ABSTRACT
The aim of this study was to test the efficacy of a chemotherapy combination of cisplatin, IFN alpha-2b, doxorubicin, Adriamycin, and 5-fluorouracil (PIAF) as treatment for radiologically measurable cancer of the biliary tree. Forty-one patients (19 gallbladder carcinoma and 22 cholangiocarcinoma) with unresectable, histologically confirmed adenocarcinoma were registered. Starting chemotherapy doses were as follows: cisplatin, 80 mg/m(2) i.v. over 2 h; doxorubicin, 40 mg/m(2) i.v. over 2 h; and 5-fluorouracil, 500 mg/m(2) by continuous infusion daily for 3 days. IFN alpha-2b (5 x 10(6) units/m(2)) was administered s.c. before the cisplatin and daily thereafter for a total of four doses. The overall response rate was 21.1% [95% confidence interval (CI), 10-37]. For cholangiocarcinoma and gallbladder carcinoma patients, the response rates were 9.5% (95% CI, 1-32%) and 35.3% (95% CI, 14-62%), respectively. Overall median survival time was 14 months (95% CI, 9.5-18.5), 18.1 months (95% CI, 12.1-24.1) for the cholangiocarcinoma patients, and 11.5 months (95% CI, 5.9-17.1) for the gallbladder carcinoma patients. This difference was not statistically significant. The most common grade III and IV toxicities were neutropenia (41%), thrombocytopenia (20%), nausea and vomiting (34%), and fatigue (20%). In conclusion, the PIAF combination seemed more active against gallbladder carcinoma than against cholangiocarcinoma but was associated with significant toxicity. Therefore, this regimen cannot be recommended for cholangiocarcinoma, but it may have a role in the treatment of gallbladder carcinoma, particularly among patients who were refractory to higher priority investigational agents.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biliary Tract Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biliary Tract Neoplasms/pathology , Cisplatin/administration & dosage , Cisplatin/adverse effects , Diarrhea/chemically induced , Dose-Response Relationship, Drug , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Fatigue/chemically induced , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Hematologic Diseases/chemically induced , Humans , Infusions, Intravenous , Injections, Subcutaneous , Interferon alpha-2 , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Male , Middle Aged , Nausea/chemically induced , Recombinant Proteins , Survival Analysis , Treatment Outcome , Vomiting/chemically inducedABSTRACT
While surgical resection and tumor ablation are the preferred therapies for hepatocellular carcinoma (HCC), these are available or appropriate in only a minority of patients. This reflects the usual comorbidity of severe underlying liver disease that either precludes surgery or makes the surgical approach extremely dangerous. Nonetheless, regional control of HCC is highly relevant and many regional strategies have been explored, including hepatic intra-arterial chemotherapy transarterial chemoembolization, lipiodol chemoembolization, radiation therapy, cryosurgery, percutaneous ethanol injection, and radiofrequency ablation. In addition, a variety of systemic chemotherapeutic agents have been tested in HCC, including various combinations of 5-fluorouracil, doxorubicin, epirubicin, etoposide, cisplatin, and mitoxantrone, as well as interferon, tamoxifen, capecitabine, thalidomide, and octreotide. Published data regarding these regional and systemic therapies will be discussed in this review.
Subject(s)
Carcinoma, Hepatocellular/complications , Carcinoma, Hepatocellular/therapy , Deoxycytidine/analogs & derivatives , Liver Cirrhosis/complications , Liver Neoplasms/complications , Liver Neoplasms/therapy , Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Capecitabine , Chemoembolization, Therapeutic , Cryosurgery , Deoxycytidine/therapeutic use , Drug Combinations , Ethanol/administration & dosage , Fluorouracil/analogs & derivatives , Humans , Hyperthermia, Induced , Infusions, Intra-Arterial , Injections, Intralesional , Interferons/therapeutic use , Octreotide/therapeutic use , Radiopharmaceuticals/therapeutic use , Radiotherapy Dosage , Tamoxifen/therapeutic use , Tegafur/therapeutic use , Uracil/therapeutic useABSTRACT
BACKGROUND: Egypt has one of the highest prevalence rates of hepatitis C virus (HCV) infection in the world; however, the risk and attribution related to HCV in Egyptian patients with hepatocellular carcinoma (HCC) remains unknown. GOALS: The current study was undertaken to estimate the risk of HCC in relation to HCV in Egypt. STUDY: Thirty-three patients with HCC and 35 healthy controls who had a similar socioeconomic status were prospectively enrolled at the University of Cairo National Cancer Institute. RESULTS: Anti-HCV antibodies were present in 75.8% of the patients and in 42.9% of the controls (p = 0.01); hepatitis B surface antigen (HBsAg) was present in 15.2% of the patients and in 2.9% of the controls (p = 0.03). In addition, the sex-and age-adjusted odds ratio (OR) for anti-HCV antibodies was 5.1 (95% CI = 1.5-17.4) and for HBsAg was 13.2 (95% CI = 1.2-148.2). Concurrent Schistosoma mansoni and anti-HCV was associated with an OR of 10.3 (95% CI = 1.3-79.8), which was higher than that for anti-HCV (6.5; 95% CI = 1.6-26.6) and S. mansoni infection (0.2; 95% CI = 0.1-6.2) alone. Finally, we estimated the attributable fraction of HCC to HCV to be 64% in this study population and 48% in the general Egyptian population. CONCLUSIONS: Both HCV and hepatitis B virus infection increase the risk of HCC in Egyptian patients, whereas isolated Schistosoma infection does not. Because of the very high prevalence rate of HCV in the general Egyptian population, it accounts for most HCC cases in Egypt.
Subject(s)
Carcinoma, Hepatocellular/virology , Hepatitis C, Chronic/diagnosis , Liver Neoplasms/virology , Adult , Aged , Antibodies, Helminth/blood , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/immunology , Case-Control Studies , Comorbidity , Egypt , Female , Hepatitis B Surface Antigens/blood , Hepatitis B, Chronic/diagnosis , Hepatitis B, Chronic/immunology , Hepatitis C Antibodies/blood , Hepatitis C, Chronic/immunology , Humans , Liver Neoplasms/diagnosis , Liver Neoplasms/immunology , Male , Middle Aged , Prospective Studies , Risk Factors , Schistosomiasis mansoni/diagnosis , Schistosomiasis mansoni/immunologyABSTRACT
The prognosis of patients with HCC remains dismal. Even in the subgroups of patients who have the most favorable characteristics and are eligible for surgical resection, the 5-year survival rate is less than 25%. For patients with more advanced disease, the median survival time is less than 1 year. The good news in HCC research is that the disease can be prevented. In Taiwan, the rate of HCC in children aged 6 to 9 years decreased from 5.2 per million population before the neonatal vaccination program began in 1984 to 1.3 per million population in the first vaccinated cohort. Treatment of viral hepatitis with IFN may decrease the rates of long-term development of HCC. Other agents that may prevent second primary tumors following resection of HCC, such as polyprenoic acid and acylic retinoid, are also being investigated.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Africa South of the Sahara/epidemiology , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/epidemiology , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/therapy , Asia, Eastern/epidemiology , Humans , Liver Neoplasms/diagnosis , Liver Neoplasms/epidemiology , Liver Neoplasms/etiology , Liver Neoplasms/therapy , Prognosis , Reoperation , Risk Factors , Survival Analysis , Survival Rate , Time Factors , United States/epidemiologyABSTRACT
Given the poor prognosis of HCC and the therapeutic challenge posed by underlying liver cirrhosis, efforts and resources must be directed towards preventive strategies. Return on the investment in such research is likely to be greater than can be expected from treatment of advanced disease.
Subject(s)
Carcinoma, Hepatocellular/therapy , Liver Neoplasms/therapy , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/radiotherapy , Chemoembolization, Therapeutic , Ethanol/administration & dosage , Humans , Hyperthermia, Induced , Infusions, Intra-Arterial , Liver Neoplasms/drug therapy , Liver Neoplasms/radiotherapyABSTRACT
BACKGROUND: This retrospective study was performed to assess the outcome among patients who underwent hepatic resection or tumor ablation after hepatic artery infusion (HAI) therapy down-staged previously unresectable hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (CRC). METHODS: Between 1983 and 1998, 25 patients with HCC and 383 patients with hepatic CRC metastases were treated with HAI therapy for unresectable liver disease. We retrospectively reviewed the records of 26 (6%) of these patients who underwent subsequent surgical exploration for tumor resection or ablation. RESULTS: At a median of 9 months (range 7-12 months) after HAI treatment, four patients (16%) with HCC underwent exploratory surgery; two underwent resection with negative margins, and the other two were given radiofrequency ablation (RFA) because of underlying cirrhosis. At a median postoperative follow-up of 16 months (range 6-48 months), all four patients were alive with no evidence of disease. At a median of 14.5 months (range 8-24 months) after HAI therapy, 22 patients with hepatic CRC metastases underwent exploratory surgery; 10 underwent resection, 6 underwent resection and RFA or cryotherapy, and 2 underwent RFA only. At a median follow-up of 17 months, 15 (83%) of the 18 patients with CRC who had received surgical treatment had developed recurrent disease; the other 3 died of other causes (1 of postoperative complications) within 7 months of the surgery. One patient in whom disease recurred underwent a second resection and was disease-free at 1 year follow-up. CONCLUSIONS: Hepatic resection or ablation after tumor downstaging with HAI therapy is a viable option for patients with unresectable HCC. However, given the high rate of recurrence of metastases from CRC, hepatic resection or ablation after downstaging with HAI should be used with caution.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Hepatocellular/surgery , Colorectal Neoplasms/pathology , Liver Neoplasms/surgery , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/secondary , Combined Modality Therapy , Female , Hepatic Artery , Humans , Infusions, Intra-Arterial , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Liver Neoplasms/secondary , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Recurrence , Retrospective Studies , Treatment OutcomeABSTRACT
Thalidomide, a sedative agent previously associated with severe fetal malformations, has anti-angiogenic activity. We describe the antitumor effects of thalidomide in a patient with hepatocellular carcinoma that was refractory to systemic and intraarterial therapy.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Thalidomide/therapeutic use , Administration, Oral , Aged , Angiogenesis Inhibitors/administration & dosage , Humans , Male , Thalidomide/administration & dosage , Tomography, X-Ray Computed , Treatment Outcome , alpha-Fetoproteins/metabolismABSTRACT
The purpose of this Phase II study was to determine the response rate, the toxicity, and the effect on survival of the combination of cisplatin, doxorubicin, 5-fluorouracil, and alpha-IFN (PIAF) in advanced unresectable hepatocellular carcinoma. Fifty patients with either unresectable or metastatic disease were treated with PIAF: cisplatin (20 mg/m2 i.v., days 1-4), doxorubicin (40 mg/m2 i.v., day 1), 5-fluorouracil (400 mg/m2 i.v., days 1-4), and alpha-IFN (5 MU/m2 s.c., days 1-4). Treatment was repeated every 3 weeks to a maximum of six cycles. All patients were evaluable for response, toxicity, and survival. As assessed by conventional imaging criteria, there were no complete responses, but 13 patients (26%) had a partial response. Among the 36 patients who had an initially high alpha-fetoprotein level (>500 ng/ml), 15 (42%) had a >50% fall after therapy. Nine patients underwent surgical resection after achieving partial response and, in 4 of these patients, histological examination of the resected specimens revealed no viable tumor cells. All these nine patients are alive, and eight patients remain in complete remission at between 7.6 and 25.8 months at the time of analysis. The overall median survival was 8.9 months. Toxicity was mainly myelosuppression and mucositis. There were two treatment-related deaths due to neutropenic sepsis. PIAF is active in hepatocellular carcinoma despite considerable hematological toxicity. Complete pathological remission is possible with this systemic combination. Apparently, persistent radiological lesions may still represent complete pathological resolution of active disease.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Cisplatin/administration & dosage , Cisplatin/adverse effects , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Male , Middle Aged , Radiography , Remission Induction , Survival Analysis , Treatment OutcomeABSTRACT
The case described here illustrates the antitumor activity of a four-drug systemic combination chemobiotherapy with platinol, recombinant interferon alpha 2b, doxorubicin (Adriamycin), and 5-fluorouracil (5-FU) (PIAF) in a patient with diffuse hepatocellular carcinoma involving the liver and lungs.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/pathology , Cisplatin/administration & dosage , Doxorubicin/administration & dosage , Female , Fluorouracil/administration & dosage , Hepatic Artery , Humans , Infusions, Intra-Arterial , Interferon alpha-2 , Interferon-alpha/administration & dosage , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/pathology , Radiography , Recombinant ProteinsABSTRACT
The authors evaluated the activity and toxicity of docetaxel given as a 1-hour infusion every 21 days in patients with unresectable cholangiocarcinoma. Seventeen patients with cytologically or histologically confirmed cholangiocarcinoma received intravenous docetaxel over 1 hour, repeated every 21 days. The initial dose of docetaxel was 100 mg/m2, with a subsequent 25% dose reduction for patients experiencing grade 3 or 4 toxicities. Treatment was continued until disease progression or occurrence of intolerable side effects. All patients received premedication with dexamethasone 8 mg by mouth twice daily for 5 days, starting 1 day before docetaxel infusion. Sixteen of the 17 patients were assessable for response and toxicity; one patient was removed from the trial for intercurrent illness. Thirty-eight cycles of docetaxel were delivered (median, two cycles). No complete or partial responses were noted. Fourteen patients had progressive disease, one patient had stable disease, and one patient died of septic shock shortly after starting treatment. Granulocytopenia was the dose-limiting toxicity. Thirteen patients had grade 4 granulocytopenia, 11 of whom required antibiotics for neutropenic fever. Granulocytopenia was the only grade 4 toxicity observed. Grade 3 toxicities included stomatitis, anemia, fatigue, vomiting, and hypotension. Grade 1 or 2 toxicities included alopecia, diarrhea, peripheral edema, myalgias, and anorexia. Administered on this dose and schedule, docetaxel lacked activity in patients with cholangiocarcinoma. The toxicity profile, including dose-limiting granulocytopenia, has been previously described in patients receiving docetaxel.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Bile Duct Neoplasms/drug therapy , Cholangiocarcinoma/drug therapy , Paclitaxel/analogs & derivatives , Taxoids , Adult , Aged , Antineoplastic Agents, Phytogenic/administration & dosage , Bile Ducts, Extrahepatic , Bile Ducts, Intrahepatic , Docetaxel , Female , Humans , Male , Middle Aged , Paclitaxel/administration & dosage , Paclitaxel/therapeutic use , Treatment OutcomeABSTRACT
Previous research showed that risk factors associated with hepatocellular carcinoma (HCC) include infection with hepatitis B (HBV) and hepatitis C (HCV) viruses, exposure to aflatoxin B1 (AFB1), and liver cirrhosis, due primarily to alcohol consumption. To determine whether AFB1 may play a role in HCC in the United States, a search for AFB1 adducts and p53 alterations, potentially induced by AFB1, was conducted in the United States in 23 HCC patients with available tissue samples. The presence of AFB1 tumor-DNA and -serum lysine adducts and mutant p53 product was determined by immunoassays and codon 249 p53 mutation by restriction enzyme analysis. HBV and HCV serology and serum HBV-DNA were also determined. Thirteen patients were positive for HBV by HBs antigen or anti-HBc antigen or by polymerase chain reaction for HBV-DNA sequences. Nine patients were free of HBV and HCV markers; 5 of 22 sera tested were anti-HCV positive. p53 Protein expression, determined by immunohistochemical staining, was present in 5 of the 23 tumor tissues, whereas p53 codon 249 mutations were not observed in the 5 cases in which tissue was available for study. AFB1 tumor-DNA adducts were present in 3 of 19 tumor tissues, and in 1 of these 3 samples p53 protein was also detected. Sera from only 5 of the patients were tested for AFB1-lysine adducts, and all were positive. In these five patients, neither p53 protein nor a mutation on codon 249 was detected. The demonstration that AFB1-DNA and -lysine adducts are present in HCC patients in the United States is intriguing but requires further substantiation because of the small number of subjects in this pilot study. To elucidate the pathogenetic significance of these findings, further investigation, including studies in larger patient cohorts and properly selected controls, is warranted.
Subject(s)
Aflatoxin B1/adverse effects , Carcinogens/adverse effects , Carcinoma, Hepatocellular/etiology , Liver Neoplasms/etiology , Adult , Aged , DNA Primers , Female , Hepacivirus/immunology , Hepatitis B virus/genetics , Hepatitis B virus/isolation & purification , Humans , Immunohistochemistry , Male , Middle Aged , Polymerase Chain Reaction , Tumor Suppressor Protein p53/analysis , Tumor Suppressor Protein p53/genetics , United StatesABSTRACT
PURPOSE: Taxol (paclitaxel) represents a new class of anticancer agent with activity against a wide variety of solid tumors. It has been found to be active in patients with adenocarcinoma and squamous cell carcinoma of the esophagus. To determine its activity against gastric adenocarcinoma, we conducted a phase II trial of Taxol in chemotherapy-naive patients with advanced disease. PATIENTS AND METHODS: Patients with measurable, unresectable, metastatic gastric carcinoma with performance status < or = 2 by Zubrod scale were eligible. Patients had to have normal liver, renal, and bone marrow functions. Written informed consent was obtained from all patients. The starting dose of Taxol was 200 mg/m2 infused over either 3 hours (in the first 15 patients) or 24 hours (in the subsequent 18 patients). Taxol was repeated every 21 days. Response was evaluated after two courses. RESULTS: Thirty-three patients were registered. The median number of courses was two (range, 1 to 12; total, 112 courses). Thirty patients were evaluable for response and toxicity. Among the first 15 patients (two inevaluable) receiving Taxol over 3 hours, there were one partial response (PR) (one of 13 patients, or 8%; 95% confidence interval, 0% to 36%) and three minor responses (MRs). However, among the 18 patients (one inevaluable) receiving Taxol over 24 hours, there were four PRs (four of 17 patients or 23%; 95% confidence interval, 7% to 50%) and three MRs. The overall PR rate was 17% (five of 30 patients; 95% confidence interval, 6% to 35%). The median duration of PR was 6.5 months (range, 2.3 months to 11.3+ months. There were no treatment-related deaths. Myelosuppression was more severe with the 24-hour schedule than with the 3-hour schedule. CONCLUSIONS: Taxol has a modest degree of activity against gastric carcinoma. It is well tolerated by the patients. Further studies of Taxol in combination with other active agents against gastric carcinoma should be considered.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents, Phytogenic/therapeutic use , Paclitaxel/therapeutic use , Stomach Neoplasms/drug therapy , Adenocarcinoma/pathology , Adult , Aged , Antineoplastic Agents, Phytogenic/adverse effects , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Paclitaxel/adverse effects , Stomach Neoplasms/pathologyABSTRACT
Primary hepatocellular carcinoma (HCC) is a common malignancy with a dismal prognosis; new modalities of treatment as alternatives to surgery have been developed for unresectable patients. The authors obtain baseline data for the natural history of HCC so that the efficacy of new treatments may be evaluated. A retrospective study of 157 untreated patients with tissue-proven or serodiagnosed HCC was conducted. Clinical characteristics including laboratory investigation, treatment received, survival from the time of diagnosis, and prognostic factors were evaluated. There were 129 men and 28 women (ratio, 4.6:1). Median age was 50.9 years (range, 14.1-85.3 years). The most common symptoms and signs were weight loss (68.2%), abdominal fullness (62.5%), abdominal pain (51.6%), hepatomegaly (73.7%), ascites (45.2%), and jaundice (40.6%). Eighteen percent had extrahepatic metastases of which the lungs were the most common site. Seventy percent were hepatitis B virus related. Overall median survival was 8.7 weeks after the time of diagnosis. Survivals by stages were: TNM II, 16.6 weeks; TNM III, 7.3 weeks; TNM IVA, 9.7 weeks; TNM IVB, 7.6 weeks; Okuda II, 10.7 weeks; and Okuda III, 7.3 weeks. Multivariate analysis revealed serum total bilirubin and albumin as independent prognostic factors of survival. Common causes of death were upper gastrointestinal hemorrhage (34.1%), cancer-related causes (cachexia, HCC rupture, metastatic disease, 31.8%), and hepatic failure (25.0%). Patients with HCC were diagnosed at late stages of their disease and the advanced nature of the tumor precluded effective therapy. Earlier tumor detection at a time when patients are better candidates for treatment may be aided by an active surveillance program of high risk groups.
Subject(s)
Carcinoma, Hepatocellular/physiopathology , Liver Neoplasms/physiopathology , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Hepatocellular/mortality , Disease Progression , Female , Humans , Liver Neoplasms/mortality , Male , Middle Aged , Multivariate Analysis , Prognosis , Retrospective Studies , Survival AnalysisABSTRACT
Although the pathogenesis of hepatocellular carcinoma (HCC) remains poorly understood, hepatitis B virus and dietary aflatoxin exposures are established etiological factors for this disease. We conducted a pilot study of 28 patients with HCC and 110 healthy controls matched for age, sex, and ethnicity to determine whether constitutional genetic instability, based on the quantification of mutagen-induced chromatid breaks in cultured lymphocytes, modifies an individual's risk of HCC development. The mean numbers of bleomycin-induced breaks per cell for cases and controls were 0.92 and 0.55, respectively (P < 0.0001). For benzo(a)pyrene diol epoxide (BPDE) sensitivity, the values were 0.90 for cases and 0.46 for controls (P < 0.0001). Nearly 68% of the cases but only 27% of the controls exhibited bleomycin sensitivity (i.e., had > or = 0.68 breaks per cell). Eighty % of the case group but only 22% of the control group exhibited BPDE sensitivity (i.e., had > or = 0.58 breaks per cell). On multivariate analyses, both bleomycin sensitivity and BPDE sensitivity were associated with significantly elevated risks for HCC, with odds ratios (95% confidence intervals) of 5.63 (2.30, 13.81) and 14.13 (3.52, 56.68), respectively. For individuals who were sensitive to both assays, the risk was 35.88. A synergistic interaction between the bleomycin sensitivity and BPDE sensitivity in HCC risk was suggested. These preliminary findings suggest that differences in host factors related to the predisposition to chromosome breakage, the capacity for DNA repair, or both may be involved in HCC development by influencing the predisposition of hepatitis B virus integration into human DNA or that the carcinogens induced DNA damage susceptibility. A larger study is needed to confirm these intriguing results.
Subject(s)
Carcinoma, Hepatocellular/genetics , Chromatids/drug effects , DNA Damage , Liver Neoplasms/genetics , 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide , Antibiotics, Antineoplastic/toxicity , Bleomycin/toxicity , Case-Control Studies , DNA Repair , Disease Susceptibility , Female , Humans , Lymphocytes/drug effects , Male , Middle Aged , Mutagenicity Tests , Mutagens , Pilot ProjectsABSTRACT
OBJECTIVE: The objective was to determine the role of arcitumomab (CEA-Scan; Immunomedics, Morris Plains, NJ), an anticarcinoembryonic antigen (CEA) Fab' labeled with technetium-99m, in the presurgical evaluation of patients with recurrent or metastatic colorectal carcinoma. SUMMARY BACKGROUND DATA: Surgical resection is the only method known to cure recurrent or metastatic colorectal carcinoma. The location and extent of disease must be determined before surgery. The role of antibody imaging, a new cancer detection modality, in preoperative evaluation for resection of locally recurrent or metastatic colorectal cancer has not been established, either alone or in combination with standard diagnostic modalities. METHODS: In a blinded analysis of 209 patients with known or suspected colorectal cancer, the accuracy of arcitumomab, alone and combined with computed tomography (CT), was compared to that of CT for predicting abdominopelvic tumor resectability by correlating the results with surgical and histopathologic findings. RESULTS: Arcitumomab alone or combined with CT was found to be significantly more accurate for predicting surgical outcome than CT alone. When the results of CT and arcitumomab were concordant for abdominopelvic resectability, nonresectability, or absence of disease, the prediction was accurate in 67%, 100%, and 64%, respectively. Thus, the concordance for nonresectability (100% correct) may obviate the need for other diagnostic modalities or exploratory surgery. When the two tests were discordant, arcitumomab was correct substantially more often than CT. Because the liver is the most common site of distant metastasis in colorectal cancer, a subset of patients with hepatic disease was also analyzed; findings were similar to the overall resectability results. The product's safety profile was excellent: the incidence of induction of an immune response against arcitumomab was <1% and that of potentially adverse events was 1.2%. CONCLUSIONS: The accuracy of arcitumomab for assessing resectability status is greater than that of CT, both in all patients undergoing evaluation for curative abdominopelvic resection of colorectal cancer and in the subset of patients with suspected or proven liver metastases. The additional use of arcitumomab with CT potentially doubles the number of patients who could be saved the cost, morbidity, and mortality of unnecessary abdominopelvic surgery and increases those who are potentially resectable for cure by 40%.
Subject(s)
Antibodies, Monoclonal , Carcinoembryonic Antigen , Colorectal Neoplasms/diagnostic imaging , Organotechnetium Compounds , Technetium , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/immunology , Colorectal Neoplasms/immunology , Colorectal Neoplasms/surgery , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Radionuclide Imaging , Reproducibility of Results , Retrospective Studies , Tomography, X-Ray ComputedABSTRACT
CI-980 (NSC 370147)--a synthetic mitotic inhibitor that binds to tubulin at the colchicine binding site--has significant activity against a broad spectrum of tumor models and greater in vitro cytotoxicity when given over > 24 hours than 4 hours or less. Phase I studies demonstrated central nervous system (CNS) toxicity to be dose-limiting when CI-980 was administered as a 24-hour infusion. When a 72-hour infusion was given, CNS toxicity was reduced and granulocytopenia became the dose-limiting toxicity. In this phase II study, CI-980, 4.5 mg/m2, was administered as a 24-hour continuous intravenous infusion for 3 consecutive days and repeated every 21 days. Fourteen patients who had measurable metastatic colorectal cancer were entered in the trial. Eight patients had received one prior chemotherapy regimen for metastatic disease. Patients were prospectively monitored by neurologic examinations and neuropsychologic assessment of cognitive functioning. No complete or partial responses were observed. Grade 4 granulocytopenia was the dose-limiting toxicity. Reversible declines in recent memory function were noted in all patients. After each course of CI-980, there were also transient non-significant declines in motor coordination, compared with the preinfusion assessment. At the stated dose and schedule, CI-980 lacks activity in metastatic colorectal carcinoma. The agent's toxicity profile (granulocytopenia and CNS effects) was comparable with previously described effects of this agent.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Carbamates/therapeutic use , Colorectal Neoplasms/drug therapy , Pyrazines/therapeutic use , Pyridines/therapeutic use , Adenocarcinoma/secondary , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Carbamates/administration & dosage , Carbamates/adverse effects , Central Nervous System Diseases/chemically induced , Colorectal Neoplasms/pathology , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Prospective Studies , Pyrazines/administration & dosage , Pyrazines/adverse effects , Pyridines/administration & dosage , Pyridines/adverse effectsABSTRACT
PURPOSE: To determine the toxicity, response rate, and survival in patients treated with hepatic arterial infusion (HAI) of fluorouracil (5-FU) plus recombinant human interferon alfa-2b (rIFN-alpha 2b) (Intron-A; Schering-Plough, Inc, Kenilworth, NJ) for colorectal carcinoma (CRC) liver metastases refractory to systemic 5-FU plus leucovorin (LCV). PATIENTS AND METHODS: Forty-eight patients were given a 6-hour HAI of rIFN-alpha 2b 5 MU/m2 followed by an 18-hour HAI of 5-FU, 1,500 mg/m2 daily for 5 days. Twenty-nine patients were treated through percutaneously placed catheters and 19 through implantable infusion pumps (Shiley Infusaid Inc, Noorwood, MA). Treatment cycles were repeated every 28 to 35 days. RESULTS: There were three (6.6%) complete remissions (CRs) and 12 (26.6%) partial remissions (PRs), for a CR plus PR rate of 33.3% among 45 assessable patients (95% confidence interval [CI], 20% to 49%). The median response duration was 7 months, while median survival duration was 15 months. Grade 3 to 4 treatment-related toxic effects included mucositis (40%), neutropenia (42%), and thrombocytopenia (12%). No hepatobiliary toxicity was encountered in any of the patients. Treatment was discontinued because of progressive liver disease in 23 patients and extrahepatic progression in 16, while six patients continue treatment through an infusaid pump. CONCLUSION: HAI of 5-FU plus rIFN-alpha 2b is well tolerated, devoid of hepatobiliary toxicity, and can produce a response rate of 33.3% among patients refractory to bolus intravenous (IV) 5-FU plus LCV. The lack of hepatobiliary toxicity may permit salvage HAI with floxuridine (FUDR) in patients whose liver tumors fail to respond to HAI of 5-FU plus rIFN-alpha 2b. Because diarrhea was not a common side effect of HAI of 5-FU plus rIFN-alpha 2b, it would be of interest to investigate whether alternating HAI of 5-FU and rIFN-alpha 2b with systemic irinotecan (CPT-11) will decrease the incidence of both hepatic and extrahepatic disease progression.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/pathology , Liver Neoplasms/drug therapy , Adult , Aged , Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Drug Administration Schedule , Female , Fluorouracil/administration & dosage , Hepatic Artery , Humans , Infusions, Intra-Arterial , Interferon alpha-2 , Interferon-alpha/administration & dosage , Leucovorin/administration & dosage , Liver Neoplasms/secondary , Male , Middle Aged , Recombinant Proteins , Survival Analysis , Treatment Failure , Treatment OutcomeABSTRACT
BACKGROUND: The goals of this study of a hepatic arterial infusion (HAI) regimen of alternating floxuridine and 5-fluorouracil were to evaluate the treatment-related toxic effects, the antitumor response rate, and patient survival. METHODS: Fifty-seven consecutive patients were treated with implanted HAI pumps and received a regimen of alternating floxuridine (0.1 mg/kg/day continuous HAI for 7 days) followed by a weekly HAI pump bolus of 5-fluorouracil (15 mg/kg for 3 weeks). Any changes in treatment plan because of toxicity, antitumor response, and survival were recorded. RESULTS: Thirty-one (54.4%) patients responded to this HAI regimen; 14 (24.5% )patients had stable disease, and 12 (21.1%) progressed during treatment. Responders or patients with stable disease had a significantly (P < 0.05) improved survival rate (19 months median) compared with patients in whom disease progressed (12 months median). Two (3.5%) patients developed biliary sclerosis and 12 (21.1%) had mild transient liver function abnormalities. The liver alone or in combination with another area was the site of first progression of disease in 40 (70.2%) patients. CONCLUSIONS: This regimen had reversible or no hepatobiliary toxicity in more than 95% of patients. Tumor reduction or stabilization of disease was observed in 79% of the patients, who had a median survival of 19 months. Reduced toxicity and more effective chemotherapeutic regimens may increase the likelihood of survival after HAI chemotherapy for unresectable colorectal liver metastases.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biliary Tract Diseases/chemically induced , Colorectal Neoplasms/pathology , Infusions, Intra-Arterial , Liver Neoplasms/secondary , Adult , Aged , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Female , Floxuridine/administration & dosage , Floxuridine/adverse effects , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Infusion Pumps, Implantable , Liver Neoplasms/drug therapy , Male , Middle Aged , Retrospective StudiesABSTRACT
BACKGROUND: Brain metastasis from colorectal cancer is rare. The present study reports the nature of this disease and analyzes factors correlated with survival in patients harboring such disease. PATIENTS AND METHODS: One hundred patients diagnosed between 1980 and 1994 with metastatic brain tumors secondary to colorectal adenocarcinoma were retrospectively reviewed. Of these patients, 36 underwent surgery, 57 underwent radiotherapy alone, and the remaining seven received steroids. RESULTS: The most common primary sites were the sigmoid colon and rectum (65%). Brain metastases with concomitant liver and/or lung metastases were seen more frequently than brain metastases alone. The median interval between the diagnosis of primary cancer and the diagnosis of brain metastasis was 26 months (95% confidence interval = 22-30). The median survival time after the diagnosis of brain metastasis was 1 month for patients who received only steroids, 3 months for those who received radiotherapy (p = 0.1), and 9 months for those who underwent surgery (p < 0.0001). The extent of noncerebral systemic disease was not correlated with survival (p > 0.05), but early onset of brain metastasis was significantly associated with poor prognosis (p = 0.04). CONCLUSION: Surgical removal of colorectal metastatic brain lesions results in significantly increased survival time, regardless of the status of the noncerebral systemic disease.
Subject(s)
Adenocarcinoma/secondary , Brain Neoplasms/secondary , Colorectal Neoplasms/pathology , Adenocarcinoma/mortality , Adenocarcinoma/therapy , Adult , Aged , Aged, 80 and over , Brain Neoplasms/mortality , Brain Neoplasms/therapy , Chemotherapy, Adjuvant , Colorectal Neoplasms/mortality , Colorectal Neoplasms/therapy , Female , Humans , Incidence , Magnetic Resonance Imaging , Male , Middle Aged , Multivariate Analysis , Proportional Hazards Models , Radiotherapy, Adjuvant , Retrospective Studies , Survival RateABSTRACT
PURPOSE: To assess the performance and the potential clinical impact of a new antibody imaging agent, CEA-Scan (Immunomedics Inc, Morris Plains, NJ), in 210 presurgical patients with advanced recurrent or metastatic colorectal carcinomas. METHODS: CEA-Scan, an anti-carcinoembryonic antigen (CEA) Fab antibody fragment labeled with technetium-99m-pertechnetate (99mTc), was injected intravenously (IV), and external scintigraphy was performed 2 to 5 and 18 to 24 hours later. Imaging with conventional diagnostic modalities (CDM) was also performed, and findings were confirmed by surgery and histology. RESULTS: The sensitivity of CEA-Scan was superior to that of CDM in the extrahepatic abdomen (55% v 32%; P = .007) and pelvis (69% v 48%; P = .005), and CEA-Scan findings complemented those of CDM in the liver. Among 122 patients with known disease, the positive predictive value was significantly higher when both modalities were positive (98%) compared with each alone (68% to 70%), potentially obviating the need for histologic confirmation when both tests are positive. Imaging accuracy also was significantly improved by adding CEA-Scan to CDM. In 88 patients with occult cancer, imaging accuracy was enhanced significantly by CEA-Scan combined with CDM (61% v 33%). Potential clinical benefit from CEA-Scan was demonstrated in 89 of 210 patients. Only two patients developed human antimouse antibodies (HAMA) to CEA-Scan after a single injection, and none of 19 assessable patients after two injections. CONCLUSION: CEA-Scan affords high-quality, same-day imaging, uses an inexpensive and readily available radio-nuclide, adds clinically significant information in assessing extent and location of disease in colorectal cancer patients, and only rarely induces a HAMA response.