This report attempts to explain the (i) implications of comorbidity for research and practice in the fieldo of oncology, (ii) the approach for dosing of anti-cancer drugs in the presence of comorbidity, as an example of its clinical application, and finally (iii) the dosing guidelines for the anticancer drugs clinically active in gastric cancer in the presence of renal or liver dysfunction. This has resulted from the idea of approaching comorbidity in a systematic way and of integrating it with oncologic decisions. Various methods have been used to assess comorbidity. However, significant work remains to be done to analyze how various diseases combine to influence the oncologic outcome. The main end-point explored so far has been mortality, but a largely open challenge remains to correlate comorbidity with treatment tolerance and functional and quality of life, as well as to integrate it in clinical decision-making. Cancer chemotherapy in comorbidity should be considered as an example of the need for dose optimization in individual patients, and it should be determined by considering the basic principles of the pharmacokinetics and the pharmacodynamics of the agents. This review analyzes the available data on the pharmacokinetics and the toxicities of anti-cancer agents in the comorbidity population.
Comorbidity* ; Drug Therapy* ; Humans ; Liver Diseases ; Mortality ; Pharmacokinetics ; Quality of Life ; Stomach Neoplasms

Gastric cancer is a major cause of cancer-related mortality. At the time of diagnosis, majority of the patients usually have unresectable or metastatic disease. The most common sites of metastases are the liver and the peritoneum, but in the advanced stages, there may be metastases to any region of the body. Bone marrow is an important metastatic site for solid tumors, and the prognosis in such cases is poor. In gastric cancer cases, bone marrow metastasis is usually observed in younger patients and in those with poorly differentiated tumors. Prognosis is worsened owing to the poor histomorphology as well as the occurrence of pancytopenia. The effect of standard chemotherapy is unknown, as survival is limited to a few weeks. This report aimed to evaluate 5 gastric cancer patients with bone marrow metastases to emphasize the importance of this condition.
Bone Marrow* ; Diagnosis ; Drug Therapy ; Humans ; Liver ; Mortality ; Neoplasm Metastasis* ; Pancytopenia ; Peritoneum ; Prognosis ; Stomach Neoplasms

OBJECTIVETo explore the inhibitory effect of combined administration of bear bile powder (BBP) and cyclophosphamide (Cytoxan, CTX) on colorectal cancer liver metastasis by regulating tumor promotion inflammation microenvironment.

METHODThe CRC liver metastasis mode in mice was established through in situ spleenic injection of SL4 tumor cells into spleens. The mice were randomly divided into 5 groups: the model group, the CTX (80 mg x kg(-1)) treatment group, the CTX + BBP high dose (300 mg x kg(-1)) group, the CTX + BBP middle dose (150 mg x kg(-1)) group and the CTX + BBP low dose (75 mg x kg(-1)) group. Mice were orally administered with drugs for 12 days, and sacrificed on the 13'h day for weighing their spleens and lives, HE staining, and immunofluorescence analysis. Their peripheral blood, and metastatic tumor in spleens and lives were analyzed with flow cytometry.

RESULTSpleen and liver weights of the: CTX treatment group and other doses groups were significantly lower than that of the model group. HE staining and immunofluorescence analysis showed that lymphocyte infiltration was detected in normal tissues, and macrophages infiltration was observed around the tumor tissues. Flow cytometry analysis showed that the number of T-lymphocytes in peripheral blood of different doses groups were much higher than that of the CTX treatment group (P < 0.05), with the rise in the ratio of CD4/CD8; the total number of lymphocytes in spleen cell suspension increased in different doses groups, compared to the CTX treatment group, with notable increase in B cells (P < 0.05) and significant decrease in CD11b, F4/80 cells (P < 0.05). The combined treatment showed less monocyte macrophages in liver metastasis than that of the CTX treatment group.

CONCLUSIONThe combined treatment of bear bile powder and cyclophosphamide has the effect in not only protecting liver and increase immunity, but also in anti-inflammation and antitumor by regulating tumor microenvironment and reducing the collection of mononuclear macrophages. Particularly, the combined administration of low dose of bear bile powder and CTX shows the most significant effect in reducing inflammatory cell infiltration.

Animals ; Bile ; chemistry ; Colorectal Neoplasms ; drug therapy ; mortality ; pathology ; Combined Modality Therapy ; Cyclophosphamide ; administration & dosage ; Humans ; Liver Neoplasms ; drug therapy ; mortality ; physiopathology ; secondary ; Male ; Mice ; Mice, Inbred C57BL ; Tumor Microenvironment ; drug effects ; Ursidae

BACKGROUNDTransarterial chemoembolization (TACE) is the most widely used primary treatment for unresectable hepatocellular carcinoma (HCC) due to its survival benefit, though its clinical effect is still far from satisfactory. Jiedufang (JDF) granule preparation is a commonly used Chinese herbal medicine formula for HCC. The aim of this study was to evaluate the effect of combined therapy with TACE and JDF granule preparation in treatment of unresectable HCC on survival.

METHODSA retrospective study of TACE was performed in 165 patients with unresectable HCC who were admitted between January 2002 and December 2007 in Changhai Hospital, Shanghai, China. Of the 165 patients, 80 patients (study group) received combined therapy consisting of TACE and a long-term maintenance treatment with oral JDF granule preparation, and the remaining 85 patients (control group) received TACE alone. The survival rates of both groups were calculated by the Kaplan-Meier method. Factors possibly affecting survival were assessed by multivariate analysis in the Cox proportional hazard model, such as maximum tumor size, number of lesions, portal vein invasion, and etc.

RESULTSThe median overall survival was 9.2 months (95% CI: 6.94 - 11.46) in the study group versus 5.87 months (95% CI: 4.21 - 7.52) in the control group. In the study group,survival rates of the 1-, 2- and 3-year follow-up were 41.2%, 18.4%, and 9.6%, respectively. Significant independent prognostic factors identified by the Cox regression analysis were as follows: serum hepatitis B surface antigen (HBsAg) (P = 0.014), maximum tumor size (P = 0.027), number of lesions (P < 0.001), portal vein invasion (P < 0.001), and the therapy model (P = 0.006).

CONCLUSIONCombination therapy of TACE and JDF granule preparation may significantly prolong survival of patients with unresectable HCC.

Adult ; Aged ; Antineoplastic Agents ; therapeutic use ; Carcinoma, Hepatocellular ; drug therapy ; mortality ; pathology ; therapy ; Chemoembolization, Therapeutic ; methods ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Humans ; Liver Neoplasms ; drug therapy ; mortality ; pathology ; therapy ; Male ; Middle Aged ; Retrospective Studies ; Survival Rate ; Treatment Outcome

OBJECTIVETo investigate the synergetic effect of general therapy of Chinese herbal medicine with surgical operation.

METHODSFourty-two patients in the integrative group were treated with jiedu xiaozheng yin for 7 days before operation, and fuzheng yiliu recipe after operation for 2 years, and 30 patients in the control group underwent operation alone. Their cellular immune function, survival rate and recurrence rate were compared and analyzed.

RESULTSThe accumulative survival rate of 6-month, 12-month, 24-month and 36-month in the integrative group was 97.6%(41/42), 85.7%(36/42), 52.3% (22/42) and 45.5(17/42)% respectively and those in the control group 96.7% (29/30), 83.3% (25/30), 50.0% (15/30) and 30.0% (9/30), respectively, among them the 36-month survival rate was significantly different between the two groups (P < 0.05). The 24-month recurrence rate in the two groups was 54.8% and 80.0% respectively, the difference between the two was significant (P < 0.05).

CONCLUSIONAdministration of compound Chinese herbal medicine in peri-operational period has definite effect on primary hepatic carcinoma in III stage, it can improve patients' immune function, decrease the recurrence rate and increase the cumulative survival rate.

Adult ; Animals ; Carcinoma, Hepatocellular ; drug therapy ; immunology ; mortality ; surgery ; Combined Modality Therapy ; Drug Administration Schedule ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Humans ; Liver Neoplasms ; drug therapy ; immunology ; mortality ; surgery ; Male ; Middle Aged ; Phytotherapy ; Survival Rate

Breast cancer has the highest incidence among those occurring in Korean women. Adjuvant treatment of breast cancer aims to reduce micro-metastatic foci and to prevent relapse after surgery. Four cycles of AC showed equal survival benefits compared with 6 cycles of CMF, and it is not clear if the addition of taxane improves the survival. Adjuvant hormonal therapy shows reduction of relapse rate and mortality rate in both pre and post-menopausal women, if hormone receptors are expressed in the tumor. Metastatic breast cancer shows 3~25% long-term survival after response to chemotherapy or hormonal therapy, and thus in this situation, it is very hard to expect cure. And in advanced and metastatic breast cancer, chemotherapy is indicated in hormone-resistant breast cancer patients. However, in patients with a low probability of hormone sensitivity, in patients with very rapid progression, and in those with extensive metastases in lungs or liver, chemotherapy is the treatment of choice. The new class of chemotherapeutic agents such as tyrosine kinase inhibitors are being developed and are tried for the treatment of breast cancer with the hope of improving QOL and prolonging survival. Pre-operative chemotherapy improved not only the survival but also the local control rate. Multidiscipli-nary approach is strongly recommended to improve the efficacy of various therapy tools for breast cancer treatment in Korea, and the very rapid development of new treatment modalities together with the markers predicting response and prognosis is expected in the near future.
Breast Neoplasms* ; Breast* ; Drug Therapy ; Female ; Hope ; Humans ; Incidence ; Korea ; Liver ; Lung ; Mortality ; Neoplasm Metastasis ; Prognosis ; Protein-Tyrosine Kinases ; Recurrence

OBJECTIVETo evaluate the influence of sirolimus on the long-term survival of patients after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC).

METHODSClinic data of 165 consecutive patients who underwent OLT for HCC from February 2005 to March 2012 was analyzed retrospectively. Among them, 94 patients were treated with a sirolimus-based immunosuppressive protocol after OLT, while the other 71 patients with a FK506-based protocol. Postoperative survival time, survival, disease-free survival (DFS) and tumor recurrence rates between the two groups were compared.

RESULTSThe 2 groups were comparable in all clinicopathologic parameters. The sirolimus-based group had higher patient survival rates than the control group at 1-year (87% vs. 97%, P = 0.03), 2-year (80% vs. 88%), 3-year (76% vs. 85%) and 5-year (63% vs. 75%). The 1-year, 2-year, 3-year and 5-year recurrence rates were 12% vs. 3%, 17% vs. 9%, 21% vs. 9% (P = 0.04) and 31% vs. 16% (P = 0.03). Early and mid-HCC (I - II stage) of 131 cases (control group 61 cases, sirolimus-based group of 70 patients). The 1-year, 2-year, 3-year and 5-year survival rates were 90% vs. 97% , 80% vs. 90%, 78% vs. 86% and 65% vs. 82% (P = 0.04) and recurrence rates were 10% vs. 3%, 16% vs. 8%, 18% vs. 8% and 29% vs. 11% (P = 0.01).

CONCLUSIONThe sirolimus-based immunosuppressive protocol reduce long-term postoperative recurrence rate and improve the survival rate of patients after OLT for HCC significantly (especially early-mid HCC).

Adult ; Carcinoma, Hepatocellular ; drug therapy ; mortality ; surgery ; Female ; Humans ; Immunosuppressive Agents ; therapeutic use ; Liver Neoplasms ; drug therapy ; mortality ; surgery ; Liver Transplantation ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Retrospective Studies ; Sirolimus ; therapeutic use ; Survival Rate ; Tacrolimus ; therapeutic use

OBJECTIVETo investigate the effects of Chinese medicine (CM) herbal treatment based on syndrome differentiation on patients with unresectable hepatocellular carcinoma (HCC).

METHODSA total of 94 patients with unresectable HCC were reviewed between June 2008 and June 2011. Survival analysis was performed between patients who received CM with/without non-curative antitumor treatments of Western medicine (WM) (CM group, 30 cases) and patients who were not treated with CM but with non-curative antitumor treatments of WM or supportive treatment alone (non-CM group, 64 cases). Then, survival analysis was performed between patients treated with CM combined with non-curative antitumor treatments of WM (combination therapy group, 25 cases) and patients with non-curative antitumor treatments of WM alone (non-curative antitumor treatments group of WM, 52 cases). The survival analysis was performed by Kaplan-Meier method and prognostic factors for overall survival (OS) were assessed by the Cox proportional hazards regression model.

RESULTSThe median survival time (MST), 1- and 2-year survival rates of the CM group and the non-CM group were 36 months, 76.7%, 56.1% and 12 months, 48.4%, 26.6%, respectively. The Log-rank test revealed significant difference between the two groups in OS (P<0.01). Cox proportional multivariate analysis revealed that CM was an independent favorable prognostic factor for OS. The MST, 1- and 2-year survival rates of combination therapy group and non-curative antitumor treatments group of WM were 36 months, 76.0%, 55.5% and 13 months, 55.8%, 30.8%, respectively. There was significant difference in OS between the two groups (P=0.004).

CONCLUSIONSCM herbs based on syndrome differentiation have positive effects on survival of patients with unresectable HCC. Furthermore, combination therapy of CM and WM are recommended in HCC treatment.

Adult ; Aged ; Carcinoma, Hepatocellular ; drug therapy ; mortality ; surgery ; Combined Modality Therapy ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Humans ; Kaplan-Meier Estimate ; Liver Neoplasms ; drug therapy ; mortality ; surgery ; Male ; Middle Aged ; Multivariate Analysis ; Prognosis ; Survival Analysis ; Syndrome

Transcatheter arterial chemoinfusion (TACI) is the main treatment modality for advanced hepatocellular carcinoma (HCC). However, the therapeutic efficacy of TACI according to anti-cancer agents and prognostic factors for advanced HCC (TNM stage IVa) has not been previously clarified. A total of 127 patients with TNM stage IVa HCC were divided into intra-arterial Adriamycin (Group I) and intra-arterial Cisplatin (Group II) infused groups, according to the anticancer agents that were used. We compared the therapeutic efficacy of TACI applied anticancer agents, and we also analyzed the prognostic factors which influenced the survival rates. Chi-square test, t- test, Cox's proportional hazard regression model, and Kaplan- Meier method were performed. The overall survival was significantly different (10.0 vs 5.7 months, respectively) and the results favored Group I. On univariate analysis, the significant prognostic factors included age, portal vein thrombosis (PVT), tumor size (diameter< 5 cm), type of tumor, the reduction rate (tumor size & alpha- fetoprotein) after 3 months of chemotherapy, serum albumin level, serum alkaline phosphatase level and total serum bilirubin levels at the time of diagnosis. After repeated chemotherapy, Group I showed better survival (14.0 vs 7.9 months). However, there was no statistical difference in the survival rate of the two groups for cases involving large tumors, PVT and diffuse type of HCC. Group I showed better survival than Group II. However, when the other prognostic factors were taken into consideration, there was no significant difference in the survival rate of the two groups, except for the cases with small or nodular HCC.
Adult ; Aged ; Antineoplastic Agents/*administration & dosage/adverse effects ; Carcinoma, Hepatocellular/*drug therapy/mortality ; Cause of Death ; Female ; Humans ; *Infusions, Intra-Arterial ; Liver Neoplasms/*drug therapy/mortality ; Male ; Middle Aged ; Prognosis ; Research Support, Non-U.S. Gov't ; Survival Rate ; alpha-Fetoproteins/analysis

Glutathione based detoxification system in tumor cells was proposed as one of the drug resistance mechanisms and appeared to play as an obstacle in anticancer chemotherapy. It was evaluated that depletion of glutathione content in MBT-2, murine bladder tumor cells by buthionine sulfoximine could enhance the chemotherapeutic effect of carboplatin. Glutathione contents were measured by an enzymatic assay and chemosensitivity was assessed by MTT colorimetric test. Twenty-four hours exposure to 1, 2.5, 5 and 10uM buthionine sulfoximine reduced intracellular glutathione levels to 84.9, 24.8, 18.3 and 11.0% of the control level, respectively, in MBT-2 tumor cell line. Pretreatment with 2.5, 5 and 10uM buthionine sulfoximine for 24 hours and continuous exposure to buthionine sulfoximine and carboplatin for 72 hours potentiated the carboplatin cytotoxicity by 1.26, 1.56 and 1.90 folds, respectively. The potentiation of antitumor effect of carboplatin in C3H/He mice MBT-2 tumor by buthionine sulfoximine was evaluated with the use of tumor growth and tumor volume-doubling time. Glutathione contents in the tumor and liver were reduced to 12.8 and 21.8% of the control level by oral administration of 30mM buthionine sulfoximine for 5 days. No significant change in serum creatinine levels and renal histology was found in the mice treated with buthionine sulfoximine. Combination of carboplatin and buthionine sulfoximine significantly reduced tumor growth rate and delayed tumor volume-doubling time compared to carboplatin alone(p <0.05), while buthionine sulfoximine alone did not influence the tumor growth(p >0.05). Weight loss or mortality due to carboplatin and buthionine sulfoximine administration was not noted. Since buthionine sulfoximine significantly enhanced the effect of carboplatin on murine bladder tumor without apparent toxicity, combination of buthionine sulfoximine and carboplatin could be a new strategy in chemotherapy against advanced bladder cancer.
Administration, Oral ; Animals ; Buthionine Sulfoximine* ; Carboplatin* ; Cell Line, Tumor ; Creatinine ; Drug Resistance ; Drug Therapy ; Enzyme Assays ; Glutathione ; Liver ; Mice ; Mortality ; Urinary Bladder Neoplasms* ; Urinary Bladder* ; Weight Loss