Randomized, double-blind, placebo-controlled trial of bovine lactoferrin in patients with chronic hepatitis C

Several studies have suggested that lactoferrin administration may decrease the serum level of hepatitis C virus (HCV) RNA in patients with chronic hepatitis C. The aim of the present study was to confirm the efficacy of orally administered bovine lactoferrin (bLF) in patients with chronic hepatitis C. The patients with chronic hepatitis C randomly received either oral bLF at a dose of 1.8 g daily for 12 weeks, or an oral placebo. The primary endpoint was the virologic response, defined as a 50% or greater decrease in serum HCV RNA level at 12 weeks compared with the baseline. The secondary endpoint was the biochemical response, which was defined as a 50% or greater decrease in the serum alanine aminotransferase (ALT) level at 12 weeks compared with the baseline. One hundred and ninety-eight of 199 patients were evaluable for efficacy and safety. bLF treatment was well tolerated and no serious toxicities were observed. A virologic response was achieved in 14 of 97 patients (14.4%) in the bLF group, and 19 of 101 (18.8%) in the placebo group. There was no significant difference in virologic response rates between the two groups (-4.4%, 95% confidence interval -14.8, 6.1). In addition, bLF intake did not have any favorable effect on the serum ALT level. The virologic responses were not different between two groups in any subgroup analysis. In conclusion, orally administered bLF does not demonstrate any significant efficacy in patients with chronic hepatitis C.     

Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer.

PURPOSE: The efficacy of adjuvant chemotherapy in gastric cancer is controversial. We conducted a phase III, randomized, multicentric clinical trial with the goal of assessing the efficacy of the combination of mitomycin plus tegafur in prolonging the disease-free survival and overall survival of patients with resected stage III gastric cancer. PATIENTS AND METHODS: Patients with resected stage III gastric adenocarcinoma were randomly assigned, using sealed envelopes, to receive either chemotherapy or no further treatment. Chemotherapy was started within 28 days after surgery according to the following schedule: mitomycin 20 mg/m(2) intravenously (bolus) at day 1 of chemotherapy; 30 days later, oral tegafur at 400 mg bid daily for 3 months. Disease-free survival and overall survival were estimated using the Kaplan-Meier analysis and the Cox proportional hazards model. RESULTS: Between January 1988 and September 1994, 148 patients from 10 hospitals in Catalonia, Spain, were included in the study. The median follow-up period was 37 months. The tolerability of the treatment was excellent. The overall survival and disease-free survival were higher in the group of patients treated with chemotherapy (P =.04 for survival and P =.01 for disease-free survival in the log-rank test). The overall 5-year survival rate and the 5-year disease-free survival rate were, respectively, 56% and 51% in the treatment group and 36% and 31% in the control group. CONCLUSION: Our positive results are consistent with the results of recent studies; which conclude that there is a potential benefit from adjuvant chemotherapy in resected gastric cancer.     

Randomized, double-blind, placebo-controlled trial of marimastat in glioblastoma multiforme patients following surgery and irradiation

SummaryPurpose Because raised matrix metalloprotease (MMP) levels are associated with glioma invasion and angiogenesis, we tested the efficacy of marimastat (MT) an orally active drug that can reduce MMP levels, in patients with gliomas.Patients and Methods A total of 162 patients with intracranial glioblastoma multiforme or gliosarcomas who had undergone surgery and radiotherapy participated in this multicenter, double-blind, placebo-controlled, parallel group study conducted at 20 institutions. Seventy-nine patients (57 male, 22 female, median age 58 years) were randomized to receive placebo (PB), and 83 patients (51 male, 32 female, median age 57 years) were randomized to receive MT, 10 mg orally twice daily, until tumor progression.Results This intention-to-treat efficacy analysis showed no statistically significant difference between MT and PB groups with respect to survival (P=0.38, log rank test). The median survival time from protocol initiation was 37.9 weeks for the PB group and 42.9 weeks for the MT group, with a hazard ratio of 1.16 (95% CI 0.83 to 1.60). There were no statistically significant differences in quality of life between the PB and MT groups, as assessed by the FACT-BR questionnaire. Musculoskeletal toxicities led to dose modification or withdrawal in 20% of MT-treated and 1.2% of PB-treated patients.Conclusion MT does not improve survival in patients with glioblastoma or gliosarcoma following surgery and radiotherapy. Therefore, single-agent MT appears unwarranted; however, MT in combination with cytotoxic chemotherapy may be warranted, as suggested by observations in our study and other studies. ^★This work was presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, on May 13, 2001, and supported by British Biotech Pharmaceuticals, Watlington Road, Oxford, OX4 6LY, UK. No author currently has a financial interest in Marimastat. Mark Baillet is currently with Origin Pharmaceutical Services Ltd.*Participating institutions are listed in Table 1. Clinician authorship required ≥10 patient accrual from participating institution.     

Randomized double-blind trial of combined modality treatment with or without amifostine in unresectable stage III non-small-cell lung cancer.

PURPOSE: Greater toxicities have been recognized to be a consequence of combined chemotherapy and radiotherapy in the treatment of locally advanced non-small-cell lung cancer (NSCLC). This study was designed to determine if the use of amifostine could reduce treatment-related toxicities associated with the use of paclitaxel plus carboplatin and thoracic radiotherapy. PATIENTS AND METHODS: Sixty patients with unresectable stage III NSCLC were treated with two cycles of paclitaxel 175 mg/m2 and carboplatin (area under the time-concentration curve = 6), followed by thoracic radiotherapy (64 Gy) with concurrent weekly paclitaxel 60 mg/m2. Patients were randomly assigned to receive 740 mg/m2 of amifostine (arm A) or placebo (arm B) before each dose of paclitaxel and carboplatin. Treatment-related toxicities were evaluated at each visit and nerve conduction tests were performed before and after treatment for the objective assessment of neurotoxicity. RESULTS: There was no significant difference between arms A and B in grade 3 to 4 neutropenia. In all 72 neurophysiological parameters measured, there was no significant difference between the two treatment arms, although there was a trend toward fewer patients showing deterioration in arm A for six of the parameters. Grade 2 to 3 esophagitis occurred in 43% of patients in arm A and in 70% of patients in arm B. The difference of -27% (95% confidence limit = -50%, 0.4%) was not statistically significant. Response rates and survival were also not significantly different between the two arms. CONCLUSION: Pretreatment with amifostine showed a trend toward reducing the severity of esophagitis associated with concurrent chemoradiotherapy, but it did not reach statistical significance. There was no significant protective effect on hematologic or neurologic toxicities induced by paclitaxel and carboplatin.     

N2肺癌手术后肿瘤复发模式的分析

目的 :探讨纵隔淋巴结转移 (N2 )的非小细胞肺癌 (non smallcellcancer ,NSCLC)患者根治术后肿瘤复发的模式 ,为手术后采取有针对性的辅助治疗措施提供依据。方法 :回顾 96例根治性切除术后病理诊断为N2 肺癌患者的临床资料。术后 2年内每 6个月对患者进行随访复查 1次 ,监测肿瘤复发情况。计算复发率 ,应用 χ2 检验比较手术后放疗及化疗对肿瘤复发模式的影响。结果 :术后 2年内肿瘤复发率为 3 7 5 % ( 3 6/ 96) ,复发模式以转移性复发为主 ,占 77 78%( 2 8/ 3 6) ,多数为脑和肺转移 ( 64 2 9% ,18/2 8)。手术后放疗者的局部复发率为5 17% ( 3 / 5 8) ,而未施行放疗者的局部复发率为 2 3 68% ( 9/ 3 8) ,两者差异有统计学意义 ,P <0 0 5 ,OR =5 69;手术后化疗者与未化疗者相比 ,局部复发和转移性复发发生率差异无统计学意义 ,P >0 0 5。结论 :转移性复发是N2 非小细胞肺癌根治术后肿瘤复发的主要模式 ,手术后放疗可以减少N2 肺癌根治术后肿瘤的局部复发。     

Factors associated with recurrence in patients with curatively resected stage I-II lung cancer

Background

Patients with stage I-II non-small cell lung cancer (NSCLC) show variability in recurrence after curative resection. Several factors have been proposed as prognostic of recurrence in previous studies. However, because of the heterogeneity of the populations studied, these reports did not yield consistent results. The aim of our study was to identify risk factors for recurrence in patients with curatively resected stage I-II NSCLC.

Methods

We reviewed the medical records of pathological stage I-II NSCLC patients after curative surgery performed in a tertiary referral center (Seoul National University Hospital) from January 2002 to December 2004. Demographic factors, radiological, histopathological, and laboratory findings, and surgery-related factors were analyzed. Patients with invasive cancer other than lung cancer that was present 5 years prior to surgery were excluded. The Cox proportional hazard regression model was used for multivariate analyses.

Results

Three hundred and ten patients were included. Among them, local recurrence occurred in 27 patients (8.7%), whereas distant recurrence occurred in 79 patients (25.5%). Adenocarcinoma histology (OR, 2.74; 95% CI, 1.14-6.58; P = 0.024), carcinoembryonic antigen (CEA) level > 2.3 ng/mL (OR, 2.26; 95% CI, 1.02-5.00; P = 0.045), and standard uptake values (SUV) of tumor in positron emission tomography (PET) > 4.5 (OR, 5.45; 95% CI, 1.82-16.31; P = 0.002) were independent predictors of recurrence in addition to TNM stage. We also constructed a recurrence prediction model based on these findings, which yielded better diagnostic performance than the TNM staging system.

Conclusion

Adenocarcinoma histology, CEA level, and SUV of PET could be considered as prognostic factors for recurrence in patients with curatively resected stage I-II NSCLC.     

Prognostic significance of K-ras codon 12 mutations in patients with resected stage I and II non-small-cell lung cancer.

PURPOSE: The aim of this study was to investigate the prognostic importance of codon 12 K-ras mutations in patients with early-stage non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We identified 260 patients with surgically resected stage I (n = 193) and stage II (n = 67) NSCLC with at least a 5-year follow-up. We performed polymerase chain reaction analysis of DNA obtained from paraffin-embedded NSCLC tissue, using mutation-specific probes for codon 12 K-ras. RESULTS: K-ras mutations were detected in 35 of 213 assessable specimens (16.4%). K-ras mutations were detected in 27 of 93 adenocarcinomas (29.0%), one of 61 squamous cell carcinomas (1.6%), five of 39 large-cell carcinomas (12.8%), and two of 20 adenosquamous carcinomas (10%) (P = .001). G to T transversions accounted for 71% of the mutations. There was no statistically significant difference in overall survival for all patients with K-ras mutations (median survival, 39 months) compared with patients without K-ras mutations (median survival, 53 months; P = .33). There was no statistically significant difference in overall or disease-free survival for subgroups with stage I disease, adenocarcinoma, or non-squamous cell carcinoma or for specific amino acid substitutions. The median survival time for stage II patients with K-ras mutations was 13 months, compared with 38 months for patients without K-ras mutations (P = .03). CONCLUSION: Codon 12 K-ras mutations were more common in adenocarcinomas than in squamous cell carcinomas. For the subgroup with stage II NSCLC, there was a statistically significant adverse effect on survival for the presence of K-ras mutations. However, when the entire group was considered, the presence of K-ras mutations was not of prognostic significance in this cohort of patients with resected early-stage NSCLC.     

DETECTION OF OCCULT TUMOR CELLS IN RESECTED LYMPH NODES OF PATIENTS WITH STAGE I CARCINOMA AND ITS CLINICOPATHOLOGICAL SIGNIFICANCE

ＤＥＴＥＣＴＩＯＮＯＦＯＣＣＵＬＴＴＵＭＯＲＣＥＬＬＳＩＮＲＥＳＥＣＴＥＤＬＹＭＰＨＮＯＤＥＳＯＦＰＡＴＩＥＮＴＳＷＩＴＨＳＴＡＧＥＩＣＡＲＣＩＮＯＭＡＡＮＤＩＴＳＣＬＩＮＩＣＯＰＡＴＨＯＬＯＧＩＣＡＬＳＩＧＮＩＦＩＣＡＮＣＥＣｈｅｎＺｈａｏｌｕｎ...     

Ⅰ期癌症患者切除淋巴结内隐匿性微小转移癌灶的检查及其临床病理…

检查癌症患者切除淋巴结内有无微小癌转移,具有临床,病理重要性。３５０例Ⅰ期癌症患者包括非小细胞肺癌９４例,乳腺癌１１２例,食管癌１１５例及外阴癌２９例病理报告无癌围歼的淋巴结３７１５枚。应用单克隆抗细胞角蛋白,抗上皮细胞膜及多克隆角蛋白体进行免疫组化染色重新检查。     

Expression of dihydrodiol dehydrogenase in the resected stage I non-small cell lung cancer

Recently, by using differential display on specimens of non-small cell lung cancer (NSCLC), we detected overexpression of dihydrodiol dehydrogenase (DDH) that was rarely expressed in the corresponding normal lung tissue. DDH overexpression was correlated with poor prognosis of patients with advanced NSCLC. Because DDH could metabolize polycyclic aromatic hydrocarbons (PAH) in the liver, DDH overexpression in NSCLC would suggest an association with carcinogenesis and disease progression. In this study, we investigated DDH expression in 103 patients with resected stage I NSCLC. Expression of DDH was detected by using immunohistochemistry. Relation between DDH expression and clinicopathological parameter (age, gender, smoking habit, tumor status, histological type, cell differentiation, local recurrence, distant metastasis or survival) was analyzed by statistical analysis. DDH overexpression was detected in 39 (37.9%) of 103 pathological sections. Frequency of DDH overexpression was significantly higher in male patients (p=0.043) and patients with squamous cell carcinoma (p<0.005). Among 103 patients, 14 patients had local recurrence and 28 patients had distant metastasis during follow-up examination. The 5-year survival rate of these patients was poorer than those who did not have local recurrence or distant metastasis (both were p<0.005, respectively). Although patients with low DDH expression had more favorable outcome than those with DDH overexpression, in terms of survival rate no statistical significance was detected (p=0.889). The results suggest that DDH expression may serve as an early but not prognostic biomarker for patients with resectable stage I NSCLC.     

Combination therapy with bestatin in inoperable lung cancer. A randomized trial

A randomized trial of combination therapy with bestatin (30 mg daily, every day) was performed in 238 patients with inoperable primary lung cancer from August, 1981 through April, 1984. Of the 238 patients, 227 were evaluable: 113 treated by bestatin combination therapy and 114 controls. There was no statistically significant difference in response rate or survival between the 2 groups. In squamous cell cancer response was observed in 34.5% of the bestatin group and 17.9% of the control group. The analysis, including Cox's proportional hazard model, revealed that the survival tended to be longer in the bestatin group (median survival 40 weeks) than in the control group (median survival 24 weeks; p = 0.051). This suggests that addition of bestatin might be beneficial in squamous cell cancer of the lung but further, more rigidly controlled, clinical trials are necessary before more definitive conclusions can be drawn.     

Considerations in designing and analyzing surgical adjuvant study in resected stage I and II carcinoma of the lung.

Single, large doses of adriamycin, cyclophosphamide and 5-fluorouracil (5-FU) have been compared to the same amount of drug given in divided doses daily over a 3 or 5 day period in a solid tumor model which metastasizes to the regional lymph nodes and lungs. No significant increase in life expectancy occurred following adriamycin or cyclophosphamide. However, a significant reduction in life expectancy occurred after 5 fractionated doses of 5-FU but not after the large single dose. The increase in mortality following fractionated doses of 5-FU is attributed to the prolongation of the onset of recovery of bone marrow. Tumor volume reduction following a single dose of each agent was equal to or greater than the fractionated doses. The results of these studies on this chemotherapeutically resistant solid tumor indicate that small daily fractionated doses of adriamycin, cyclophosphamide or 5-FU result in increased morbidity and mortality without therapeutic benefit in tumor control. The time sequence of recovery of the limiting organ of the host (i.e., bone marrow) is similar to the time sequence of recovery of the tumor. Large intermittent single doses of chemotherapeutic agents given following recovery of the host from a previous treatment would be expected to be less toxic to the host and equally effective in control of tumor growth. None of the 3 chemotherapeutic agents was successful in tumor eradication. Previous studies of this series have shown that the utilization of sequential chemotherapy combined with radiotherapy can be successfully used for eradication of another solid tumor which did not metastasize. A similar therapeutic strategy using sequential combined modality therapy should also be effective in the control of the primary H-4-II-E tumor as well as its metastatic dissemination. Information gained from these experimental studies should eventually provide information which should be helpful in the clinical management of chemotherapeutically resistant solid tumors in man.     

Adjuvant immunotherapy with nonviable Mycobacterium smegmatis in resected primary lung carcinoma. A randomized clinical trial of 219 patients

Two hundred and nineteen patients with resected lung carcinoma were randomized 3 weeks after surgery between two treatment arms: a control group (110 cases) and an immunotherapy group (109 cases). The immunostimulant was a nonviable saprophytic mycobacterium, M. smegmatis, given monthly by subcutaneous injection in four sites. The two groups were equivalent in terms of prognostic factors, including a nonsignificant difference favoring the control group based on the N (node) classification. This interim analysis was carried out on June 1, 1981. Treatment comparison by the log-rank test did not show any significant differences between these two groups in regards to disease-free interval and overall survival. There was no significant difference between the two groups after stratification of the comparison according to the N classification or adjustment with a subset of eight prognostic parameters through the Cox model. The initially expected difference (20% 1-year survival) will probably not be achieved, given these interim results, but patients will continue to be treated and followed-up according to the protocol as to allow further evaluation of this nonspecific immunotherapy.     

Randomized, double-blind, placebo-controlled phase II trial of maintenance sunitinib versus placebo after chemotherapy for patients with advanced urothelial carcinoma: scientific rationale and study design

Systemic chemotherapy is the primary treatment modality for patients with advanced urothelial cancer. However, despite a high initial response rate, durable responses are rare. Angiogenesis has been shown to be important in the development and progression of urothelial cancer. Sunitinib, an oral, multi-targeted, small-molecule inhibitor of multiple tyrosine kinases, is known to inhibit angiogenesis and therefore might decrease progression of urothelial cancer. This phase II trial was designed to investigate the role of sunitinib as maintenance therapy in patients with advanced urothelial cancer. The specific hypothesis of this trial is that sunitinib will decrease progression rates in patients with advanced urothelial cancer who have obtained stable disease or better after standard chemotherapy.     

Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer.

PURPOSE: The development of bone metastases depends on tumor-induced osteoclastic resorption of bone, which may be inhibited by the antiosteolytic bisphosphonate clodronate. Given to patients with primary breast cancer, clodronate might reduce the subsequent incidence of bone metastases. PATIENTS AND METHODS: This double-blind, multicenter trial accrued 1,069 assessable patients with operable breast cancer between 1989 and 1995. All patients received surgery, radiotherapy, chemotherapy, and tamoxifen as required. Patients were randomized to receive oral clodronate 1,600 mg/d or a placebo for 2 years starting within 6 months of primary treatment. The primary end point was relapse in bone, analyzed on an intent-to-treat basis, during the medication period and during the total follow-up period (median follow-up, 2,007 days). Secondary end points were relapse in other sites, mortality, and toxicity. RESULTS: During the total follow-up period, there was a nonsignificant reduction in occurrence of bone metastases (clodronate, n = 63; placebo, n = 80; hazards ratio [HR], 0.77; 95% confidence interval [CI], 0.56 to 1.08; P =.127). During the medication period there was a significant reduction in the occurrence of bone metastases (clodronate, n = 12; placebo, n = 28; HR, 0.44; 95% CI, 0.22 to 0.86; P =.016). The occurrence of nonosseous metastases was similar (clodronate, n = 112; placebo, n = 128; P =.257), but there was a significant reduction in mortality (clodronate, n = 98; placebo, n = 129; P =.047) during the total follow-up period. CONCLUSION: Clodronate, given to patients with primary operable breast cancer, may reduce the occurrence of bone metastases, although this reduction was only significant during this medication period. There was a significant reduction in mortality.