelop method and perspective observation of comparison was made.

(2) Treatment method

a) For KLT treatment group during the intervention, catheter was confirmed by angiography to enter bronchoartery via femoral artery. 100ml of KLT was slowly injected into the hepatic artery within 30 minutes followed by MMC 8mg+DDP 100mg+VDS 6mg for adeno-carcinoma and VP-16 200mg+DDP 100mg for quamous cell carcinoma. 100ml KLT, once daily for 20 days as a cycle and the second cycle started 6 weeks later (2 cycles in all).

b) Chemotherapy group

Adenocarcinoma cases were administered with MMC 8mg+DDP 100mg+VDS 6mg and squamous carcinoma cases were given VP-16 200mg+DDP 100mg, both for 2 cycles and the second cycle started 6 weeks after the intervention. No other anti-tumor therapy or specific immune preparation was applied during the administration of KLT.

1.4 Observation indexes and method

According to the function of KLT, variations in tumor response rate, TCM syndrome-sign, bodyweight, survival quality, immunity, heart, liver and kidney functions, blood picture and AFP,etc. were mainly observed before and after treatment.

(1) Tumor

Changes before and after treatment were observed by B-supersonic, X-ray, CT or MRI.

(2) Traditional Chinese Medical (TCM) syndrome-sign

TCM symptom-sign like mental depression and weakness, fever, aching in hypochondria, poor appetite, nausea and vomit, ascites and jaundice, etc. were mainly observed in the hepatic carcinoma group while syndrome-sign like cough, bloody sputum, short breath, oppression in chest, fever, mental depression and weakness and poor appetite, etc. were observed in the pulmonary carcinoma group. Variations in above syndrome-sign before and after treatment were recorded once weekly.

(3) Body weight

Body weight was measured once monthly before and after treatment.

(4) Physical condition

Physical condition was graded on the basis of Karnofsky scores once monthly before and after treatment.

(5) AFP 

AFP was recorded respectively before, during and after treatment.

(6) Immune function

CD₄⁺/CD₈⁺ was recorded before and after treatment.

(7) Blood picture

Leucocytes, hemoglobin and platelets were checked once weekly.

(8) Liver & renal function 

SGPT, bilirubin/Cr, BUN, 3 items in blood-lipid and EKG exam were checked once monthly.

1.5 Evaluation standard of curative effect

1.5.1 Objective evaluation of curative effect was based on the evaluation standard of chemotherapy effect for primary hepatic carcinoma in Volume II of  “Diagnostic Principles of Common Malignant Tumors in China” issued by the Ministry of Public Health and also on the evaluation standard of chemotherapy effect for primary pulmonary carcinoma in Book VI of the above diagnostic principles in the same book. 

(1) Complete response (CR): Tumor disappeared for more than 1 month

(2) Partial response (PR): Product of the two longest vertical diameters of a tumor was reduced ≥50% for over 1 month.

(3) No change (NC): Product of the two longest vertical diameters of a tumor was reduced ＜50% or increased ＜25% for 

     over 1 month.

(4) Progressive disease (PD): The above product had ＞25% increase.

Comparison was based on chest film, CT and B-supersonic before and after treatment and curative effect = CR+PR.

1.5.2 Evaluation curative effect standard of clinical syndrome-sign

2/3 decrease in clinical symptom points was defined as “remarkably improved” and 1/3 decrease as “partially improved" and no change as "not improved”. 

1.5.3 Life quality

Based on the Karnofsky scoring before and after treatment 20 points increase after treatment was “remarkably improved”, 10 points as “improved” and  no increase/decrease as “stable” and 10 points decrease after treatment as “declined”, ≥1 kg increase or decrease in body weight as " increased" or "decreased" and that ＜1 kg as "stable".

1.5.4 Evaluation of Immune function

Evident increase in CD4+/CD8 after treatment was defined as “elevated” and that with no change as “stable” and with evident decrease as “declined”.

1.5.5 Toxic reaction

Toxic reaction was based on WHO's standard.

1.6 Observation on adverse reaction

Adverse reaction occurred in KLT treatment group was observed during treatment and the time, duration, degree and measures adopted were recorded.

2. Results

2.1 General data and test of inter-group comparability

2.1.1 Source of cases

Cases were inpatients selected form the Traditional Chinese Medicine Hospital of Zhejiang Province and the People’s Hospital of Zhejiang Province from October 1995 to May 1997. Altogether 198 subjects were in hepatic carcinoma group of which 130 were in the KLT group and 68 in control group. 218 subjects were in pulmonary carcinoma group of which 142 in KLT group and 76 in control group. All cases met the clinical diagnostic standard of primary hepatic carcinoma and of primary ulmonary carcinoma. See Table 1.

Table 1. Clinical case distribution

2.1.2 Analysis of clinical materials

(1) Sex distribution

Hepatic carcinoma group: male 172 (86.87%), female 26 (13.13%), male:female=6.62:1

Pulmonary carcinoma group: male 193 (88.53%), female 25 (11.47%), male:female=7.72:1, no remarkable difference 

existed between the two groups (p>0.05). See table 2.

Table 2. Sex Distribution

    P>0.05

(2) Age distribution

In hepatic carcinoma group, age was ranged from 28 to 70 with the oldest as 68 and the youngest 28. The average age was 56.21. No remarkable difference in age distribution between the two groups (p>0.05). See Table 3.

Table 3. Age distribution 

    Ridit test: P>0.05

(3) Carcinoma staging 

A total of 198 subjects in the hepatic carcinoma group were diagnosed of substantive space-occupying lesion in liver before treatment by imaging examinations such as B-supersonic diagnosis or CT. Subjects with hepatic hemanogioma or metastatic hepatic carcinoma were ruled out. Among them 7 subjects were at Phase I (3.54%), 74 at Phase II (37.37%), 117 at Phase III (59.09%). No remarkable difference in clinical phases existed between the two groups (P>0.05). See Table 4. Overall 218 subjects in the pulmonary carcinoma group were diagnosed by cytopathological examination and classified on the bases of the TNM classification standard of pulmonary carcinoma formulated by UICC in 1986, among them 24 at Phase III, (11.01%) and 194 in Phase III-IV (88.99%). No remarkable difference in clinical phase classification of squamous cell carcinoma, adenocarcinoma and squamo-adenocarcinoma was observed (p>0.05). See Table 5.

Table 4. Clinical stage of hepatic carcinoma

    P>0.05

Table 5. Pathological diagnosis and clinical stage of pulmonary carcinoma