NCCN Practice Guidelines for Prostate Cancer.

Systemic therapies for prostate cancer are likely to improve, and as they do, they will have enormous impact on the treatment of high-risk and locally advanced cancers. Further technical improvements in radiotherapy and alternative local modalities, such as cryoablation, are also likely, and will bring even more options for local control. It is certain these guidelines will continue to evolve.

Cryosurgical ablation of the prostate.

Cryosurgery for the treatment of prostatic disease, a technique that originated in the mid-1960s and was almost abandoned in the mid-1970s, has re-emerged in the 1990s for the treatment of cancer of the prostate. This renewed interest is due to several factors, including the development of intraoperative ultrasound, the refinement of percutaneous access techniques, and improvements in cryosurgical apparatus. The modern technique features the transperineal percutaneous placement of several (generally five or six) metal probes, each 3 mm in diameter, in the prostate under ultrasound guidance. After insertion, the probes are cooled in a manner that produces complete freezing of the prostate and, if required, extraprostatic extensions of disease. The freezing process is monitored by ultrasound, which provides an image of the boundary of freezing as it advances through the prostate and thereby provides control of the extent of freezing. This review describes the historical background of prostatic cryosurgery and the current status of this new procedure, including the important issues of case selection, technique, and results. The recent nature of this experience precludes judgment of long-term merit, but the favorable short-term results of cryosurgical ablation of the prostate encourage further selective use of this technique in the treatment of prostate cancer. Definition of appropriate patient selection and optimal technique are needed to improve treatment by cryosurgery.

Pathology and its importance in evaluating outcome in patients with superficial bladder cancer.

Subtle cytologic and histologic nuances have a major impact on diagnosis and, consequently, on therapy for superficial bladder cancer. Therefore, the urologist and the pathologist must carefully assess all clinical findings before a course of treatment can be determined. The urologist must advise the pathologist of all the circumstances surrounding a biopsy--whether its purpose is for preliminary clinical impression or diagnosis, the patient's recent treatment history, the availability of previous biopsy specimens for comparison, a thorough history of treatments that may induce characteristic cytologic changes that might lead to misdiagnosis, and alternate diagnostic possibilities drawn from initial pathology and treatment history. Armed with this information, the task of the pathologist is to provide as much data as possible regarding tumor histopathology from the biopsy specimens. Thus, establishment of a close working relationship between the urologist and the pathologist is an important tool for (1) initially characterizing superficial bladder cancer, which is essential in determining an appropriate course of treatment, and (2) accurately evaluating follow-up biopsies to determine the effectiveness of that treatment.

Intravesical chemotherapy versus immunotherapy for superficial bladder cancer.

The decision to treat superficial bladder cancer with intravesical therapy should be predicated primarily on disease stage and grade as well as the patient's clinical history. Once the decision to proceed with intravesical therapy has been made, the clinician must select the appropriate agent. Several agents are available and the choice of which agent to use should be based on careful consideration of the potential benefit of a given drug versus its inherent risk of complications. The first drug to be administered intravesically, thiotepa is an alkylating agent used as first-line treatment for low-grade lesions; it has limited use against higher-grade tumors or carcinoma in situ. In addition, the low molecular weight of thiotepa results in significant systemic absorption, which often results in myelosuppression. Mitomycin, also an alkylating agent, has shown significant activity as both first-line therapy and in patients with recurrent disease. Unlike thiotepa, mitomycin has a relatively high molecular weight, and the incidence of significant bladder absorption and systemic side effects is low. Doxorubicin, which also possesses a high molecular weight, is used intravesically against superficial bladder cancer more frequently in Europe and Japan than in the United States. Immunotherapy with bacille Calmette-Guérin is the treatment of choice for carcinoma in situ and high-grade T1 lesions. It is associated with the highest incidence of both minor and major adverse reactions, however, and its use should be tempered by its potential toxicity.

Primary renal sarcoma.

Primary renal sarcoma represents approximately 1 per cent of all primary tumors of the kidney. The purpose of this study is to review the experience at Roswell Park Cancer Institute with the treatment of primary renal sarcoma. Four patients with a diagnosis of primary renal sarcoma admitted from 1976 to 1983 form the basis of this review. All patients underwent radical nephrectomy. The tumor was localized in two patients, and locally invasive in two patients. All patients had recurrence of metastatic disease. Patients with localized disease recurred at 19.0 and 25.0 months respectively. Patients with invasive disease recurred at 4.0 and 5.0 months respectively. Patients presenting with localized disease survived a mean of 34.0 months. Patients presenting with invasive disease died at 6.0 and 10.0 months from time of diagnosis. Primary renal sarcoma is a rare entity. Only patients presenting with localized disease have a reasonable chance for prolonged survival.

Effect of perioperative chemoimmunotherapy with cyclophosphamide and autologous tumor vaccine in murine MBT-2 bladder cancer.

The in vitro cytotoxic activity of splenocytes from C3H/He mice implanted subcutaneously with 10(6) syngeneic MBT-2 tumor cells on day 0 was significantly enhanced after cyclophosphamide (100 mg./kg., intraperitoneally) given 2 days before tumor resection on day 17, with or without active specific immunization with BCG plus autologous irradiated tumor cells (vaccine) 1 week after tumor resection. Furthermore, a significantly lower tumor incidence was seen in mice challenged with 10(5), but not 10(6), tumor cells per mouse 24 hours after tumor resection on day 17 and treated with cyclophosphamide on day 15 and postoperatively with vaccine than was found in nontreated tumor resected mice. Phenotypic analysis of cells from spleen showed that cyclophosphamide pretreatment and postoperative vaccine, either singly or in combination, induced a significant increase of both CD44+ memory T cells and CD11b+ myeloid/macrophage cells. Thus, in addition to a specific antitumor immune response, a nonspecific cytolytic mechanism may also play a role in the observed antitumor effect.

Adrenal adenocarcinoma: a review of 53 cases.

PROBLEM: Fifty-three patients (30 men, 23 women) with histologically proven adrenal carcinoma were reviewed. Nineteen (36%) had endocrine manifestations from functioning tumors. Arteriography was positive in 95% (19/20), CT scan in 94% (17/18), and ultrasound in 92% (12/13). Seventy-six percent of the patients, at the time of diagnosis, were stage III and IV. Most common metastatic sites were the liver, lymph nodes, bone, and lungs. Local recurrence developed in 39% of cases (15/38). METHOD: Forty-one patients underwent an operation. Complete surgical removal of all gross tumor was achieved in 24 patients. RESULT: The overall median survival time was 8 months, and the estimated 5-year survival rate 19%. There were significant differences in survival between the various stages (P = 0.01) and between the group of patients who underwent complete excision of the tumor and those with incomplete resection (P = 0.002). CONCLUSIONS: Complete surgical excision offers the best prospect for long-term survival in localized adrenal carcinoma.

A new approach in the diagnosis and follow-up of bladder cancer. FISH analysis of urine, bladder washings, and tumors.

The aim of the present study was to ascertain whether fluorescence in situ hybridization (FISH) of urine could be a useful approach in bladder cancer. Herein, we present the cytogenetic and FISH findings in patients with and without bladder cancer. The samples examined with FISH consisted of urine, bladder washings, and tumor tissue, when available. The results obtained show that the FISH technique, particularly when used on urine, is a very useful tool in the diagnosis, early detection, and management of bladder cancer.

Prognostic factors in survival of bladder cancer.

Clinical and pathologic data of 36 patients with transitional cell carcinoma of the bladder were investigated to determine the significance on patient survival of these factors: pathologic grade and stage; the immunohistochemistry of eight cell and tumor markers; nuclear DNA flow cytometric parameters; and patient smoking status. The bivariate and multivariate statistical analysis significantly correlated patient survival rates with the immunohistochemical expression of blood group, isoantigens A (P less than 0.05), O(H) (P = 0.001), the oncogene-related protein ORP-p21 (P less than 0.05), the pathologic grade and stage (P = 0.002), and the tumor DNA ploidy (P less than 0.05). Smoking status correlated aneuploidy (P less than 0.05) and tumor expression of ORP-p21 (P less than 0.05) with the patient survival rate. Despite the relatively small number of patients in this study, the results suggest that the clinicopathologic variables are significant factors in survival of bladder cancer.

Growth of human renal cortical tissue on collagen gel.

A model system for 3-dimensional "native-state" culture of tissues on collagen gels (Proc. Natl. Acad. Sci. USA 86:2013-2017; 1989) has been applied in this study to histologically normal human renal cortical tissue from 11 patients undergoing nephrectomy for renal cell carcinoma elsewhere in the kidney. Microbial contamination occurred in 12/90 cultures, the rest (78) were studied by visual inspection, histology, immunohistochemical analysis for pankeratin (epithelial cell origin), vimentin (mesenchymal cell origin), and p-glycoprotein (associated with proximal tubules), transmission electron microscopy (EM), incorporation of tritiated thymidine (3HTdR). In the first 10 days, explants showed 3HTdR-labeled cells in tubule structures. The surrounding gel was invaded by cells forming tubule structures, sometimes with basement membrane. Some of these cells showed labeling by 3HTdR and immunostaining positive for pankeratin and p-glycoprotein. EM showed well-polarized epithelial cells in tubule structures with tight junctions, interdigitating lateral processes, and microvilli characteristic of proximal and distal convoluted tubules. 3HTdR-labeled cells in tubule structures were observed even 2 mo. after Passage 1, 6 mo. after the initial explantation. Tubule growth was most active and fibroblast proliferation was negligible from 2 to 4 wk postexplantation. The proliferation of tubulelike cells and formation of tubulelike structures in this system represents an opportunity to study human renal cortical tissue in vitro, under conditions more closely resembling in vivo circumstances than are present in other in vitro systems suitable for long-term study. This model has potential use for in vitro toxicology studies and studies of renal physiology.

Hormone therapy of prostatic bone metastases.

When present at diagnosis or when developing in the course of disease, the presence of bone metastases from prostate cancer is generally considered an indication to begin endocrine therapy, as this is clearly the most effective form of treatment for this problem. Endocrine therapy can stop progression of prostate cancer in 80-85% of cases. Endocrine therapy can relieve pain, prevent pathologic fractures, and prevent neurologic complications from bone metastases from prostate cancer. Rarely, bone scans may become normal after the start of endocrine therapy, but partial improvement or stabilization of bone scans are more commonly seen. While endocrine therapy has been the first line of treatment of metastatic prostate cancer for the past 50 years, the recent development of newer forms of endocrine therapy have increased the options in the past few years. In addition to orchiectomy and estrogens, newer alternatives include inhibitors of androgen synthesis, the class of agents termed "antiandrogens", and luteinizing hormone releasing-hormone (LHRH) analogues either alone or in combination. Orchiectomy causes a prompt fall in serum testosterone and is regarded by many as the "standard" form of endocrine therapy, but there is concern about the psychologic impact of surgery. Estrogens are being used less frequently today because of their real or potential side-effects, including cardiovascular and thromboembolic complications. The development of analogues of LHRH has resulted in another major choice for endocrine therapy, and one which is therapeutically equivalent to orchiectomy or estrogens. Since LHRH analogues may cause an early rise or "flare" in serum testosterone before it drops to castrate level, these agents should not be given alone to patients with severe pain or neurologic problems. The newly available antiandrogen flutamide can block the "flare", and may also improve survival when used with LHRH analogues or orchiectomy, especially when disease is less advanced. Not all studies of "combination therapy" support this conclusion. However, the use of flutamide is increasing significantly in the United States. Both the LHRH analogues and flutamide are fairly safe, but they are very expensive. Their use, in combination, is likely to become a progressively more common form of initial endocrine therapy in the future. The growing application of prostate specific antigen (PSA) as a tumor marker for prostate cancer has made the difficulty in interpreting changes in bone scans a much less critical problem in determining response to endocrine or other forms of therapy for advanced prostate cancer.

Chylous ascites and lymphocyst management by peritoneovenous shunt.

Although lymphocyst (retroperitoneal lymphocele) is not an uncommon complication after retroperitoneal surgery, with a reported incidence ranging from 0.6% to 48%, the occurrence of chylous ascites is a rare phenomenon. Most reports are anecdotal, and hospital records list the incidence of diagnosis as 0.001% of admissions. Diagnosis of chylous ascites is usually not difficult, inasmuch as aspiration and chemical analysis of the fluid yield the answer. Visualization of retroperitoneal fluid collection by computerized tomography or ultrasonography, however, does always raise the possibility of recurrence of tumor in cases where the primary operation was for cancer. Treatment of smaller lesions can be expectant. Respiratory exercises causing an increase in negative intrathoracic pressure may aid in the movement of fluid through the lymphatics. For larger collections, elemental diets and total parenteral nutrition are also often enough, but surgery is sometimes required. Simple insertion of a peritoneovenous shunt, as in this patient, can be as effective as major operations such as identification and ligation of the offending lymphatic or marsupialization of the cyst.

Drug therapy of prostatic cancer.

While hormonal therapy has been the usual and appropriate treatment of advanced or metastatic prostatic cancer for the past 50 years, the recent development of new therapeutic agents as medical alternatives to orchidectomy has drastically altered the options and perspectives in the treatment of this disease. Estrogens had been the only commonly used drug therapy in the United States. Newer alternatives include androgen synthesis inhibitors, a class of agents termed antiandrogens, and gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH)] analogues, either alone or in combination. As the result of basic scientific studies and prospective clinical trials which have examined the issue of risk versus benefit, several trends have emerged. In the United States, orchidectomy is waning as the primary treatment option for metastatic prostatic cancer, while estrogen use has declined drastically; GnRH analogues are being prescribed more frequently. Furthermore, combination therapy with GnRH analogues (or orchidectomy, to a lesser extent) and the antiandrogen flutamide is gaining wider acceptance as a primary treatment option. The rationale, advantages, and real or potential disadvantages of these various treatment options are discussed.

Clinical stage I nonseminomatous germ cell tumors of testis. Observation vs retroperitoneal lymph node dissection.

Between 1980 and 1989, 186 patients with testicular tumors were seen at Roswell Park Memorial Institute. Of these, 66.6 percent (124/186) were diagnosed to have nonseminomatous germ cell tumors (NSGT) and 22 percent (41/186) were clinically determined to have Stage I disease. Patients with clinical Stage I NSGT either underwent observation or retroperitoneal lymph node dissection (RPLND). Recurrence in the observation group of patients was 23.5 percent (4/17) between four and eighteen months (mean 10 months) with the retroperitoneum being the most common site. All but 1 patient (80%) were salvaged with platinum-based combination chemotherapy. Of the 24 patients who had RPLND, 21 percent (5/24) had a false-negative metastatic evaluation. All the patients who had surgically documented metastatic disease were successfully treated with chemotherapy. The similar recurrence rates in the observation group and the false-negative RPLND group suggest that the failure rate in the observation group is a result of the inability to stage accurately patients with NSGT. RPLND continues to be the standard therapy in patients with clinical Stage I disease. Despite its high recurrence rate, observation should, however, be offered to well-motivated and selected patients since salvage platinum-based combination chemotherapy is very effective and the majority of patients in this group are spared a major operative procedure.

In vitro study of the interaction of doxorubicin, thiotepa, and mitomycin-C, agents used for intravesical chemotherapy of superficial bladder cancer.

Several cytotoxic agents have been identified as effective in the treatment of superficial transitional cell carcinoma of the bladder, including doxorubicin, thiotepa and mitomycin-C. An in vitro study was conducted to assess the interactions of these three drugs against a well differentiated human bladder tumor cell line, RT-4, to identify and evaluate synergistic combinations among these agents. Cytotoxicity was evaluated by a colorimetric assay based on the capacity of viable cells to metabolize a tetrazolium dye, MTT, to produce a colored formazan product. The analyses of drug interactions were done by the isobolographic method (construction of isoeffect plots). The combination of doxorubicin and thiotepa was found to be the most synergistic, followed by the combination of doxorubicin and mitomycin-C. The combination of mitomycin C and thiotepa demonstrated an unpredictable effect. These findings suggest the combination of doxorubicin and thiotepa has potential advantage for chemotherapy of superficial bladder tumors.

Locally recurrent endometrioid adenocarcinoma of the prostate after radical prostatectomy.

Endometrioid carcinoma of the prostate is considered a variant of classical prostatic ductal carcinoma. Endometrioid carcinoma variant often has the unique clinical presentation of gross hematuria. The propensity of this tumor to spread within the urothelium makes local failure of curative therapy commonplace. We present 2 representative cases with a review of followup surveillance procedures and treatment options for the local recurrence once identified.

The use of transrectal ultrasound in the detection and evaluation of local pelvic recurrences after a radical urological pelvic operation.

Transrectal ultrasound was performed in 20 patients with suspected local pelvic recurrence after a radical pelvic operation: 9 had undergone radical prostatectomy and 11 had undergone radical cystoprostatectomy. Transrectal sonography verified the presence of recurrence in 19 of 20 patients (95%) and this was confirmed by biopsy of the visualized lesions. Analysis of the sonographic echo patterns encountered revealed that in 14 of 19 recurrent neoplasms (71.5%) the echogenic pattern was hypoechoic. In the remaining 6 patients (31.5%) the echo pattern was isoechoic. No hyperechoic lesions were noted. Based upon our findings and because of the low costs compared to other diagnostic modalities transrectal ultrasound represents an ideal technique to compliment the digital rectal examination in evaluation of patients suspected of harboring a local pelvic recurrence after a radical pelvic operation.