Samuel Wieand

Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18.

PURPOSEnTo determine whether preoperative doxorubicin and cyclophosphamide (AC) permits more lumpectomies to be performed and decreases the incidence of positive nodes in women with primary breast cancer.nnnPATIENTS AND METHODSnWomen (n = 1,523) were randomized to National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18; 759 eligible patients received postoperative AC and 747, preoperative AC. The clinical size of breast and axillary tumors was determined before each of four cycles of AC and before surgery. Tumor response to preoperative therapy was clinically complete (cCR), partial (cPR), stable (cSD), or progressive disease (cPD). Tissue from patients with a cCR was evaluated for a pathologic complete response (pCR).nnnRESULTSnBreast tumor size was reduced in 80% of patients after preoperative therapy; 36% had a cCR. Tumor size and clinical nodal status were independent predictors of cCR. Twenty-six percent of women with a cCR had a pCR. Clinical nodal response occurred in 89% of node-positive patients: 73% had a cCR and 44% of those had a pCR. There was a 37% increase in the incidence of pathologically negative nodes. Before randomization, lumpectomy was proposed for 86% of women with tumors < or = 2 cm, 70% with tumors 2.1 to 5.0 cm, and 3% with tumors > or = 5.1 cm. Clinical tumor size and nodal status influenced the physicians decision. Overall, 12% more lumpectomies were performed in the preoperative group; in women with tumors > or = 5.1 cm, there was a 175% increase.nnnCONCLUSIONnPreoperative therapy reduced the size of most breast tumors and decreased the incidence of positive nodes. The greatest increase in lumpectomy after preoperative therapy occurred in women with tumors > or = 5 cm, since women with tumors less than 5 cm were already lumpectomy candidates. Preoperative therapy should be considered for the initial management of breast tumors judged too large for lumpectomy.

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)

PURPOSEnAlthough 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.nnnPATIENTS AND METHODSnThe 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.nnnRESULTSnForty-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.nnnCONCLUSIONnPatients 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.

Overexpression of Glut-1 and increased glucose metabolism in tumors are associated with a poor prognosis in patients with oral squamous cell carcinoma.

The overexpression of glucose transporters, especially of Glut‐1, is a common characteristic of human malignancies, including head and neck carcinoma. Recently, the assessment of glucose metabolism in the tumor with [18F]‐2‐fluoro‐2 deoxy‐D‐glucose (FDG) and positron emission tomography (FDG‐PET) has been used to identify particularly aggressive tumors. The authors tested the hypothesis that both glucose transport and its metabolism play a key role in the progression of oral squamous cell carcinoma (OSCC).

Immunomodulatory effects of high-dose and low-dose interferon α2b in patients with high-risk resected melanoma: The E2690 Laboratory Corollary of Intergroup Adjuvant Trial E1690

The clinical antitumor activity of recombinant interferon α2b (IFNα2b) has been well documented in patients with advanced and high‐risk melanoma; however, its mechanism of action remains conjectural. Trial E2690 evaluated the immunomodulatory effects of IFNα2b in vivo during treatment at high doses (the HDI arm; n = 51 patients) and at low doses (the LDI arm; n = 54 patients) in relation to standard observation (OBS; n = 43 patients).

Lack of influence of cytokeratin-positive mini micrometastases in "Negative Node" patients with colorectal cancer: findings from the national surgical adjuvant breast and bowel projects protocols R-01 and C-01.

AbstractPURPOSE: Results of the few extant reports concerning thenclinical significance of so-called “occult micrometastases” ofnlymph nodes of patients with Dukes A and B colorectalncancer have been variable. We examined the presumablynnegative nodes of a larger cohort of such patients who werenenrolled in the National Surgical Adjuvant Breast and BowelnProject clinical trials R-01 and C-01 for the influence of whatnwe preferably designate as nodal mini micrometastases onnparameters of survival. METHODS: Mini micrometastasesnwere detected by immunohistochemical staining of thenoriginal lymph node sections with anticytokeratin A1/A3 inna total of 241 Dukes A and B patients with rectal and 158nwith colonic cancers. Their frequency, as well as that ofnnuclear and histologic grades, and an estimation of theirnrelationship to relative risks were correlated with overallnand recurrence-free survival by univariate and multivariatenanalyses. RESULTS: Nodal mini micrometastases were detectednin 73 of 399 (18.3 percent) patients of this cohort.nThey failed to exhibit any significant relationship to overallnor recurrence-free survival. No association between thenassessments of tumor differentiation and mini micrometastasesnwas found. Nuclear and histologic grades also failed tonfurther discriminate overall or recurrence-free survival innpatients with A or B stages of colonic or rectal cancers innthis cohort. CONCLUSION: The immunohistochemicalndemonstration of nodal mini micrometastases failed to discriminatenhigh- and low-risk groups of patients with colorectalncancer who were designated as being node-negativenafter routine pathologic examination.

Methodological Issues in the Analysis of Quality of Life Data in Clinical Trials: Illustrations from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial

We present two Quality of Life (QOL) endpoints collected in conjunction with the recently completed Breast Cancer Prevention Trial (BCPT) performed by the National Surgical Adjuvant Breast and Bowel Project. The analyses of these endpoints (depression and hot flashes) indicate the importance of randomization and give some insight about the impact of missing data in a large randomized trial.

A phase I/II study of trimetrexate and capecitabine in patients with advanced refractory colorectal cancer

Objective:We tested the hypothesis that the combination of trimetrexate (TMTX) and capecitabine (CAP) would be active in patients with previously treated metastatic colorectal cancer (CRC). Because the optimum dose of this combination was unknown, we used a phase I/II design. Methods:In the phase I cohort, patients received 110 mg/m2 TMTX intravenously weekly ×6 and CAP starting at 750 mg/m2 orally twice daily from days 2 to 15 and 23 to 36 (one cycle). Cycles were repeated every 8 weeks. The phase II doses were 110 mg/m2 TMTX and 1000 mg/m2 CAP orally twice daily. Results:Thirty-two patients were entered. All patients had prior 5-fluorouracil therapy and 94% had prior exposure to irinotecan. Grade 3/4 toxicities included abdominal pain in 4 patients (12.5%) and vomiting in 3 patients (9.4%). Twenty-seven patients were evaluable for response: one patient each had a complete response and a partial response for an overall response rate of 7.4%. The median time to progression was 3.3 months (95% confidence interval [CI], 1.6–3.7 months) and the median overall survival was 5.9 months (95% CI, 5.2–10.2 months). Conclusions:The combination of TMTX and CAP is well tolerated. However, recent studies have shown more active regimens in the second- and third-line metastatic setting.

A Commentary on Treatment at Random: The Ultimate Science or the Betrayal of Hippocrates?

Spyros Retsas, MD, addresses a controversial issue in oncology (and medicine in general): the proper role of randomized trials when treating individual patients. He ultimately concludes, “...the randomized trial emerges as a deficient research tool both on deontologic and methodologic grounds.” We have been asked to provide a commentary as a companion to his discussion. Dr Retsas has divided his discussion into three broad categories, with a corresponding position regarding each category: philosophical (equipoise, or absolute uncertainty, cannot exist in clinical practice); ethical (beneficence does not allow the physician to randomly assign patients because randomized clinical trials are not treatment, but research); and methodologic (randomized clinical trials are deficient research).

Decision Analysis for a Data Monitoring Committee of a Clinical Trial

A data monitoring committee holds a position of great trust within the structure of a US clinical trial, as it alone receives the accumulating data and decides whether to continue the trial. The committee generally meets at regularly scheduled intervals, e.g. six months. Recent advances in computation allow us to find optimal group-sequential strategies for each member of such a committee. This paper reviews how we plan to use the newly available computational ability to advise members of a data monitoring committee.