John P. Long

Five-year retrospective, multi-institutional pooled analysis of cancer-related outcomes after cryosurgical ablation of the prostate

OBJECTIVES To define the potential role of cryosurgical ablation of the prostate (CSAP) as a treatment option for patients with localized prostate carcinoma (PCA), we performed a retrospective outcomes analysis of a large database of patients undergoing CSAP constructed from five institutions and compared this with matching outcomes from contemporary reports of patient outcomes after radiotherapy. METHODS A total of 975 patients who underwent CSAP as primary therapy from January 1993 to January 1998 with sufficient outcomes data available were identified. Patients were stratified into three groups on the basis of their clinical features. Biochemical-free survival (BFS), post-CSAP biopsy results, and post-CSAP morbidities were calculated and recorded. RESULTS The median follow-up for all patients was 24 months. The percentages of patients in the low, medium, and high-risk groups were 25%, 34%, and 41%, respectively. For prostate-specific antigen thresholds of less than 0.5 and less than 1.0 ng/mL, the 5-year actuarial BFS ranged from 36% to 61% and 45% to 76%, respectively, depending on the risk category. Overall, the positive biopsy rate was 18%. Morbidities included impotence in 93%, incontinence in 7.5%, rectourethral fistula in 0.5%, and transurethral resection of the prostate in 13% of patients (10% approved warming catheters versus 40% nonapproved). CONCLUSIONS For each risk group, the 5-year BFS and positive biopsy rate after CSAP was comparable to matching outcomes reported after radiotherapy. Morbidities also seemed comparable, with impotence rates higher and rectal injury rates lower after CSAP than after radiotherapy. These data indicate that CSAP can be performed with low morbidity and can produce cancer-related results comparable to those reported for patients undergoing radiotherapy.

NEPHRECTOMY BEFORE INTERLEUKIN-2 THERAPY FOR PATIENTS WITH METASTATIC RENAL CELL CARCINOMA

PURPOSE The management of metastatic renal cell carcinoma remains challenging and controversial. There is some evidence of improved response to interleukin-2 (IL-2) based immunotherapy in patients who undergo nephrectomy before systemic treatment. However, recent reports have suggested that surgery prior to immunotherapy may not be an efficient strategy, since many patients will not be able to receive systemic treatment after nephrectomy. We describe our criteria for determining which patients are candidates for nephrectomy before immunotherapy and present our series of patients treated with this approach. MATERIALS AND METHODS Based on our initial experience with IL-2 based immunotherapy we developed certain inclusion criteria for treatment with initial nephrectomy followed by systemic immunotherapy, including greater than 75% debulking of tumor burden possible, no central nervous system, bone or liver metastases, adequate pulmonary and cardiac function, and Eastern Cooperative Oncology Group performance status of 0 or 1. In addition, patients in whom biopsies show other than predominantly clear cell type histology are excluded. From 1991 through 1996, 28 patients met these criteria and were treated with this approach. Patients were followed to determine the number receiving immunotherapy as well as overall response and survival rates. RESULTS Radical nephrectomy was performed in all patients. One patient died of respiratory failure from disease progression 1 month after nephrectomy. Another patient had poor pulmonary function and, therefore, was treated with an alternative cytokine therapy. The remaining 26 patients (93%) received at least 1 course of IL-2. Median interval between nephrectomy and initiation of immunotherapy was 1.5 months (range 1 to 3). Overall response rate was 39% with 5 complete (18%) and 6 partial (21%) responses. Actuarial median survival of the entire group was 20.5 months (range 1 to 66) from the initiation of treatment. Currently 13 patients are alive, including 8 who are disease and/or progression-free. CONCLUSIONS Using these strict criteria nephrectomy can be effectively performed before immunotherapy without compromising the likelihood that patients will receive systemic treatment. The activity of IL-2 in patients treated with this approach is encouraging and justifies its consideration in properly selected patients.

PRELIMINARY OUTCOMES FOLLOWING CRYOSURGICAL ABLATION OF THE PROSTATE IN PATIENTS WITH CLINICALLY LOCALIZED PROSTATE CARCINOMA

PURPOSE Cryosurgical ablation of the prostate is a novel therapeutic modality that induces cell lysis in the prostate by direct application of low temperatures. We have been conducting an ongoing prospective pilot study of the use of cryosurgical prostate ablation in treating patients with nonmetastatic prostate adenocarcinoma since January 1993. Results in 145 consecutive patients with mean 36 months and minimum 12 months of followup are presented. MATERIALS AND METHODS Accrual was open to patients with clinical stages T1a to T3c prostate adenocarcinoma. Pelvic lymph node dissections were recommended but not required for patients with prostate specific antigen (PSA) greater than 15 ng./ml. before study entry. PSA changes, random prostate biopsy findings and morbidities after cryosurgical prostate ablation were recorded for each patient. RESULTS Overall actuarial rates at 42 months for maintaining PSA less than 0.3 and less than 1.0 were 59% and 66%, respectively. The overall actuarial progression-free rate at 60 months was 56%. Among 160 biopsies performed 16% showed some evidence of residual carcinoma. Overall crude rates of maintaining either a negative biopsy or PSA less than 0.3 at 6 and 24 months after cryosurgical prostate ablation were 87% and 73%, respectively. Significantly higher morbidities were seen in previously radiated patients undergoing cryosurgical prostate ablation compared to those with no prior radiation. Among nonradiated patients 85% experienced no significant morbidity after cryosurgical prostate ablation. CONCLUSIONS Although preliminary, short-term outcomes after cryosurgical prostate ablation appear to be comparable to identical outcomes reported for external beam radiotherapy. Based on these results cryosurgical prostate ablation appears to be an effective therapeutic alternative for treating patients with localized prostate adenocarcinoma.

Altered expression of BRCA1, BRCA2, and a newly identified BRCA2 exon 12 deletion variant in malignant human ovarian, prostate, and breast cancer cell lines

Germline mutations of BRCA1 and BRCA2 predispose to hereditary breast, ovarian, and possibly prostate cancer, yet structural mutations in these genes are infrequent in sporadic cancer cases. To better define the involvement of these genes in sporadic cancers, we characterized expression levels of BRCA1 and BRCA2 transcripts in cancer cell lines derived from neoplasms of the ovary, prostate, and breast and compared them with those expressed in primary cultures of normal epithelial cells established from these organs. We observed upregulation of BRCA1 and/or BRCA2 expression in six of seven ovarian cancer cell lines (OVCA420, OVCA429, OVCA432, ALST, DOV13, and SKOV3) when compared with levels found in normal ovary surface epithelial cells. Furthermore, five cancerous or immortalized prostatic epithelial cell lines (BPH‐1, TSU‐Pr1, LNCaP, PC‐3, and DU145) also expressed higher levels of BRCA1 and/or BRCA2 mRNA than did primary cultures of normal prostatic epithelial cells. In contrast, only the estrogen receptor–positive MCF‐7 cell line overexpressed these messages, whereas the estrogen receptor–negative breast cancer cell lines Hs578T, MDA‐MB‐231, and MDA‐MB‐468 showed no change in expression levels when compared with normal breast epithelial cells. In addition, expanding on our recent identification of a novel BRCA2 transcript variant carrying an in‐frame exon 12 deletion (BRCA2Δ12), we report increased expression of this variant in several ovarian, prostate, and mammary cancer cell lines (OVCA420, OVCA433, ALST, DOV13, SKOV3, TSU‐Pr1, DU145, and MDA‐MB‐468). Most notably, high levels of BRCA2Δ12 mRNA were detected in an estrogen receptor–positive breast cancer cell line, MCF‐7, and in an androgen‐independent prostate cancer cell line, DU‐145. Interestingly, the wild‐type BRCA2 transcript was barely detectable in DU145, which could be used as a model system for future investigations on BRCA2Δ12 function. Taken together, our data suggest disruption of BRCA1 and/or BRCA2 gene expression in certain epithelial cancer cell lines of the ovary, prostate, and breast. Because wild‐type BRCA1 and BRCA2 gene products increase during cell‐cycle progression and are believed to exert growth‐inhibitory action, enhanced expression of these genes in cancer cells may represent a negative feedback mechanism for curbing proliferation in fast‐growing cells. At present, the functionality of BRCA2Δ12 remains elusive. Mol. Carcinog. 28:236–246, 2000.

Expression of RFG/ELE1alpha/ARA70 in normal and malignant prostatic epithelial cell cultures and lines: regulation by methylation and sex steroids.

RET fused gene (RFG)/ELE1α/androgen receptor–associated protein 70(ARA70) was first found to be involved in the activation of the RET proto‐oncogene in thyroid neoplasm and has recently been shown to be a ligand‐dependent transcriptional coregulator for androgen receptor (AR). The functionality of RFG/ELE1α/ARA70 remains controversial, and little is known about factors regulating its expression in the prostate. Of significant interest is whether this molecule is involved in prostate carcinogenesis. Using reverse transcriptase–polymerase chain reaction semiquantitation, we compared RFG/ELE1α/ARA70 mRNA levels in four prostate cancer cell lines (LNCaP, TSU‐Pr1, DU‐145, and PC‐3) with those found in primary cultures of normal prostatic epithelial cells (PrECs). In addition, we examined the effects of androgen and antiandrogen, estrogen and antiestrogen, and a demethylating agent on RFG/ELE1α/ARA70 mRNA expression levels in AR− and AR+ PC‐3 cells. Reduced levels of RFG/ELE1α/ARA70 message were observed in all four prostate cancer cell lines when compared with normal PrECs in primary cultures. RFG/ELE1α/ARA70 mRNA levels in PC‐3 cells, which express both estrogen receptor subtypes, were upregulated by 17β‐estradiol and inhibited by the antiestrogen ICI‐182780. In PC‐3(AR+) cells, which were genetically engineered to express AR, exposure to androgen upregulated RFG/ELE1α/ARA70 mRNA expression, whereas treatment with 4‐hydroxyflutamide lowered expression of this transcript. Furthermore, treatment of DU‐145 cells, which did not express RFG/ELE1α/ARA70 transcripts, with a demethylating agent reactivated transcription of this gene. Polymerase chain reaction analyses of monochromosomal human‐rodent hybrid panels localized a putative RFG/ELE1α/ARA70 isoform on human chromosome 5q31.1‐31.2. In summary, we identified sex hormones and DNA hypermethylation as regulators of RFG/ELE1α/ARA70 expression in prostate cancer cells. In addition, we found reduced levels of RFG/ELE1α/ARA70 expression in prostate cancer cell lines when compared with expression levels in normal PrECs in culture. These findings suggest that RFG/ELE1α/ARA70 may be involved prostate carcinogenesis and that it may serve as a key mediator of estrogen–androgen synergism. Mol. Carcinog. 30:1–13, 2001.

Metachronous Renal Cell Carcinoma Metastases to Spermatic Cord and Penis

Metastasis of renal cell carcinoma (RCC) to the penis or spermatic cord is rare. We present an unusual case of initial metastasis to the cord with delayed involvement of the penis. This is the first report of metachronous involvement of the genitalia from RCC metastases.

Intraoperative Ultrasound in the Evaluation of Tumor Involvement of the Inferior Vena Cava

The successful excision of genitourinary malignancies extending to the inferior vena cava relies heavily on accurate preoperative imaging. For the majority of these patients magnetic resonance imaging, inferior venacavography, abdominal ultrasound or abdominal computerized tomography will reliably predict the extent of inferior vena caval involvement by tumor. However, occasionally the results of these studies will conflict or be called into question intraoperatively. We report on 8 patients considered to be at risk for inferior vena caval involvement by tumor and for whom intraoperative ultrasound was obtained to clarify the presence or extent of thrombus. Five patients had renal cell carcinoma and 3 had adrenal carcinoma. In all patients concern as to the extent or presence of tumor was based on either inconclusive preoperative studies or unexpected intraoperative findings. In each case intraoperative ultrasound clearly visualized the inferior vena cava and established the presence or extent of tumor invasion. In 4 patients venacavotomy was avoided as a consequence of these findings. Intraoperative ultrasound is a useful tool that can accurately assess the inferior vena cava for possible tumor invasion, especially when the presence or extent of tumor involvement is not definitively established preoperatively.

IS THERE A ROLE FOR CRYOABLATION OF THE PROSTATE IN THE MANAGEMENT OF LOCALIZED PROSTATE CARCINOMA

It is impossible to adequately answer the question of whether there is a role for CSAP in the management of localized prostate carcinoma without considering the relative advantages and limitations of using other therapies to manage this disease (radical prostatectomy, radiation therapy, hormonal therapy, brachytherapy, expectant observation, and so on). Obviously, this is beyond the scope of this article. It is probably fair to point out, however, that the management of localized prostate carcinoma in the United States is generally quite controversial at the present time, and that despite a considerable amount of data pertaining to these therapeutic alternatives, it is difficult to discern a standard approach that can be broadly applied for all men with this disease. Therefore, if an absence of consensus on the management of localized prostate carcinoma does exist, it seems evident that investigations into alternative therapies are justified, and the preliminary results and efforts investigating CSAP fall well into this paradigm. In this context, several points can be made based on the available information. Significant numbers of patients who undergo CSAP can sustain undetectable levels of PSA for durable periods of time (more than 24 months). Thus, on a clinical level it seems possible to ablate the entire prostate with percutaneous CSAP, although rates of achieving this may be lower than originally anticipated. The reasons for persistence of carcinoma post CSAP are likely technical and related to the difficulties in determining the effective probe placements, number of probes to be used, number of freeze-thaw-freeze cycles to be used, and so on. Previous radiation exposure appears to confer an increased risk of CSAP-related morbidity, with incontinence, tissue sloughing, and rectal injury most prominent. Among nonradiated patients, incontinence is rare, and the most prominent postoperative concern involves BOO/tissue sloughing in a minority of patients. The longest follow-up data available on CSAP suggests that for patients with nonmetastatic prostate carcinoma, CSAP is associated with persistence of carcinoma in only 25% of patients. This compares favorably with the available biopsy data following external beam radiotherapy, in which most reports document positive biopsy results ranging between 30% and 100%, with the majority in the 40% to 50% range. Notably, the positive biopsy rate among patients with stage T3 disease following CSAP at 2 years can be less than 30%, which compares very favorably with previously reported positive biopsy result for these patients following external beam radiation therapy, which ranged between 40% and 100%. The management of patients with persistent carcinoma following CSAP poses fewer concerns to physicians than for those with persistent carcinoma following radiation therapy. Given the number of patients with prostate carcinoma who currently undergo radiotherapy as primary management, these data indicate that CSAP can now be considered a very viable therapeutic alternative for selected patients. With standardizations of technique as well as improved modifications in equipment, these preliminary CSAP results may well improve steadily in the near future. In the absence of randomized, comparative trials, it is difficult to draw meaningful comparisons between CSAP and radical prostatectomy. Based on available information, CSAP appears to be associated with a much lower incidence of stress and total incontinence than is radical prostatectomy. The rates of impotence following CSAP are somewhat comparable to those seen after radical prostatectomy, with wide variation among individual series. For patients who would be ideal candidates for radical prostatectomy (for example, less than stage T2c disease, PSA less than 10 ng/mL, and Gleason score of 7 or less), several authors have noted that the positive biopsy rate between 6 and 12 months is less than 10%.

The Management of Isolated Renal Recurrence of Renal Cell Carcinoma Following Complete Response to Interleukin-2 Based Immunotherapy

The role of interleukin-2 based immunotherapy in advanced renal cell carcinoma is gradually expanding. Among patients who achieve significant responses to these regimens the subsequent development of isolated recurrences raises difficult management questions. We report 2 unusual cases of isolated recurrence in the remaining kidney following a sustained, complete response to interleukin-2 based adoptive immunotherapy. Both patients were treated with interleukin-2 based therapy following surgical resection of the primary renal tumor. The disease course of each patient is described and the literature is reviewed. Both patients were free of disease after relatively short-term followup. Surgery for patients with limited recurrence of renal cell carcinoma following an objective response to immunotherapy may, in select cases, be a reasonable treatment alternative.

Intensity-modulated radiotherapy of the prostate after cryotherapy: initial experience.

OBJECTIVES To analyze results of intensity-modulated radiotherapy after cryotherapy ablation for adenocarcinoma of the prostate. METHODS Patients were either treated adjuvantly after targeted cryotherapy or treated for salvage after local failure of standard whole-prostate cryotherapy. Patients were treated with intensity-modulated radiotherapy to a minimum dose of 73 Gy (mean dose, >75Gy). Prostate-specific antigen (PSA) failure was defined according to the Radiation Therapy Oncology Group-American Society for Therapeutic Radiology and Oncology 2006 consensus definition. Late gastrointestinal and genitourinary toxicity were graded according to the Radiation Therapy Oncology Group late toxicity scale and the Late Effects of Normal Tissue-Subjective, Objective, Management, and Analytic scale. RESULTS A total of 16 patients were treated from 1997 to 2007. Three patients were treated adjuvantly, and 13 patients were treated for local failure. The mean pre-cryotherapy PSA value was 8.7 ng/mL. The mean PSA value before irradiation was 6.0 ng/mL. Most patients were intermediate to high risk (8 intermediate risk, 7 high risk). Median follow-up was 33 months. No grade 3 or greater toxicity was seen. Biochemical (PSA) control was achieved in 12 of the 16 patients at last follow-up. CONCLUSIONS Full-dose intensity-modulated radiotherapy after cryotherapy is well tolerated, without excess late morbidity. This study supports the use of radiation for cryotherapy failure salvage. Furthermore, the combination of cryotherapy and irradiation may be considered in a phase II trial.