Paul F. Engstrom

Prognostic effect of weight loss prior tochemotherapy in cancer patients

The prognostic effect of weight loss prior to chemotherapy was analyzedusing data from 3,047 patients enrolled in 12 chemotherapy protocols of the Eastern Cooperative Oncology Group. The frequency of weight loss ranged from 31 percent for favorable non-Hodgkins lymphoma to 87 percent in gastric cancer. Median survival was significantly shorter in nine protocols for the patients with weight loss compared to the patients with no weight loss. Chemotherapy response rates were lower in the patients with weight loss, but only in patients with breast cancer was this difference significant. Decreasing weight was correlated with decreasing performance status except for patients with pancreatic and gastric cancer. Within performance status categories, weight loss was associated with decreased median survival. The frequency of weight loss increased with increasing number of anatomic sites involved with metastases, but within categories of anatomic involvement, weight loss was associated with decreased median survival. These observations emphasize the prognostic effect of weight loss, especially in patients with a favorable performance status or a limited anatomic involvement with tumor.

Clinical practice guidelines in oncology

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

Factors associated with repeat adherence to breast cancer screening

This study identified barriers and facilitators of repeat participation in mammography and breast physical examination among women ages 50 years and over. Telephone interviews were conducted with 910 women in this age group. Forty percent of respondents had never had a mammogram. Only 38% had had one in the past 12 months. Of women who had a prior mammogram, 43% had had only one. Only 60% of women had had a breast exam in the past 12 months. A physician recommendation was the single best predictor of adherence to mammography. However, only 60% of women reported that their physicians had ever recommended mammography. Several other barriers to mammography were revealed, including anxiety, embarrassment, and concerns about cost and radiation. Both a family history of breast cancer and heightened perceived vulnerability to breast cancer were associated positively with repeat mammography participation; anxiety about screening reduced the likelihood of this outcome. These findings suggest that physicians can play a powerful role in motivating women to participate in initial and subsequent breast cancer screening. Reassurance may reduce womens anxiety and embarrassment and increase utilization further.

Psychological and Behavioral Implications of Abnormal Mammograms

OBJECTIVE To evaluate womens psychological responses to abnormal mammograms and the effect on mammography adherence. To identify psychological responses and other factors that predict mammography adherence in women with normal or abnormal mammograms. DESIGN Survey study with prospective analysis of factors associated with mammography adherence. SETTING Health Maintenance Organization of Pennsylvania and New Jersey (HMO PA/NJ). PATIENTS Study patients, members of HMO PA/NJ who were 50 years of age or older, and who had had mammography done 3 months earlier, included women with normal mammograms (n = 121), women with low-suspicion mammograms (n = 119), and women with high-suspicion mammograms (n = 68), but not women with breast cancer. MEASUREMENTS Psychological responses 3 months after mammography and adherence to subsequent annual mammography were assessed. MAIN RESULTS Women with high-suspicion mammograms had substantial mammography-related anxiety (47%) and worries about breast cancer (41%). Such worries affected the moods (26%) and daily functioning (17%) of these women, despite diagnostic evaluation excluding malignancy. For each variable, a consistent trend (P greater than 0.05) was seen with degree of mammogram abnormality. Sixty-eight percent of women with normal results, 78% of women with low-suspicion results, and 74% of women with high-suspicion results obtained their subsequent annual mammograms (P greater than 0.05). The number of previous mammograms (odds ratio, 3.2; 95% CI, 1.6 to 6.2) and the effect of the previous results on concerns about breast cancer (odds ratio, 0.5; CI, 0.2 to 1.0) were independent predictors of adherence in logistic regression analyses (P less than 0.05). CONCLUSIONS A substantial proportion of women with suspicious mammograms have psychological difficulties, even after learning that they do not have cancer. Such sequelae do not appear to interfere with subsequent adherence.

Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil--an Eastern Cooperative Oncology Group study.

One hundred ninety-one patients with pathologically confirmed, locally unresectable adenocarcinoma of the stomach (57 patients) and pancreas (91 patients), were randomly allocated to therapy with 5-fluorouracil (5-FU) alone, 600 mg/m2 intravenously (IV) once weekly, or radiation therapy, 4,000 rad, plus adjuvant 5-FU, 600 mg/m2 IV, the first three days of radiotherapy, then follow-up maintenance 5-FU, 600 mg/m2, weekly. Forty-three patients (22%) could not be analyzed because of ineligibility or cancellation, thus 148 patients were evaluable. The median survival time was similar for both treatment programs and for both types of primary carcinoma, and was as follows: gastric primary carcinoma, 5-FU, 9.3 months; 5-FU plus radiotherapy, 8.2 months; pancreatic primary carcinoma, 5-FU, 8.2 months; 5-FU plus radiotherapy, 8.3 months. Substantially more toxicity was experienced by patients treated with the combined modality arm than by those patients receiving 5-FU alone. Severe or worse toxicity experienced by patients with gastric primary carcinoma treated by 5-FU was 19%, and the combined modality arm was 31%. The toxicity experienced by patients with pancreatic primary carcinoma treated with 5-FU was 27%, and the combined modality arm was 51%. Significant prognostic variables included: weight loss in stomach-cancer patients; and performance status, degree of anaplasia, and reduced appetite in pancreas-cancer patients.

Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis.

PURPOSE To determine the activity and toxicity of combination paclitaxel (24 hours) and carboplatin in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Eligibility required measurable disease (stage IV or stage IIIB with malignant pleural effusion), Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, absolute neutrophil count > or = 2,000/microL, platelet count > or = 100,000/microL serum creatinine concentration < or = 1.5 mg/dL, and bilirubin level < or = 2 mg/dL. Paclitaxel was initially administered at a dose of 135 mg/m2/d, followed by carboplatin on day 2 at a targeted area under the concentration-time curve (AUC) of 7.5 using the Calvert formula. Granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously (SC) on days 3 to 17 was introduced during the second and subsequent cycles. In patients who sustained less than grade 4 myelosuppression, the paclitaxel dose was sequentially escalated 40 mg/m2 per cycle to a maximum of 215 mg/m2. Treatment was repeated at 3-week intervals for six cycles. RESULTS From June 1993 through February 1994, 54 patients were enrolled; 53 are assessable for toxicity and response. The median age was 62 years (range, 34 to 84). Sixty-nine percent were male, 65% had adenocarcinoma, and 93% had stage IV disease. Two hundred sixty-eight cycles were administered; 32 patients (59%) completed all six cycles. Twenty-five unanticipated hospitalizations occurred during treatment (9.3% of cycles) in 20 patients (37%). Myelosuppression was the principal toxicity; grade 3 or 4 granulocytopenia occurred in 57% of patients after the first cycle, but decreased to 35% during the second cycle after introduction of G-CSF and consistently remained < or = 22% during subsequent cycles. Seven episodes of neutropenic fever occurred, all during the first cycle. Grade 3 or 4 thrombocytopenia and anemia occurred in 47% and 33% of patients, respectively. Eight patients (15%) required platelet transfusions and 16 (30%) required packed RBC support. Neuropathy, myalgias/arthralgias, and thrombocytopenia, although generally mild, were cumulative. The paclitaxel dose was boosted to 215 mg/m2 in > or = 70% of patients who received three or more cycles. At an AUC of 7.5, the median first-cycle carboplatin dose was 424 mg/m2 (range, 273 to 709 mg/m2). The objective response rate was 62%, with five (9%) complete responses and 28 (53%) partial responses. The median progression-free survival time was 28 weeks and the median survival time 53 weeks. The 1-year survival rate is 54%. CONCLUSION The paclitaxel-carboplatin combination is active in advanced NSCLC and may enhance survival; it merits further investigation in phase III trials.

Progress in Chemoprevention Drug Development: The Promise of Molecular Biomarkers for Prevention of Intraepithelial Neoplasia and Cancer—A Plan to Move Forward

This article reviews progress in chemopreventive drug development, especially data and concepts that are new since the 2002 AACR report on treatment and prevention of intraepithelial neoplasia. Molecular biomarker expressions involved in mechanisms of carcinogenesis and genetic progression models of intraepithelial neoplasia are discussed and analyzed for how they can inform mechanism-based, molecularly targeted drug development as well as risk stratification, cohort selection, and end-point selection for clinical trials. We outline the concept of augmenting the risk, mechanistic, and disease data from histopathologic intraepithelial neoplasia assessments with molecular biomarker data. Updates of work in 10 clinical target organ sites include new data on molecular progression, significant completed trials, new agents of interest, and promising directions for future clinical studies. This overview concludes with strategies for accelerating chemopreventive drug development, such as integrating the best science into chemopreventive strategies and regulatory policy, providing incentives for industry to accelerate preventive drugs, fostering multisector cooperation in sharing clinical samples and data, and creating public-private partnerships to foster new regulatory policies and public education.

Long-term results of infusional 5-FU, mitomycin-C, and radiation as primary management of esophageal carcinoma

An analysis of the results of 90 patients with esophageal cancer treated prospectively with combined chemotherapy and radiation without surgery and with a median follow-up of 45 months is presented. Fifty-seven patients with Stage I or II disease received definitive treatment consisting of 6,000 cGy in 6 to 7 weeks and 5-FU (1,000 mg/m2/24 hr) as a continuous intravenous (IV) infusion for 96 hours, starting on days 2 and 29. Mitomycin C (10 mg/m2) was administered as a bolus injection on day 2. Thirty-three patients received palliative treatment (5,000 cGy plus above chemotherapy) for Stage III, IV, or otherwise advanced disease (extraesophageal spread, distant metastases, multiple primary tumors). Follow-up ranged from 1 month to 96 months. Overall median survival of Stage I and II patients was 18 months with 3- and 5-year actuarial survival of 29% and 18%, respectively, while the median disease specific survival was 20 months with an actuarial disease specific survival of 41% and 30% at 3 and 5 years, respectively. A multivariate analysis of sex, histology, tumor location, and tumor size on survival revealed that the effect of stage was highly significant (Stage I versus II, 73% versus 33% at 3 years, p = .01), whereas the effect of sex approached significance (females versus males, 57% versus 34% at 3 years, p = less than .1). The actuarially determined local relapse-free rate for Stage I and II patients at both 3 and 5 years was 70%. Multivariate analysis again indicated stage to be highly significant (Stage I versus II, 100% versus 60% at 3 years, p = less than .01), whereas sex approached significance (female versus male, 75% versus 66% at 3 years, p = .07). The pattern of failure may be altered with this treatment regimen from local to one dominated by distant metastases. Of 29 patients who have failed, 14 (48%) had any component of local failure, whereas 21 (72%) had a distant failure as a component of failure. The median survival of patients with Stage III or IV disease was 9 months and 7 months, respectively. Palliation in this group of patients with advanced disease was good as 77% were rendered free of dysphagia post-treatment, and 60% were without dysphagia until death with a median dysphagia-free duration of 5 months. Severe toxicities were uncommon and nearly all were transient. Eleven of 90 patients (12.2%) had severe acute toxicities, whereas only 3 patients (3.3%) developed significant late treatment-related complications requiring hospitalization for management.

HOW VALID ARE MAMMOGRAPHY SELF-REPORTS ?

We compared mammography reports in medical records to self-reports obtained during a 1989 telephone interview survey for a sample of 100 women members of a health maintenance organization (HMO) who indicated they had mammograms within the past year and 100 who said they had not had mammograms within the past year. Of the women reporting they had not had mammograms within the past year, none had mammogram reports in the HMO data center. Of the 100 women reporting they had mammograms within the past year, 94 had confirmatory radiology records.

Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor.

EST 5275 is a phase II and III study of fluorouracil plus streptozocin (5-FU plus STZ) or doxorubicin in patients with measurable progressive carcinoid tumor. Among one hundred seventy-two cases with no prior chemotherapy and no heart disease, the response rate was 22% for 5-FU plus STZ and 21% for doxorubicin, while the median response duration and median survival were 31 weeks and 64 weeks for the combination and 26 weeks and 48 weeks for doxorubicin. Thirty-three patients who failed 5-FU plus STZ crossed over to doxorubicin and achieved an 18% response. Of the thirty-five patients who failed on doxorubicin, 29% responded to 5-FU plus STZ. Hematologic toxicity was similar for both treatments; however, the 5-FU plus STZ patients experienced more vomiting but acceptable renal toxicity. Both chemotherapy regimens have antitumor activity in carcinoid tumors.