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

Transcription

1 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, Xu Peimin, Chen Li *An Hui Tumor Hospital Abstract Kanglaite Injection (KLT) was developed by Hospital affiliated to Zhejiang TCM Institute and manufactured by Zhejiang Kanglaite Pharmaceutical Co., Ltd. The drug was extracted from a Chinese traditional herb "semen coicis" through modern technology. Phase II clinical trial for this drug was approved by the Ministry of Public Health [Approval No. 93ZL-22] and carried out by Longhua Hospital affiliated to Shanghai TCM University, Shanghai Chest Disease Hospital and Shanghai Second Lung Disease Hospital in July The trial was completed in Dec.1994 and passed the new drug evaluation by the Ministry of Public Health. KLT was approved as a "Second Category New Drug" [Approval No. 97WYSZ-03]. Phrase III clinical trial was performed from Feb to May 1997 in 14 hospitals organized by the Ministry of Public Health so as to further evaluate therapeutic efficacy, indications and side effects. The procedures were in accordance with the Principles of Clinical Directions for New (TCM) Drugs issued by Drug Administration Bureau affiliated to Ministry of Public Health. With entrustment from the Ministry the study was under the auspices of Anhui Tumor Hospital and cooperative hospitals included Beijing Hospital (attached to Ministry of Public Health), Aug. 1P st of PLA (Nanjing), Shandong Tumor Hospital, Tumor Hospital affiliated to China Medical University, Anhui Provincial Hospital, Henan Provincial Tumor Hospital, Shaanxi Provincial Tumor Hospital, Tumor Hospital affiliated to Anhui Medical University, Jiangxi Provincial Tumor Hospital, Hubei Provincial Tumor Hospital, Shuguang Hospital attached to Anshan Iron and Steel Company, Anyang Tumor Hospital (Henan), Hospital affiliated to Wannan Medical College. These 14 hospitals formed a multi-center cooperation group focusing on the Phrase III clinical trial. Following is the Tsummary of Phase TIII clinical trialt of Kanglaite injection on relief Tof Tous pain and improvement of TlifeT quality Tin patients with advanced. 1. Materials and methods 1.1 Clinical materials 1.1.1Source of subject 376 qualified subjects with advanced were collected from the above 14 hospitals in which 328 cases had ous pain Standard for cases selected or excluded

2 1 Confirmed by pathological, cytologic or screen examination and suffered from advanced 2 Consciousness with objective lesion available for evaluating therapeutic efficacy 3 Karnofsky scores: Physical 30, QOL (quality of life) 15 with estimated survival time> 3 months years old 5 Withdrawal of radiotherapy, chemotherapy or other therapy for over 1 month 6 Pain closely related to 7 Voluntary acceptance of KLT treatment 8 Excluded cases including those who did not meet the above criteria, those who did not administer the drug in accordance with the requirement or was loss of visit, those from whom efficacy could not be evaluated, died during treatment, had life threatening complications, had allergic reactions or other severe side effects Patient data Among the 376 advanced patients, 233 were male and 143 were female. Their age ranged from 26 to 74 years with a mean of Out of 328 patients with pain 197 were male and 131 were female with an average age of 57.2 years old (Table 1 and 2). Table 1. Distribution of sex Group Total(n) Male Female Ratio of M to F Advanced :1 Cancerous pain :1 Table 2. Distribution of age Group >70 Total Advanced Cancerous pain Classification of s (Table 3) Classification Pulmonary Table 3. Classification of s Mammary Stomach Hepatic Esophagus Large intestine Advanced Cancerous pain Classification Pancreatic Osteo- Thyroid sarcoma Others Total Advanced Cancerous pain *others including gynecologic tumor, lymphoma and leukemia, etc Spot of ous pain (Table 4)

3 Cancer Head Table 4. Spot of ous pain Spot of pain Chest Waist & back Abdomen Pelvic cavity Extremities Pulmonary Mammary Stomach Hepatic Esophagus Large intestine Cancer Pancreatic Thyroid Osteosarcoma Others Total Total Level of pain According to WHO numerical rating system of pain level (NRS), 1-3 is mild pain; 4-7 is moderate pain; 8-10 is severe pain (Table 5). Cancer Table 5. Level of pain Level of pain Mild Moderate Severe Total Pulmonary Mammary Stomach Hepatic Espohagus Carcinoma of large intestine Pancreatic Thyroid Osteosarcoma Others Total Karnofsky scores of patient (Table 6) Table 6. Karnofsky scores of patient No. of patient Scores of life quality in patient (Table 7)

4 Table 7. Scores of life quality in patient No. of patient Drug used for clinical trial KLT injection was supplied by Zhejiang Kanglaite Pharmaceutical Co., Ltd. Administration: ml intravenous drip, qd x 20 days 1.3 Index for observation (1) Evaluation of pain level (2) Karnofsky score (3) Evaluation of life quality (4) Change of body weight and blood routine (5) Criteria for evaluation of toxic reaction and side effect 2. Result 2.1 Degree of ous pain relief (Table 8) Pain level Table 8. Degree of ous pain relief No. of Degree of pain relief patient Remission rate (%) Mild Moderate Severe Total After KLT treatment 100% of mild pain was controlled (62/62) and 86.18% of moderate pain (131/152) could be relieved and 62.28% of severe pain (71/114) also relieved. 0: Pain was not relieved as 19.51% (64/328); 1-3: Pain was partially relieved as 56.10% (184/328); 4: Pain was completely relieved as 24.39% (80/328). Total remission rate was 80.49% (264/328). Pain was relieved gradually 1-3 days after treatment. 96 patients had used morphine analgesics before treatment. During the treatment, dosage of morphine could be decreased and there were 31 patients who finally withdrew from morphine completely. The rate of morphine withdrawal was 32.29% (31/96). After KLT treatment, the pain relief effect could last for 1~7 days or even longer. 2.2 Degree of various ous pain relief (Table 9)

5 Cancer Table 9. Degree of various ous pain relief Pain remission rate (relief after treatment/before treatment) Mild Moderate Severe Total Remission rate(%) Pulmonary 12/12 45/46 32/38 89/ Mammary 12/12 25/27 8/12 45/ Stomach 9/9 30/32 4/7 43/ Hepatic 1/1 9/16 16/30 26/ Esophagus 12/12 8/10 2/4 22/ Large intestine Cancer 8/8 9/11 3/4 20/ Pancreatic 0/0 1/1 4/14 5/ Thyroid 7/7 1/1 0/0 8/ Osteosarcoma 0/0 1/3 1/4 2/ Others 1/1 2/5 1/1 4/ Table 9 shown that KLT was most effective in patients with advanced pulmonary carcinoma (remission rate 92.71%), but less effective in patients with osteosarcoma (28.57%) and pancreatic (33.33%). 2.3 Change of KPS scores after treatment (Table 10) Table 10. Effect of KLT on KPS scores in patients with advanced Increase of KPS scores after treatment No. of patient % The KPS scores were increased in 92.02% of the patients (346/376) after KLT treatment and 76.60% (288/376) had their scores increased more than Change of QOL(quality of life) scores after treatment (Table 11) Table 11. Effects of KLT on QOL scores in patients with advanced Increase of QOL scores No. of patient % The QOL scores were increased in 91.22% of the patients (543/376) after KLT treatment and 72.61% (273/376) had their scores increased more than Effect of KLT on body weight in patients with advanced (Table 12) The situation that body weight decreased or increased more than 1 kg after treatment was termed as decreased or increased respectively. The change of body weight less than 1kg termed as stable

6 Table 12. Effect of KLT on body weight in patients with advanced Change of body weight Decreased Stable Increased No. of patient % Body weights were increased in 42.29%(159/376) patients after KLT treatment and stable in 52.13%(196/376) patients. 2.6 Effect of KLT on peripheral white blood cells (Table 13) 9 Table 13. Effect of KLT on peripheral WBC ( 10P P/L) < 1.0 BT* AT** BT AT BT AT BT AT BT AT No. of patient * ** Notes: BTP P- before treatment, ATP P-after treatment Comparison before and after KLT treatment: Ridit test: P<0.05 The immune function in most advanced patients was impaired and WBC was decreased. The 9 white blood cells were increased in most cases to more than 4.0 x 10P P/ L after KLT treatment and the difference was of statistic significance. This series of data showed that KLT had no influence on blood erythrocytes and platelets in patients with advanced. 2.7 Toxic reaction and side effect No adverse effect on heart, liver and kidney were observed and no allergic reaction e.g. chill, skin eruption appeared. 9 patients had mild phlebitis (2.3%) (9/376). The occasional slight fever (below 38 ) usually occurred 2-3 days after administration and could be relieved 1-3 days later spontaneously. 3. Discussion (1) Pain is a common and chief symptom in patients with. According to WHO statistics about 50% sufferers are associated with pain, 60-90% patients with advanced are at different levels of pain and 70% of them are those whose main symptoms are pains. In our series of data all patients were advanced cases and the rate of ous pain was 87.23% (328/376). Cancerous pain control has been one of the 4 major points in WHO comprehensive control program. The 3-stage control plan put forward by WHO has been widely accepted in many countries and morphine analgesics is the first choice for patients with severe pain. Although these kinds of drugs have strong palliative effect for ous pain, however they inevitably result in physical and psychological drug dependence

7 KLT is a new type of dual-function broad-spectrum anti drug. Clinical trial showed that it could inhibit tumor growth, prevent metastasis, improve immune function, supply high-energy nutrition and relieve ous pain at the same time. The clinical observation made by Doctor Wu Liangcun et al. showed that the ous pain remission rate of KLT was more than 90%. In our data the remission rate in 328 patients associated with ous pain was 80.40% in which the partial remission rate was 56.10% and the complete remission rate was 24.39%. Mild pain could be controlled completely and moderate pain was relieved in 86.18% patients and completely controlled in 9.87% (15/152) patients. The remission rate of severe pain was 62.28% and 2.63% (3/114) were completely controlled. KLT was most effective in patients with advanced pulmonary carcinoma (remission rate 92.71%) but less effective in patients with osteosarcoma (28.57%) and pancreatic (33.33%). In some patients morphine analgesics could be withdrawn after the administration of KLT. The mechanism of KLT's effect on ous pain needs further investigation. KLT is extracted from [4] coix seeds and coixol has the effect of curing muscle pain and arthralgiap P. As one of the important active components in coix seeds, coixol showed an analgesic action in the experiment of rats tail [5] stimulusp P. In the newly published Chinese and Westen Medicine Clinical Oncology it has been emphasized that the ous pain caused by weakness is one of the symptoms in advanced sufferers. It also pointed out some herbs had therapeutic effects like Radix Ginseng, Rhizoma [6] Atractyloidis Macrocephalae and Coix seedsp P. Animal test demonstrated that semen-coicis-oil could [7] reduce muscular convulsion and contraction and shorten fatigue curve to relieve the painp P. Moreover the decrease in tumor size after KLT therapy could lessen the infiltration and pressure on tissues and nerves which also played an important role in the abatement of ous pain. (2) The palliative treatment in patients with advanced is a worldwide matter. Although man has been fighting against for more than a century, the curing rate in developed countries reaches 45-50% and it is only about 10% in china. It is imperative that we should find some effective methods or drugs to control the symptoms of advanced and improve patients' life quality. It has become a hot topic in the research area of tumor prevention and cure worldwide. KLT has a significant effect on improving quality of life in patients with advanced. There were 92.02% patients who had their KPS increased after KLT treatment and 91.72% had their QOL(qualify of life) scores improved and 42.29% had their body weights increased. In addition the peripheral leukocytes in most patients were also raised to normal level after KLP treatment. (3) Clinical observation revealed that KLT had no influence on heart, liver and kidney function. No adverse effects such as chill, fever, nausea, vomit and skin rash, etc. were observed. Only 2.39% patients had mild phlebitis and could subside spontaneously. It proved that KLT was clinically safe and reliable. 4.Typical case report Case 1: Liang, female, age 51, Admit No

8 P ribs P and P intercostal A She was admitted on Feb. 28, 1997 because of cough, expectoration, blood in sputum, chest suffocation and severe chest pain with tumor mass on right chest wall. Three months ago, she received treatment of interventional chemotherapy for squamous, but the effect was not good. She was currently diagnosed as right pulmonary squamous carcinoma with chest wall metastasis on admission. The examination revealed as pulmonary carcinoma. She had shortness of breath with distressful facial feature. A solid mass about 6 5cm was palpable between right 8P th 9P th space. X-ray chest test showed a large amount of pleural fluid. The patient took slow-released morphine tablet orally, 30g, q12h or buprenorphine 4mg, q 8h. The KLT injection,100ml i.v. drip. qd 20 was administered from March 1, The morphine drug was withdrawn 2 days later and the pain could be controlled better afterwards. After one cycle of treatment, the patient got a follow-up observation for 1day and no pain was occurred. The KPS was increased by 20 scores (from 50~70) and the cough was relieved. X-ray test on chest revealed that pleural fluid was absorbed in certain degree as compared with the situation before the treatment. Case2: Lan, male, age 66 He was admitted to the oncological ward on May 18,1996. The patient suffered from cough and severe short breath for two months. X-ray test on chest demonstrated a shadow of mass in left lung. The X-ray and CT revealed a shadow of mass about cm in left hilum of lung with mediastinal lymph nodes metastasis and bilateral pleural effusion. Fibrobronchoscope biopsy confirmed it was squamous. Nuclein bone scan revealed the left 7P th P- 8P th metastasis. Diagnosis: Left lung central type squamous with mediastinal lymph nodes metastasis, pleura metastasis and skeleton metastasis. C-T4N2M1, phase IV. The clinical symptoms were paroxysmal cough, impeded expectoration, evident short breath, moderate pain on chest and back, dry mouth, poor appetite, lay in bed, reddened tongue, thin tooth, thin fur with thready and rapid pulse. The differentiation of symptom-sigh according to the theory of TCM was deficiency of both Qi and Yin. The treatment with KLT 200ml i.v. drip started on May 30,1996, once daily. The appetite and pain on chest and back were improved and the symptom of cough was relieved after the treatment. The patient could get up and do a little exercise about 10 days later. 20 days later he could take care of himself. After two cycles (42 days later) of treatment with KLT injection the symptoms were basically disappeared except occasional slight cough. The re-examination of X-ray test on chest demonstrated that the left lung mass shadow was shrunk to cm and the bilateral pleural effusion disappeared. ECT revealed certain improvement in skeleton metastasis. The body weight increased by 3 kg, KPS increased by 20 scores (40~60), liver and kidney functions were all within normal range. The patient was discharged from hospital on Aug., 26,1996.There was no evident discomfort except slight cough. The therapeutic efficacy was significant. 5. Conclusion (1) The result of KLT treatment on 328 patients suffering from ous pain in 9 hospitals showed that the total effective rate to control ous pain reached 80.49% (partial remission rate 56.10%, complete remission rate 24.39%). KLT can partially or completely replace morphine analgesics in controlling ous pain. After stopping administration the pain relief effect could still last for about

9 1~7 days without drug-addiction. (2) Among the 376 patients with advanced subject to KLT treatment, more than 90% patients' life quality and body immune function got improved and peripheral blood picture increased. (3) The observation on the clinical safety of KLT injection indicated that KLT had no evident adverse effect on heart, liver and kidney function. Only 2.39% (9/376) of the total had slight phlebitis which could disappear spontaneously. No other adverse reactions such as fever, nausea, vomit or anaphylaxis occurred. In a word, KLT Injection has the effect of controlling tumor growth, preventing metastasis of cells, improving immune function, supplying nutrition with high energy and controlling carcinoma effusion. In addition, it can obviously control ous pain and improve life qualities of patients suffering from advanced without evident toxic reactions and side effects. Reference (1) Li Tongdu, Oncology(Volume II): Control of Cancer Pain, Beijing, People's Public Health Publishing House,1996. (2) Pharmaceutical Affairs Administration of the Ministry of Public Health of PRC, Guidance Principles of Three-Stage Analgesic Therapy for Cancer Patients, 1994, p20~22. (3) Wu Liangcun, Summary of Phase I Clinical Study on KLT Injection, Zhejiang Anti Drug Information, Aug. 22, (4) The Annual Report of 1997 by the Ministry of Public Health of PRC, p650. (5) State TCM & Drug Administration, Manual of Botanical Drug's Active Ingredients, People's Public Health Publishing House,1986, p2. (6) Li Peiwen, Chinese and Western Medicine Clinical Oncology, China TCM & Drug Publishing House, Dec.,1996, p420. (7) Assembly of Chinese Medicinal Herbs. People's Public Health Publishing House.1975, p