Robin T. Vollmer

Eligibility and Response Guidelines for Phase II Clinical Trials in Androgen-Independent Prostate Cancer: Recommendations From the Prostate-Specific Antigen Working Group

PURPOSE Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters. RESULT We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point. CONCLUSION Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point.

Basaloid-squamous carcinoma of the tongue, hypopharynx, and larynx: report of 10 cases.

Ten cases of an unusual form of carcinoma involving the mucosa and underlying tissue of the tongue, hypopharynx, and larynx are described. All ten of the tumors were evaluated by light microscopy; five were also studied by electron microscopy. The major histopathologic feature is carcinoma with a basaloid pattern in intimate association with squamous cell carcinoma, carcinoma in situ, or focal squamous differentiation. The basaloid tumor consists of small crowded cells with hyperchromatic nuclei, scant cytoplasm, small cystic spaces, and foci of tumor necrosis. Prominent hyalinosis is evident. Ultrastructurally, the basaloid epithelial cells possess rare tonofilaments and varying amounts of desmosomes. The cystic spaces contain either loose stellate granules or replicated basal lamina arranged in parallel stacks or globoid masses. This unique tumor was found to be highly malignant, with histologically proved metastases in 80 per cent of the cases. Most of the patients were treated by radical surgery supplemented with radiation and/or chemotherapy. It is concluded that tumors with these characteristic features constitute a distinct histopathologic entity, not previously described, for which basaloid-squamous carcinoma is an appropriate term.

Gefitinib in Patients with Malignant Mesothelioma: A Phase II Study by the Cancer and Leukemia Group B

Purpose: The Cancer and Leukemia Group B conducted a phase II study of gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, in patients with previously untreated malignant mesothelioma. Experimental Design: Eligible patients had unresectable pleural or peritoneal mesothelioma, measurable disease, no prior therapy, and performance status 0-1 by Cancer and Leukemia Group B criteria. Gefitinib (500 mg p.o.) was administered once a day for 21 days. Patients underwent restaging after every two cycles. Therapy was continued until disease progression or unacceptable toxicity. Results: The most common grade 3 toxicities were diarrhea (16%) and nausea (12%). Of 43 patients enrolled, 1 patient (2%) had a complete response, 1 patient (2%) had a partial response, 21 (49%) had stable disease lasting two to eight cycles, 15 (35%) had progressive disease, and 5 (12%) had early deaths. One-year survival was 32% [95% confidence interval (CI), 21-50%]. Median survival and failure-free survival were 6.8% (95% CI, 3.5-10.3) and 2.6 months (95% CI, 1.5-4.0), respectively. The 3-month failure-free survival was 40% (95% CI, 25-56%). EGFR expression score by immunohistochemistry done in 28 patients was categorized as low (EGFR 1+ or 2+) or high (EGFR 3+) expression: 97% had EGFR overexpression (2+ or 3+). The median and 3-month failure-free survival were 3.6 months and 40% for those patients with low EGFR expression compared with 8.1 and 40% for those with high EGFR expression. Conclusions: Although 97% of patients with mesothelioma had EGFR overexpression, gefitinib was not active in malignant mesothelioma. EGFR expression does not correlate with failure-free survival.

PILOT STUDY OF DIETARY FAT RESTRICTION AND FLAXSEED SUPPLEMENTATION IN MEN WITH PROSTATE CANCER BEFORE SURGERY: EXPLORING THE EFFECTS ON HORMONAL LEVELS, PROSTATE-SPECIFIC ANTIGEN, AND HISTOPATHOLOGIC FEATURES

OBJECTIVES Dietary fat and fiber affect hormonal levels and may influence cancer progression. Flaxseed is a rich source of lignan and omega-3 fatty acids and may thwart prostate cancer. The potential effects of flaxseed may be enhanced with concomitant fat restriction. We undertook a pilot study to explore whether a flaxseed-supplemented, fat-restricted diet could affect the biomarkers of prostatic neoplasia. METHODS Twenty-five patients with prostate cancer who were awaiting prostatectomy were instructed on a low-fat (20% of kilocalories or less), flaxseed-supplemented (30 g/day) diet. The baseline and follow-up levels of prostate-specific antigen, testosterone, free androgen index, and total serum cholesterol were determined. The tumors of diet-treated patients were compared with those of historic cases (matched by age, race, prostate-specific antigen level at diagnosis, and biopsy Gleason sum) with respect to apoptosis (terminal deoxynucleotidyl transferase [TdT]-mediated dUTP-biotin nick end-labeling [TUNEL]) and proliferation (MIB-1). RESULTS The average duration on the diet was 34 days (range 21 to 77), during which time significant decreases were observed in total serum cholesterol (201 +/- 39 mg/dL to 174 +/- 42 mg/dL), total testosterone (422 +/- 122 ng/dL to 360 +/- 128 ng/dL), and free androgen index (36.3% +/- 18.9% to 29.3% +/- 16.8%) (all P <0.05). The baseline and follow-up levels of prostate-specific antigen were 8.1 +/- 5.2 ng/mL and 8.5 +/- 7.7 ng/mL, respectively, for the entire sample (P = 0.58); however, among men with Gleason sums of 6 or less (n = 19), the PSA values were 7.1 +/- 3.9 ng/mL and 6.4 +/- 4.1 ng/mL (P = 0.10). The mean proliferation index was 7.4 +/- 7.8 for the historic controls versus 5.0 +/- 4.9 for the diet-treated patients (P = 0.05). The distribution of the apoptotic indexes differed significantly (P = 0.01) between groups, with most historic controls exhibiting TUNEL categorical scores of 0; diet-treated patients largely exhibited scores of 1. Both the proliferation rate and apoptosis were significantly associated with the number of days on the diet (P = 0.049 and P = 0.017, respectively). CONCLUSIONS These pilot data suggest that a flaxseed-supplemented, fat-restricted diet may affect prostate cancer biology and associated biomarkers. Further study is needed to determine the benefit of this dietary regimen as either a complementary or preventive therapy.

Lung cancer heterogeneity: A blinded and randomized study of 100 consecutive cases

The heterogeneity of lung carcinomas was recognized in the past, but few previous studies attempted to quantitate this heterogeneity. In the present study 100 consecutive cases of lung carcinoma (65 surgical resections and 35 autopsies) were collected, and either the entire tumor or ten blocks were examined in a blinded and randomized fashion using the revised (1981) WHO classification. At least three of five panelists agreed on the major histologic type present for 94 per cent of the slides. Agreement for the diagnosis of small cell carcinomas (at least four of five observers) was 98 per cent, but only 72 per cent agreement was attained for the subtyping of small cell carcinomas (e.g., oat cell versus intermediate). Only 34 per cent of the cases were homogeneous according to the majority of the panelists. An additional 21 per cent of the cases showed minor (subtype) heterogeneity (e.g., mixtures of acinar and papillary patterns in adenocarcinoma). Forty-five per cent of the cases showed major heterogeneity, i.e., at least one slide from the case showed a major histologic type different from that of the remainder. Seven small cell carcinomas were homogeneous, whereas in eight cases mixtures of small cell and other cell types were seen. In all but one of the cases involving bronchioloalveolar cell patterns, other patterns of adenocarcinoma were present elsewhere in the tumor. In all six cases involving giant cell carcinoma patterns, adenocarcinoma patterns were also present in some sections. Heterogeneity was identified by extensive sampling of the entire tumor and was seldom recognized in biopsy specimens.

Interferon alfa-2a in the treatment of cutaneous T cell lymphoma*

Twenty-two patients with Stages Ia to IVa cutaneous T cell lymphoma were entered into a controlled trial of interferon alfa-2a (Roferon-A). Patients initially received either 3 million IU interferon alfa-2a, or their dosage was escalated to 36 million IU intramuscularly daily for a 10-week induction period. At the end of induction, 14/22 (64%) of patients had an objective antitumor response: three patients had a complete response, ten patients had a partial response (greater than or equal to 50% resolution of clinical disease), and one patient had a minor response. Responders included those with Stages Ia to IVa cutaneous T cell lymphoma, and remissions have lasted at least 4 to 27.5 months. Three patients progressed from a partial to complete response with further treatment, for an overall complete response rate of 27%. Acute flu-like side effects were generally minor and transient. Malaise/fatigue, depression, anorexia, and weight loss were common chronic dose-related side effects and the most frequent reasons for dose reduction or discontinuation of drug. Leukopenia was the most common laboratory side effect and was also dose-related. Recombinant human leukocyte interferon alfa-2a is an effective and well-tolerated single-agent therapy for early and advanced cutaneous T cell lymphoma.

Lethal “Thin” Malignant Melanoma: Identifying Patients at Risk

Thin melanomas can metastasize and be lethal. The purpose of this review was to identify negative risk factors in patients with melanomas less than 0.76 mm thick. Six hundred and eighty-one (681) such patients are reviewed in this study. Of those referred without metastatic disease (583 patients), metastases developed in 4.8% after a mean followup of 3.6 years. Of those referred with metastatic disease (98 patients), mortality was 35% after a mean followup of 5.9 years. Male patients (p < 0.04) and patients with axial primaries (p < 0.05) were at an increased risk of metastasis. Severe histologie regression was present in 40% of the primary lesions that metastasized and in only 17% of similar lesions that did not (p < 0.001). Increased age was associated with increased local skin metastases, but not with increased nodal or distant metastases. A prognostic model was designed, using two clinical risk factors (axial primary site and male sex) and two histologie risk factors (Clarks Level IV and severe histologie regression). The prognostic model identified a low-risk population—women with extremity primaries—with an actuarial risk of metastasis at 10 years that was less than 3%. Patients with either (1) both clinical risk factors or (2) one clinical risk factor and one histologie risk factor were identified as high-risk patients. Their actuarial risk of metastasis was 11% at 5 years and 22% at 10 years (p = 0.0084). Identifying high-risk and low-risk patients with thin melanomas may improve guidelines for the application of adjuvant therapies to this population.

Malignant melanoma and pregnancy.

Confusion exists concerning the influence of pregnancy on survival in patients with malignant melanoma. To evaluate this problem a retrospective computer‐aided study was performed of women in the child‐bearing years treated for Stage I cutaneous melanoma at the Duke University Comprehensive Cancer Center. Fifty‐eight women were identified who had melanoma arise during pregnancy (Group 1) and 43 patients were noted who became pregnant within 5 years of diagnosis of their melanoma (Group 2). Appropriate control groups matched for the clinical variables of age, primary site, and stage of disease and the pathologic variables of Clarks Level, tumor thickness, ulceration, and histologic type were selected from the cohort of 2938 melanoma patients seen at Duke. Actuarial survivals for Group 1 and 2 patients did not differ from their respective controls, although the small number of deaths in each group resulted in wide confidence intervals. When actuarial disease‐free intervals were plotted, there was a significant difference beween women who had melanoma develop during pregnancy when compared to their controls (P = 0.04). In a multivariate regression analysis, after adjustment for the influence of the more significant prognostic factors for Stage 1 melanoma, including Clarks Level, ulceration, and tumor thickness, the effect of pregnancy on disease‐free interval became more apparent (P = 0.02). No difference in actuarial disease‐free interval was noted in the melanoma patients who elected to become pregnant within 5 years of diagnosis (P = 0.31). A multivariate regression analysis confirmed this finding. These data indicate that although an intercurrent melanoma during pregnancy has a worse prognosis than the control groups, once a woman has been diagnosed as having a cutaneous melanoma, a subsequent pregnancy has no effect on recurrence rate or survival. Cancer 55:1340‐1344, 1985.

Pancreatic FNA in 1000 cases: a comparison of imaging modalities

BACKGROUND Image-guided FNA is a popular method for evaluating pancreatic lesions, but few large studies on pancreatic FNA exist. METHODS Cytologic material, imaging reports, and clinical follow-up information were reviewed from pancreatic FNA cases performed over a 5-year period. RESULTS A total of 1050 pancreatic FNAs were obtained by EUS (n = 843), US (n = 140), and CT (n = 67). On-site assessment was performed in 89.2% (n = 937) of cases. Findings were as follows: positive for neoplasm 48.9% (n = 503), negative 29.1% (n = 306), descriptive 10% (n = 105), suspicious 5.9% (n = 62), atypical/inconclusive 4.6% (n = 48), and nondiagnostic/inadequate 1.5% (n = 26). Follow-up in the form of histology or at least 6 months of clinical observation was available for 61.2% (n = 643). There was an overall false-positive rate of 0.3% and a false-negative rate of 14.3%. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were as follows: 79.4, 99.0, 99.4, 67.9, 84.5 for the total series, respectively; 79.9, 98.8, 99.2, 72.5, 86.5 for EUS, respectively; 77.9, 100, 100, 48.6, 81.7 for US, respectively; and 78.6, 100, 100, 47.1, 82.0 for CT, respectively. In general, accuracy was not influenced by lesion size or site, number of FNA passes, or number of procedures per patient. After controlling for lesion size, EUS resulted in greater accuracy than US or CT when evaluating lesions <3 cm ( p = 0.015). CONCLUSIONS All imaging modalities showed moderate to high sensitivity, specificity, and accuracy. Logistic regression analysis showed that for lesions <3 cm, the EUS method had higher accuracy than US or CT. No statistically significant difference was seen for larger lesions or for the number of FNA passes.

Intraglandular tumor extent and prognosis in prostatic carcinoma: Application of a grid method to prostatectomy specimens

The extent of tumor in prostatectomy specimens was determined by a grid method in 117 patients with prostatic adenocarcinoma. A plastic strip or ruler with squares of 3.0 mm was used, and the ratio of squares overlying carcinoma to the total number of squares overlying prostate tissue was calculated. This grid ratio, which represents an estimate of the percentage of the prostate involved by tumor, was a significant prognosticator closely tied to the likelihood of tumor progression and to survival time, as assessed by logistic regression analysis and a proportional hazard model. The grid ratio was better than histologic grade in predicting tumor progression and patient survival; also, the ratio was more objective than histologic grade as judged by interobserver agreement values. Only slight improvement in prognostication was obtained with concurrent use of both extent and grade. The grid ratio method was slightly better in predicting tumor progression and patient survival than a second method of assessing the percentage of prostatic tissue involved by tumor, the pathologists percentage estimate. These results indicate that it is important to quantitate tumor extent within prostatectomy specimens; such quantitation need not require step-sectioning of the entire prostate and an expensive and time-consuming method such as computerized morphometrics but rather may be performed by a simple estimate of the percentage of the prostate involved by tumor. Reporting of histologic grade and tumor extent in the prostate gland is recommended as both appear to be important in identifying those patients at risk for a poor outcome after prostatectomy for prostatic carcinoma.