Cancer conferences. Can they be improved?

PURPOSE: Cancer conferences are required for hospital cancer program approval by the American College of Surgeons. These conferences are important educational and clinical opportunities and can influence the management of patients with cancer. Nationally, they represent an enormous expenditure of time and effort by physicians, associated healthcare personnel, and tumor registrars. The educational aspects of cancer conferences have been previously reviewed. The purpose of this investigation was to evaluate the clinical aspects of cancer conferences. DESCRIPTION OF STUDY: A questionnaire, inquiring about various elements of cases presented at six consecutive cancer conferences, was sent to 93 Illinois hospitals. These elements included presentation at conference (presenter, time of presentation), clinical aspects (symptoms, history, physical examination, and laboratory tests), pathology (TNM stage and markers), therapeutic options, and quality-of-life issues. RESULTS: The person (or persons) presenting the case was most frequently the attending physician (n = 805, 52%); followed by the pathologist (n = 427, 28%); the cancer committee chairperson (n = 318, 21%); the resident (n = 138, 9%); and other members of the multidisciplinary healthcare team (n = 525, 34%), such as the nurse practitioner or radiation therapist. Of the 1547 cases reviewed, history, physical examination, and diagnostic tests were discussed in 93%, 91%, and 93% of conference presentations, respectively. However, staging by the required TNM system, tumor markers, and quality-of-life issues were discussed in only 28%, 34%, and 38% of presentations, respectively. CLINICAL IMPLICATIONS: Although clinical characteristics were adequately documented and discussed at the cancer conferences studied, other important parameters, such as TNM staging, tumor markers, and quality-of-life issues, were less often discussed. The former topic frequencies are expected, the latter unacceptable. Although cancer conferences currently enhance patient care, these findings indicate that there is potential for improvement through discussion of TNM staging, tumor markers, and quality of life.

Renal cell carcinoma: tumor size, stage and survival. Members of the Cancer Incidence and End Results Committee.

In an attempt to define the relationship among tumor size, stage and survival, the Cancer Incidence and End Results Committee of the American Cancer Society, Illinois Division, Inc. reviewed the records of 2,473 patients with a histological diagnosis of renal cell carcinoma. Tumor size was related to stage and survival. Larger tumors were generally associated with an increased stage (p < or = 0.0005) as well as poorer survival (p < or = 0.005). For Robson stages II, III and IV, tumor size may contribute additional prognostic information for patient survival.

Value of tumor size in predicting survival from renal cell carcinoma among tumors, nodes and metastases stage 1 and stage 2 patients.

Results in the literature are inconsistent regarding the value of tumor size in predicting survival from renal cell carcinoma, and its use as a staging variable in the current tumors, nodes and metastases system has been questioned. In this study tumor size had no prognostic significance in Kaplan-Meier or Cox regression models examining survival differences between 93 patients with stage T1N0M0 and T2N0M0 renal cell carcinoma dichotomized by tumor size cutoffs at 2.5, 5, 7.5 or 10 cm. In multivariate Cox regression models for 122 patients with stage T1NallMall or T2MallMall renal cell carcinoma, metastatic disease was the strongest predictor of survival, and patients with smaller tumors had significantly longer survival than those with larger tumors at all cutoffs except 2.5 cm., for which differences were insignificant. A 5 cm. cutoff maximized the value of tumor size in predicting survival. If tumor size is to remain the variable by which tumors, nodes and metastases stages T1 and T2 disease are differentiated, a 5 cm. cutoff should replace the current 2.5 cm. definition.

Primary renal sarcoma in adults. A natural history and management study by the American Cancer Society, Illinois Division.

BACKGROUND: Primary renal sarcomas in adults are rare and unusual neoplasms. This study was performed to better define the natural history and current management of these sarcomas in a typical medical setting in the United States. METHODS: The hospital records of 4018 adult patients with renal neoplasms treated in the state of Illinois from 1975 to 1985 were examined by American Cancer Society professional volunteers. RESULTS: A primary renal sarcoma occurred in 34 patients (0.8% incidence). Eleven adult patients had Wilms tumor, 21 had primary renal sarcoma (47% leiomyosarcoma), and 2 were not found to have sarcoma on review. The median age of the patients with Wilms tumor was 30 years, whereas that of the patients with non-Wilms sarcoma was 65 years. Four of the patients with Wilms tumor (36%) are long-term survivors and all received adjuvant chemotherapy after radical nephrectomy. Six of the patients with non-Wilms sarcoma (29%) are long-term survivors after radical nephrectomy alone. CONCLUSIONS: Primary renal sarcomas, when treated with radical nephrectomy and, in the case of Wilms tumor, adjuvant chemotherapy, appear to be curable in 29-36% of cases. Histologic review of patients younger than 40 years of age with renal neoplasia is recommended.

Coordinate loss of growth regulatory factors following castration of rats carrying the Dunning R3327 G prostatic tumor.

Hormonal manipulation of prostate cancer is an effective therapy for metastatic disease. Unfortunately, following an initial response tumors reestablish themselves as hormone independent variants and progress. This study was designed to assess the interrelationship of cytokeratin P (Cyto P), vimentin, epidermal growth factor receptor (rEGF) and tissue testosterone following androgen deprivation therapy. Animals bearing the hormone dependent Dunning R3327 G subline prostatic adenocarcinoma were surgically castrated and progressing tumors from both hormone intact and castrated groups were quantitatively assayed for immunohistologic reactivity against the described markers. The results demonstrate a significant (p < 0.05) decrease in cytokeratin (Cyto P), rEGF and testosterone levels following castration. When the expression of both rEGF and Cyto P are related to the tissue testosterone content, it is observed that the ratio between rEGF and testosterone remains essentially unchanged (0.65 +/- 0.21 to 0.65 +/- 0.41), suggesting that in the Dunning R3327 G subline, rEGF expression is coordinately under androgen control. At least some cytokeratin expression also appears to be particularly sensitive to androgen levels, since the ratio between Cyto P and testosterone decreased from 0.92 +/- 0.39 to 0.35 +/- 0.41 following castration. In contrast, following castration, the expression of vimentin was unaffected.

Tumor infiltrating lymphocytes: the effect of bacillus Calmette Guerin on helper/suppressor-T cell ratios of treated and untreated tumors.

Copenhagen X Fischer rats bearing single and bilateral Dunning R3327 AT-3 tumors were either treated or not treated at a single site with bacillus Calmette Guerin (BCG). One week later tumors were removed, tumor infiltrating lymphocytes (TIL's) isolated, and then characterized for total-T, helper-T and suppressor-T cell subsets utilizing monoclonal antibodies. The purpose was to determine the effect of BCG on TIL's in treated as well as untreated tumors. In summary: 1) BCG treatment significantly alters TIL distributions at both injected and noninjected sites; 2) a noninjected contralateral tumor compromises the effectiveness of BCG therapy at the suppressor T cell level; 3) contralateral tumors, whether inoculated or not, have similar TIL distributions.

Cytoreductive surgery impedes metastasis and enhances the immune response: a preliminary report.

In an effort to determine the effect of cytoreductive surgery on the metastatic process, MAT-LyLu flank tumors were excised from Copenhagen x Fischer rats and the effects of this surgery on metastatic lung lesions were observed. Cytoreduction resulted in a decrease in lung lesions (P less than 0.05). Adjuvant cyclophosphamide (CTX) further enhanced this beneficial effect. A concurrent increase in the helper/suppressor ratios suggested that this beneficial response might be mediated by the host's immune response.

Effect of BCG upon functional and phenotypic immune markers in rats bearing the Dunning R3327 MAT-LyLu prostatic adenocarcinoma.

Rats bearing (or not bearing) the Dunning R3327 MAT-LyLu prostatic adenocarcinoma were treated with Bacillus Calmette-Guérin (BCG) and evaluated for immune competence using functional and phenotypic markers. Tumor presence significantly depressed total T and helper T cell representation along with the helper/suppressor T cell ratio. Functional immunity, measured by phytohemmagglutinin (PHA) induced blastogenesis, was also significantly depressed. When BCG was administered to non-tumor bearing animals, it had no effect upon T cell subset distributions but significantly reduced PHA induced blastogenesis. BCG similarly administered to tumor bearing animals did not alter the depressed helper/suppressor T cell ratio found in tumor bearing rats, but did significantly elevate PHA induced blastogenesis. However, these elevated levels of functional immunity in BCG treated tumor-bearing rats remained significantly below normal. These data demonstrate a poor correlation between functional and phenotypic assessments of immune capability.

Review of acid phosphatase in the diagnosis and prognosis of prostatic cancers.

Acid phosphatase is a secretory product frequently utilized as a tumor marker for disseminated, late stage (D2) prostatic cancer. In the 40 years since this association has been recognized, this enzyme has been subjected to extensive biochemical and immunological characterizations. These techniques have also been adapted for rapid and specific determinations of the prostatic isoenzyme levels using a variety of techniques. Since acid phosphatase levels do not become significantly elevated until late stage cancer, newer markers such as prostate-specific antigen have been sought which appear earlier and may be more useful for the screening and monitoring of high risk populations. At this time it is appropriate to review the current and future status of acid phosphatase as a diagnostic aid.

Combination therapy using polyamine synthesis inhibitor alpha-difluoromethylornithine and adriamycin in treatment of rats carrying the Dunning R3327 MAT-LyLu prostatic adenocarcinoma.

Prostate cells of human and rat origin produce polyamines in high content, whose apparent functions relate to cellular proliferation and secretory activities. Formation is dependent on the enzyme ornithine decarboxylase (ODC) which is irreversibly inhibited by alpha-difluoromethylornithine (DFMO). It has been postulated that pretreatment with DFMO may render cells more susceptible to subsequent chemotherapy. Copenhagen X Fischer F1 rats bearing the Dunning R3327 MAT-LyLu prostatic adenocarcinoma were given DFMO or adriamycin (ADR), alone or in combination. Those receiving DFMO were continuously provided the drug ad libitum, in water (2.5%), for the duration of the experiment, beginning 2 days prior to ADR administration. At intervals, tumor sizes were measured, animal survivals noted and comparisons made to nontreated, tumor-bearing controls. The results indicate that ADR alone or in combination with DFMO significantly reduced tumor progression, but that only combination therapy significantly prolonged survivals. Decreased tumor progression produced by DFMO alone was not statistically significant. Differences produced with combined use were additive and suggest that DFMO may augment ADR chemotherapy.

Immunoregulatory markers in rats carrying Dunning R3327 H, G, or MAT-LyLu prostatic adenocarcinoma variants.

The Dunning R3327 tumor represents a system for studying prostate cancer in Copenhagen X Fischer rats. Animals bearing variant sublines (H, G, and MAT-LyLu) differing in growth rate, differentiation, hormone responsiveness, and metastatic ability were assayed for three immunological markers. Spleens were passed through a tissue sieve, and mononuclear cells were obtained by Ficoll-Hypaque centrifugation. These were assayed for leukocytic subsets using monoclonal antibodies. An adherent population was isolated and evaluated using thin-layer chromatography for conversion of radiolabeled arachidonic acid to E series prostaglandins. Finally, sera from these animals were assayed for levels of circulating immune complexes using polyethylene glycol precipitation. Data from 52 rats bearing the various tumors were obtained, correlated with subline aggressiveness, and compared to 15 controls. Each tumor group demonstrated significantly lower helper/suppressor T-cell ratios than controls, probably due to general tumor presence. In addition, the most aggressive R3327 MAT-LyLu variant had significantly increased prostaglandin E synthesis by adherent spleen cells compared to the H or G sublines and significantly increased levels of circulating immune complexes relative to the H subline. G subline values for both prostaglandin E and circulating immune complexes levels were intermediate, suggesting that these markers correlate better with tumor aggressiveness than helper/suppressor T-cell ratios.

Administration of recombinant tumor necrosis factor to rats bearing the Dunning R3327 MAT-LyLu prostatic adenocarcinoma.

Copenhagen X Fischer F1 rats bearing palpable Dunning R3327 MAT-LyLu prostatic adenocarcinomas were treated by intraperitoneal (i.p.) or intratumor (i.t.) injection with either human serum albumin alone or in combination with recombinant tumor necrosis factor (rTNF). At intervals tumors were measured and survivals noted. A maximum tolerable dose and least toxic route of administration was then determined. Those treated i.t. with rTNF survived significantly longer and ultimately developed significantly smaller tumors than untreated controls. Those administered rTNF by the i.p. route had less significant increases in survival with intermediate final tumor sizes.

Effect of cyclophosphamide on leukocytic subset distributions in rats carrying the Dunning R3327-MAT-LyLu prostatic adenocarcinoma.

The Dunning R3327 adenocarcinoma represents a model for studying prostate cancer in rats; early studies have indicated its utility for studying relationships between tumor growth, immunologic markers, and chemotherapy. Normal animals and those bearing the metastatic Dunning R3327 MAT-LyLu tumor were treated with 10, 30, and 100 mg/kg doses of cyclophosphamide (CTX) and their spleens assayed for leukocytic subset distributions using monoclonal antibodies. Tumor-bearing animals had significant reductions in helper T cell content as well as reduced helper/suppressor T cell ratios, compared to controls. These effects occurred rapidly following implantation and were not reversed by chemotherapy. When administered to both tumor- and non-tumor-bearing animals, CTX also depleted T cell populations. Despite reductions produced in all subsets, two administrations of CTX (30 mg/kg) were capable of retaining (in non-tumor-bearing animals) or restoring (in tumor-bearing) normal helper/suppressor T cell ratios. Such studies aid in identifying therapeutically effective dosages of cytotoxic drugs that minimize their deleterious effects on the immune system.

Leukocytic subset distributions of spleen cells obtained from rats bearing variants of the Dunning prostatic adenocarcinoma.

Employing monoclonal antibodies, the relative frequencies of mononuclear cell types found in spleen cell populations were compared between rats bearing variants of the Dunning prostate adenocarcinoma and a series of non-tumor bearing control animals. The identification and quantitation of such subsets greatly expands our knowledge of immune status and function. The results indicate that the spleen cell populations from animals bearing either the Dunning R3327-H, G or MAT-LyLu sublines have significant decreases in their helper T cell/suppressor T cell ratios when comparisons are made to cells obtained from non-tumor bearing animals. In addition decreases in total T cell content and increases in splenic monocytes were noted. It appears that most of these deviations are the result of general Dunning tumor presence, rather than due to any particular subline characteristic. These changes may be analogous to similar alterations reported in the peripheral blood of humans bearing Stage D prostatic cancer, suggesting that the Dunning tumor may provide an appropriate model for evaluating interactions between the immune response, the tumor and therapy.

Adherent spleen cell production of E series prostaglandins in rats bearing variants of the R3327 Dunning prostatic adenocarcinoma: effect of cyclophosphamide.

Prostaglandins of the E series (PGE) have been implicated in many facets of immunoregulation, as well as having a possible role in metastatic dissemination. Variant sublines of the Dunning R3327 rat prostatic adenocarcinoma, differing in growth rate, hormonal responsiveness and in propensity for metastasis, were carried in Fisher X Copenhagen F1 animals. Adherent spleen cells were assayed in vitro for their ability to convert arachidonic acid to prostaglandins of the E series. These glass adherent cells presumably include the monocytic and T cell populations which have been implicated as being immunoregulatory. The results indicated that those spleen cells obtained from animals carrying the metastatic R3327-MAT-LyLu subline tumor converted more arachidonic acid to PGE's than cells derived from animals bearing non-metastatic sublines. Cyclophosphamide therapy did not alter such conversion. Multiple regulatory mechanisms for prostaglandin metabolism are suggested.

Immunobiology of the Dunning R-3327 rat prostate adenocarcinoma sublines: plasma and tumor effusion prostaglandins.

Enhanced production of prostaglandins (PGs) by experimentally-induced and naturally occurring tumors and their effect on tumor growth and immunosurveillance have been noted. Directed toward further evaluation of the relationship between prostatic tumor growth and its milieu, i.e., microenvironment, we investigated the possible correlation between levels of PGs, tumor size, and metastatic potential. For this purpose, the levels of PGE2 and PGF2 alpha in plasma and tumor effusions of three tumor sublines of the Dunning R-3327 rat prostate adenocarcinoma were measured: R-3327H, well-differentiated, slow-growing, and poorly metastatic; R-3327G, poorly differentiated, fast-growing, and poorly metastatic; and R-3327 Mat LyLu, anaplastic, fast-growing, and highly metastatic. The level of PGF2 alpha was highly variable with no significant differences being noted between the tumor sublines. The mean values of PGF2 alpha were, however, higher, although not significantly so, in the smaller tumors within each of the sublines. The levels of PGE2 were significantly higher in Mat LyLu effusions than those from the nonmetastasizing R-3327G and H sublines. Evaluation and comparison of the relationship between tumor burden, i.e., size versus levels of PGE2 and PGF2 alpha showed no significant differences. A vasodilator and regulator of immunological responsiveness, PGE2, may function as a modulator of tumor metastases. In consonance with studies by others elevated levels of PGE2 may possibly serve as a prognostic marker for the high metastatic potential of neoplastic cells.

Effect of transfer factor on tumor-associated immunity and tumor growth of the Dunning R-3327G rat prostate adenocarcinoma.

Of importance in the design and application of improved or new modalities of treatment are their evaluation on relevant animal models. In the case of prostate cancer (PCa) the Dunning R-3327 rat prostate adenocarcinoma (PCa), and its variant sublines, is one such experimental tumor model of its human counterpart. In a preliminary study, the effect of transfer factor (TF), one form of passive immunotherapy, on tumor-associated immunity (TAI) and tumour growth and histology of the G subline (a poorly differentiated, fast-growing, androgen sensitive, and poorly metastatic tumour of the Dunning R-3327 rat PCa) has been evaluated. TF prepared from the leukocytes of tumor-bearing animals and nontumor-bearing animals referred to as sensitized (STF) and unsensitized (UTF), respectively, had no significant effect on TAI or tumor size. The only noticeable effect of TF in this study was the presence of variable and moderate lymphocytic infiltrates, necrosis, and degenerative-type cells in tumors of animal recipients of STF. The failure to observe significant differences in TAI among tumor bearing and nontumor bearing animals raises doubt in part, of the immunogenicity of the G subline tumor and its appropriateness, at least for subsequent immunological studies. Further factors considered in this regard, are questions of tumor load, including the possible need for the use of adjuvant, and the parameters and sensitivity of immune responsiveness selected for evaluation and immunocompetency. Subsequent evaluation of the effect of TF on other more immunogenic variant sublines of the Dunning R-3327 rat tumor may yet provide further and more useful information.