The role of the sphingomyelin pathway and protein kinase C in radiation-induced cell kill.
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Animals↗
Biomedical subjects
Z Fuks
Publications and source records attributed to Z Fuks.
Changing pattern of expression of the epidermal growth factor receptor and transforming growth factor alpha in the progression of prostatic neoplasms.
The autocrine/paracrine interaction of the epidermal growth factor receptor (EGFr) and transforming growth factor alpha (TGF-alpha) has been implicated in prostate cancer cell growth and proliferation. To evaluate the role of EGFr and TGF-alpha in prostate cancer progression, we studied the immunohistochemical staining pattern of EGFr and TGF-alpha in malignant primary and hormone-independent metastatic prostate lesions. The specimens evaluated included 37 primary carcinomas (34 hormone-naive and 3 hormone-refractory tumors) and 22 metastases. For each specimen, the pattern of expression was evaluated and staining reactivities graded from 0-3, with 0 representing no staining and 3 representing homogeneous and intense staining. Primary malignant prostate epithelial cells in areas with discrete gland formation showed strong EGFr immunostaining, while stromal cells were generally nonreactive. In untreated primary tumors, TGF-alpha expression was primarily in the stroma, while epithelial cells were weakly positive in several cases. Malignant epithelial cells adjacent to neural elements that stained positive for TGF-alpha was frequently observed. A homogeneous staining pattern for EGFr was noted in 17 (89%) of 19 evaluable androgen-independent-refractory metastases, while TGF-alpha expression was found in 14 (78%) of 18 evaluable cases. Overall, 14 of 18 androgen-independent metastases coexpressed the receptor and the ligand. These results suggest that, unlike primary prostate tumors where a paracrine relationship between EGFr and TGF-alpha appears to predominate, the potential for autocrine stimulation may exist in the majority of metastatic androgen-independent tumors. Furthermore, the changing pattern of expression as the disease evolves from the localized hormone-naive to metastatic androgen-independent condition suggests that strategies aimed at blocking this growth factor pathway may be of therapeutic importance for androgen-independent disease.
Adrenal Gland Neoplasms↗
Initial clinical experience with computer-controlled conformal radiotherapy of the prostate using a 50-MeV medical microtron.
PURPOSE: We have described previously a model for delivering computer-controlled radiation treatments. We report here on the implementation and first year's clinical experience with such treatments using a 50 MeV medical microtron. METHODS AND MATERIALS: The microtron is equipped with a multileaf collimator and is capable of setting up and treating a sequence of fixed fields called segments, under computer control. An external computer derives machine parameters for the segments from a three-dimensional treatment planning system, transfers them to the microtron control computer, checks the machine settings before allowing dose delivery to begin, and records the treatment. We describe the patient treatment methodology, portal film acquisition, electronic portal imaging, and quality assurance. RESULTS: Patient treatments began in July 1992, comprising six-segment conformal treatments of the prostate. Using the recorded treatment data, the system performance has been examined and compared to other treatment machines. The average treatment time is 10 min, of which 4 min is for computer-controlled setup and irradiation; the remaining time is for patient positioning and checking of clearances. Long-term reproducibility of computer-controlled setup of the gantry and multileaf position is better than 0.5 degrees and 1 mm, respectively. Termination due to a machine fault has occurred in 5.5% of treatments, improving to 2.5% in recent months. CONCLUSION: Our initial experience indicates that computer-controlled segmental therapy can be performed reliably on a routine basis. Treatment times with the microtron are significantly shorter than with conventional linacs, and setup accuracy is consistent with that needed for conformal therapy. We believe that treatment times can be further improved through software upgrades and integration of electronic portal imaging.
Humans↗
Short-term freedom from disease progression after I-125 prostate implantation.
PURPOSE: To evaluate short-term clinical and chemical disease progression following computed tomography (CT)-based transperineal I-125 prostate implantation. METHODS AND MATERIALS: Sixty-two patients with clinical Stage T1 or T2 prostatic carcinoma had outpatient, CT-based transperineal I-125 prostate implantation and have been followed for 6-55 months (median: 19 months). Fifty-six patients had an elevated prostate specific antigen (PSA) before implantation (> 4.0 ng/mL). Twenty patients had well-differentiated tumors, 39 were moderately differentiated, 2 were poorly differentiated, and 1 was indeterminate. A total of 32-73 mCi I-125 was implanted (median: 47 mCi). The prescribed minimum prostatic dose was 140-160 Gy, and the actual matched peripheral dose ranged from 109-258 Gy (median: 160 Gy). Lymph node dissection or postimplantation prostatic biopsies were not routinely performed. RESULTS: Of 54 patients with an elevated PSA prior to implantation and no prior hormonal treatment, 96% returned to normal within 24 months of treatment. In 85% of patients, the PSA fell below 2.0 ng/mL and in 74% of patients, the PSA value fell to below 1.0 ng/mL. Seven patients had disease progression, one of whom has an isolated, rising PSA. The actuarial rate of chemical (rising PSA) or clinical failure at 3 years following implantation was 17%. Of 38 patients who were sexually potent prior to implantation, 81% remained potent at 3 years. Five patients developed radiation-induced rectal ulcerations, 11-22 months following implantation. Three patients required a transurethral resection of the prostate for postimplant urinary symptoms. CONCLUSIONS: The short-term clinical and chemical freedom-from-progression rates following I-125 implantation are comparable to that achieved with prostatectomy, with high preservation of sexual potency and moderate morbidity.
Aged↗
Effect of epidermal growth factor on the growth and radiation sensitivity of human breast cancer cells in vitro.
PURPOSE: To study the effect of epidermal growth factor (EGF) on the radiation sensitivity of MCF-7 breast cancer cells. METHODS AND MATERIALS: Radiation dose survival curves were generated for MCF-7 cells under conditions of hormonal deprivation. Epidermal growth factor and/or a monoclonal antibody to its receptor (mAb-225) were added prior to irradiation. Cell cycle distribution was determined by flow cytometry and cellular glutathione (GSH) levels were measured by a glutathione reductase assay. RESULTS: Under hormonal deprivation (control), more than 90% of the MCF-7 cells were arrested in G0/G1 phase and the D(o) of their survival curve was 0.66 +/- .01 Gy. The addition of EGF resulted in (a) growth stimulation; (b) increased percentage of cells in the S-phase of the cell cycle; (c) increased radioresistance (D(o) = 0.81 +/- .04 Gy; p < .05, compared with controls); (d) increased cellular GSH level. The EGF effect on radiation response was observed in a time- and dose-dependent manner. The addition of mAb-225 blocked the ability of EGF to enhance growth and radioresistance (D(o) = 0.68 +/- .03 Gy). CONCLUSION: Epidermal growth factor stimulates the growth and when administered prior to irradiation increases the radioresistance of hormone-deprived MCF-7 cells. These effects are inhibited by a specific antibody to the EGF receptor. Epidermal growth factor concomitantly increased the fraction of S-phase cells and intracellular GSH levels. This system of growth factor-altered radiosensitivity in human breast cancer cells provides a useful model for the study of the radiation response mechanisms in human malignancy.
Antibodies, Monoclonal↗
Radiation induction of immediate early genes: effectors of the radiation-stress response.
Recent studies have demonstrated that the early response genes c-jun, Egr-1, c-fos, and NF kappa B are induced following exposure of mammalian cells to ionizing radiation. We propose that the products of these early response genes regulate downstream genes that are important in the adaptation of cells and tissues to radiation-induced stress. Potential downstream targets include cytokine and growth factor genes as well as deoxyribonucleic acid (DNA) repair genes. Early response gene products may also regulate cell cycle progression following cellular x-irradiation. Signal transduction pathways that allow cells to adapt to radiation may provide molecular targets to modify tumor and normal responses to radiotherapy.
Animals↗
Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis.
Recent investigations provided evidence that the sphingomyelin signal transduction pathway mediates apoptosis for tumor necrosis factor alpha (TNF-alpha) in several hematopoietic and nonhematopoietic cells. In this pathway, TNF-receptor interaction initiates sphingomyelin hydrolysis to ceramide by a sphingomyelinase. Ceramide acts as a second messenger stimulating a ceramide-activated serine/threonine protein kinase. The present studies show that ionizing radiation, like TNF, induces rapid sphingomyelin hydrolysis to ceramide and apoptosis in bovine aortic endothelial cells. Elevation of ceramide with exogenous ceramide analogues was sufficient for induction of apoptosis. Protein kinase C activation blocked both radiation-induced sphingomyelin hydrolysis and apoptosis, and apoptosis was restored by ceramide analogues added exogenously. Ionizing radiation acted directly on membrane preparations devoid of nuclei, stimulating sphingomyelin hydrolysis enzymatically through a neutral sphingomyelinase. These studies provide the first conclusive evidence that apoptotic signaling can be generated by interaction of ionizing radiation with cellular membranes and suggest an alternative to the hypothesis that direct DNA damage mediates radiation-induced cell kill.
Animals↗
Neoadjuvant hormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy.
PURPOSE: To determine the extent of reduction of volume of normal tissue structures exposed to high doses of radiation therapy (RT) after administration of neoadjuvant hormonal therapy (NHT) in patients with bulky, geometrically unfavorable prostatic cancers. METHODS AND MATERIALS: Twenty-two patients with bulky prostatic cancers were treated with a 3 month course of neoadjuvant leuprolide acetate and eulexin prior to three-dimensional (3-D) conformal radiotherapy. Patients were included if 3-D treatment planning revealed that either > 30% of the rectal wall would receive 95% of the prescription dose (D95) (n = 13); > or = 50% of the bladder wall would receive D95 (n = 10); or that any volume of small bowel would receive > or = 65% of the prescription dose (n = 16). All patients underwent simulation and conformal treatment planning before and after NHT. Pre and posthormone cumulative dose volume histogram (DVH) calculations for all normal tissue structures were analyzed and compared for each patient. RESULTS: The median percentage of target volume reduction after NHT was 25% (range: 3-52%). Ten of 13 patients (78%) whose prehormone rectal DVH demonstrated > 30% of the rectal wall receiving D95 responded to NHT with a median 25% (range: 16-48%) reduction of rectal volume receiving the D95. A median reduction of 50% (range: 6-64%) of the bladder volume receiving D95 was observed in nine of ten patients (90%), while 13 of 16 (81%) showed a reduction of small bowel volume to a median percentage of 88% (range: 67-100%) of the prehormonal values. CONCLUSION: Neoadjuvant hormonal therapy is an effective method for decreasing the size of bulky prostatic tumors as well as for optimizing the geometry of the target volume in relation to the adjacent normal tissue structures prior to radiation therapy. Such an approach allows for reduction of the volume of normal tissues exposed to high doses in the majority of treated patients. Currently, studies are underway to determine whether NHT will lead to a decreased likelihood of long-term complications associated with radiotherapy of bulky, geometrically unfavorable prostatic tumors, and permit the safe delivery of escalated dose levels using conformal treatment techniques.
Aged↗
Fluoroscopic visualization of the prostatic urethra to guide transperineal prostate implantation.
PURPOSE: To describe a novel way to assure proper needle positioning within the prostate during transperineal implantation, using the urethra as the primary radiographic landmark. METHODS AND MATERIALS: Preoperative computerized tomography (CT) images through the prostate are used to plan optimal transperineal needle-seed placement. When performing the procedure, a Foley catheter, with radio-opaque wire is used to visualize the prostatic urethra fluoroscopically in anterior-posterior and lateral projections. Proper needle placement is determined by their position relative to the urethra. RESULTS: Sixty patients have been implanted with this method at Memorial Sloan-Kettering Cancer Center from 1990-1992. CONCLUSION: The method described here is an improvement over previously described CT-based techniques. It could be used to supplement or replace ultrasound imaging.
Brachytherapy↗
Basic fibroblast growth factor protects endothelial cells against radiation-induced programmed cell death in vitro and in vivo.
Apoptosis (programmed cell death) serves as a common mechanism of interphase cell death after radiation exposure in thymic, lymphoid, and hematopoietic cells but has infrequently been documented in other adult mammalian cell types. The present study demonstrates that apoptotic interphase cell death occurs in endothelial cells after exposure to clinically relevant radiation doses and that basic fibroblast growth factor (bFGF) protects endothelial cells against this mode of the lethal effects of radiation. Radiation exposure produced heterologous double-stranded DNA breaks in endothelial cells, but the cells exhibited a similar competence for repair of this damage in the presence or absence of bFGF. However, subsequent to the completion of this repair process, a second process of DNA fragmentation became apparent, which was detected only in the absence of bFGF and was associated with a DNA ladder of oligonucleosomal fragments characteristic of apoptosis. The apoptotic DNA degradation occurred mainly in G0-G1 phase cells and was inhibited by bFGF stimulation. C3H/HeJ mice exposed to lethal doses of whole lung irradiation exhibited similar apoptotic changes in the endothelial cell lining of the pulmonary microvasculature within 6-8 h after radiation exposure. bFGF given i.v. immediately before and after irradiation inhibited the development of apoptosis in these cells and protected mice against the development of lethal radiation pneumonitis. These findings suggest that interphase apoptosis may represent a biologically relevant mechanism of radiation-induced cell kill in nonlymphoid mammalian cells both in vitro and in vivo and that natural protection mechanisms against this effect may be associated with the level of radiation resistance in normal and malignant tissues in vivo.
Animals↗
Protein kinase C mediates basic fibroblast growth factor protection of endothelial cells against radiation-induced apoptosis.
Basic fibroblast growth factor (bFGF) was found to protect bovine aortic endothelial cells against the lethal effects of ionizing radiation by inhibiting the programmed cell death (apoptosis) induced in these cells by radiation exposure. The involvement of the bFGF receptor tyrosine kinase in this function was demonstrated by abrogation of the radioprotective effect of bFGF by a specific inhibitor of the bFGF receptor tyrosine kinase, the tyrphostin AG213. The downstream signaling after stimulation of the bFGF receptor tyrosine kinase in bovine aortic endothelial cells involved translocation of the alpha isotype of cytoplasmic protein kinase C (PKC) into the membrane and its activation within 30 s after bFGF stimulation. The involvement of PKC in the radioprotective effect conferred by bFGF was suggested by the demonstration that nonspecific PKC activation by short-term exposure (30 min) to the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA; 30 ng/ml) mimicked the radioprotective effect of bFGF. Furthermore, treatment of the cells with the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (20 microM) abrogated the radioprotective effect of bFGF, as was observed after the depletion of cellular PKC by overnight preincubation with high-dose TPA (200 nM). Agarose gel electrophoresis of DNA extracted from irradiated bovine aortic endothelial cells showed that both TPA (30 ng/ml; 30 min) and bFGF (1 ng/ml) inhibited the apoptotic degradation of DNA induced in these cells by radiation exposure (500 cGy). Both the bFGF- and the TPA-mediated inhibition of apoptosis could be reversed by the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (20 microM). These data demonstrate the involvement of PKC in the inhibition of radiation-induced apoptosis by bFGF and the rescue of endothelial cells from this mode of radiation-induced cell death.
Animals↗
Treatment-related symptoms during the first year following transperineal 125I prostate implantation.
PURPOSE: To summarize the urinary, rectal, and sexual symptoms occurring during the first 12 months following 125I prostatic implantation. METHODS AND MATERIALS: Thirty-one patients with Stage T1 or T2 prostatic carcinoma were evaluated for morbidity following computed tomography-guided transperineal 125I implants from 1988 to 1991. The median total activity used was 47 mCi (range 35-73 mCi). Toxicity was evaluated using a modification of the Radiation Therapy Oncology Group grading system. RESULTS: Nocturia was the most common treatment-related symptom, reported by 80% of patients within 2 months after implantation, and persisted at 12 months in 45% of the patients. Mild dysuria developed in 48% of patients within 2 months of implantation; two patients needed analgesics for their dysuria. Terazosin hydrochloride (2-10 mg qd) provided subjective improvement of urinary symptoms in seven of eight patients in whom it was tried. Rectal urgency, soft stools, and increased frequency of bowel movements was reported by 25% of the patients within 1-2 months after implantation. The incidence of asymptomatic rectal bleeding or ulceration occurring at any time after implantation was 47%, but resolved in all patients with expectant treatment. Self-limited ulceration of the rectal mucosal occurred in 16%, but only one patient developed a prostato-rectal fistula, managed with an ileal conduit. Five of the 18 potent patients experienced discomfort on erection or ejaculation, beginning within several weeks of their implant. The discomfort resolved within 6 months in three of the patients, but persisted for 18 and 24 months in the other two. CONCLUSION: 125I implantation, as performed in this series, is generally associated with only mild-moderate genitourinary and rectal symptoms that may persist 6 months or more after implantation. Prostatic carcinoma, Brachytherapy, Morbidity.
Aged↗
The effects of local and regional treatment on the metastatic outcome in prostatic carcinoma with pelvic lymph node involvement.
PURPOSE: The effect of local and regional treatment on the development of distant metastases in patients with localized node negative and node positive carcinoma of the prostate is examined. METHODS AND MATERIALS: Distant metastases-free survival was evaluated in 1078 patients with Stage B-C node negative (733 patients) or node positive (345 patients) carcinoma of the prostate, staged with pelvic lymph node dissection and treated with retropublic 125I implantation at the Memorial Sloan-Kettering Cancer Center between 1970 and 1985. RESULTS: The 15-year actuarial distant metastases-free survival rate for the entire group of patients was 27%. Lymph node involvement was the most significant covariate affecting distant metastases-free survival, although local failure, stage, and grade were also independent variables. Distant metastases-free survival varied with the extent of lymph node involvement (N0 vs. N1, p < 0.0001; N1 vs. N2, p < 0.0001). However, the difference between N1 and N2 patients was due to a faster rate of development of distant metastases in N2 patients. The ultimate 10-year distant metastases-free survival rate was similar for the two patient groups (11% for N1 and 9% for N2). Local failure correlated with the metastatic outcome in patients with B-C/N0 disease (p < 0.00001), but not in N1 or N2 patients. Although distant metastases-free survival in locally controlled N1 patients was improved compared to N2 patients (p = 0.004), when stratified by primary tumor stage and grade, the differences were no longer significant. CONCLUSION: Essentially all node positive patients with carcinoma of the prostate will develop distant metastatic disease if followed for sufficiently long periods of time. This is consistent with the hypothesis that in such patients distant micrometastatic dissemination already exists at the time of initial diagnosis. The data suggest that clinical trials designed to test whether improvements in local therapy impact on survival should be restricted to node negative patients. The data also raise concerns regarding the therapeutic value of elective whole pelvic irradiation.
Adenocarcinoma↗
The potential and limitations of the inverse radiotherapy technique.
The objective of the work presented in this paper is to explore the scope of the applicability of the inverse radiotherapy technique for designing optimized intensity distributions to achieve a desired dose distribution. A specified desired uniform dose to the target volume is inverted, subject to constraints on the surrounding normal tissue dose, to produce optimum intensity distributions in a set of beams arranged around the target volume. We employed the inverse technique and software developed by Bortfeld and evaluated results both qualitatively and quantitatively using dose distribution displays, dose-volume histograms and biological indices including tumor control probability and normal tissue complication probabilities. So far we have applied this methodology to prostate and lung treatment plans. For prostate the inverse technique produces satisfactory approximations of the desired dose distributions. However, for lung its performance is considerably inferior. Our investigations point to a number of factors for this difference, the primary ones being differences in the tolerance doses of neighboring normal tissues, magnitudes of volume effect, tissue architectures, and the achievability of the specified desired dose distributions. We conclude that, for certain clinical situations, it is not sufficient to specify the objectives of optimization purely in terms of the desired pattern of the dose. The objectives must also include dose-volume effects and biological indices. Furthermore, the mathematics of optimization must be able to incorporate these factors into the process. We find that the inverse technique is not suitable for situations where dose-volume considerations and biological indices are important and that other methods of optimization of intensity distributions should be explored.
Adenocarcinoma↗
An equation for the dose response of radiation-induced apoptosis: possible incorporation with the LQ model.
Based on in vitro and in vivo data, we proposed an equation to describe the dose response of radiation-induced apoptosis. This equation can be incorporated into the LQ model to account for the contribution of apoptosis-mediated cell death in clonogenic survival curve. The modified LQ equation is a composite of the dose responses of two subpopulations, one susceptible and the other resistant to apoptotic cell death. For the apoptosis-resistant fraction, the size of which varies for different biological systems, the conventional LQ relation applies. For the susceptible subpopulation, the LQ equation is modified by e-zeta D, a functional form consistent with the observed dose-rate independence of this mode of cell death.
Algorithms↗
Three-dimensional conformal radiation therapy in localized carcinoma of the prostate: interim report of a phase 1 dose-escalation study.
Acute morbidity, late complications and tumor response were evaluated in 324 prostate cancer patients treated with 3-dimensional conformal radiation therapy in a phase I dose-escalation study. This radiotherapy technique targeted the prostate and seminal vesicles but effectively excluded the surrounding normal tissues. The minimum tumor dose was 64.8 to 66.6 Gy. in 87 patients, 70.2 Gy. in 138, 75.6 Gy. in 69 and 81.0 Gy. in 30. The treatment was well tolerated with minimal acute morbidity, observed in 15% of the patients who required medication for relief of rectal symptoms and in 34% for urinary symptoms. Two patients (0.6%) to date have had grades 3 and 4 late complications (Radiation Therapy Oncology Group morbidity grading system). The 3-year actuarial probability of survival with a normal serum prostate specific antigen level was 97% for patients with stages T1c and T2a, 86% with stage T2b, 60% with stage T2c and 43% with stage T3 disease. A multivariate analysis demonstrated that initial prostate specific antigen (20 ng./ml. or less versus more than 20 ng./ml.), stage (T2c or less versus T3) and Gleason score (6 or less versus 7 or more) were each significant independent variables that affected subsequent chemical relapse. The acute and long-term toxicities have been less compared with traditional treatment techniques. After the maximal tolerable dose with 3-dimensional conformal radiotherapy is established, future studies will test whether high dose conformal therapy has the potential to improve local tumor control and survival of patients with localized prostatic carcinoma.
Adenocarcinoma↗
Immunohistochemical determination of p53 protein nuclear accumulation in prostatic adenocarcinoma.
Abnormalities of the TP53 gene are currently the most common genetic alterations associated with human malignancy. The study of altered patterns of p53 protein expression in primary prostate cancer has to date yielded a much lower incidence of alteration compared to bladder, colon, lung and breast cancer. However, the analysis of prostate cancer metastases has been limited. The objective of our study was to determine the prevalence of p53 nuclear accumulation in primary, metastatic and hormone refractory prostatic adenocarcinoma, and to characterize its relationship with conventional clinicopathological variables. We used 2 antibodies (mouse monoclonal PAb 1801 and rabbit polyclonal CM-1) and an immunohistochemical method in 93 paraffin embedded tumors (48 primary tumors, 29 lymph node metastases and 16 bone metastases) to assess p53 nuclear accumulation. Overall, p53 nuclear accumulation was observed in 19 tumors (20%), including 17 with PAb 1801 and CM-1 immunoreactivities, and 2 with CM-1 immunoreactivity only. The pattern of p53 immunoreactivity was heterogeneous in most tumors, with only 3 cases exhibiting homogeneous staining. Primary, lymph node and bone metastases exhibited p53 nuclear staining in 9 of 48 (19%), 2 of 29 (7%) and 8 of 16 (50%) cases, respectively (p = 0.003). In 6 of 10 primary hormone refractory tumors (60%) and in 3 of 38 primary hormone naive tumors (8%) p53 nuclear immunoreactivity was expressed (p = 0.002). P53 nuclear accumulation was significantly more common in higher grade primary tumors (p = 0.007). Our results suggest that p53 nuclear accumulation is relatively uncommon in prostate cancer. However, p53 nuclear accumulation appears to be associated with advanced stages of disease, as illustrated by its relatively higher occurrence in hormone refractory tumors and bone metastases. Furthermore, the significantly greater prevalence of p53 accumulation in bone metastases is currently the highest reported for prostate cancer.
Adenocarcinoma↗
Patterns of failure following surgical resection of renal cell carcinoma: implications for adjuvant local and systemic therapy.
PURPOSE: This report is a patterns-of-failure analysis of resected renal cell carcinoma (RCC) performed to determine the relative incidences of local failure (LF) and distant failure, to identify the pathologic features predicting for each using a multivariate analysis, and to assess the relative impact of each form of failure on overall survival (OS). In this way, the potential value of and selection of patients for adjuvant local and/or systemic therapy can be better evaluated. MATERIALS AND METHODS: The records of 172 patients with unilateral, nonmetastatic RCC who were treated with definitive surgery between 1978 and 1988, and who had a minimum follow-up duration of 1 year, were identified through the Memorial Sloan-Kettering tumor registry. Distribution by stage included T1, 10 patients; T2, 102; T3a, 32; T3b, 27; and T4, one. The incidences of positive lymph nodes (LNs) and positive margins were 5.8% and 6.4%, respectively. RESULTS: LF developed in only six patients, yielding a 7-year actuarial incidence of 5%. In this subset, four patients developed distant metastases (DM), three occurring concurrently with or before LF. DM developed in 30 patients, yielding a 7-year actuarial incidence of 26%. Among the variables that had an impact on the development of DM according to univariate log-rank tests, only positive LNs (P = .026) and renal vein extension (P = .001) remained as significant independent prognosticators. The overall 7-year actuarial survival rate was 80%. Eleven patients died of RCC during follow-up, nine of whom (82%) died of metastatic disease. CONCLUSION: LF is rare following surgical management of RCC, and shows no clear causal relationship with the development of DM. Patients die of DM, and not LF. These data do not support the role of adjuvant radiation therapy in this disease. Patients with LN involvement or renal vein extension have a significantly increased risk for developing DM, and are therefore appropriate candidates for trials investigating systemic therapy.
Actuarial Analysis↗