JNCI Journal of the National Cancer Institute

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Online ISSN: 1460-2105
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Article
Three hundred sixty-eight male rats were fed 0.025 percent N-2-fluorenyldiacetamide in a semisynthetic diet for varying periods until there were hyperplastic lesions of the liver. The carcinogenic diet was then discontinued so that the evolution of such lesions could be studied. Cirrhosis developed simultaneously with hyperplasia of the parenchymal cells as long as the carcinogen was fed. After feeding of the carcinogen was discontinued, the cirrhosis decreased in severity and regressed whereas the hyperplastic hepatic cells continued to grow. The change of the parenchymal cells from hyperplastic to neoplastic took place gradually over a long period. Before becoming well-developed carcinomas, areas of hyperplasia passed through the stages of nodules of hyperplasia, nodules with atypical cells, and small hepatocellular carcinomas. Most carcinomas were well differentiated histologically, with the remaining highly or poorly differentiated. Only a few of the earliest hyperplastic lesions progressed to carcinomas. Some of them disappeared. Most underwent degenerative cytoplasmic changes. On the other hand, the nodules of hyperplasia, present when the carcinogen was discontinued, usually developed into hepatocellular carcinomas or remained as nodules. The rate at which the hyperplastic lesions grew depended on the duration of carcinogen administration; the lesions developed most typically after 16 weeks on carcinogenic diet. With shorter or longer periods of feeding, it was more difficult to distinguish histologically between hyperplastic nodules and well-differentiated hepatocellular carcinomas because the cords were so well formed in the carcinomas. The biological behavior of the carcinomas depended on the morphologic pattern, size, and duration of carcinogen feeding.
 
Article
The dependence of hepatic carcinogenesis on the testes was studied in inbred A X C male rats ingesting 0.025% N 2 fluorenyldiacetamide (F diAA). The experimental groups consisted of intact rats with normal testes, rats with 1 normal testis, rats with 1 atrophic testis related to a congenital defect, and rats without testes. The incidence of carcinomas and the number of rats with large carcinomas, multiple carcinomas, and metastases were highest in intact rats. The incidence and size not only decreased in animals with 1 or both testes removed, but also the decrease was directly related to the bulk and weight of the testis in rats in the other groups. The incidence was lowest in rats with both testes removed. This experiment confirmed the importance of the testes in F diAA hepatic carcinogenesis, and also demonstrated the extreme sensitivity of the liver to the level of male sex hormone.
 
Article
Background: The National Surgical Adjuvant Breast and Bowel Project C-01 trial reported in 1988 that, for patients with adenocarcinoma of the colon, compared with surgery alone, 1) postoperative chemotherapy with 1-(2-chloroethyl)-3-(4-trans-methylcyclohexyl)-1-nitrosourea (i.e., MeCCNU or semustine), vincristine, and 5-fluorouracil was associated with better 5-year disease-free and overall survival and 2) postoperative immunotherapy with bacillus Calmette-Guerin was associated with better 5-year overall, but not disease-free, survival. We now provide a 10-year update of this trial. Methods: Between November 11, 1977, and February 28, 1983, 1166 patients with resected Dukes' stage B and C adenocarcinoma of the colon were stratified by Dukes' stage, sex, and age (<65 years or ≥65 years) and then randomly assigned to receive no further treatment (surgery alone; 394 patients), adjuvant chemotherapy (379 patients), or adjuvant immunotherapy (393 patients). Those eligible for follow-up included 375 (95.2%) patients in the surgery-alone group, 349 (92.1%) patients in the adjuvant-chemotherapy group, and 372 (94.7%) patients in the adjuvant-immunotherapy group. All statistical tests were two-sided. Results: No difference was observed between patients in the chemotherapy group and those in the surgery-alone group in 10-year disease-free survival (hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 0.94 to 1.39; P =.17) or overall survival (HR = 1.12, 95% CI = 0.91 to 1.38; P =.27). Immunotherapy did not appear to prevent tumor relapse after 10 years (for surgery alone versus immunotherapy, relative risk [RR] = 0.99, 95% CI = 0.78 to 1.25; P =.93) but had a beneficial effect on 10-year overall survival (for surgery alone versus immunotherapy, RR = 1.27, 95% CI = 1.03 to 1.56; P =.02) that apparently results from a reduction in deaths associated with comorbidities in the immunotherapy group. Conclusion: The disease-free and overall survival benefit associated with chemotherapy in this patient population is of limited duration, disappearing after 10 years.
 
Article
The National Surgical Adjuvant Breast and Bowel Project C-01 trial reported in 1988 that, for patients with adenocarcinoma of the colon, compared with surgery alone, 1) postoperative chemotherapy with 1-(2-chloroethyl)-3-(4-trans-methylcyclohexyl)-1-nitrosourea (i.e., MeCCNU or semustine), vincristine, and 5-fluorouracil was associated with better 5-year disease-free and overall survival and 2) postoperative immunotherapy with bacillus Calmette-Guérin was associated with better 5-year overall, but not disease-free, survival. We now provide a 10-year update of this trial. Between November 11, 1977, and February 28, 1983, 1166 patients with resected Dukes' stage B and C adenocarcinoma of the colon were stratified by Dukes' stage, sex, and age (<65 years or > or =65 years) and then randomly assigned to receive no further treatment (surgery alone; 394 patients), adjuvant chemotherapy (379 patients), or adjuvant immunotherapy (393 patients). Those eligible for follow-up included 375 (95.2%) patients in the surgery-alone group, 349 (92.1%) patients in the adjuvant-chemotherapy group, and 372 (94.7%) patients in the adjuvant-immunotherapy group. All statistical tests were two-sided. No difference was observed between patients in the chemotherapy group and those in the surgery-alone group in 10-year disease-free survival (hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 0.94 to 1.39;P =.17) or overall survival (HR = 1.12, 95% CI = 0.91 to 1.38; P=.27). Immunotherapy did not appear to prevent tumor relapse after 10 years (for surgery alone versus immunotherapy, relative risk [RR] = 0.99, 95% CI = 0.78 to 1.25; P =.93) but had a beneficial effect on 10-year overall survival (for surgery alone versus immunotherapy, RR = 1.27, 95% CI = 1.03 to 1.56; P =.02) that apparently results from a reduction in deaths associated with comorbidities in the immunotherapy group. The disease-free and overall survival benefit associated with chemotherapy in this patient population is of limited duration, disappearing after 10 years.
 
Article
Arrest of the cell cycle in G2 phase following DNA damage helps protect cell viability by allowing time for DNA repair before entry into mitosis (M phase). Abrogation of G2 arrest sensitizes cells to the effects of DNA-damaging agents. UCN-01 (7-hydroxystaurosporine), a protein kinase C inhibitor that may block G2 checkpoint regulation, has been reported to enhance the cytotoxicity of mitomycin C, a known DNA-damaging agent. We studied the effect of UCN-01 on G2 checkpoint control in human lymphoma CA46 cells, whose sensitivity to various DNA-damaging agents and G2 response to DNA damage have been characterized. We also assessed the ability of UCN-01 to enhance the cytotoxicity of gamma irradiation in CA46 cells and human colon carcinoma HT-29 cells, both of which are mutant for p53 function. The influence of p53 function on UCN-01-mediated abrogation of the G2 checkpoint and enhancement of DNA-damaging agent cytotoxicity was studied in transfected human breast carcinoma MCF-7 cells that either expressed or did not express the human papillomavirus type-16 E6 protein. MCF-7 cells have normal p53 function, and the E6 protein binds p53 protein and promotes its destruction. The effect of UCN-01 on cell cycle arrest induced by gamma irradiation was studied in CA46 cells and in transfected MCF-7 cells by use of flow cytometry. A histone H1 phosphorylation assay was employed to measure cyclin B1/Cdc2 kinase activity in extracts derived from irradiated and nonirradiated CA46 cells that had been either treated or not treated with UCN-01; the phosphorylation status of Cdc2 kinase protein in the same extracts was determined by use of western blotting. The effect of UCN-01 on the cytotoxicity of gamma irradiation in CA46 and HT-29 cells was determined by use of MTT (thiazolyl blue) and clonogenic (colony-forming) assays, respectively; a clonogenic assay was also used to measure the effect of UCN-01 on the cytotoxicity of cisplatin in transfected and nontransfected MCF-7 cells. G2 arrest induced in CA46 cells by gamma irradiation was minibited by treatment with UCN-01 in a dose-dependent manner; arrest in G2 was completely abrogated by exposure to 300 nM UCN-01. Biochemical markers indicative of the G2/M transition, including the activation of cyclin B1/Cdc2 kinase and the suppression of Cdc2 threonine-14 and tyrosine-15 phosphorylation, were detected in irradiated cells treated with UCN-01. UCN-01 enhanced the cytotoxicity of gamma irradiation in CA46 and HT-29 cells. MCF-7 cells with functional p53 protein were more resistant to G2 checkpoint abrogation by UCN-01 than MCF-7 cells with disrupted p53 function. UCN-01 markedly enhanced the cell-killing activity of cisplatin in MCF-7 cells defective for p53 function. UCN-01 is a potent abrogator of G2 checkpoint control in cancer cells with disrupted p53 function. UCN-01 might be capable of enhancing the effectiveness of DNA-damaging agents in the treatment of tumors with cells lacking normal p53 function.
 
Article
The oncogenic activity of 2,6 dimethyl m dioxan 4 ol acetate (also known as 6 acetoxy 2,4 dimethyl m dioxane and under the brand names Dimethoxane and Dioxin) was investigated. This broad spectrum antimicrobial agent of low toxicity, widely used for the control of microorganisms in aqueous systems, was selected because of its structural relationship to dioxane, a moderately oncogenic solvent. The m dioxane derivative, administered orally, produced hepatomas in 8 of 25 rats and tumors of kidney, skin, subcutaneous and lymphoid tissues, and leukemia in 5 other rats.
 
Clusterin mRNA expression in prostate cancer cells of men with prostate cancer who were treated with OGX-011 prior to prostatectomy and in historical control subjects. In both panels, the boxes represent the interquartile range, lines extending from the boxes represent the closer of either 1.5 times the interquartile range or the most extreme observation, the line across the box indicates the median, and circles represent outliers (values between 1.5 and 3 box lengths from the upper or lower edge of the box). NT = no prior treatment; <2M NHT = less than 2 months of neoadjuvant hormone therapy historical controls. A ) Clusterin mRNA expression as assayed by quantitative real-time polymerase chain reaction (QRT-PCR) from laser-captured microdissected prostate cancer cells. Levels in untreated historical control samples were set at 100%, and levels in other samples are shown relative to the control. Total RNA was extracted from approximately 100 000 laser-captured cells, and RNA was reverse transcribed, with the resulting fi rst-strand cDNA used as the template for QRT-PCR. Two replicates per sample were performed and both shown. B ) Clusterin mRNA expression by in situ hybridization. Sections were prepared and analyzed as described in Materials and Methods. Three slides per patient and 10 fi elds per slide were evaluated for staining intensity (0 to 3, representing negative to strong staining, respectively) and graded independently by two pathologists (L.F. and E.C.J). The overall score was determined as follows: overall score = [(% cells with visual score 1) × 1] + [(% cells with visual score 2) × 2] + [(% cells with visual score 3) × 3]. 
Box plot of clusterin expression in normal lymph nodes of men with prostate cancer who were treated with OGX-011 prior to prostatectomy and in untreated historical control subjects. Clusterin expression was assayed by A ) immunohistochemistry and B ) quantitative real-time polymerase chain reaction. The boxes represent the interquartile ranges, lines extending from the boxes represent the closer of either 1.5 times the interquartile range or the most extreme observation, the lines across the boxes indicate the median, circles indicate outliers, and stars show extreme outliers (values more than three box lengths from the upper or lower edge of the box). NT = no prior treatment historical control. Values from 40-and 80-mg treatment groups were combined.
Box plot of apoptotic indeces in prostatectomy specimens. Apoptosis was evaluated with the terminal deoxynucleotidyltransferase-mediated dUTPbiotin nick end labeling assay. The percentage of apoptotic cells and bodies per 10 high-power fi elds (Apoptotic Index) were independently counted by the two pathologists (L.F. and E.C.J.). The boxes represent the interquartile range, lines extending from the box represent the closer of either 1.5 times the interquartile range or the most extreme observation, lines across the boxes indicate the median, and circles indicate outliers. NT = no prior treatment; <2M NHT = less than 2 months of neoadjuvant hormone therapy. Values from 40-and 80-mg treatment groups were combined.
Article
Clusterin is a cytoprotective chaperone protein that promotes cell survival and confers broad-spectrum treatment resistance. OGX-011 is a 2'-methoxyethyl modified phosphorothioate antisense oligonucleotide that is complementary to clusterin mRNA and has been reported to inhibit clusterin expression and enhance drug efficacy in xenograft models. The primary objective of this clinical study was to determine a biologically effective dose of OGX-011 that would inhibit clusterin expression in human cancer. Subjects (n = 25) with localized prostate cancer with high-risk features who were candidates for prostatectomy were treated with OGX-011 by 2-hour intravenous infusion on days 1, 3, and 5 and then weekly from days 8-29 combined with androgen blockade starting on day 1; prostatectomy was performed on days 30-36. Six different doses were tested, from 40 to 640 mg. OGX-011 plasma and prostate tissue concentrations were measured by an enzyme-linked immunosorbent assay method, and the pharmacokinetics of OGX-011 were determined from these data. Prostate cancer tissue, lymph nodes, and serial samples of peripheral blood mononuclear cells were assessed for clusterin expression using quantitative real-time polymerase chain reaction and immunohistochemistry. All statistical tests were two-sided. Only grade 1 and 2 toxicities were observed. The plasma half-life of OGX-011 was approximately 2-3 hours, and the area under the concentration versus time curve and CMAX (peak plasma concentration) increased proportionally with dose (Ptrend < .001). OGX-011 in prostate tissue increased with dose (Ptrend < .001). Dose-dependent decreases in prostate cancer and lymph node clusterin expression were observed by polymerase chain reaction of greater than 90% (Ptrend = .008 and Ptrend < .001, respectively) and by immunohistochemistry (Ptrend < .001 and Ptrend = .01, respectively). OGX-011 is well tolerated and reduces clusterin expression in primary prostate tumors. The optimal biologic dose for OGX-011 at the schedule used is 640 mg.
 
Article
Data are presented from 1,166 patients with Dukes B and C carcinoma of the colon who were entered into the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol C-01 between November 1977 and February 1983. Patients were randomized to one of three therapeutic categories: 1) no further treatment following curative resection (394 patients); 2) postoperative chemotherapy consisting of 5-fluorouracil, semustine, and vincristine (379 patients); or 3) postoperative BCG (393 patients). The average time on study was 77.3 months. A comparison between patients receiving postoperative adjuvant chemotherapy and those treated with surgery alone indicated that there was an overall improvement in disease-free survival (P = .02) and survival (P = .05) in favor of the chemotherapy-treated group. At 5 years of follow-up, patients treated with surgery alone were at 1.29 times the risk of developing a treatment failure and at 1.31 times the likelihood of dying as were similar patients treated with combination adjuvant chemotherapy. Comparison of the BCG-treated group with the group treated with surgery alone indicated that there was no statistically significant difference in disease-free survival (P = .09). There was, however, a survival advantage in favor of the BCG-treated group (P = .03). At 5 years of follow-up, patients randomized to the surgery-alone arm were at 1.28 times the risk of dying as were similar patients treated with BCG. Further investigation disclosed that this survival advantage in favor of BCG was a result of a diminution in deaths that were non-cancer related. When analyses were conducted on which events not related to cancer recurrence were eliminated, the survival difference between the BCG and control groups became nonsignificant (P = .40); the cumulative odds at 5 years decreased from 1.28 to 1.10. The findings from this study are the first from a randomized prospective clinical trial to demonstrate that a significant disease-free survival and survival benefit can be achieved with postoperative adjuvant chemotherapy in patients with Dukes B and C carcinoma of the colon who have undergone curative resection.
 
Article
Information is presented from 555 patients with Dukes B and C rectal cancers treated by curative resection who were entered into the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol R-01 between November 1977 and October 1986. Their average time on study was 64.1 months. The patients were randomized to receive no further treatment (184 patients), postoperative adjuvant chemotherapy with 5-fluorouracil, semustine, and vincristine (MOF) (187 patients), or postoperative radiation therapy (184 patients). The chemotherapy group, when compared with the group treated by surgery alone, demonstrated an overall improvement in disease-free survival (P = .006) and in survival (P = .05). Employing the proportional hazards model, a global test was used to determine the presence of treatment interactions. Investigation of stratification variables employed in this study indicated that sex, and to a lesser extent age and Dukes stage, made individual contributions to the disease-free survival and the survival benefit from chemotherapy. When evaluated according to sex, the benefit for chemotherapy at 5 years, both in disease-free survival (29% vs. 47%; P less than .001; relative odds, 2.00) and in survival (37% vs. 60%; P = .001; relative odds, 1.93), was restricted to males. When males were tested for age trend with the use of a logistic regression analysis, chemotherapy was found to be more advantageous in younger patients. When the group receiving post-operative radiation (4,600-4,700 rad in 26-27 fractions; 5,100-5,300 rad maximum at the perineum) was compared to the group treated only by surgery, there was an overall reduction in local-regional recurrence from 25% to 16% (P = .06). No significant benefit in overall disease-free survival (P = .4) or survival (P = .7) from the use of radiation has been demonstrated. The global test for interaction to identify heterogeneity of response to radiation within subsets of patients was not significant. In conclusion, this investigation has demonstrated a benefit from adjuvant chemotherapy (MOF) for the management of rectal cancer. The observed advantage was restricted to males. Postoperative radiation therapy reduced the incidence of local-regional recurrence, but it failed to affect overall disease-free survival and survival.
 
Article
Docetaxel is more effective than doxorubicin for patients with advanced breast cancer. The Breast International Group 02-98 randomized trial tested the effect of incorporating docetaxel into anthracycline-based adjuvant chemotherapy and compared sequential vs concurrent administration of doxorubicin and docetaxel. Patients with lymph node-positive breast cancer (n = 2887) were randomly assigned to one of four treatments: 1) sequential control (four cycles of doxorubicin at 75 mg/m2, followed by three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]); 2) concurrent control (four cycles of doxorubicin at 60 mg/m2 plus cyclophosphamide at 600 mg/m2, followed by three cycles of CMF); 3) sequential docetaxel (three cycles of doxorubicin at 75 mg/m2, followed by three cycles of docetaxel at 100 mg/m2, followed by three cycles of CMF); 4) concurrent docetaxel (four cycles of doxorubicin at 50 mg/m2 plus docetaxel at 75 mg/m2, followed by three cycles of CMF). The primary comparison evaluated the efficacy of including docetaxel regardless of schedule and was planned after 1215 disease-free survival (DFS) events (ie, relapse, second primary cancer, or death from any cause). Docetaxel and control treatment groups were compared by log-rank tests, and hazard ratios (HR) of DFS events were calculated by Cox modeling. All statistical tests were two-sided. Due to a lower-than-anticipated rate of relapse, this analysis was performed after 5 years with 732 events. Patients in control arms had a 5-year DFS of 73% (95% confidence interval [CI] = 70% to 75%). Docetaxel treatment resulted in an improvement in DFS of borderline statistical significance compared with control treatment (HR = 0.86, 95% CI = 0.74 to 1.00; P = .05). However, DFS in the sequential docetaxel arm was better than that in the concurrent docetaxel arm (HR = 0.83, 95% CI = 0.69 to 1.00) and in the sequential control arm (HR = 0.79, 95% CI = 0.64 to 0.98). Incorporating docetaxel into anthracycline-based therapy resulted in an improvement in DFS that was of borderline statistical significance. However, important differences may be related to doxorubicin and docetaxel scheduling, with sequential but not concurrent administration, appearing to produce better DFS than anthracycline-based chemotherapy.
 
Article
The conviction that postoperative radiotherapy and chemotherapy represent an acceptable standard of care for patients with Dukes' B (stage II) and Dukes' C (stage III) carcinoma of the rectum evolved in the absence of data from clinical trials designed to determine whether the addition of radiotherapy results in improved disease-free survival and overall survival. This study was carried out to address this issue. An additional aim was to determine whether leucovorin (LV)-modulated 5-fluorouracil (5-FU) is superior to the combination of 5-FU, semustine, and vincristine (MOF) in men. Eligible patients (n = 694) with Dukes' B or C carcinoma of the rectum were enrolled in National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol R-02 from September 1987 through December 1992 and were followed. They were randomly assigned to receive either postoperative adjuvant chemotherapy alone (n = 348) or chemotherapy with postoperative radiotherapy (n = 346). All female patients (n = 287) received 5-FU plus LV chemotherapy; male patients received either MOF (n = 207) or 5-FU plus LV (n = 200). Primary analyses were carried out by use of a stratified log-rank statistic; P values are two-sided. The average time on study for surviving patients is 93 months as of September 30, 1998. Postoperative radiotherapy resulted in no beneficial effect on disease-free survival (P =.90) or overall survival (P =.89), regardless of which chemotherapy was utilized, although it reduced the cumulative incidence of locoregional relapse from 13% to 8% at 5-year follow-up (P =.02). Male patients who received 5-FU plus LV demonstrated a statistically significant benefit in disease-free survival at 5 years compared with those who received MOF (55% versus 47%; P =.009) but not in 5-year overall survival (65% versus 62%; P =.17). The addition of postoperative radiation therapy to chemotherapy in Dukes' B and C rectal cancer did not alter the subsequent incidence of distant disease, although there was a reduction in locoregional relapse when compared with chemotherapy alone.
 
Kaplan-Meier curves for locoregional control. A) Patients are divided into three groups of nearly equal size based on pretreatment metabolic tumor volume. B) Patients are dichotomized using the identified optimal cutpoint. All statistical tests were two-sided. For each strata, the number of patients still at risk is listed below the curves. CI = confidence interval; MTV = metabolic tumor volume; NA = not applicable, which signifies that the corresponding quantity cannot be estimated. 
Multivariable Cox proportional hazards regression modeling for predictors of overall survival, including clinical factors and pretreat- ment PET metrics (n = 214)
Article
Background: ACRIN 6668/RTOG 0235 evaluated the prognostic value of positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET) uptake before and after definitive, concurrent, platinum-based chemoradiotherapy for locally advanced non-small cell lung cancer (NSCLC). In this secondary analysis, we evaluate volumetric pretreatment PET measures as predictors of clinical outcomes. Methods: Patients with stage III NSCLC underwent FDG-PET prior to treatment. A commercially available gradient-based segmentation tool was used to contour all visible hypermetabolic lesions on each scan. For each patient, the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total glycolytic activity (TGA) for all contoured lesions were recorded. Cox proportional hazards regression models were used to evaluate clinical variables and PET metrics as predictors of overall survival (OS) and locoregional control (LRC). Time-dependent covariables were added to the models when necessary to address nonproportional hazards. All statistical tests were two-sided. Results: Complete data were available for 214 patients in the OS analysis and 189 subjects in the LRC analysis. In multivariable analysis incorporating clinical and imaging data available prior to treatment, MTV was an independent predictor of OS (HR = 1.04 per 10 cm(3) increase, 95% CI = 1.03 to 1.06, P < .001). High MTV was also associated with increased risk of locoregional failure at baseline (HR = 1.16 per 10 cm(3) increase, 95% CI = 1.08 to 1.23, P < .001) and at six months (HR = 1.05 per 10 cm(3) increase, 95% CI = 1.02 to 1.07, P < .001) but not at 12 months or later time points. Conclusion: Pretreatment MTV is a predictor of clinical outcomes for NSCLC patients treated with chemoradiotherapy. Quantitative PET measures may serve as stratification factors in clinical trials for this patient population and may help guide novel trial designs.
 
Article
In anorectal cancer patients, an acute side effect of chemoradiotherapy is gastrointestinal toxicity, which often impedes treatment delivery. Based on previous trials, octreotide acetate is widely recommended for the control of chemotherapy-induced diarrhea. However, the effectiveness of octreotide in preventing or controlling radiation- and chemoradiation-induced diarrhea is not known. A randomized, double-blinded, placebo-controlled trial was designed to determine the efficacy of long-acting octreotide acetate (LAO) in preventing the onset of acute diarrhea in patients undergoing chemoradiation therapy for rectal or anal cancer. Between 4 and 7 days before the start of radiation therapy, patients received a 30-mg dose of LAO (109 patients) or placebo (106 patients) via intramuscular injection. A second dose was given on day 22 (+/-3 days) of radiation treatment. A total of 215 patients were included in the final analysis. The primary endpoint was the incidence of grade 2-4 acute diarrhea; secondary endpoints included treatment compliance, medical resource utilization, patient-reported bowel function, and quality of life (QoL). Statistical tests were one- or two-sided, as specified. After a median follow-up time of 9.64 months, incidence rates of grades 2-4 acute diarrhea were similar in both groups (49% placebo vs 44% LAO; P = .21). No statistically significant treatment differences in chemotherapy or radiation delivery, medical resource utilization, patient-reported bowel function, or QoL were observed. In this study, the prophylactic use of LAO did not prevent the incidence or reduce the severity of diarrhea and had no notable impact on patient-reported bowel function or QoL.
 
Article
Prior studies suggest that elevated markers of bone turnover are prognostic for poor survival in castration-resistant prostate cancer (CRPC). The predictive role of these markers relative to bone-targeted therapy is unknown. We prospectively evaluated the prognostic and predictive value of bone biomarkers in sera from CRPC patients treated on a placebo-controlled phase III trial of docetaxel with or without the bone targeted endothelin-A receptor antagonist atrasentan (SWOG S0421). Markers for bone resorption (N-telopeptide and pyridinoline) and formation (C-terminal collagen propeptide and bone alkaline phosphatase) were assayed in pretreatment and serial sera. Cox proportional hazards regression models were fit for overall survival. Models were fit with main effects for marker levels and with/without terms for marker-treatment interaction, adjusted for clinical variables, to assess the prognostic and predictive value of atrasentan. Analysis was adjusted for multiple comparisons. Two-sided P values were calculated using the Wald test. Sera from 778 patients were analyzed. Elevated baseline levels of each of the markers were associated with worse survival (P < .001). Increasing marker levels by week nine of therapy were also associated with subsequent poor survival (P < .001). Patients with the highest marker levels (upper 25th percentile for all markers) not only had a poor prognosis (hazard ratio [HR] = 4.3; 95% confidence interval [CI] = 2.41 to 7.65; P < .001) but also had a survival benefit from atrasentan (HR = 0.33; 95% CI = 0.15 to 0.71; median survival = 13 [atrasentan] vs 5 months [placebo]; P interaction = .005). Serum bone metabolism markers have statistically significant independent prognostic value in CRPC. Importantly, a small group of patients (6%) with highly elevated markers of bone turnover appear to preferentially benefit from atrasentan therapy.
 
Article
National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol C-03 showed a benefit from leucovorin (LV)-modulated 5-fluorouracil (5-FU) adjuvant therapy (5-FU + LV) in patients with Dukes' stage B or C carcinoma of the colon. Preclinical and clinical phase I/II data suggested that interferon alfa-2a (IFN) enhanced the efficacy of 5-FU therapy. Accordingly, in NSABP protocol C-05, the addition of recombinant IFN to 5-FU + LV adjuvant therapy was evaluated. Data are presented for 2176 patients with Dukes' stage B or C cancer entered onto protocol C-05 during the period from October 1991 through February 1994. Individuals with an Eastern Cooperative Oncology Group performance status of 0-2 (ranges from fully active to ambulatory and capable of self-care but unable to work), a life expectancy of at least 10 years, and curative resection were stratified by sex, disease stage, and number of involved lymph nodes and were randomly assigned to receive either 5-FU + LV or 5-FU + LV + IFN; the mean time on the study as of June 30, 1997, was 54 months. All statistical tests were two-sided. There was no statistically significant difference in either disease-free survival (5-FU + LV, 69%; 5-FU + LV + IFN, 70%) or overall survival (5-FU + LV, 80%; 5-FU + LV + IFN, 81%) at 4 years of follow-up. Toxic effects of grade 3 or higher were observed in 61.8% of subjects in the group treated with 5-FU + LV and in 72.1% of subjects in the group treated with 5-FU + LV + IFN; fewer patients in the latter group completed protocol-mandated 5-FU + LV therapy than in the former group (77.1% versus 88.5%). The addition of IFN to 5-FU + LV adjuvant therapy confers no statistically significant benefit, but it does increase toxicity.
 
Article
The hypoxic cell sensitizer misonidazole (Ro 07-0582),1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol, significantly enhanced the local control of the weakly immunogenic C3H mouse mammary carcinoma MDAH-MCa-4 (8-mm diameter) by single doses of radiation. The dose modification factor (DMF) was 2.33 when the drug was given ip to inbred C3Hf/Bu mice in a dose of 1 mg/g body weight 30 minutes before irradiation of the tumor. The DMF in a highly immunogenic 3-methylcholanthrene-induced C3H fibrosarcoma (FSa) was 1.65 in normal mice and 1.86 in mice immunosuppressed by 600 rads whole-body irradiation 1 day before tumor transplantation. In mice treated iv with 0.25 mg Corynebacterium parvum when tumors were 6 mm in diameter and irradiated at 8 mm, local control of FSa was enhanced at low doses of radiation but was similar to that in normal mice at higher doses. In mice treated with both misonidazole and C. parvum, local control at lower doses of radiation was similar to that in mice treated with C. parvum alone but was enhanced at higher doses in mice that failed to respond to C. parvum. Cytotoxicity of misonidazole, as reflected in tumor growth, was not detected.
 
List of variables examined and their interaction with bevacizumab 
Article
National Surgical Adjuvant Breast and Bowel Project protocol C-08 tested the worth of adding 1 year of bevacizumab to oxaliplatin-based standard adjuvant chemotherapy regimen in the treatment of stage II/III colon cancer. Although the overall result was negative, the possibility that a molecularly defined subset could benefit from bevacizumab cannot be ruled out. We performed post hoc Cox regression analyses to test for marker-by-treatment interactions for standard pathological features and survival analyses using the Kaplan-Meier method. All statistical tests were two-sided and considered statistically significant at the .05 level. Patients diagnosed with mismatch repair defective (dMMR) tumors derived statistically significant survival benefit from the addition of bevacizumab (hazard ratio [HR] = 0.52; 95% confidence interval [CI] = 0.29 to 0.94; P = .02) in contrast with no benefit in patients diagnosed with mismatch repair proficient tumors (HR = 1.03; 95% CI = 0.84 to 1.27; p = .78; P interaction = .04). Although a post hoc finding, this data suggests that a molecularly defined subset of colon cancer patients may derive clinical benefit from antiangiogenesis agents and underscores the need for independent validation in other clinical trials.
 
Article
Mammography programs have received extensive study, but little is known about the outcome of clinical breast examinations (CBEs) performed in community settings. Consequently, we analyzed data from the National Breast and Cervical Cancer Early Detection Program on CBEs provided to low-income women from 1995 through 1998 and determined the percentage of CBEs considered to be abnormal, suspicious for cancer; the rates of cancer detection; and the sensitivity, specificity, and positive predictive value of CBEs. We analyzed data from 752081 CBEs and found that 6.9% of all CBEs were coded abnormal, suspicious for cancer, and that 5.0 cancers were detected per 1000 examinations (95% confidence interval [CI] = 4.9-5.2). The values observed for sensitivity (58.8%) and specificity (93.4%) were comparable to those reported for the CBE component of clinical trials. The observed positive predictive value was 4.3%. About 74% of all records also reported mammography results. The cancer-detection rate among records reporting an abnormal CBE and normal mammography was 7.4 cancers per 1000 records (95% CI = 6. 3-8.4). When the CBE was normal but the mammography was abnormal, the rate was 42.0 cancers per 1000 records (95% CI = 39.9-44.1). When both CBE and mammography results were abnormal, the rate was 170.3 cancers per 1000 records (95% CI = 162.7-177.9). Cancer detection could not be attributed entirely to CBE or mammography on 38% of the records in the latter subset because the tests were performed on the same day. CBEs performed in community-based screening programs can detect breast cancers as effectively as CBEs performed in clinical trials and may modestly improve early-detection campaigns.
 
Article
A short (4-hr) exposure to 1-4 X 10(-7) M 1,25-dihydroxyvitamin D3 [(1,25(OH)2D3); 1-alpha,25-dihydroxycholecalciferol] induced transient differentiation in a clone (R2AB2) of human promyelocytic leukemia cells (HL-60) but caused no permanent growth impairment and no detectable cytotoxicity. This treatment with 1,25(OH)2D3 also produced an inhibition of DNA synthesis that was promptly reversed when 1,25(OH)2D3 was removed. When such treatment with 1,25(OH)2D3 immediately followed a sublethal exposure to drugs that inhibit DNA synthesis, including the cancer chemotherapeutic agents cytarabine and hydroxyurea, the proportion of HL-60 cells lethally damaged was increased. This finding was demonstrated by morphologic evidence of cell damage and disintegration, an increased permeability to trypan blue, loss of cells from culture, and a reduced clonogenic potential of the treated cells. Exposure to 1,25(OH)2D3 before treatment with a cytotoxic agent had a slightly protective rather than a damaging effect. These observations suggest that the presence of 1,25(OH)2D3 markedly reduces the capacity of HL-60 cells to repair DNA damage or to reduce the intracellular concentration of cytotoxic agents.
 
Top-cited authors
Ahmedin Jemal
  • American Cancer Society
Walter C Willett
  • Harvard University
Graham A Colditz
  • Washington University in St. Louis
Mitchell H Gail
  • National Institutes of Health
Mark Schiffman
  • National Cancer Institute