A Research On Integrated Traditional Chinese And Western Medicine For The Treatment Of Advanced Pancreatic Cancer

IntroductionThere has been a significant increasing trend in the incidence of pancreatic cancer. Besides surgical resection, modern medicine has provided barely any effective way of treating the disease. Overally, the mortality is almost equal to the incidence. Resistance of advanced pancreatic caner to conventional chemotherapy and radiation leads to a very dismal prognosis, with the 1 year survival of about 10%. Former researches indicated that traditional Chinese medicine (TCM) had some advantages in treating pancreatic cancer patients, especially those in advanced stages. However, most of those researches were small retrospective studies or case reports. Experimental researches on TCM for pancreatic cancer were even fewer. So it is urgent to carry out systemic and comprehensive clinical trails as well as experimental researches to better expose the exact effects of TCM in multidisciplinary management of pancreatic cancer.ObjectivesWe aimed to understand the way, effects and mechanism of integrated traditional Chinese and western medicine (ITCWM) in treating advanced pancreatic cancer through retrospective and prospective clinical researches and experimental studies, which may help to define the value of the integrative modality for the management of advanced pancreatic cancer.Materials and Methods1. Researches on TCM treatment for pancreatic cancer:Via literature review, we tried to find out the TCM basis of onset and types of pancreatic cancer, and to define the treatment principle of TCM for the disease.Afterward, a retrospectvie review on 60 cases with advanced pancreatic cancer (herbal decoction for 32 cases and intra-arterial chemotherapy for 28 cases) wereperformed to define the effects and characteristics of TCM for advanced pancreatic cancer, comparing with chemotherapy.2. Researches on ITCWM treatment for pancreatic cancer:A prospective randomized controlled clinical trail was performed, in which 42 patients with locally advanced or metastatic pancreatic cancer received 3-dimensional conformal radiotherapy 36-40 Gy at 1.8-2.0 Gy/d fractions for pancreatic lesions as well as intra-arterial regional chemotherapy of gemcitabine and cisplatin or Oxaliplatin. The patients were randomized to receive QingYiHuaJi herbal decoction (QYHJ group: 21 cases) or control decoction (control group: 21 cases). The effects of the two treatment arms were evaluated and compared according to objective response, clinical benefit rate, survival and treatment-related adverse-effects.A multifactorial Cox proportional hazard model analysis was introduced into the retrospective clinical study to examine the prognostic factors in advanced pancreatic cancer treated by ITCWM, to elucidate the effect of TCM in this therapeutic modality.3. Effect of QingYiHuaJi (QYHJ) herbs on the proliferation of experimental pancreatic cancer and the exploration of its mechanism:Human pancreatic cancer cell SW1990 burdened nude mice were randomized to receive QYHJ decoction at different doses and chemotherapy. Inhibiting rates of tumor growth in vivo were calculated. The ratio of the cell cycles was measured by flow cytometry. Genes with different expression after treatment of the decoction were identified through analysis of gene expression profile with cDNA microarray. The expression levels of a selected gene and the corresponding protein were tested by real-time fluorescence quantitative PCR (FQ-PCR) and immunohistochemistry.Results1. Researches on TCM treatment for pancreatic cancer:The results of the literature study showed that there is a close relationship with pancreatic cancer and excess of "dampness, heat, and toxicity" and the later disorder of function. Clearing up heat and resolving toxicity, regulating the Qi and dispelling dampness is the main principal of TCM treatment for the disease.The retrospective study showed no significant difference of objective response rate between the two groups treated with herbal decoction mainly composed of QYHJ herbs or intra-arterial chemotherapy (P>0.05). The herbal group had an advantage ofsurvival over chemotherapy group, with a 1-year overall survival of 34.4% vs 11.3%, median survival 6.1 months vs 4.2 months (P<0.05), and time to progression 2.9 months vs 1.6 months (P<0.05). Toxicities in herbal group were less than those in chemotherapy group.2. Researches on ITCWM treatment for pancreatic cancer:In the randomized trial, 10% partial response rate was found in the TCM group, while no PR happened to the control group (P>0.05). The clinical benefit rates were 44.4% in the QYHJ group and 21.4% in the control group (P>0.05). Overall median survival were 6.1 months in the QYHJ group and 4.3 months in the control group, and half year survival 50.7% vs 26.8%, 1 year survival 16.4% vs 0, respectively (P>0.05). Rate of treatment related adverse effects is of no significant difference between the groups(P>0.05).The retrospective study on 134 advanced pancreatic cancer patients who received ITCWM showed an overall median survival time of 5.7 months and overall half, 1, 2, and 3 year survival of 46.8%, 21.0%, 8.9% and 8.9%. Multivariate analysis disclosed the correlation of survival with QYHJ decoction, serum CA19-9 > 500U/ml, obstructive jaundice and radiotherapy for pancreatic lesions (P<0.05), with the relative hazard of 0.492, 1.702, 1.773, and 0.641. Prognostic index PI=-0.445X₄ -0.709X₅ + 0.573X₆ + 0.532X₈ was established. Survivals calculated from PI well conformed to the real survivals of the patients. With the increasing of PI, the overall median survival time and half, 1 year survival rate showed a tendency of decline (P<0.05), which indicating PI evaluation a way to anticipate prognosis of the patients and may contribute to treatment decision.3. Effect of QingTiHuaJi (QYHJ) herbs on the proliferation of experialmental pancreatic cancer and the exploration of its mechanism:QYHJ decoction could inhibit the growth of human pancreatic cancer cell SW1990 in vivo. Tumor weight in the QYHJ groups was significantly lower than that in control group (P<0.05). Inhibiting rate of tumor growth of the HYHJ groups varied from 13 to 38% in 3 experiments. The group with median dose of QYHJ decoction had an average inhibiting rate of about 31%. No difference was observed among the treatment groups at high, median or low dose (P>0.05), indicating that there was no dose-effect regulation. Results of cytometry analyses indicated that proliferation index of tumor cells in the QYHJ groups was lower than that in the control group. The proportion of cells in G₀/G₁ phase was larger, and that in G₂/M phase was smallerthan that of the control group (P<0.05). Apoptosis of SW1990 cells did not show difference between the groups (P>0.05). 7 genes with reduced expression over 2 times were identified using microarray after intervention of QYHJ decoction. FQ-PCR found the downregulation of Ski mRNA expression in the QYHJ group, which validated the results of microarray. Immunohistochemistry test found high expression rate (87.5%) of Ski protein in the control group, most of which showed intensive positiveness. Intervention of the decoction reduced the rate and degree of Ski expression. The positive expression rate of 25% in the group with high dose was significantly lower than that in the control group (P<0.05).Conclusions1. Excess of "dampness, heat, and toxicity" plays a critical role in the onset of the pancreatic cancer. Clearing up heat and resolving toxicity, regulating the Qi and dispelling dampness is the main principals of TCM treatment for the disease.2. Herbal decoction mainly composed of QYHJ decoction may benefit to advanced pancreatic cancer patients by stabilizing tumors and prolonging life expectancy, with longer therapeutic effects and fewer side effects than chemotherapy.3. QYHJ herbal decoction may benefit patients with locally advanced or metastatic pancreatic cancer treated by regional intra-arterial chemotherapy and radiation, which probably offer a better clinical benefit rate and life expectancy. Larger number of patients is warranted to meet a statistically significance and final conclusions.4. Jaundice and tumor marker CA19-9>500U/ml may be negative prognostic factors for patients with advanced pancreatic cancer after treatment. While application of radiotherapy for pancreatic lesions and QYHJ herbal decoction may be the important protective factors to achieve a good survival.5. QYHJ decoction may inhibit the proliferation of human pancreatic cancer SW1990 in vivo without dose-effect tendency.6. QYHJ decoction may inhibit the proliferation of pancreatic cancer by rearranging cell cycles of tumor cells, down-regulating the expression of oncogene Ski, Ski protein and regulating the related signal transduction.