Phase III Clinical Trial on Kanglaite Injection Combined with Surgical Operation in the Treatment of Primary Pulmonary Carcinoma

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Caren Rogers
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1 Phase III Clinical Trial on Kanglaite Injection Combined with Surgical Operation in the Treatment of Primary Pulmonary Carcinoma Abstract Fu Yu*, Li Shiye*, Zhang Haiqing*, Zhang Rugang, Liu Fusheng, Wang Minzhi, Ta Mingyi Beijing Thoracic Tumor Hospital* Kanglaite Injection (KLT) is a new type anticancer injection which was developed by Zhejiang TCM Hospital. It was extracted from the Traditional Chinese Medicine semen coicis through modern scientific technology. Approved by the Ministry of Public Health [Approval No: (3) ZL-], the Longhua Hospital Affiliated to Shanghai TCM University took the responsibility of Phase II clinical study. The results showed that the effective rate of Kanglaite in treating non-small-cell lung cancer(nsclc) () was.6%, meanwhile neither side nor toxic effects were observedp P. In our phase II trial, we applied KLT to patients with lung cancer before surgical operation, its curative effect was proved by () pathological examination of the tumor specimens after surgical operation (6/)P P. In order to further observe the curative effect of KLT on lung cancer and its possible side effect, KLT was approved by the Ministry of Public Health to carry out Phase III clinical trial. Beijing Thoracic Tumor Hospital together with its cooperative units The Tumor Hospital Affiliated to China Academy of Medical Science and Beijing Tumor Hospital formed the cooperative group focusing on the Phase III clinical study. The result showed that 6.% of subjects treated with KLT before surgical operation had necrotic tumor tissue area bigger than 5% vs only 6.67% in the control group with significant difference between the two groups (P<.5). Observation of side effect: 3 cases were reported having slight fever (below 38 ) which lasted for -3 days and disappeared spontaneously. No adverse effect on liver, kidney function and peripheral blood picture was observed.. Selection of subject and research methods. Selection of subject () Standard of selection Subject testified pathologically and cytologically Subject highly suspected via diagnosis of X-ray, CT or MRI 3 Subject adaptable to surgical operation Subject free from previous radiotherapy and chemotherapy 5 Subject voluntary to receive the treatment () Standard of unquolification Subject unable to meet the above standard Subject with lung metastasis 3 Subject younger than or older than 75 (3) Standard of case withdrawal Subject inadaptable to surgical operation with worse condition after one course of treatment Subject suspected of lung carcinoma by image diagnosis but without cytologic evidence 3 Subject suffering from fatal complications during treatment Subject hypersensitive to drugs 5 Subject receiving exploratory thoracotomy

2 . Clinical study methods () Division of groups All selected 75 inpatients were divided into two groups randomly by Envelop-method. Preoperative KLT-treatment group Preoperative control group. () Method of treatment KLT-treatment group: KLT Injection ml iv. qd d, surgical operation followed the treatment 3-7 days later Control group: No tumor-related drug was administered before operation..3 Observation index and method () Pathological changes of pulmonary tumor specimens excised after operation Classification based on necrotic area Necrotic area <5% Necrotic area 5-5% 3 Necrotic area 5-75% There were grades according to reactions of carcinoma cells and tissues to KLT Grade : No reaction Grade I: Slight reaction Grade II: Moderate reaction Grade III: Severe reaction () The objective evaluation of therapeutic effect on tumor was based on the evaluation standard of curative effect on primary broncho-pulmonary carcinoma in Book VI of Standard for the Diagnosis of Chinese Frequently Encountered Malignant Tumors issued by the Ministry of Public Health. Complete response (CR): tumor fully disappeared Partial response (PR): product of two max vertical diameters in a tumor having reduced more than 5% 3 No change (NC): product of two max vertical diameters in a tumor reduced <5% or increased <5% Progressive disease (PD): product of two max vertical diameters in a tumor increased >5% (3) State of life quality Based on Karnofsky score standard, those whose scores increased or decreased more than before and after treatment were defined as improved or "declined" respectively and those with less than were defined as stable.. Observation of adverse reaction Adverse reaction was observed in Kanglaite group during the treatment and time of occurrence, duration, degree and the measures adopted were recorded

3 . Results. General information and group comparability () Source of subject From February 6 to May 7, 75 subjects were selected from inpatients in Beijing Thoracic Tumor Hospital, Tumor Hospital Affiliated to China Academy of Medical Science and Beijing Tumor Hospital. They were divided into two groups. The Kanglaite-treatment group included 5 subjects and the control group had 3. All subjects met clinical diagnostic criteria of primary bronchopulmonary carcinoma (Table ). Table. Distribution of clinical cases Hospital KLT group Control group Total Beijing Thoracic Tumor Hospital 3 Tumor Hospital Affiliated to China Academy of Medical Science 5 5 Beijing Tumor Hospital Total () Analysis of clinical data Sex 6 male (%), 6 female (8%), male : female=.5 :, no difference between groups (P>.5) (Table ) Table. Sex of two groups No. of patients Male Female Male : Female Kanglaite 5 3 : Control : Total : Age Age ranged from to 7 with the eldest as 7 and the youngest as years old, average age as 5.36, no significant difference between two groups (P>.5) (Table 3) Table 3. Age of two groups ~ 5~ 6~ 7~ Total Kanglaite Control Total Ridit test: P>.5 3 Pathology and staging Subjects were clinically divided into groups on the basis of TNM staging standard of lung cancer formulated by UICC in 86. Among them, there were 5 cases in stage I (6.67%), 5 cases in stage II (6%) and 5 cases in stage III (33.33%), no significant difference in clinical staging of squamous, adenocarcinoma and squamo-adenocarcinoma between two groups (P>.5) (Table )

4 Table. Pathological diagnosis of lung cancer and clinical staging Pathology I II III IV Total Kanglaite Squamous Adenocarcinoma Squamo-adenocarcinoma Chemotherapy Squamous Adenocarcinoma Squamo-adenocarcinoma Total Squamous, Ridit test: P>.5 Adenocarcinoma, Ridit test: P>.5 Squamo-adenocarcinoma, Ridit test: P>.5 Karnofsky scores in groups The Karnofsky scores in the two groups before treatment were between 7~. no significant difference between two groups (P>.5) (Table 5) Table 5. KPS in two groups Number of patient 7~ 8~ ~ Kanglaite Control Ridit test: P>.5 5 Comparison of surgically excised sites in two groups, see Table 6 Table 6. Surgically excised sites in two groups No. of patients RWL LWL RUL RLL RML LUL LLL Kanglaite Control Ridit test: P>.5 RWL: right whole lung, LWL: left whole lung, RUL: right upper lung, RLL: right lower lung, RML: right middle lung, LUL: left upper lung, LLL: left lower lung. Comparison of therapeutic effect () Comparison of the necrotic area of excised specimens in two groups In Kanglaite group there were 7 cases (37.78%) with necrotic area < 5%, 5 cases (33.33%) with necrotic area between 5%~5%, 3 cases (8.8%) with the area between 5-75%. In control group figures were (73.33%), (3.33%) and (3.33%) respectively with significant difference between the two groups (P<.5) (Table 7). Table 7. Comparison of necrotic area in excised specimens in two groups No. Tumor necrotic area <5% 5-5% 5-7% Kanglaite Control 3 Total P<

5 () Comparison of reaction of carcinoma cells and tissues in two groups (Table 8) Table 8. Reaction of carcinoma cells and tissues in two groups Number Reaction of carcinoma cells and tissues Grade Grade I Grade II Grade III KLT 5 Control 3 Total P<.5 The above table showed that after KLT treatment reaction of carcinoma cells and tissues in Kanglaite group was obviously better than that in control group. The percentage of grade I-II reaction in treatment group was 5.56% (3/5) while only 53.33% (6/3) in control group. There was significant difference between two groups (P<.5). (3) Comparison of objective therapeutic effect Based on imaging examination, response rate (CR+PR) in KLT group was.% (/5) (Table ). Table. Therapeutic effect in KLT group Total patients (n) CR PR NC PD Response rate (CR+PR)% () Comparison of physical condition Karnofsky scores: Kanglaite group: Improved cases, Declined cases Control group: Improved case, Declined cases No significant difference between two groups, Table Table. Karnofsky changes in two groups No. of patient Karnofsky score Improved Stable Declined Kanglaite 5 Control 3 8 Ridit test : P>.5 (5) Change of peripheral blood picture before and after treatment Leucocyte count Leucocyte count > P P/L was normal and < P P/L indicated decline. From Table there were 68.8% subjects in Kanglaite group with leucocyte count > P P/L before treatment and the percentage got increased to 3.33% after the treatment. In control group the percentage remained unchanged(p<.5). This demonstrated that Kanglaite had the effect of increasing amount of leucocytes (Table )

6 Table. Change of peripheral leucocytes before and after treatment (P P/L) Patient ~. ~3. ~. ~. <. No BT* AT* BT AT BT AT BT AT BT AT KLT Control 3 8 BT* = before treatment AT*= after treatment, Ridit test before and after KLT treatment: P<.5, Ridit test between KLT and control groups: P<.5 Change of hemoglobin There was no significant difference in KLT effect on hemoglobin before and after treatment (P>.5) and there was no difference between the Kanglaite-treatment group and the control group (P>.5) either. This indicated that Kanglaite had no impact on hemoglobin (Table ). Table. Change of hemoglobin before and after treatment (g/ml) Patient ~. ~.5 ~8. ~6.5 <6.5 No BT* AT* BT AT BT AT BT AT BT AT KLT Control BT* = before treatment AT*= after treatment, Ridit test before and after KLT treatment: P>.5, Ridit test between KLT and control groups: P>.5 3 Change of Platelets No remarkable change of platelet was observed before and after treatment (P>.5) and there was no significant difference existed between treatment group and control group (P>.5) indicating that KLT had no impact on platelets (Table 3). 3 Table 3. Change of platelets before and after treatment (P P/mmP P) Patient ~. ~7.5 ~5. ~.5 <.5 No BT* AT* BT AT BT AT BT AT BT AT KLT Control BT* = before treatment AT*= after treatment, Ridit test before and after KLT treatment: P>.5, Ridit test between KLT and control group: P>.5.3 Observation of adverse reactions () Effect on heart, liver and kidney function The statistic results which were processed under the WHO Classification Standard of acute, sub-acute toxicity of anticancer drugs showed that Kanglaite had no effect on heart, liver and kidney function (Table )

7 Function Liver function 3 Kidney function 3 Heart function 3 Table. Effect on heart, liver and kidney function KLT Chemotherapy Point Before Before After treatment treatment treatment After treatment Liver Function Index: SGPT, Bilirubin; Kidney Function Index: BUN, Gr Liver Function: before treatment vs after treatment, Ridit test: P>.5 Kidney Function: before treatment vs after treatment, Ridit test: P>.5 Heart Function: before treatment vs after treatment, Ridit test: P>.5 () Allergic reaction No allergic reaction or rash occurred during the treatment. (3) Major adverse reactions There were 3 cases (6.67%) suffering from slight fever, generally under 38. The fever occurred on the first day of administration, lasted for -3 days disappeared spontaneously without interfering with the medication. No other side effects were observed in the trial. 3. Discussion Pulmonary carcinoma is the main death factor in patients with cancer. And 7%~8% of the lung cancers are NSCLC. Currently the overall cure rate is only about %. How to improve resection rate and cure rate becomes a key point in clinical study on lung cancer. Li Shijiu et al [] had KLT injection combined with surgery in the treatment of primary lung cancer and the effect was quite good. Liu Jiaxiang et al [] confirmed in the summary of Phase II clinical study of KLT that the total effective rate was.6% in KLT monotherapy for the treatment of primary NSCLC. With extract from coix seed KLT Injection had effects on inhibiting cancer cells, preventing metastasis and improving body immune function which had been confirmed by a series of basic and clinical studies. In this study, surgically excised tumor specimens suggested that the tumor tissues had large area necrosis after KLT treatment. There were 6.% of the subjects treated with KLT had necrotic areas over 5%. The statistic difference was significant (P<.5) as compared with control group. Some patients didn't get PR or better status in imaging examination. However, pathological results appeared big-area necrosis indicating that administration of KLT combined with surgical operation could eventually improve the cure rate. Through microscopy observation the reaction of lung cancer cells and cancer tissues to KLT - 6 -

8 demonstrated that KLT action on cancer cells was similar to the process of cancer cell apoptosis. Anyhow the mechanism still needed further investigation. During the treatment of 5 patients with primary lung cancer using KLT combined with surgery, the safety observation showed no evident toxic reactions or side effects except in 3 cases with slight fever (below 38, occurred on the first day of administration, lasted for ~3 days and disappeared spontaneously). No allergic reaction and other adverse effects were observed. The product had no impact on heart, liver or kidney function and did not inhibit bone marrow hematopoiesis function and KLT could raise peripheral blood cell levels.. Summary () Administration of KLT Injection before surgical operation could decrease tumor size of primary lung cancer with effective rate (CR+PR) as.%. KLT could help improve resection rate and cure rate of operation. () Based on the observation of surgically excised tumor specimens, there were 6.% of the subjects (8/5) treated with KLT whose necrotic areas were over 5%. Compared with the situation in control group(6.67% and 8/3) the statistic difference was significant (P<.5). The reaction of cancer cells and tissues in KLT group was obviously better than that in control group. The percentage of Grade I-II reactions in KLT group was 5.56% and only 53.33% in control group. The difference had statistic significance (P<.5). (3) Three cases with slight fever were observed in the KLT group. It could disappear spontaneously without impact on heart, liver or kidney function. No other side effects like allergy were observed during the trial. The product had no interference in bone-marrow hematopoiesis function but had effect of increasing amount of leucocytes. According to our clinical research results, we believe that KLT Injection has remarkable effect in inhibiting cancer cells and inducing liquefaction and necrosis of lung carcinoma cells. KLT Injection is a novel anticancer drug with unique effects. References []. Liu Jiaxiang et al, Summary of Phase II Clinical Trial of KLT Injection in the Treatment of Primary Lung Cancer, Zhejiang Anticancer Drug Information, []. Li Shijiu et al, Evaluation of the Therapeutic Effects of KLT Combined with Surgery in Treatment of cases with Lung Cancer, Zhejiang Anticancer Drug Information,

Li Tongdu, Liu Aiguo, Qin Shukui, Xu Peimin, Chen Li *An Hui Tumor Hospital

P Hospital A Summary of Phase III Clinical Trial of Kanglaite Injection on Relief of Cancerous Pain and Improvement of Life Quality in Patients with Advanced Cancer *Li Tongdu, *Liu Aiguo, Qin Shukui,