The correlation of proliferation rates to prognosis in human renal cell carcinoma.
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Antigens, Neoplasm↗
Biomedical subjects
J Atzpodien
Publications and source records attributed to J Atzpodien.
Lack of therapeutic efficacy of tamoxifen in advanced renal cell carcinoma.
In the present study, we treated a total of 62 patients with advanced renal cell carcinoma with high-dose tamoxifen (100 mg/m2/day). Patients were treated in the outpatient setting, and were evaluated 8-12 weeks after initiation of therapy or sooner, when clinical disease progression was evident; a total of 15 patients were seen at short regular intervals for evaluation of clinical and laboratory parameters. Of these 62 patients, 59 were evaluable for treatment response, survival and systemic toxicity. One partial remission was achieved (1.7%; 95% confidence interval, 0.04-9.09%), response duration was 3 months. 10 patients presented with stable disease, for a median duration of 4.0 months, and 48 patients exhibited disease progression upon and after therapy. Systemic toxicity was significant; severe fatigue occurred in 5% of patients, and moderate anaemia, dyspnea, alopecia and malaise in almost 20% of patients. Antineoplastic efficacy of tamoxifen at this dosage in this cohort of patients was at best marginal and well in the range associated with the occurrence of spontaneous remissions. Toxicity was substantial, and it was not balanced by therapeutic benefit. This is consistent with the known lack of therapeutic efficacy of endocrine therapy in advanced renal cell carcinoma.
Adult↗
A comparison of 2 modes of administration of recombinant interleukin-2: continuous intravenous infusion alone versus subcutaneous administration plus interferon alpha in patients with advanced renal cell carcinoma.
PURPOSE: To compare 2 treatment modalities with recombinant Interleukin-2 (rIL-2) for patients with advanced Renal Cell carcinoma (RCC): continuous intravenous infusion (CIV) alone versus subcutaneous (s/c) rIL-2 + Interferon-alpha (IFN-alpha). PATIENTS AND METHODS: Data have been collected on 425 patients with RCC, treated CIV rIL-2 alone, (225 patients), or rIL-2 by the s/c route (200 patients). Patients receiving s/c rIL-2 also received s/c IFN-alpha both drugs being administered on an outpatient basis. Patients receiving CIV rIL-2 were treated as inpatients. Patient eligibility criteria were similar on all studies, and included patients with progressive, advanced disease, but with an ambulatory performance status. RESULTS: The overall response rate for the CIV schedules was not significantly different from the s/c regimens: 15% (95% confidence limits (CL) 10-20%) vs 20% (95%CL 14-26%) with 4% CR in both approaches. Durable responses were seen in both CIV and s/c schedules and there was no evidence of a significant difference in survival in multivariate analysis. There was however an important shift in the toxicity profile. The s/c regimens do not induce a clinically detectable capillary leak syndrome, which is the dose limiting toxicity for CIV regimens. CONCLUSION: Although the introduction of CIV regimens of rIL-2 was a major step forward compared to high-dose bolus, because most patients could be treated in a normal oncology ward, the s/c schedule of rIL-2 + IFN-alpha offers the possibility of outpatient (home) therapy, with no evidence of a reduction in efficacy.
Adult↗
Clinical and preclinical evaluation of recombinant PEG-IL-2 in human.
High dose interleukin-2 alone or in combination with lymphokine activated killer (LAK) cells has demonstrated antitumor activity in a variety of malignant diseases. The currently formulated recombinant human interleukin-2 (IL-2) has limited solubility and short circulatory half life resulting in limited bioavailability. To improve the bioavailability of IL-2 the protein was covalently bound to activated Polyethylenglycol (PEG). We designed a phase I/II trial to evaluate the bioactivity of PEG-IL-2 in man, given as intravenous (iv) bolus injection every two weeks, and to determine safety, efficacy, and the maximum tolerated dose (MTD) in patients with advanced malignancies. Assessment of cytokine levels, phenotypic analyses and differential blood counts were performed to investigate the effects of PEG-IL-2 in-vivo. To compare in-vitro PEG-IL-2 activity to activities of IL-2 we evaluated proliferation, cytotolytic activity, morphology, and phenotype of cytokine activated lymphocytes. Among seven patients treated with PEG-IL-2, there was no objective remission, three patients exhibited stabilisation of disease. Four patients presented with further disease progression. Treatment-related toxicity was mild to moderate (mainly WHO grades I and II) in patients receiving dose levels up to 10 x 10(6) IU/m2 (maximum tolerated single dose in the outpatient setting). No toxic deaths occurred. In comparison to IL-2, the pharmacokinetic profile of PEG-IL-2 exhibited increased plasma levels and a decreased clearance (alpha and beta half-life estimates of 4 and 14 hours, respectively). The analysis of a variety of immunologic parameters demonstrated that PEG-IL-2 has significant biologic activity both in vitro, and in man.
Adult↗
Subcutaneous recombinant interleukin-2 and alpha-interferon in patients with advanced renal cell carcinoma: results of a multicenter Phase II Study.
A phase II multiinstitutional clinical trial was conducted to evaluate the safety and efficacy of the subcutaneous outpatient administration of recombinant human interleukin-2 and alpha-interferon in patients with progressive metastatic renal cell carcinoma. One hundred and forty-five patients were entered on this study between October 1989 and May 1991. Among 134 patients evaluable for treatment response, there were six complete (4.5%) and twenty partial (14.9%) responders, with an overall response rate of 19.4% (95% confidence interval, 13-26%). The median duration of complete remissions was 228 (range 51(+)-520+) days; the median duration of partial tumor regressions was calculated at 226 (range 112-473+) days. The overall median survival from start of therapy was 14.2 (range 1-23+) months. Fever, chills and general fatigue occurred in the majority of patients treated and were measured at grade II, III and IV in up to 55%, 24% and 3% of all evaluable patients, respectively. Three patients each developed grade III hypotension, dyspnea and diarrhea; two patients each had grade III and grade IV elevations of alkaline phosphatase; two and one patients respectively, exhibited grade III anemia and grade IV thrombocytopenia; two patients experienced severe cutaneous toxicity. The majority of patients received treatment in the outpatient setting. In summary, the outpatient use of subcutaneous interleukin-2 and alpha-interferon was effective in patients with advanced metastatic renal cell carcinoma; it was associated with less toxicity and thus, could improve the therapeutic index of interleukin-2 based biologic therapy when compared against high dose intravenous therapy.
Adult↗
Limited efficacy of interferon-alpha and vinblastine as second line biochemotherapy regimen in patients with progressive metastatic renal cell carcinoma.
We report on thirty-four patients with metastatic renal cell carcinoma who were treated with a combination of subcutaneous recombinant interferon-alpha and intravenous vinblastine upon progression after previous antineoplastic therapy. Pretreatment included chemotherapy (n = 3), hormonal therapy (n = 6) and immunotherapy (interleukin-2/interferon-alpha, n = 25). In this study, treatment courses consisted of subcutaneous doses thrice weekly of recombinant interferon-alpha at 6 million U/m2 (20 patients, group 2), respectively. Treatment was given over 8 consecutive weeks. Additionally, in all patients, vinblastine was administered intravenously at a dose of 6 mg/m2 in weeks 2, 5 and 8. Of 14 patients treated in group 1, one had a partial response for 6 months (overall response rate 7.14%; 95% confidence interval, 0.18-33.87%), and four had disease stabilization (median duration, 5.0 months). Of 20 patients treated in group 2, there was one patient who achieved a complete response (response duration, 34+ months); in addition, two patients had a partial response (median response duration, 10.5+ months; overall response rate, 15%; 95% confidence interval 3.21-37.89%), and 13 patients exhibited disease stabilization (median duration 5.9+ months). Response rates showed no significant differences when comparing treatment results in patients in group 1 vs group 2. In contrast, significantly less patients treated in group 2 had progressive disease (p = 0.024), as compared to patients in group 1. This treatment combination was overall well tolerated with low to moderate systemic toxicity. In addition, there were no significant differences in frequency or intensity of therapy-related systemic toxicities when comparing patients in group 1 and group 2, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Low dose megestrol acetate can abrogate cachexia in advanced tumor patients receiving systemic interferon-alpha and/or interleukin-2 based antineoplastic therapy.
The progression of advanced malignancies is often associated with anorexia and cachexia, especially when patients receive concomitant systemic antitumor treatment. Megestrol acetate has been reported to increase appetite and body weight, and a linear dose-response relation for doses from 160 up to 1600 mg/day has been proposed. In our study, we were able to show that megestrol acetate at doses as low as 60 mg/day was sufficient to abrogate anorexia and weight loss. In contrast to previous studies, this effect was achieved while patients continued systemic antineoplastic therapy.
Anorexia↗
Conformational polymorphisms of cRNA of T-cell-receptor genes as a clone-specific molecular marker for cutaneous lymphoma.
A novel molecular assay for the detection and characterization of monoclonal lymphoid populations in clinical specimens was developed. The assay is based on the principle that upon non-denaturing polyacrylamide gel electrophoresis RNA molecules separate into several metastable conformational forms. These conformational polymorphisms strictly depend on the nucleotide sequence of the individual molecule. Using DNA from formalin-fixed, paraffin-embedded tissue of patients with mycosis fungoides, highly variable junctional sequences of rearranged T-cell receptor gamma genes were amplified by polymerase chain reaction. Subsequently, the polymerase chain reactions products were transcribed into complementary RNA and analyzed by non-denaturing polyacrylamide gel electrophoresis. In clinical specimens with a monoclonal lymphoid population, a clone-specific pattern of bands was identified representing conformational polymorphisms of cRNA molecules of rearranged T-cell receptor gamma genes of the predominant lymphoid clone. Three biopsies from one patient taken from different sites of the body over 3 years yielded an identical pattern of bands. This methodology provides a novel and rapid tool for the molecular identification and characterization of clonal lymphoid populations in clinical specimens. It is likely to be of special value for studies on the clonal evolution of lymphoid disorders of the skin.
Base Sequence↗
Molecular detection of clone-specific DNA in hypopigmented lesions of a patient with early evolving mycosis fungoides.
A specific molecular probe for the malignant lymphoid clone of lesions of a patient with mycosis fungoides was developed. As a clone-specific marker the junctional region of rearranged T-cell-receptor-gamma (TCR-gamma) genes was used. An oligonucleotide primer complementary to these sequences was designed. Using this primer and polymerase chain-reaction technology, early hypopigmented lesions of the patient, which were previously unclassifiable by conventional microscopy, were analysed. The study demonstrates, on the molecular level, that these hypopigmented lesions contain tumour clone-specific DNA and may represent early manifestations of mycosis fungoides.
Adult↗
Low-dose interleukin-2 in combination with interferon-alpha effectively modulates biological response in vivo.
Phenotypic characterization of peripheral blood lymphocytes was performed in patients with advanced metastatic cancer receiving low-dose recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha (rIFN-alpha) as subcutaneous home therapy. A total of 31 patients with progressive metastatic renal cell carcinoma, malignant melanoma, colorectal cancer, B-cell lymphoma, and Hodgkin's disease, were evaluated. Patients were treated with a combination of low-dose subcutaneous rIL-2 and rIFN-alpha, consisting of a 2-day rIL-2 pulse at 9.0 million IU/m2 twice daily, followed by 6 weeks of combined low-dose rIL-2 at 1.8 million IU/m2 twice daily, 5 days per week, and rIFN-alpha at 5.0 million U/m2 3 times per week. This treatment regimen resulted in an overall significant (p < 0.002) increase in peripheral blood lymphocyte subsets expressing CD3, CD8, CD16, CD25, and CD56. Expansion of peripheral blood natural killer (NK) cells was correlated to treatment response. Thus, treatment-related increase in CD56-positive lymphocytes was 1.8-fold higher in complete or partial responders when compared to progressive disease patients (p = 0.0). Increase in NK cells upon low-dose rIL-2 and rIFN-alpha was associated with a significant expansion (p = 0.0) of peripheral blood eosinophils (r = 0.71). Patient pretreatment using rIL-2, rIL-2 and rIFN-alpha, or chemotherapy abrogated the treatment-induced induction of NK cells and IL-2 receptor- (CD25) positive T lymphocytes, respectively. Peripheral blood NK cells were significantly decreased (p < 0.05) in patients developing neutralizing antibodies specific to rIL-2.
Antibodies↗
Hematotoxicity of interleukin-2 in man: clinical effects and comparison of various treatment regimens.
BACKGROUND: Immunotherapy using recombinant human interleukin-2 (rIL-2) produces objective responses in a proportion of advanced cancer patients. While early investigators employed intravenous (i.v.) treatment regimens, recent clinical trials applied therapy schedules via subcutaneous (s.c.) injection, mostly in combination with recombinant human interferon-alpha (rIFN-alpha). There were no significant differences in reported response rates between i.v. and s.c. treatment regimens. METHODS: We retrospectively evaluated 148 treatment cycles of s.c. immunotherapy administered to 107 outpatients. Adverse effects of s.c. cytokine therapy were described with regard to hematotoxicity, and compared to adverse effects reported upon high- or intermediate-dose i.v. rIL-2 therapy. Our study population consisted of 15 patients who received s.c. rIL-2 at doses of 4.8-14.4 million IU/m2/day on 5 days per week, 20 patients who were treated with rIFN-alpha 2b at 3.0-6.0 million U/m2/day thrice weekly, and 72 patients who were given s.c. rIFN-alpha 2b at 6.0 million U/m2/day thrice weekly plus s.c. rIL-2 at 14.4-18.0 million IU/m2/day on days 1 and 2, followed by 4.8 million IU/m2/day, 5 days per week. RESULTS: Subcutaneous immunotherapy as administered in this study was well tolerated in the outpatient setting. Thus, there were no treatment-related deaths, and no patient developed grade III or IV (WHO) toxicity. Subcutaneous rIL-2 as a single agent produced grade II anemia and granulocytopenia in 7% of patients, respectively. In combination with s.c. rIFN-alpha, s.c. rIL-2 yielded grade II anemia and granulocytopenia in 8 and 14% of patients, respectively. In comparison, rIFN-alpha as a single agent produced grade III anemia and grade I granulocytopenia in 5 and 20% of patients, respectively. Upon s.c. rIL-2/rIFN-alpha combination therapy, a mean hemoglobin nadir of 114.4 g/l (p < 0.0001 when compared to baseline) was noted, and the mean granulocyte nadir was 2.3/nl (p < 0.0005). These mild laboratory changes due to cytokine-induced hematotoxicity were in marked contrast to severe anemia, thrombocytopenia, and granulocytopenia reported upon i.v. rIL-2 therapy. CONCLUSIONS: Palliative s.c. rIL-2-based immunotherapy as used in this study abrogates profound hematotoxicity, previously seen upon rIL-2-based i.v. immunotherapy. Subcutaneous rIL-2/rIFN-alpha combination therapy can be given in the ambulatory setting with good practicability and excellent safety. This outpatient regimen is as effective in advanced renal cell cancer as the most aggressive i.v. rIL-2-based protocols reported.
Adult↗
Expansion of peripheral blood natural killer cells correlates with clinical outcome in cancer patients receiving recombinant subcutaneous interleukin-2 and interferon-alpha-2.
Natural killer (NK) cells are believed to contribute to the clinical efficacy of cancer immunotherapy using recombinant interleukin-2 (rIL-2) in humans. In previous trials of high-dose i.v. rIL-2, however, no correlation has been established between circulating NK cells and treatment response. Between January 1989 and October 1990, we treated a total of 47 outpatients with advanced tumors using low-dose s.c. rIL-2 and interferon-alpha-2 (rIFN-alpha). Therapy consisted of a 2-day rIL-2 pulse at 18 million IU/m2/day, followed by 6 weeks of rIL-2 (3.6 x 10(6)-4.8 x 10(6) IU/m2/day x 5 days/week) and rIFN-alpha (5 x 10(6)-6 x 10(6) U/m2 x 3/week). Before and after therapy, we phenotypically evaluated circulating lymphocytes and correlated them with clinical response. During 6-week therapy, peripheral blood lymphocytes bearing the CD56 (NK-cell-associated) surface antigen were increased significantly (p < or = 0.005) in treatment responders [complete response (CR) and partial response (PR), n = 10; 3.8-fold] and stable disease (SD) patients (n = 20; 2.1-fold), while patients with progressive disease (PD, n = 17) exhibited no significant expansion of circulating NK cells (p > 0.1). After one 6-week treatment cycle, CR/PR patients had significantly more peripheral NK cells, when compared with patients in SD (1.6-fold) and PD (1.9-fold) (p < 0.04). The overall number of circulating lymphocytes was also increased upon therapy (1.6-fold; p < or = 0.001), but remained independent of response (p > 0.4). These data demonstrate that s.c. rIL-2 and s.c. rIFN-alpha produce a significant increase in peripheral blood NK cells; this expansion correlates significantly with treatment response in advanced tumor patients receiving long-term combination immunotherapy at outpatient doses.
Antigens, CD↗
Prognostic significance of Ki-67 immunostaining in nonmetastatic renal cell carcinoma.
PURPOSE: Fresh tissue samples from nonmetastatic renal cell carcinoma (RCC) patients were analyzed by Ki-67 immunostaining to determine the prognostic significance of this tumor-biologic parameter. MATERIALS AND METHODS: In a prospective study, Ki-67 immunostaining was performed on frozen sections of histologically proven node-negative RCC from 58 patients operated on between 1986 and 1988 to examine the method's prognostic value and its association with other clinicopathologic parameters such as tumor stage (pT) and grade (G). RESULTS: The percentage of Ki-67-positive cells (ie, the proliferation rate [PR]) of all 58 RCC tumors ranged between 1% and 23%, while normal renal tissue exhibited PRs up to 2% only. In almost all cases, the highest PRs were observed in the peripheral zone of malignant tissue close to the normal renal tissue. PR did not correlate with pT, whereas a strongly significant correlation was observed between PR and G, as well as recurrence rate. Twenty-three of 58 patients (39.6%) developed tumor recurrence. Disease-free survival was strongly associated with PR. In a multivariate analysis, G and PR were independent prognostic markers. CONCLUSION: The tumor-specific PR obtained by Ki-67 labeling seems to be an independent marker to describe the proliferative activity and aggressiveness of individual tumors. This new tumor-biologic marker detects RCC patients at high risk for recurrent disease, especially in those cases with identical pT and G.
Adult↗
European studies of interleukin-2 in metastatic renal cell carcinoma.
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Adult↗
Cytokines and infection in cancer patients.
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Humans↗
Effects of cytokines on growth in vitro of primary human renal cell carcinoma.
In clinical trials different haematopoietic active cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) have been proven to alleviate myelosuppressive side effects of intensive chemotherapy in different non-urological malignancies. On the other hand, these cytokines can directly stimulate the proliferation of cells originating from some non-urological tumours. To clarify the impact of these cytokines on the proliferative behaviour of human renal cell carcinoma (RCC), 29 previously untreated RCC tumours were prepared for culturing in vitro using the cell cluster technique. The success rate for growth in vitro was 82.8% (24/29). The malignant renal cells were treated with different cytokines (GM-CSF, G-CSF and interleukin-3) in different dosages. Cell number and proliferation rates detected by immunostaining were used for treatment evaluation. A dosage-dependent stimulation of cell growth could not be observed compared to untreated cells. From the data presented in this study, proliferative stimulation of RCC by administering colony-stimulating factors in clinical trials cannot be assumed.
Carcinoma, Renal Cell↗
Comparison of growth fraction with tumour stage and grade in renal cell carcinoma.
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Carcinoma, Renal Cell↗
Prognostic factors for survival in patients with advanced renal cell carcinoma treated with recombinant interleukin-2.
A database of 327 patients with advanced Renal Cell Carcinoma (RCC) has been analyzed in order to identify potential baseline prognostic factors predicting for survival, following recombinant Interleukin-2 treatment (rIL-2). All patients received a continuous infusion (CIV). Eligibility criteria were uniform across studies, and included patients with an ambulatory performance status (PS), measurable disease, no CNS metastases, and no major organ compromise. Multivariate analyses identified baseline PS (ECOG 0 vs. 1), time from diagnosis to treatment (DTI greater than 24 months vs. less than or equal to 24 months), and the number of metastatic sites (1 vs. greater than or equal to 2, where lung, bone and other sites are considered as separate sites) as important predictors for survival. Patients can be classified into 4 subgroups, which are a function of the number of risk factors present. Median survival for each subgroup is 28, 17, 10 and 5 months, respectively. The model was validated in an independent cohort of 125 patients with RCC treated with subcutaneous (s/c) rIL-2, and predicted for survival accurately. By determining in which risk group category patients may fall, treating physicians may be better equipped to decide on patient management. The model may also be of value in order to stratify patients in randomized clinical trials.
Aged↗