Summary of Phase III Clinical Trial of Kanglaite Injection in the Treatment of Primary Bronchogenic Pulmonary Carcinoma

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1 B Bradio Summary of hase III Clinical Trials of Kanglaite Injection in China Summary of hase III Clinical Trial of Kanglaite Injection in the Treatment of rimary Bronchogenic ulmonary Carcinoma iao Bingkui, Lin Hongsheng, Li eiwen, Li Xue, Guo Yadong, Wu Liangcun, Liu iguo, Zhu Yafang Guang n Men Hospital ffiliated to China cademy of Traditional Chinese Medicine bstract Kanglaite injection (KLT) developed by Zhejiang TCM Hospital was extracted from a traditional Chinese medicinal herb "semen coicis" with modern scientific technology. pproved by the Ministry of ublic Health [pproval No.(9) ZL-] and the Drug dministrative Bureau of Zhejiang ublic Health Department, a phase III clinical trial for KLT was performed from July 199 to Dec in the Clinical harmacologic Basis of Shanghai Traditional Chinese Medicine and harmaceutical University. Cooperative units were Shanghai Longhua Hospital, Shanghai Chest Disease Hospital and Shanghai Second ulmonary Disease Hospital. The trial passed an examination by the New Drug ppraisal Committee under the Ministry of ublic Health and won a certificate of state second-category new drug and document for production permit in The phase III clinical trial of KLT was carried out from Feb to May 1997 on patients suffering from primary lung cancer to evaluate therapeutic effect and side reaction i.e. efficacy and safety. The trial was performed in line with the rinciples & Guidelines for New Drug (TCM) Clinical Trials" formulated by the Drug dministrative Bureau of the Ministry of ublic Health. The units involved in this trial were Beijing Guang n Men Hospital (Chair), Beijing Sino-Japanese Friendship Hospital, Hospital ttached to Zhejiang TCM Institute, Jilin rovincial Tumor Hospital, Nantong Municipal Tumour Hospital and nhui rovincial Tumor Hospital. The results showed that the effective rate of KLT for primary bronchogenic pulmonary carcinoma (CRR) was 1.15% and that for control (chemotherapy) group was 14.9%. ccording to the TCM classification, KLT had better effect for patients with deficiency of both Qi and Yin. Major clinical symptoms got improved markedly (total efficacy rate 78-97%) among which chest pain, weakness and fatigue, cough and short breath were significantly improved. The survival quality, NK-cell activity, IL- level and CDB4B /CDB8B were raised and patients' immune function became enhanced after the treatment which suggested remarkable differences between KLT group and control group. The effect of KLT on peripheral blood picture was not evident. No adverse reactions on heart, liver or renal functions were observed. The major side reactions were fever, nausea, phlebitis (with incidence rates.74%,.74% and 4.67% respectively) and diarrhea (0.47%). 1. atients and methods 1.1 Selection of patients TCM diagnosis and criteria for differentiation of symptoms and signs (1) TCM diagnosis TCM diagnosis was based on symptoms of cough, blood in sputum, short breath, chest pain and poor appetite, etc

2 Summary of hase III Clinical Trials of Kanglaite Injection in China () Criteria for TCM differentiation of symptom-sign was divided into following 5 types. -Lung-energy-deficiency Cough with weakness, clean and thin sputum, low voice with languidness, oppression in chest and short breath, spontaneous perspiration and aversion to wind, susceptible to common cold, loss of appetite with fatigue, pale complexion, loose stool, pale tongue with whitish fur or enlargement of tongue with teeth marks and feeble pulse; -Endogenous heat from Yin-deficiency Dry cough without sputum or with a little sticky sputum or with blood in sputum, dry mouth and throat, emaciated, afternoon fever, burning sensation in palms, soles and chest, night sweat and flushing in zygomatic region, dry stool with dark-yellow urine, hoarseness, reddened tongue and dry, thready rapid pulse; -Deficiency of both Qi and Yin Cough with little sputum, languidness, sweating with short breath, dry mouth with smothery sensation, afternoon fever, burning sensation in palms and soles, palpitation, poor appetite and abdominal flatulence, oliguria and dry stool, reddened tongue with thin fur or corpulent tongue with teeth marks, weak with thready rapid pulse; -Stagnation of vital energy and blood Distention, fullness or stabbing pain in chest, cough with short breath, dark purple tongue with ecchymosis and whitish thin fur with wiry or uneven pulse; -Stagnation of phlegm and dampness Cough with copious sputum, oppression and pain in chest, mass with stabbing pain in lower part of ribs, fever with yellow sticky sputum, dry stool and oliguria, dark tongue with ecchymosis, whitish yellow fur in greasy appearance with wiry but rapid pulse; 1.1. Criteria for western medicine diagnosis Based on the diagnostic criteria for primary bronchogenic pulmonary carcinoma in Standard for the Diagnosis and Treatment of Chinese Common Malignant Tumors Book VI published by the Ministry of ublic Health in1989, clinical diagnosis of squamous or adenocacinoma of primary bronchogenic pulmonary carcinoma should be confirmed with pathological or cytological evidence through means of X-ray examination, bronchoscopy (biopsy, brush or irrigating biopsy), thoracic fluid, sputum, lung puncture, lymph node puncture, etc. (1) athological diagnosis For pulmonary exogenic primary lesions, the diagnosis should be confirmed at least by one of the following. -athologic and cytologic examination of specimen taken from pulmonary operation -Cytologic examination of specimen taken from lung or bronchus through exploratory thoracotomy, lung puncture or fiber-bronchoscopy - -

3 Summary of hase III Clinical Trials of Kanglaite Injection in China -Biopsy taken from metastatic lesions in lymph nodes of neck, auxiliary fossa, nodes of chest wall, pleura or subcutaneous nodes is confirmed by histological examination. Suspicious lesions are present in lung or bronchial wall and diagnosis of primary carcinoma in other organs can be excluded clinically. () Cytological diagnosis Observation of specimen taken from sputum, fibrebronchoscopic brush, aspiration or irrigating under microscope agrees with cytologic criteria of pulmonary carcinoma and primary carcinoma in upper respiratory tract and esophagus should be excluded clinically. () Clinical diagnosis Diagnosis should be confirmed by one of the following. -X-ray chest film showed opaque shadow of solitary nodule or mass with gyrus sides and in the form of lobulation and spicule which was rapidly increasing in size within a short period (- months). Tuberculosis or other inflammatory lesions could be ruled out after a short period of active drug therapy. -Segmental pneumonia progresses to lobar atelectasis in a short period (usually to months) or lobar atelectasis develops to a total lung atelectasis within a short period or a mass particularly a growing mass appears in corresponding radix pulmonis. -The above pulmonary lesions were complicated with advanced metastasis, invasion or compression of adjacent organs such as adjacent bone erosion, evident enlargement of hilar or/and mediastinal lymph nodes, rapid progressive venous cava compression, paralysis of ipsilateral recurrent laryngeal nerve (exclusion of tuberculosis or aortic lesion) and invasion in cervical sympathetic ganglion (exclusion of operative trauma), brachial plexus and phrenic nerve Clinical staging Clinical staging was conducted according to the "TNM Staging of rimary Bronchogenic ulmonary Carcinoma" in Criteria for Diagnosis and Treatment of Chinese Common Malignant Tumors Book VI edited by the Ministry of ublic Health in Grading of the general state of patients The grading was performed according to the "Karnofsky score grading" in Criteria for Diagnosis and Treatment of Chinese Common Malignant Tumors" Book VI edited by the Ministry of ublish Health in Criteria for enrollment and exclusion of patients (1)Criteria for enrollment of patients atients with measurable lesions and confirmed by X-ray or CT as primary pulmonary carcinoma and met with following condition were enrolled. - -

4 Summary of hase III Clinical Trials of Kanglaite Injection in China -rimary bronchogenic pulmonary carcinoma (squamous, adenocarcinoma or squamo-adenocarcinoma) was proven cytologically and/or pathologically. -Conformed with TCM clinical symptom-sign criteria; -Inoperable stage II-IV or stage II patients refusing operation; -Karnofsky score 50, ge 18 but <75 with expectant survival > months; -Non-treated or ineffectively treated with chemotherapy or radiotherapy and at least months after the therapy; -In-patient only; -Volunteer only ()Criteria for exclusion of patients -Those not conformed with the criteria of enrollment, administration not following scheme, loss of follow-up, not evaluated for therapeutic effect or safety due to lack of data, etc.; -Liver, brain or bone metastasis ( excluding symptomless patient); - fter operation (excluding relapsed cases) or radiotherapy treatment (excluding those with new lesions); -Severe heart, liver, kidney diseases or marked abnormal blood picture, hepatic or renal function disorder. Method.1 05 admitted in-patients were divided into groups. (1) KLT treated group () Sole chemotherapy control group The study was performed prospectively, double blind controlled and randomized.. Treatment scheme (1)Treatment group (14 cases), KLT 00ml/day IV drip, once daily, 1 days as one treatment cycle for treatment cycles ()Control group (91 cases) Chemotherapy scheme Scheme for adenocarcinoma MV - 4 -

5 Summary of hase III Clinical Trials of Kanglaite Injection in China MMC, 6-8mg/m, iv infusion, day 1; VDS, mg/m day and 4 Scheme for squamous carcinoma, iv infusion, day 1 and 8; DD, 50mg/m, iv drip, E V-16, 10mg/m, iv drip, day 1, and 5; DD, 60mg/ m, iv drip, day 1 (with hydrate) One chemotherapy cycle consisted of 6 weeks. Other anti-cancer measures or specific immunologic agents were not applied during treatment in both groups.. Observation data and methods Unified forms for observation data were used. Based on the action and indication of KLT Injection, observations were mainly made on data changes before and after treatment including tumor size, TCM symptom-sign, body weight, physical state, immune function, heart, liver and kidney functions and blood picture. (1) TCM symptom-sign Cough, blood in sputum, short breath, chest pain, fever, languidness, poor appetite, etc. were mainly observed (once a week and recorded). () Tumor X-ray film (frontal and lateral positions) before treatment and once a month after treatment () Body weight Before treatment and once a month after treatment (4) hysical state Gave out Karnofsky scores and evaluated before treatment and once a month after treatment (5) Immune function NK-cell activity, Interleukin II (IL-), T-lymphocyte and its sub-groups (CD, CD4 before treatment and once a month after treatment (6) Blood picture (WBC, Hgb., platelets) 1- times weekly (7) Liver, kidney functions and EKG Before treatment and once a month after treatment 4. Criteria for evaluating therapeutic effect 4.1 Criteria for evaluation of objective treatment effect - 5 -, CD8, CD4 / CD8 ) The criteria for evaluating chemotherapy treatment effect on primary bronchogenic pulmonary carcinoma in the Criteria for diagnosis and treatment of Chinese Common Malignant Tumors Book VI edited by the Ministry of ublic Health was applied.

6 and Summary of hase III Clinical Trials of Kanglaite Injection in China Rate of response Based on X-ray film, if the sum of maximum diameter of a tumor multiplied by its vertical diameter had decreased for more than 50% after treatment it was termed as effective and that less than 50% termed as ineffective. Based on degree of absorption, the efficacy could be divided into: (1) CR (X-ray film and/or fiber-bronchoscopy revealed complete absorption of the lesion); () R (lesion decreased 50%); () NC (lesion decreased less than 50% or increased less than 5%); (4) D (progressive, lesion increased more than 5% after treatment). Efficacy was evaluated after cycles of treatment and the effective rate=crr. Based on the comparison of chest X-ray or CT films before and after treatment, the efficacy was evaluated as (1) complete response (CR), () partial response (R), () no change (NC) and (4) progressive disease (D). 4. Life quality (change of physical state) ccording to Karnofsky scores evaluation was done before and after each treatment cycle. 10 points increase after treatment was termed as improved and 10 points decrease as reduced and less than 10 points in increase or decrease as stable. 4. Body weight Body weight increased or decreased more than 1kg before and after treatment cycle was termed as increase or decrease and that less than 1kg termed as stable. 4.4 Evaluation of immune function NK, IL-, CD, CD4, CD8 CD4 /CD8 were observed. Index increased notably after treatment was termed as improved, no evident change as stable and index decreased after treatment as reduced. 4.5 Evaluation of therapeutic effect on symptoms The lowering of integral value for symptoms by / was termed as markedly improved; that by 1/ as partially improved and that without change as stable. 4.6 Evaluation of toxic reaction Evaluation of toxic reaction was based on the WHO's "Criteria for Evaluation of cute and Sub-acute Toxic and dverse Reactions". 5. Observation on adverse reaction Observation was mainly made on adverse reaction occurred during KLT treatment and recorded the time, duration, severity, characteristics and management for reaction, etc. 6. Results 6.1 General data and tests for comparability between study groups Source of cases Cases were collected from Guang n Meng Hospital ttached to China cademy of TCM, Beijing Sino-Japanese Friendship Hospital, Hospital ttached to Zhejiang TCM Institute, Jilin rovincial Tumur Hospital, Nantong Municipal Tumor Hospital and nhui rovincial Tumour Hospital. Total number was 05 admitted from Feb to May 1997 of which 14 cases were in treatment group and 91 in control group. ll cases were conformed with diagnosis criteria of primary bronchogenic pulmonary - 6 -

7 X Summary of hase III Clinical Trials of Kanglaite Injection in China carcinoma and received cytological and/or pathological examinations. (Table 1) Table 1. Distribution of clinical cases Hospital KLT treated Chemotherapy Total group (n) group(n) (n) Guang n Men Hospital Sino-Japanese Friendship Hospital Jilin Tumor Hospital 1 1 Zhejiang TCM Institute Hospital Nantong Municiple Tumor Hospital 5 5 nhui rovincial Tumor Hospital Total nalysis of clinical data (1) Sex Male: 18 (71.48%), female: 87 (8.5%), M:F=.51:1, no significant difference between both groups (>0.05) (Table ) Table. Distribution of sex in groups No. of cases Male (n) Female (n) M:F KLT group :1 Chemotherapy group :1 Total (n) :1 =.6, = () Distribution of age ge ranging from 0 to 74 years with average as 57.1, no significant difference between both groups (>0.05) (Table ) Table. Distribution of age >71 Total KLT group Chemotherapy group Total (n) Ridit test >0.05 () athological staging Cytopathological examination was conducted for all 05 patients before treatment and pathological staging was based on the TNM staging criteria for pulmonary carcinoma formulated by UICC in Stage II: 8 (9.%) and stage III-IV: 77 (90.8%). No significant difference among squamous, adenocarcinoma and squamoadenocarcinoma between both groups (>0.05) (Table 4). Table 4. athological diagnosis and clinical stage of pulmonary carcinoma (WHO) athologic Type I II III IV Total (n) (n) (n) (n) (n) KLT group Squamous denocarcinoma Squamo-adenocarcinoma Chemotherapy group Squamous

8 X X Summary of hase III Clinical Trials of Kanglaite Injection in China denocarcinoma Squamo-adenocarcinoma Data from both groups was statistically processed. Ridit test for squamous carcinoma: >0.05 Ridit test for adenocarcinoma: >0.05 Ridit test for squamo-admocarcinoma: >0.05 (4)Karnofsky score The Karnofsky score of both groups before treatment was between No significant difference between both groups (>0.05) (Table 5 ). Table 5. Distribution of KS points before treatment atient 60~ 70~ 80~ 90~ (n) (n) (n) (n) (n) KLT group Chemotherapy group Ridit test >0.05 (5)Distribution of TCM differentiation of symptom-sign and major clinical symptoms No significant difference in TCM differentiation of symptom-sign between both groups (>0.05) (Table 6). The distribution of major clinical symptoms such as cough, sputum with blood, short breath, chest pain, fatigue, poor appetite, etc. had no notable difference between both groups (>0.05), but that for fever was different notably between the two groups (<0.05) (Table7). Table 6. Types of differentiation of TCM differentiation of symptom-sign Lung energy Stagnation of Heat due to Deficiency Stagnation of deficiency phlegm & (n) Yin-deficiency of Qi & Yin (n) Qi & blood (n) dampness (n) KLT group Chemotherapy Total =6.60, = Total (n) Table 7. nalysis of symptom Symptom KLT group (n=14) Chemotherapy group (n=91) n % n % Cough Sputum with blood Short breath Chest pain Fever Fatigue oor appetite (6)Distribution of tongue texture, tongue coating and pulse condition - 8 -

9 X X X Summary of hase III Clinical Trials of Kanglaite Injection in China No statistically significant difference between both groups (>0.05) (Table 8, 9, 10). Table 8. TCM analysis of tongue texture Symptom-sign KLT group (n) Chemotherapy group (n) Light red 7 8 Red and reddish 80 Crimson 61 1 =0.96, =0.601 Table 9. nalysis of fur on the tongue Symptom-sign KLT group (n) Chemotherapy group (n) Thin and white Thin and yellow 40 1 White and sticky 46 0 Yellow and sticky 48 Bright and uncoated 9 17 =0.91, =0.94 Table 10. TCM analysis of pulse condition Symptom-sign KLT group (n) Chemotherapy group (n) Thready 81 7 Wiry Slippery 9 0 Deep =1.8, = Comparison of therapeutic efficacy 6..1 Objective therapeutic effect 05 patients were observed. The response rate (CRR) in KLT group (14 cases) was 1.15% (6 cases) and that in control group (91 cases) was 14.9% (1 cases). No significant difference between both groups (>0.05) (Table 11). The response rate (CRR) in each hospital was shown in Table 1. Table 11. Change of cancer lesions after treatment in both groups atient CR R NC D Effective rate (%) KLT groups Chemotherapy group Ridit test: >0.05 Table 1. Comparison of response rate (CRR) between two groups and among hospitals Hospital KLT group (%) Chemotherapy group (%) Guang n Men Hospital Sino-Japanese Friendship Hospital Jilin rovincial Tumor Hospital 1.90 nhui rovincial Tumor Hospital 9.80 Nantong Municipal Tumor Hospital 14.9 Zhejiang TCM Institute Hospital

10 X X Summary of hase III Clinical Trials of Kanglaite Injection in China 6.. Relationship between pathological types and therapeutic effect athological statistical data among squamous, adenocarcinoma and squamo-adenocarcinoma had no significant difference between both groups (>0.05) (Table 1). Table 1. Relationship between pathological types and therapeutic effect athology atient CR R NC D (n) (n) (n) (n) (n) Effective rate Squamous KLT Chemotherapy denocarcinoma KLT Chemotherapy Squamo- KLT denocarcinoma Chemotherapy 9 5. Comparison in squamous groups, Ridit test: >0.05 Comparison in adenocarcinoma groups, Ridit test: >0.05 Comparison in squamo-adenocarcinoma groups, Ridit test: > Relationship between therapeutic effect and TCM differentiation of symptom-sign Results showed that there was no significant difference between KLT and chemotherapy groups (>0.05). However, the comparison of TCM differentiation of symptom-sign in both groups suggested marked difference in group of deficiency of both Qi and Yin (<0.05). The effect of KLT in group of stagnation of Qi and Blood and the group of endogenous heat from Yin-deficiency was poor and in chemotherapy group the type of pathogenic heat had poor effect (Table 14). Table 14. Relationship between therapeutic effect and TCM differentiation of symptom-sign Differentiation of symptom-sign KLT group Effective (CRR) Chemotherapy Effective (CRR) Lung energy deficiency Endogenous heat from Yin-deficiency Deficiency of both Qi and Yin Stagnation of Qi and Blood Stagnation of phlegm and dampness 0 0 =7.44, > Relationship between therapeutic effect and symptom Symptoms such as cough, blood in sputum, chest pain, fever, languidness, poor appetite, etc. were improved to a certain extent after treatment in both KLT and chemotherapy groups. The total efficacy rates were 78.97% in KLT group and 47.5% in chemotherapy group, a notable difference between both groups ( <0.05) among which the effective improvement in KLT group for cough, short breath, poor appetite, chest pain and languidness was far better than that in chemotherapy group (<0.05) (Table 15 and 16)

11 X X X X Summary of hase III Clinical Trials of Kanglaite Injection in China Table 15. Therapeutic effect for symptoms improvement after treatment Symptom KLT group (n=14) Chemotherapy group (n=91) Before Effective Effective Before Effective Effective Treatment Rate (n) Rate (n) Treatment Rate (n) Rate (n) Cough Blood in sputum Short breath Chest pain Fever Languidness oor appetite Table 16. Improvement of symptom Good(n) Effective(n) Ineffective(n) Total effective rate(%) KLT group Chemotherapy group Ridit test: < Relationship between therapeutic effect and tongue texture, tongue fur and pulse conditionno significant changes after treatment in both groups (>0.05) (Table 17,18,19). Table 17. nalysis of tongue texture before and after treatment KLT group Chemotherapy group Tongue texture Before fter Before fter treatment treatment treatment treatment ale red Red & reddish Crimson Table18. nalysis of tongue fur before and after treatment KLT group Chemotherapy group Tongue fur Before fter Before fter treatment treatment treatment treatment Thin white Thin yellow White sticky Yellow sticky Bright & uncoated Table 19. nalysis of pulse condition before and after treatment KLT group Chemotherapy group ulse condition Before fter Before fter treatment treatment treatment treatment Thready Wiry Slippery Deep Total

12 were Summary of hase III Clinical Trials of Kanglaite Injection in China 6..6 Comparison of physical state Kanofsky score: In KLT group the KS was increased in 101 cases and decreased in 16 cases after treatment. In chemotherapy group the KS was increased in 9 cases and decreased in 40 cases after treatment. This showed a marked difference between both groups statistically (<0.05) and indicated that KLT was able to markedly increase patients' quality of life. Change in body weight: 6 cases had body weight decreased after treatment in KLT group and 50 cases decreased in chemotherapy group. 71 cases had body weight increased after treatment in KLT group and 10 in chemotherapy group, suggesting a significant difference between both groups (<0.05). nd this showed that KLT could notably increase body weight (Table 0). Table 0. Comparison of physical state KS (%) Body weight (%) Increase Stable Decrease Increase Stable Decrease KLT group Chemotherapy group KS ridit test: <0.05 Body weight ridit test: < Change of immune functions before and after treatment mong 05 cases immune functions such as NK cell activity, IL-, CDBB examined in 1 cases of KLT group and 0 cases of chemotherapy group with following result. (1) Change in NK cell activity, CDB4B, CDB8B, CDB4B / CDB8B There was a significant difference in NK cell activity before and after the treatment in KLT group (<0.05) while that in chemotherapy group had no notable difference (<0.05). Comparison of NK cell activity after treatment between both groups shown a very remarkable difference (<0.001) indicating that KLT could improve NK cell activity notably and better than chemotherapy (Table 1). Table 1. Change of NK cell activity before and after treatment atient No. Before treatment fter treatment (X±SD) (X±SD) t KLT group ± ± <0.01 Chemotherapy group ± ± >0.05 Normal value of NK cell: 18.4±.8 Comparison after treatment between the two groups: t=6.8, <0.001 () Change in IL- value No notable increase of IL- after treatment in KLT group (>0.05). Remarkable increase of IL- was also not found after treatment in chemotherapy group (>0.05). However, the difference after treatment between both groups was evident (<0.05) indicating that KLT could increase IL- better than chemotherapy (Table )

13 CDBB CDB4B ratio and and ratio CDBB CDB4B CDB8B CDBB CDB4B CDB8B and and CDB4B CDB8B were ratio after after before before and had Summary of hase III Clinical Trials of Kanglaite Injection in China Table. Change of IL- before and after treatment atient Before treatment fter treatment No. (X±SD) (X±SD) t KLT group ± ± >0.05 Chemotherapy group 0 5.9± ± >0.05 Normal value of IL-: 15-80pg/ml Comparison after treatment between the two groups, t=.19, <0.05 () Change of T lymphocytes and sub-group, CDB4B in KLT group increased markedly after treatment (<0.05). CDBB, CDB4B CDB8B no marked changes in chemotherapy group after treatment. Comparison between groups after treatment showed that CDBB, CDB4B CDB8B increased notably and had significant difference statistically (<0.05) (Table ). / CDB8B In KLT group CDB4B was increased after treatment with marked difference (<0.05) and the /CDB8B in chemotherapy group after treatment had no significant difference. Comparison between both groups after treatment revealed that the increase of ratio had significant difference between the groups (<0.05) (Table 4). Table. Change of T-lymphocyte sub groups before and after treatment atient No. Before treatment fter treatment (X±SD) (X±SD) t KLT group 60.15± ± ± ± ± ± Chemotherapy group 58.48± ± ± ± ± ± fter treatment between both groups: CDBB : t=.4 =0.001 : t=4.99 = : t=.4 =0.0 / CDB8BB Table 4. Change of CDB4BB before and after treatment atient No. Before treatment fter treatment (X±SD) (X±SD) t KLT group ± ± Chemotherapy group ± ± Comparison after treatment between the two groups t=.60, = Change of peripheral blood picture after treatment (1) WBC count WBC>4000/mm was normal and <4000/ mm meant decreasing. s shown in Table 4, 96.6% of the KLT group patients had WBC>4000/mm and.74% less than 4000/mm treatment and 97.0% with WBC>4000/mm.80% with WBC<4000/ mm treatment. In chemotherapy group 95.60% had WBC>4000/mm 4.40% less than 4000/mm treatment and 79.1% with WBC>4000/mm 0.88% with WBC<4000/mm treatment. Comparison between both groups showed that there was a significant difference (<0.05) suggesting that KLT had no notable inference on peripheral WBC whereas chemotherapy could reduce peripheral WBC drastically

14 Summary of hase III Clinical Trials of Kanglaite Injection in China Table 5. Change of WBC before and after treatment (x1000/mm ) ~4.0 ~.0 ~.0 ~1.0 <1.0 Cases BT* T* BT T BT T BT T BT T KLT group Chemotherapy group *BT: before treatment T: after treatment Comparison before & after treatment in KLT group: Ridit test: >0.05 Comparison between the two groups after treatment: Ridit test: <0.05 () Change in hemoglobin (Hgb) Change of Hgb before and after treatment in KLT group had no notable difference (>0.05). However, the comparison between both groups after treatment suggested significant difference (<0.05) indicating that chemotherapy could reduce Hgb markedly after treatment and that KLT had no evident influence on Hgb (Table 6). Table 6. Change of Hgb (g/100 ml ) before and after treatment ~11.0 ~9.5 ~8.0 ~6.5 <6.5 Cases BT* T* BT T BT T BT T BT T KLT group Chemotherapy group *BT: before treatment T: after treatment Comparison before & after treatment in KLT group: Ridit test: >0.05 Comparison between the two groups after treatment: Ridit test: <0.05 () Change in blood platelets (BC) In KLT group no significant change of BC was noted after treatment (>0.05) but the comparison between both groups after treatment had significant difference (<0.05) indicating that chemotherapy could decrease BC markedly and KLT had no influence on BC (Table 7). Table 7. Change of BC before and after treatment (x10000/mm ) ~10.0 ~7.5 ~5.0 ~.5 <.5 Cases BT* T* BT T BT T BT T BT T KLT group Chemotherapy group *BT: before treatment T: after treatment Comparison before & after treatment in KLT group: Ridit test: >0.05 Comparison between the two groups after treatment: Ridit test: < Observation on adverse reaction 7.1 Effect on liver and renal function ccording to the WHO's criteria for grading acute and sub-acute toxic reactions of anti-cancer drugs, the integral values of hepatic and renal function before and after treatment ( 0, 1,, and 4 stand for Grade-0, Grade I, Grade II, Grade III, Grade IV or No,,,, respectively.) were collected. Results from 14 patients in KLT group showed that the hepatic and renal functions were not affected after treatment (>0.05). However, comparison between both groups after treatment had significant difference (<0.05) indicating that KLT had no adverse effect on hepatic and renal function (Table 8)

15 Summary of hase III Clinical Trials of Kanglaite Injection in China Table 8. Effect on hepatic and renal functions before and after treatment Integral KLT group Chemotherapy group value BT* T* BT T Hepatic function Renal Function *BT: before treatment T: after treatment Hepatic function: SGT & bilirubin Renal function: urea nitrogen, greatinine Hepatic function: before and after KLT treatment: Ridit test: >0.05 Hepatic function: comparison between KLT and chemotherapy groups after treatment: Ridit test: <0.05 Renal function: before and after KLT treatment: Ridit test: >0.05 Renal function: comparison between KLT and chemotherapy groups after treatment: Ridit test: < Effect on Cardiac function ccording to WHO's criteria of grading acute and sub-acute toxic reaction of anti-cancer drugs, the integral values of cardiac function before and after treatment ( 0, 1,, and 4 stand for Grade-0, Grade I, Grade II, Grade III, Grade IV or No,,,, respectively.) were collected. Results from 05 pulmonary carcinoma patients in KLT group (n=14) showed that the cardiac function had no marked difference before and after treatment (>0.05). However comparison between KLT and chemotherapy groups after treatment had significant difference (<0.05) indicating that there was no adverse effect to cardiac function during KLT treatment (Table 9). Table 9. Effect on cardiac function before and after treatment Integral KLT group Chemotherapy group value BT* T* BT T Cardiac function *BT: before treatment T: after treatment Cardiac function: before and after KLT treatment: Ridit test: >0.05 Cardiac function: comparison between KLT and chemotherapy groups after treatment: Ridit test: < llergic reaction No allergic reaction or skin rash was occurred in KLT group during treatment. 7.4 dverse reaction The adverse reaction occurred was mainly fever in 8 patients (.74%) usually between C

16 Summary of hase III Clinical Trials of Kanglaite Injection in China and appeared on day 1 of KLT treatment, lasted for 1- days and subsided after symptomatic treatment (e.g. indomethacin suppository). 8 patients had slight nausea (.74%) lasted for to 7 days and subsided spontaneously. 10 patients had slight phlebitis (4.67%) and no treatment was necessary. One patient had diarrhea (0.47%) and relieved after symptomatic treatment (Table 0). Table 0. dverse reaction Incidence Symptom Severity Duration Treatment 8 fever 7.8~8.5 C 1- days symptomatic 8 nausea slight -7 days Not treated 10 phlebitis slight -7 days Not treated 1 diarrhea slight 1 day symptomatic 8. Outcome of treatment Out of 05 patients, 88 had their regulated cycles of treatment completed within scheduled period and 17 patients had not completed cycles (11 in KLT group and 6 in chemotherapy group). Comparison between both groups showed no significant difference (>0.05). 4 patients in KLT group were excluded from the study due to cost burden, combination with chemotherapy or radiotherapy or loss of follow-up. In chemotherapy group, 45 cases were excluded due to severe bone marrow inhibition, severe gastro-intestinal toxic or side reaction or loss of follow-up (Table 1, ). Table 1. Comparison of outcome of treatment between both groups atient Two cycles Two cycles Main cause No. completed incomplete KLT group Cost, D* Chemotherapy group * D: rogressive Disease, X =0.07, =0.79 Bone marrow inhibition, GI-adverse reaction, D* Table. nalysis on the cause for exclusion of patients atient Main cause No. KLT group 4 Combined with radio or chemotherapy, cost, loss of follow-up Chemotherapy group 45 Bone marrow inhibition, severe GI reaction, loss of follow-up 9. Case report Case 1: Case No Bai, a 7-year-old male, presented with a complaint of a shadow found on X-ray examination in his left hilus of lung during health examination in May, CT scan of chest was done at our OD and he was diagnosed as tumor in left lung hilus and central type pulmonary carcinoma was suspected. He was treated for the diagnose of acute cholysistitis at OD on Oct. 0, 1996 and admitted to hospital on Nov. 8, 1996 after symptom had been relieved. The patient had cough occasionally on admission. His general health condition was fair. Stool and urination were normal. He had pale tongue texture with white sticky fur and sunk-type pulse. Karnofsky score=80. Body weight as 6kg. Sputum cytologic examination revealed a few squamous carcinoma cells. Chest CT scan on Nov. 6, 1996 showed a.5x4.0cm irregular shadow of mass with spicule edge and then was diagnosed as "left lung squamous carcinoma". The TCM diagnosis was "pulmonary accumulation and deficiency of Qi in lung

17 cycle Summary of hase III Clinical Trials of Kanglaite Injection in China KLT injection 00ml daily, iv drip, was given from Nov. 8-8, 1996 for 1 days. Chest CT examination on Dec.15 demonstrated that the mass on left lung lilus was decreased to xcm, there was a remarkable decrease as compared with the size on Nov.6. The general health condition remained unchanged with KS as 80 and body weight as 61kg. No notable adverse or allergic reaction was found. No prominent changes in cardiac, hepatic and renal function were noted and the efficacy grade was evaluated as R. He was discharged from hospital on Dec.1, No increase in tumor size was found during regular follow-up. Case : Case No.1666 Chen, a 71-year-old male, complained cough and blood in sputum for months after an operation for removing carcinoma in lower left lung 14 months ago. The patient had cough in late July, 1995 and blood in sputum became severe. CT scan performed at Hospital affiliated to Bethune Medical University confirmed the diagnosis of carcinoma in lower left lung. surgical operation for left lower lobectomy was applied on Sept. 5, ost operational pathological diagnosis proved the diagnosis as squamous carcinoma. The symptoms of cough and blood in sputum were disappeared after operation and no chemotherapy or radiotherapy was received. The symptoms of cough and blood in sputum reappeared in late Nov., 1996 and sputum cytological re-examination performed at the above hospital showed that squamous cancer cells were found. Chest CT in Dec.,1, 1996 revealed that on the posterior wall of left main bronchus a 1 x 1.cm shadow and on the lateral wall a 0.5 x 1.0cm shadow with protruded nodules were found. The diagnosis of relapsed lower left lung carcinoma was established and he was admitted to the hospital. The patient had cough, blood in sputum, general malaise, poor appetite and had a history of diabetes. KS was 80 with body weight as 78kg. The TCM diagnosis was "lung accumulation (deficiency of Qi in lung)". Diagnosis from Western medicine was recurrence of lower left lung carcinoma after operation and type II diabetes". The patient refused to accept operation, radiotherapy or chemotherapy. Then, KLT injection 00ml iv infusion daily was given for cycles (16 bottles) from Dec.,10, 1996 to Feb.,, 1997 with a rest for days between two cycles. The symptoms of cough and blood in sputum were relaxed after the first cycle of treatment and completely disappeared after the second cycle. CT scan on Jan., 8, 1997 showed that compared with the scan on Dec.,, 1996 the nodule of posterior wall in main bronchus was disappeared and that on the lateral wall was decreased to 0.x0.5cm. Efficacy was evaluated as R rd and The of treatment was applied to further improve the therapeutic effect. The Karnofsky score was 90 after the treatment and body weight as 78kg. The treatment was smooth and he was discharged on Feb.,4, 1997 and now under follow-up. 10. Discussion KLT injection was developed by Zhejiang rovincial TCM Hospital and extracted from the traditional Chinese herb "semen coicis" through advanced technology. rimary bronchogenic pulmonary carcinoma (lung cancer) was termed in TCM as lung accumulation, cough, "pulmonary mass" or hemoptysis, etc. The mechanism was explained in TCM as "deficiency of positive Qi and invasion of pathogen" and "lung as tender organ was susceptible to accumulation of toxic exogenous and pathogenic factors". The normal function of lung was then disturbed and stagnation of lung Qi and blood obstructed the meridianal collateral, affecting the circulation and distribution of body fluid. Sputum was formed due to stagnation of body fluid and lung accumulation was formed as a result. "Semen coicis" tasted sweet and plain, non-toxic. It entered lung-spleen channels and had functions in invigorating spleen, replenishing Qi and disintegrating masses. From Feb.,1996 to May 1997 based on stage II clinical trial, the stage III clinical trial for KLT injection was carried out in cooperative hospitals with an objective to determine its clinical therapeutic effect and safety. 05 patients were enrolled with confirmed clinical diagnosis of primary bronchogenic pulmonary

18 Summary of hase III Clinical Trials of Kanglaite Injection in China carcinoma supported with definite cytological and/or pathological facts and II-IV TNM stages. atients were divided randomly into KLT treated group (48 patients, 4 excluded) and chemotherapy group (16 patients, 45 excluded). ctual cases in KLT group for evaluation were 14 and 91 in chemotherapy group. Comparison in sex, age, pathological type, TCM differentiation of syndrome-sign, clinical symptom, tongue texture, tongue fur, pulse condition and survival and quality of life, etc. between the two groups had no significant difference (>0.05) and the two groups had comparability. Results The response rate (CRR) for primary lung carcinoma was 1.15% in KLT group vs 14.9% in chemotherapy group. KLT had better effect for patients with deficiency of both Qi and Yin symptom-sign and could remarkably improve major clinical symptoms (total effective rate as 78.97% ) such as cough, short breath, chest pain, loss of appetite and languidness while KS of patients and body weight could get increase and life quality became better than that in chemotherapy group. Immune function examination showed that KLT could raise NK cell activity, IL- level and CDB4B ratio value and had no adverse effect on peripheral blood picture. / CDB8B No liver or renal damage was noted in KLT treated group. No allergic reaction was occurred. The major adverse reactions were fever, nausea, vomit and phlebitis usually lasting for 1-7 days. Fever was subsided after symptomatic treatment and nausea, vomit and phlebitis could disappear spontaneously