Clinical studies on the prognostic factors in prostate cancer

To evaluate the prognostic factors and the outcome of treatment, a retrospective study was done on 141 patients with prostate cancer who were newly diagnosed at Kitano Hospital between January 1985 and November 1996. In recent years, the number of patients and the ratio of low stage cancer have increased. The overall 5-year crude survival rate was 49.9%. The 5-year crude survival rate for clinical stage A, B, C and D was 67%, 70%, 62% and 30% respectively. The overall 5-year disease-specific survival rate was 65.6%. The 5-year disease-specific survival rate for clinical stage A, B, C and D was 100%, 89%, 72% and 42%, respectively. By univariate analysis, clinical stage, Gleason score, prostate specific antigen (PSA) level, and patient age were prognostic factors for disease-specific survival of prostate cancer. According to Cox's regression analysis by the stepwise forward regression method, clinical stage and Gleason score were selected as more valuable prognostic factors than PSA level, patient age, comorbidity, and initial treatment. In Gleason score 2 to 8, the prognosis became significantly worse as clinical stage advanced, but in Gleason score 9 and 10 the prognosis was poor regardless of clinical stage.     

Tumor-related prognostic factors for breast cancer

Interest in prognostic factors for breast cancer has been stimulated by the success of systemic adjuvant therapy for early-stage operable disease. Patients destined for recurrence can be selected for systemic adjuvant therapy, while patients not likely to recur can be spared the morbidity of unnecessary treatment. The number of tumor-related features available for prognosis has grown impressively in recent years. The purpose of this article is to review tumor-related biologic factors and relate them to prognosis and treatment objectives.     

Statistical modeling using preoperative prognostic variables in predicting extracapsular extension and progression after radical prostatectomy for prostate cancer

OBJECTIVE: To predict the risk of extracapsular extension and postoperative recurrence before radical prostatectomy (RP) for prostate cancer. METHODS: We performed multivariate Cox regression analysis on preoperative variables in 260 clinically localized prostate cancer patients who underwent RP. With these data, we constructed a relative risk of recurrence (Rr) equation and an equation to predict the probability of extracapsular extension (PECE) before RP. RESULTS: Rr is calculated as exp[(0.47 x race + 0.14 x PSAST) + (0.13 x worst biopsy Gleason sum) + (1.03 x stage T1c) + (1.55 x stage T2b,c)], where PSAST indicates a sigmoidal transformation of prostate-specific antigen. PECE is calculated as 1/[1 + exp(-Z)], where Z = -2.47 + 0.15 (PSAST) + 0.31 (worst biopsy Gleason sum) + 0.18 (race) + 0.16 (stage T1c) + 0.38 (stage T2b,c). CONCLUSION: These two equations can be used preoperatively to predict the probability of extracapsular disease and the risk of prostate-specific antigen recurrence in patients undergoing RP.     

Growth factor involvement in progression of prostate cancer

Understanding how the regulation of growth factor pathways alters during prostate cancer (PC) progression may enable researchers to develop targeted therapeutic strategies for advanced disease. PC progression involves the shifting of cells from androgen-dependent growth to an androgen-independent state, sometimes with the loss or mutation of the androgen receptors in PC cells. Both autocrine and paracrine pathways are up-regulated in androgen-independent tumors and may replace androgens as primary growth stimulatory factors in cancer progression. Our discussion focuses on growth factor families that maintain homeostasis between epithelial and stromal cells in the normal prostate and that undergo changes as PC progresses, often making stromal cells redundant. These growth factors include fibroblast growth factor, insulin-like growth factors, epidermal growth factor, transforming growth factor alpha, retinoic acid, vitamin D3, and the transforming growth factor beta families. We review their role in normal prostate development and in cancer progression, using evidence from clinical specimens and models of PC cell growth.     

Clinical and molecular prognostic factors in sphincter-preserving surgery for rectal cancer

As many as a third of patients with rectal cancers may be candidates for sphincter preservation surgery. The goal of the conservative management of adenocarcinoma of the distal rectum is to preserve rectal sphincter function without sacrificing local tumor control. To achieve this goal, a combined modality approach is necessary because multimodality therapy for more advanced disease has improved both local control and survival. Candidates for local excision are those with adenocarcinomas with a maximal diameter of less than 4 cm, mobile, and not poorly differentiated or mucinous and within 10 cm of the anal verge--usually within 6 cm. These criteria should be defined objectively by biopsy combined with state-of-the-art endorectal imaging. Newer molecular markers that are associated with prognosis and response to therapy may also be important for assessing prognosis, probability of local recurrence, and whether conservative treatment is appropriate. Patients with T0-3 N0 lesions meeting these standard clinicopathologic criteria have been treated successfully with wide local excision combined with chemotherapy and radiotherapy. Patients with larger or more advanced lesions may undergo low anterior resection with coloanal anastomosis. After resection, radiotherapy to at least 45 to 50 Gy is delivered to the pelvis and tumor bed often with concomitant chemotherapy. The overall rate of local failure in prospective single-institution trials in which local excision is performed with postoperative chemoradiotherapy has been 5% for T1 lesions, 7% for T2 lesions and 24% for T3 lesions. Although single-institution studies have supported the concept of conservative therapy, the safety and efficacy of this approach must still be confirmed in a multicenter, prospective trial, such as that underway in several of the cooperative oncology groups, before it may be considered a standard of practice.     

Androgen receptor gene mutations in prostate cancer. Implications for disease progression and therapy

Increasing numbers of cancer survivors and the tradition of long-term follow-up in the outpatient clinic has resulted in overcrowded oncology clinics and long waiting times. Little is known about patients' perceptions of their clinic attendance. This survey of 252 oncology patients investigated patients' satisfaction with the clinic, anxiety associated with clinic attendance and the strengths and weaknesses of the oncology service. Results demonstrated high levels of satisfaction. Far from being perceived as anxiety-provoking, the clinic was looked upon as a valuable source of reassurance, 92% of patients reporting they were 'always' or 'usually' reassured as a consequence of their visit. Qualitative data showed that clinic staff were the most important source of satisfaction. Waiting was overwhelmingly the worst aspect of the clinic, described by 27% of patients as 'excessively long'. One-fifth of the total sample had attended the clinic for 10 years or more and over a third of this group reported they would be worried at the prospect of being discharged to the care of their general practitioners. Despite disadvantages associated with long waits, the clinic was perceived as providing a valuable source of reassurance which a proportion of patients were clearly reluctant to be without.     

Immunosuppressive factors: role in cancer development and progression

The concept of the immunological surveillance against neoplastic cells was initially proposed by Erlich in 1909 and later elaborated by Burnet. This hypothesis states that the normal function of the immune system, in particular the cell-mediated immunity, is to recognize and destroy the transformed and proliferating tumor cells. The role of cell-mediated immunity during the first steps of tumorigenesis remains controversial. However, there is certain evidence about its importance in the progression and dissemination of cancer. The frequent immunosuppressed condition of cancer patients at tumor relapse or recurrence of secondary tumors is a clinical sign supporting this hypothesis, and many studies have demonstrated a defective immune response in patients diagnosed with advanced cancer. Several mechanisms of escape from the immune surveillance have been described, including the immunoselection of tumor antigen-negative variants, the downregulation of MHC class I expression, suppressive T cells, and the elaboration of immunosuppressive cytokines and other factors. Because of the technical difficulty of isolating the very small amounts from culture supernatants or body fluids, only a few of these substances have been characterized and studied with respect to their biological activity: transforming growth factor-beta (TGF-beta), the protein p15E, interleukin 10 (IL-10), prostaglandin E2 (PGE2), mucins, suppressive E-receptor (SER), immunosuppressive acidic protein (IAP), and adhesion molecules. The possibility of monitoring cancer patients by testing biochemical factors related to cancer growth led to a proposal to measure a number of these factors as tumor markers. Some of them, e.g. mucins, enjoy the consensus of the oncologic community, as for some indications they can help the clinician in the management of cancer patients. Except for the class of mucins, the other above-mentioned immunosuppressive factors have not found any clinical application in the laboratory routine because the information deriving from their measurement, although of speculative and scientific interest, has limited clinical value at present. Nevertheless, even if they have no impact on patient management, these substances do have a potential role to play in the study of cancer patients, and should be taken into account when developing new therapeutic strategies.     

Is prostate specific antigen density an important prognostic indicator for patients with prostate cancer treated with external beam therapy?

The purpose of this study was to determine if prostate specific antigen density (PSAD) is a predictor of outcome following external beam radiotherapy for prostate cancer, and to compare it with other prognostic factors. Between January 1990 and December 1993, 205 patients with T1-T3 adenocarcinoma of the prostate received a radical course of external beam irradiation, with no prior or adjuvant hormonal therapy. All patients had pre- and post-treatment serum prostate specific antigen (PSA) evaluation. They were followed up for at least 24 months. PSAD was defined as the ratio of pre-treatment serum PSA to the prostate volume, as determined from CT treatment planning scans. Prostate volumes were calculated using the prostate ellipse formula. Median PSA density was 0.37, with a range 0.01-6.7. Biochemical failure was defined as three consecutive rises in serum PSA, regardless of the magnitude of elevation. 4-year biochemical disease-free survival (BDFS) for patients with PSAD < or = 0.3 was 60%, compared with 22% for patients with PSAD > 0.3 (p = < 0.001). In a multivariate analysis, pre-treatment PSA (p = < 0.001), Gleason score (p = 0.002), and stage (p = 0.03) were independent predictors of BDFS, while PSAD was not an important prognosticator (p = 0.62). Pre-treatment serum PSA is the most important prognosticator of BDFS, following external beam radiotherapy, for patients with prostate cancer. PSA density did not predict treatment outcome.     

E-cadherin and associated molecules in the invasion and progression of prostate cancer

Prostatic carcinoma is the most common type of male cancer found in the Western world and its distant metastasis becomes a life threatening event in tumour bearing patients. However, the biology of prostate cancer and metastasis is poorly understood. We review the progress made in the last decade on the molecular and cellular biology of cell-cell adhesion molecules in the invasion and progression of prostate cancer, with emphasis being placed on E-cadherin and its associated molecules.     

p53 expression in breast cancer related to prognostic factors

In this article the results of molecular marker p53 examinations were presented in relation to the following established breast cancer prognostic factors: age, histologic type, histologic grade, lymph node involvement, tumor size as well as estrogen a progesterone receptor status. Twenty one percent of these primary breast cancer specimens exhibited the overexpression of p53 protein. Significant associations were found between p53 overexpression and younger age, high histologic grade and low content of estrogen and progesterone receptors. Identification of p53-positive breast carcinomas potentially represents a clinically useful indicator of breast cancer aggressiveness.     

Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer

Cells possess within their epigenetic repertoire the ability to undergo an active process of cellular suicide termed programmed (or apoptotic) cell death. This programmed cell death process involves an epigenetic reprogramming of the cell that results in an energy-dependent cascade of biochemical and morphologic changes (also termed apoptosis) within the cell, resulting in its death and elimination. Although the final steps (i.e., DNA and cellular fragmentation) are common to cells undergoing programmed cell death, the activation of this death process is initiated either by sufficient injury to the cell induced by various exogenous damaging agents (e.g., radiation, chemicals, viruses) or by changes in the levels of a series of endogenous signals (e.g., hormones and growth/survival factors). Within the prostate, androgens are capable of both stimulating proliferation as well as inhibiting the rate of the glandular epithelial cell death. Androgen withdrawal triggers the programmed cell death pathway in both normal prostate glandular epithelia and androgen-dependent prostate cancer cells. Androgen-independent prostate cancer cells do not initiate the programmed cell death pathway upon androgen ablation; however, they do retain the cellular machinery necessary to activate the programmed cell death cascade when sufficiently damaged by exogenous agents. In the normal prostate epithelium, cell proliferation is balanced by a equal rate of programmed cell death, such that neither involution nor overgrowth normal occurs. In prostatic cancer, however, this balance is lost, such that there is greater proliferation than death producing continuous net growth. Thus, an imbalance in programmed cell death must occur during prostatic cancer progression. The goal of effective therapy for prostatic cancer, therefore, is to correct this imbalance. Unfortunately, this has not been achieved and metastatic prostatic cancer is still a lethal disease for which no curative therapy is currently available. In order to develop such effective therapy, an understanding of the programmed death pathway, and what controls it, is critical. Thus, a review of the present state of knowledge concerning programmed cell death of normal and malignant prostatic cells will be presented.     

Screening for prostate cancer

In an attempt to detect prostate cancer when the tumor is still confined to the prostate, a screening program was established. We studied the efficacy of digital rectal examination (DRE) and serum prostate-specific antigen (PSA) in the early detection of prostate cancer. One thousand men aged 50-75 years underwent DRE and serum PSA determination. Transrectal ultrasound-guided biopsies were obtained in each case of a suspicious DRE. Six systematic biopsies were performed if the PSA level was > 10 ng/ml, even if DRE and transrectal ultrasonography revealed no areas suspicious of cancer. A suspicious DRE was noted in 11.5% of the subjects; 16% had elevated levels of serum PSA (> 4 ng/ml) and 3.9% had serum PSA > 10 ng/ml. Biopsies were obtained from 90 patients, of which 31 were positive for prostate cancer. The cancer detection rate was 2.2% for DRE, 2.0% for PSA > 10 ng/ml, and 3.1% for the two methods combined. Clinical staging revealed that in 29 of the 31 patients with prostate cancer, the tumor was confined to the prostate: Stage A in 9 cases and stage B in 20 cases. Only two patients had clinically advanced cancer, and 22 patients underwent radical prostatectomy. Pathological examination disclosed biologically significant tumors in 91% of the cases in terms of tumor volume and grade. Although there is little evidence that screening will result in the reduction of the disease-specific mortality rate, early detection of prostate cancer by DRE, serum PSA, and transrectal ultrasound should be encouraged.     

Clustered p53 immunostaining: a novel pattern associated with prostate cancer progression

Abnormal p53 protein accumulation is typically defined as present when greater than 5 or 10% of cancer cells stain positively. We present a novel approach whereby immunopositivity is defined when 15 or more cells within a 300 x 400-micrometer(2) field exhibit p53 protein accumulation; a feature that we have called "clustered" staining. We assessed p53 immunostaining of moderately differentiated, clinically localized prostate cancers derived from two patient groups: those without cancer recurrence 5 years after radical prostatectomy, and those in whom cancer had recurred following radical prostatectomy. Clustered p53 immunopositivity was present in 10 (63%) of 16 patients in the recurrent group and in only 7 (21%) of 33 in the nonrecurrent group. Clustered p53 staining was clearly associated with cancer recurrence (P < 0.01). This refinement of a commonly used assay may help define the biological aggressiveness of a cancer.     

Trisomy 7 by dual-color fluorescence in situ hybridization: a potential biological marker for prostate cancer progression

Smear preparations from fine-needle aspirates of 30 prostatic carcinomas obtained from radical prostatectomy specimens were examined by a dual-color fluorescence in situ hybridization (FISH) method for the presence of chromosome 7 trisomy (chromosome 9 was used as a control). The frequency of cells with trisomy 7 was determined in tumor cells and normal prostatic epithelial cells in each specimen. Comparison between the tumor and normal cells from the same patients showed that within all stages, the frequency of trisomy 7/disomy 9 cells in the tumor cells was significantly higher than that observed in the normal cells (P < 0.0001). Furthermore, the mean frequency of cells with trisomy 7/disomy 9 in advanced stages was significantly elevated over the mean frequency observed in organ-confined tumors (P = 0.02). These results are consistent with our previous data on paraffin-embedded prostate tissue sections using single-color FISH procedures. However, the method used in the present study enhances the accuracy of distinguishing trisomic 7 cells from potentially triploid (trisomy 7/trisomy 9) cells. Furthermore, the use of fine-needle aspirates rather than paraffin sections provides an easy method to examine whole nuclei. Our study also suggests that FISH provides a better measure of genetic instability (e.g., aneuploidy) in prostate tumors than flow cytometry.     

Influence of delayed diagnosis on established prognostic factors in endometrial cancer

To evaluate the influence of delayed diagnosis on prognostic factors in endometrial cancer, we conducted a retrospective chart analysis based on the data of 116 postmenopausal patients with FIGO stage I-IV endometrial carcinoma. The interval from the first episode of post-menopausal vaginal bleeding to definitive, histological diagnosis (bleeding interval) was compared with tumor stage and various histomorphologic features in endometrial cancer. The mean bleeding interval was 12.7 +/- 17.8 weeks in 74 patients with FIGO stage IA, IB endometrial carcinoma and 35.2 +/- 69.3 weeks in 42 patients with stage IC-IV disease (t-test, p: 0.011). FIGO stage IA, IB disease was diagnosed in 23/26 (88%) patients with a bleeding interval <4 weeks, and in 22/34 (64%) and 29/56 (51%) patients with bleeding intervals of 4-8 weeks and >8 weeks, respectively (Chi-square 10.358, p=0.006). The correlation with histologic grade, lymph-node status, vessel invasion and histologic subtypes did not reach statistical significance. Our data confirm the clinical impression that postmenopausal vaginal bleeding is an early symptom in patients with endometrial cancer, and that advanced disease in the majority of cases might come from delayed diagnosis in women with poor compliance.     

Chemotherapy for hormone-refractory prostate cancer

Chemotherapy may be an appropriate treatment for patients with evidence of disease progression despite of antiandrogen withdrawal or secondary hormonal therapy. But none of the chemotherapeutic regimens, neither monotherapy nor combination therapy, were shown to be superior to another with regard to survival. The criteria to assess the effect of chemotherapy on disease-related symptoms and quality of life is expected to be framed. Preclinical investigations and well-designed, well-powered clinical trials remain key to altering the natural history of hormone-refractory prostate cancer.