Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01.

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.

Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01.

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.

Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Leukemia in breast cancer patients following adjuvant chemotherapy or postoperative radiation: the NSABP experience.

Since 1971, 8,483 women with primary breast cancer participated in seven trials evaluating adjuvant chemotherapy. Leukemia occurred in only three of 2,068 patients treated by operation alone. The cumulative risk was 0.06% after 10 years in those free of metastases or a second primary tumor, and 0.27% in those with tumor. Thus, leukemia is not an important factor in the natural history of breast cancer. Five of 646 women receiving postoperative regional radiation developed leukemia, an overall risk of 1.39 +/- .49% at 10 years. Twenty-seven cases of leukemia (0.5%) and seven of myeloproliferative syndrome (0.1%) were recorded in 5,299 patients who received L-phenylalanine mustard (L-PAM)-containing regimens. The maximum cumulative risk of leukemia in chemotherapy recipients (leukemia of any type and myeloproliferative syndrome) was 1.68 +/- .33% at 10 years following operation. The risk excluding those with myeloproliferative syndrome was 1.29 +/- .28%. The risk of leukemia in patients free of metastases or a second primary was 1.11 +/- .30% at 10 years, and when combined with myeloproliferative syndrome, it was 1.54 +/- .36%; risks not significantly greater than observed following radiation (P = .58 and .29). No cases of leukemia were observed during the 2 years of chemotherapy and none have occurred after the seventh postoperative year. Comparisons with the surveillance, epidemiology, and end results tumor registries (SEER) data indicate an increased relative risk of acute myelogenous leukemia following postoperative regional radiation (P less than .01) and adjuvant chemotherapy (P less than .001). The findings indicate that hematologic disorders are side effects of both radiation and alkylating agents used in the adjuvant treatment of primary breast cancer. The risk of such events is lower than that reported following treatment of other solid tumors and hematologic malignancies by chemotherapy. The benefit from adjuvant chemotherapy for breast cancer exceeds the risk of leukemia. Since chemotherapy is not uniformly beneficial, efforts should be directed toward identifying responders so that only those who will benefit are exposed to the risk.

Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B versus Dukes' C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04)

PURPOSE: Although the benefit from adjuvant chemotherapy has been clearly established in patients with Dukes' C colon cancer, such benefit has been questioned in patients with Dukes' B disease. To determine whether patients with Dukes' B disease benefit from adjuvant chemotherapy and to evaluate the magnitude of the benefit, compared with that observed in Dukes' C patients, we examined the relative efficacy of adjuvant chemotherapy according to Dukes' stage in four sequential National Surgical Adjuvant Breast and Bowel Project trials (C-01, C-02, C-03, and C-04) that compared different adjuvant chemotherapy regimens with each other or with no adjuvant treatment. PATIENTS AND METHODS: The four trials included Dukes' B and C patients and were conducted between 1977 and 1990. The eligibility criteria and follow-up requirements were similar for all four trials. Protocol C-01 compared adjuvant semustine, vincristine, and fluorouracil (5-FU) (MOF regimen) with operation alone. Protocol C-02 compared the perioperative administration of a portal venous infusion of 5-FU with operation alone. Protocol C-03 compared adjuvant 5-FU and leucovorin (LV) with adjuvant MOF. Protocol C-04 compared adjuvant 5-FU and LV with 5-FU and levamisole (LEV) and with the combination of 5-FU, LV, and LEV. RESULTS: Forty-one percent of the patients included in these four trials had resected Dukes' B tumors. In all four studies, the overall, disease-free, and recurrence-free survival improvement noted for all patients was evident in both Dukes' B and Dukes' C patients. When the relative efficacy of chemotherapy was examined, there was always an observed reduction in mortality, recurrence, or disease-free survival event, irrespective of Dukes' stage, and in most instances, the reduction was as great or greater for Dukes' B patients as for Dukes' C patients. When data from all four trials were examined in a combined analysis, the mortality reduction was 30% for Dukes' B patients versus 18% for Dukes' C patients. The mortality reduction in Dukes' B patients occurred irrespective of the presence or absence of adverse prognostic factors. CONCLUSION: Patients with Dukes' B colon cancer benefit from adjuvant chemotherapy and should be presented with this treatment option. Regardless of the presence or absence of other clinical prognostic factors, Dukes' B patients seem to benefit from chemotherapy administration.

Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: preliminary results of National Surgical Adjuvant Breast and Bowel Project Protocol C-02.

Between March 1984 and July 1988, 1,158 patients with Dukes' A, B, and C carcinoma of the colon were entered into National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol C-02. Patients were randomized to either no further treatment following curative resection or to postoperative fluorouracil (5-FU) and heparin administered via the portal vein. Therapy began on day of operation and consisted of constant infusion for 7 successive day. Average time on study was 41.8 months. A comparison between the two groups of patients indicated both an improvement in disease-free survival (74% v 64% at 4 years, overall P = .02) and a survival advantage (81% v 73% at 4 years, overall P = .07) in favor of the chemotherapy-treated group. When compared with the treated group, patients who received no further treatment had 1.26 times the risk of developing a treatment failure and 1.25 times the likelihood of dying after 4 years. Particularly significant was the failure to demonstrate an advantage from 5-FU in decreasing the incidence of hepatic metastases. The liver was the first site of treatment failure in 32.9% of 82 patients with documented recurrences in the control group and in 46.3% of 67 patients who received additional treatment. Therapy is administered via a regional route to affect the incidence of recurrence within the perfused anatomic boundary. Since, in this study, adjuvant portal-vein 5-FU infusion failed to reduce the incidence of hepatic metastases, it may be concluded that its use thus far is not justified. It may also be speculated that the disease-free survival and survival advantages (the latter of borderline significance) are a result of the systemic effects of 5-FU.

The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03.

PURPOSE: This study was designed to evaluate the efficacy of leucovorin-modulated fluorouracil (5-FU) as adjuvant therapy for patients with Dukes' stage B and C colon cancer. PATIENTS AND METHODS: Data are presented from 1,081 patients with Dukes' stage B and C carcinoma of the colon entered into National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol C-03 between August 1987 and April 1989. Patients were randomly assigned to receive either lomustine (MeCCNU), vincristine, and 5-FU (MOF), or leucovorin-modulated 5-FU (LV + 5-FU). The mean time on study was 47.6 months. RESULTS: Comparison between the two groups indicates a disease-free survival advantage for patients treated with LV + 5-FU (P = .0004). The 3-year disease-free survival rate for patients in this group was 73% (95% confidence interval, 69% to 77%), compared with 64% (95% confidence interval, 60% to 68%) for patients receiving MOF. The corresponding percentage of patients surviving was 84% for those randomized to receive LV + 5-FU and 77% for the MOF-treated cohort (P = .003). At 3 years of follow-up, patients treated with postoperative LV + 5-FU had a 30% reduction in the risk of developing a treatment failure and a 32% reduction in mortality risk compared with similar patients treated with MOF. CONCLUSION: Treatment with LV + 5-FU significantly prolongs disease-free survival and results in a significant benefit relative to overall survival. These findings, when considered together with results from a recent meta-analysis demonstrating a benefit from LV + 5-FU in advanced disease, provide evidence to support the concept of metabolic modulation of 5-FU.

The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer.

PURPOSE: We assessed the prognostic importance of the level of thymidylate synthase (TS) expression in patients with primary rectal cancer and whether, for Dukes' B and C cancer patients, the benefit of chemotherapy was associated with TS expression. PATIENTS AND METHODS: The level of TS expression in the primary rectal cancers of 294 of 801 patients enrolled on protocol R-01 of the National Surgical Adjuvant Breast and Bowel Project (NSABP) was immunohistochemically assessed with the monoclonal antibody TS 106. RESULTS: Forty-nine percent of patients whose tumors had low TS levels (n = 91) were disease free at 5 years compared with 27% of patients with high levels of TS (n = 203; P < .01). Moreover, 60% of patients with low TS levels were alive after 5 years compared with 40% of patients with high TS levels (P < .01). The level of TS protein was significantly associated with Dukes' stage (P < .01); patients with a more advanced Dukes' stage had a significantly higher level of TS. The level of TS expression remained prognostic for both disease-free survival (P < .01) and survival (P < .05) independent of Dukes' stage and other pathologic characteristics evaluated. Thirty-eight percent and 54% of patients with high TS levels (n = 71) were disease free and alive, respectively, after 5 years when treated with chemotherapy, compared with 17% and 31%, respectively, of similar patients when treated with surgery alone (n = 64) (P < .01). No difference was noted in disease-free survival (P = .46) or survival (P = .43) in patients with low TS levels. CONCLUSION: The expression of TS is an important independent prognosticator of disease-free survival and survival in patients with rectal cancer. Adjuvant fluorouracil (5-FU)-based chemotherapy demonstrated significant improvement in disease-free and overall survival for patients with high TS levels. Prospective studies measuring TS levels will be needed to understand further the role of TS as a prognosticator of survival and chemotherapeutic benefit.

Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04.

PURPOSE: To compare the efficacy of leucovorin-modulated fluorouracil (FU+LV) with that of fluorouracil and levamisole (FU+LEV) or with the combination of FU+LV and levamisole (FU+LV+LEV). PATIENTS AND METHODS: Between July 1989 and December 1990, 2,151 patients with Dukes' B (stage II) and Dukes' C (stage III) carcinoma of the colon were entered onto National Surgical Adjuvant Breast and Bowl Project protocol C-04. Patients were randomly assigned to receive FU+LV (weekly regimen), FU + LEV, or the combination of FU+LV+LEV. The average time on study was 86 months. RESULTS: A pairwise comparison between patients treated with FU+LV or FU+LEV disclosed a prolongation in disease-free survival (DFS) in favor of the FU+LV group (65% v 60%; P =.04); there was a small prolongation in overall survival that was of borderline significance (74% v 70%; P =.07). There was no difference in the pairwise comparison between patients who received FU+LV or FU+LV+LEV for either DFS (65% v 64%; P =.67) or overall survival (74% v 73%; P =.99). There was no interaction between Dukes' stage and the effect of treatment. CONCLUSION: In patients with Dukes' B and C carcinoma of the colon, treatment with FU+LV seems to confer a small DFS advantage and a borderline prolongation in overall survival when compared with treatment with FU+LEV. The addition of LEV to FU+LV does not provide any additional benefit over and above that achieved with FU+LV. These findings support the use of adjuvant FU+LV as an acceptable therapeutic standard in patients with Dukes' B and C carcinoma of the colon.

Efficacy of 20- versus 10-day antimicrobial treatment for acute otitis media.

OBJECTIVE: The purpose of this trial was to determine whether 20 days of antimicrobial treatment is more efficacious than 10 days of treatment for acute otitis media (AOM) in clearing middle ear effusion and preventing recurrences of AOM, and whether changing to a beta-lactamase-stable antimicrobial agent after the initial 10-day treatment with amoxicillin for AOM is advantageous. METHODS: Children between 7 months and 12 years of age with AOM were randomly assigned to three treatment groups: (1) amoxicillin for days 1 through 10, then amoxicillin for days 11 through 20; (2) amoxicillin for days 1 through 10, then amoxicillin-clavulanate for days 11 through 20; and (3) amoxicillin for days 1 through 10, then a placebo for either amoxicillin or amoxicillin-clavulanate for days 11 through 20. Medication was dispensed in a double-blind manner. Children underwent tympanocentesis at entry and were re-examined on days 10, 20, 30, 60, and 90 after entry. RESULTS: Two hundred sixty-seven children entered the trial. At the 20-day visit, the percentages of children who were effusion free in the amoxicillin, amoxicillin-clavulanate, and placebo groups were 72.4%, 80.8%, and 52.5%, respectively. There was no statistically significant difference in the percentage of children who were effusion free between the amoxicillin and amoxicillin-clavulanate groups (95% confidence interval, -21.7, 4.9). Subsequent to the day 10 visit, the average proportions of time with middle ear effusion were not significantly different in the amoxicillin, amoxicillin-clavulanate, and placebo groups (0.29, 0.27, and 0.34, respectively), nor were there significant differences in the rates of recurrent episodes of AOM (0.56, 0.59, and 0.68, respectively). Regardless of treatment group, approximately 75% of children were effusion free at the time of their last visit. CONCLUSIONS: More children were effusion free by the day 20 visit if given antimicrobial treatment for 20 days rather than for 10 days, but this advantage was present for only a short time; by the end of the 90-day study period, the treatment groups were comparable with regard to effusion status. Recurrence of AOM during the study period was not prevented by the additional 10 days of treatment. Routine use of an additional 10-day course of antimicrobial treatment is therefore not recommended if a child is symptom free after the initial 10 days of treatment for AOM.

Amoxicillin or myringotomy or both for acute otitis media: results of a randomized clinical trial.

A total of 536 infants and children with acute otitis media were randomly assigned to one of six consistent year-long regimens involving the treatment of nonsevere episodes with either amoxicillin or placebo, and severe episodes with either amoxicillin, amoxicillin and myringotomy, or, in children aged 2 years or older, placebo and myringotomy. Nonsevere episodes had more favorable outcomes in subjects assigned to treatment with amoxicillin than with placebo, as measured by the proportions that resulted in initial treatment failure (3.9% vs 7.7%, P = .009) and the proportions in which middle-ear effusion was present at 2 and 6 weeks after onset (46.9% vs 62.5%, P less than .001; and 45.9% vs 51.5%, P = .09, respectively). In subjects whose entry episode was non-severe, those assigned to amoxicillin treatment had less average time with effusion during the succeeding year than those assigned to placebo treatment (36.0% vs 44.4%, P = .004), but recurrence rates of acute otitis media in the two groups were similar. In the 2-year-and-older age group, severe episodes resulted in more initial treatment failures in subjects assigned to receive myringotomy alone than in subjects assigned to receive amoxicillin with, or without, myringotomy (23.5% vs 3.1% vs 4.1%, P = .006). In the study population as a whole, severe episodes in subjects assigned to receive amoxicillin alone, and amoxicillin with myringotomy, had comparable outcomes. It is concluded that children with acute otitis media should routinely be treated with amoxicillin (or an equivalent antimicrobial drug). The data provide no support for the routine use of myringotomy either alone or adjunctively.

Statistical issues in carcinogenic risk assessment.

Considerable progress has been made on the development of a variety of analytical methods to aid in the carcinogenic risk associated with exposure to both occupational and environmental agents. Although the development of these methods has been accompanied by consideration of many statistical issues, there are many areas where additional effort could be directed if these analytical methods are to provide the most appropriate interpretation of risk. These issues include methods of combining multiple studies to obtain an overall risk estimate, the robustness of the statistical model, methods of selection among competing models, an assessment of the effect of different measures of exposure on the estimated dose-response relationship, and development of surveillance methodology. These issues are discussed, and productive areas of future research are indicated.

Prognostic significance of eosinophils and mast cells in rectal cancer: findings from the National Surgical Adjuvant Breast and Bowel Project (protocol R-01).

The numbers of eosinophils and mast cells observed at the tumor border of 331 rectal cancers from patients enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP), protocol R-01, were correlated according to overall survival rate, as well as Dukes' stage, tumor differentiation, nodal status, degree of lymphoid and stromal reactions, sex, and age. Life table plots disclosed a significantly better overall survival rate when ten or more eosinophils per 30 oil immersion fields were found. However, the numbers of eosinophils were strongly associated with Dukes' stage and, when life table plots were adjusted for Dukes' stage, this relationship to survival rate was not evident. On the other hand, overall survival rate was significantly higher in patients in whom 0 to three mast cells per 30 oil immersion fields were found than in those patients in whom four or more mast cells were found. This relationship persisted even when life table plots were adjusted for treatment, Dukes' stage, or nodal status, and indicated that the number of mast cells further defined survival rate among patients exhibiting Dukes' A, B, and C stages. It is concluded that numbers of eosinophils and mast cells may play a role in the natural history of rectal cancer but only the latter represents a prognostic parameter independent of Dukes' stage or nodal status. The mechanism whereby mast cells may exert this effect is at present unknown.

A comparative evaluation of cefaclor and amoxicillin in the treatment of acute otitis media.

In an earlier study of 214 children with acute otitis media (AOM) randomly assigned to a 14-day course of either cefaclor or amoxicillin, 55.7% of cefaclor-treated subjects were effusion-free compared with 41.2% of amoxicillin-treated subjects at the end of treatment. The present study was conducted to determine whether, in a 1-year period, subjects treated with cefaclor for each episode would have middle ear effusion for significantly less time than those treated with amoxicillin for each episode. One hundred fifty-seven subjects with AOM were enrolled. No statistically significant differences were found between the cefaclor-treated and amoxicillin-treated groups in number of subjects effusion-free immediately after first treatment (47.9% vs. 42.3%, respectively), average percent of time with effusion (22.2% vs. 23.4%, respectively), or in rate of new episodes of AOM (3.05 vs. 3.26, respectively). We conclude that there is no clinically significant advantage to the use of cefaclor rather than amoxicillin as the routine first line drug in the treatment of AOM.

Efficacy of myringotomy with and without tympanostomy tubes for chronic otitis media with effusion.

In a previous trial involving 109 children with chronic otitis media with effusion of at least a 2 months' duration that had been unresponsive to medical treatment, we compared the efficacy of myringotomy with tube insertion, myringotomy alone and no surgical intervention with regard to time with middle ear effusion, hearing status and other indices over a 3-year period. Because interpretation of the results was rendered difficult by certain complexities of study design, the present trial with a revised protocol was carried out in an additional group of 111 children. As in the previous trial, myringotomy with tube insertion resulted in less time with effusion and better hearing than did either myringotomy alone or no surgery. However, acute and chronic otorrhea and tympanic membrane perforation developed not uncommonly after tube insertion. Myringotomy alone offered no advantage over no surgery regarding the percent of time with effusion or the number of episodes of acute otitis media. Currently for children with long-standing middle ear effusion, we recommend either watchful waiting with periodic hearing assessment or myringotomy with tube insertion, individualizing the recommendation for each child.

Comparative efficacy of erythromycin-sulfisoxazole, cefaclor, amoxicillin or placebo for otitis media with effusion in children.

We randomly assigned children with otitis media with effusion to receive either erythromycin-sulfisoxazole, cefaclor, amoxicillin or placebo for a 2-week period, primarily to determine whether either erythromycin-sulfisoxazole or cefaclor would have greater short term efficacy than that found previously for amoxicillin, and secondarily to supplement earlier data on outcomes in placebo-treated subjects. Interim analyses showed no statistically significant (P less than 0.05) differences between the three antimicrobial treatment groups in the primary outcome measures, i.e. the prevalence of middle-ear effusion 2 and 4 weeks after entry, and indicated that postulated differences favoring the erythromycin-sulfisoxazole and cefaclor groups over the amoxicillin group were unlikely to be found even if the originally calculated sample size were attained. Subject accrual was therefore terminated. Final analysis showed no significant between-group differences in other outcome measures as well. In antimicrobial vs. placebo comparisons neither erythromycin-sulfisoxazole nor cefaclor gave more favorable outcomes than placebo, whereas more children were effusion-free in the amoxicillin group than in the placebo group at 2 weeks (31.6% vs. 14.1%, P = 0.007), but not at 4 weeks. We conclude that when antimicrobial treatment for otitis media with effusion is deemed advisable, neither erythromycin-sulfisoxazole nor cefaclor should replace amoxicillin as first line treatment.

Efficacy of antimicrobial prophylaxis for recurrent middle ear effusion.

OBJECTIVES: This trial compared the efficacy of amoxicillin prophylaxis with that of placebo for the management of recurrent middle ear effusion (MEE) in children. METHODS: Children between 7 months and 12 years of age who were effusion-free at entry but had histories of chronic or recurrent MEE were randomly assigned to receive either amoxicillin (20 mg/kg once daily) or placebo for 1 year. They were examined monthly and when there were symptoms of ear, nose or throat disease. Acute otitis media (AOM) and new episodes of otitis media with effusion (OME) were treated with amoxicillin-clavulanate; tympanocentesis was performed when possible for episodes of AOM. Throat cultures were obtained at entry; 4, 8 and 12 months after entry; and with new episodes of AOM and OME. Tympanometry was performed at each visit and audiometry was performed at entry and 4, 8 and 12 months after entry. RESULTS: One hundred eleven children were entered in this study. The rates per person year of new episodes of disease in the amoxicillin and placebo groups, respectively, were: MEE, 1.81 vs. 3.18 (P < 0.001); AOM, 0.28 vs. 1.04 (P < 0.001); and OME, 1.53 vs. 2.15 (P = 0.016). Subjects in the amoxicillin group had less time with MEE than the placebo group (19.7 and 33.2%, respectively; P = 0.002). Middle ear and throat cultures did not reveal any increase in beta-lactamase-producing organisms or in Streptococcus pneumoniae attributable to daily use of amoxicillin. CONCLUSIONS: Amoxicillin prophylaxis lowered the rates of occurrence of MEE, AOM and OME and decreased the percentage of time with MEE. However, because of present day concerns regarding antibiotic resistance, management should be individualized.

Efficacy of antimicrobial prophylaxis and of tympanostomy tube insertion for prevention of recurrent acute otitis media: results of a randomized clinical trial.

To determine the efficacy of amoxicillin prophylaxis and of tympanostomy tube insertion in preventing recurrences of acute otitis media, we randomized 264 children 7 to 35 months of age who had a history of recurrent otitis media but were free of middle ear effusion to receive either amoxicillin prophylaxis, bilateral tympanostomy tube insertion or placebo. The average rate of new episodes per child year of either acute otitis media or otorrhea was 0.60 in the amoxicillin group, 1.08 in the placebo group and 1.02 in the tympanostomy tube group (amoxicillin vs. placebo, P less than 0.001; tubes vs. placebo, P = 0.25). The average proportion of time with otitis media of any type was 10.0% in the amoxicillin group, 15.0% in the placebo group and 6.6% in the tympanostomy tube group (amoxicillin vs. placebo, P = 0.03; tubes vs. placebo, P less than 0.001). At the 2-year end point, the rate of attrition was 42.2% in the amoxicillin group, 45.5% in the placebo group and 26.7% in the tympanostomy tube group. Adverse drug reactions occurred in 7.0% of the amoxicillin group and persistent tympanic membrane perforations developed in 3.9% of the tympanostomy tube group. The observed degree of efficacy of amoxicillin prophylaxis and of tympanostomy tube insertion must be viewed in light of the fact that study subjects proved not to have been at as high risk for acute otitis media as had been anticipated and in view of the differential attrition rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Amoxicillin-clavulanate potassium compared with cefaclor for acute otitis media in infants and children.

One hundred thirty-three infants and children with documented acute otitis media (OM) were randomized to receive the oral suspension of either amoxicillin-clavulanate potassium or cefaclor. Beta-lactamase-producing bacteria were found in 10.9 and 14.5% of subjects treated with amoxicillin-clavulanate potassium and cefaclor, respectively. Subjects were reexamined at 5, 10, 30, 60 and 90 days after the initiation of therapy and whenever signs/symptoms of acute otitis media recurred. All but two children had resolution of otalgia/otorrhea during the initial treatment period. The drug groups were not significantly different in the percentage of evaluable subjects with otitis media with effusion at each scheduled follow-up visit. Recurrence of acute OM/otorrhea [corrected] developed in a similar percentage of subjects in both treatment categories. Both subjects with and those without middle ear effusion at 10 days had approximately a 50% recurrence rate of subsequent middle ear disease. Adverse side effects/complaints, which occurred in significantly more children treated with amoxicillin-clavulanate potassium, were generally mild and primarily gastrointestinal.

Nonparametric estimation of degenerate ROC data sets used for comparison of imaging systems.

Maximum likelihood estimation, assuming a binormal model, has been used extensively to estimate the area under receiver operating characteristic (ROC) curves and thus provide an index of diagnostic accuracy for the comparison of two imaging systems. However, in some instances, a degenerate data set results in a fitted ROC curve of inappropriate shape. In those instances, a nonparametric Wilcoxon statistic may be used to compare the areas under two ROC curves. Simulation of this approach indicates that the procedure has relatively high statistical power and its use in specific degenerate data sets shows its applications potential.