Dose intensity in germ cell tumors: lessons learned?
Explore the source record for details and available documents.
Antineoplastic Agents↗
Biomedical subjects
C J Logothetis
Publications and source records attributed to C J Logothetis.
Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer.
BACKGROUND: The clinical behavior of the tumor in patients with locally advanced bladder carcinoma is unpredictable. Current predictors of clinical behavior include depth of muscle invasion, presence of vascular invasion, proliferation rate, and loss of blood group antigens. Treatment selection would be facilitated by the development of a reliable marker of tumor progression. Functional retinoblastoma (RB) gene loss has been reported to occur in bladder carcinoma, but the significance of this loss is unknown. PURPOSE: We have evaluated the frequency of functional loss of the RB gene in locally advanced bladder carcinoma and have compared the results to known prognostic factors in the same cohort. METHODS: Forty-three study patients with pathologically well-characterized, locally advanced bladder carcinoma, who were placed in a protocol incorporating surgery and chemotherapy, were studied for known clinical and pathological prognostic indicators as well as for their Rb status. Formalin-fixed and paraffin-embedded archival primary tumor tissues were used for histological and immunohistochemical analyses. RESULTS: Altered Rb protein expression was documented in 37% of the tumor specimens. The high rate of altered Rb expression found in this cohort with advanced urothelial tumors strongly suggests that RB functional loss may be associated with tumor progression in this malignancy. Altered Rb protein expression was found to be independent of other known prognostic variables. A significantly poorer tumor-free survival rate also was noted for those patients who had a tumor with an altered Rb protein with or without vascular invasion. CONCLUSION: The high frequency of Rb alteration in locally advanced bladder carcinomas, plus the fact that a significant correlation could not be found between the Rb status and other known prognostic markers in this preliminary study, suggests that altered RB expression may be an independent prognostic marker of tumor progression in bladder cancer.
Gene Expression Regulation, Neoplastic↗
Small cell carcinoma of the urinary bladder. A clinicopathologic analysis of 22 cases.
Small cell carcinoma of the urinary bladder is an uncommon tumor. The authors report the clinicopathologic findings in a series of 22 cases. Fifteen men and 7 women were studied; their ages ranged from 51 to 87 years (mean, 62.4 years). The most frequent presentation was hematuria (94.4%). At diagnosis, three patients had Stage B disease, six had Stage C, and ten had Stage D (unknown stage in three). Histologically, 6 were oat cell type tumors, 11 were of intermediate cell type, and 5 were of combined cell type. Immunohistochemical studies demonstrated positivity for neuron-specific enolase in ten of ten cases, cytokeratin in seven of ten cases, chromogranin in eight of nine cases, serotonin in seven of nine cases, and S-100 protein in four of ten cases. Neuroendocrine differentiation was seen in five of seven cases examined by electron microscopy. Treatment and follow-up data were available for 19 patients: 10 (52.6%) were dead of disease, 5 (26.3%) were alive and well, 3 (15.8%) were alive with disease, and 1 (5.3%) died of an unrelated cause. The 2-year survival rate was 50% for patients with Stage B, 25% for patients with Stage C, and 33% for patients with Stage D disease. Although overall survival was poor, some cases responded well to therapy. Based on the authors' experience, radical cystectomy with adjuvant chemotherapy appears to be the treatment of choice.
Aged↗
Human prostate cancer model: roles of growth factors and extracellular matrices.
A human prostate cancer model was established by inoculating a prostate specific antigen (PSA)-producing LNCaP cell line with either prostate or bone fibroblasts. Alternatively, this human prostate cancer model can also be established by inoculating LNCaP cells with growth factor(s) (GFs) and extracellular matrix (ECM) immobilized on Gelfoam. The resulting LNCaP tumors were used to evaluate PSA production and excretion in athymic hosts. This model was also employed to examine the biochemical nature of mesenchymal cell-derived growth-promoting protein(s) and to assess the efficacy of potential chemotherapeutic agents. Because of the propensity of human prostate cancer to metastasize to the bone, this study defined a 1.0 M NaCl-eluted fraction, MS1, from the conditioned medium of a bone stromal cell line (MS) by heparin-affinity column chromatography. The growth-promoting activity was assayed both in vivo (e.g., tumor formation) and in vitro (e.g., soft agar colony formation). We found that the growth-promoting activity was trypsin- and heat-sensitive, and partially degraded by acid and dithiothreitol. Immunochemical studies indicated that the polyclonal antibody raised against MS1 blocked the growth-promoting effect elicited by the bone-conditioned media. This growth-promoting factor was found to be immunochemically dissimilar to KGF, HGF, and bFGF. However, addition of bFGF, HGF and NGF, but not aFGF, TGF beta, IGF1, IGF2, PDGF, EGF, TGF alpha and KGF, stimulated anchorage-independent growth of prostate cells, a condition closely parallel to tumor formation in vivo. We found that the MS1 fraction also contained fibronectin and tenascin but not laminin or collagen IV.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Chemotherapy resistant transitional cell carcinoma as a target for chemoprevention.
alpha-Interferon combined with 5-fluorouracil results in significant antitumoral activity in metastatic bladder carcinoma refractory to standard MVAC chemotherapy. As a single agent, alpha-interferon is ineffective for invasive or metastatic disease, but appears to contribute to the increased response rate of patients with invasive chemotherapy-refractory disease. Although most patients with superficial bladder carcinoma will not develop invasive disease, patients in complete remission from invasive disease are at high risk for relapse. In vitro assays indicate that fenretinide (4-HPR), alpha-interferon, and 5-fluorouracil possess significant antitumoral activity in human transitional cell carcinoma (TCC) lines. Some features of postchemotherapy-refractory TCC are similar to those of initial superficial disease (sensitivity to biological therapy). The biological study of patients with residual postchemotherapy disease may permit the development of strategies which will prevent the recurrence of malignancy within the bladder following an initial complete remission, in addition to developing strategies for the selection and treatment of patients with high risk superficial disease.
Antineoplastic Combined Chemotherapy Protocols↗
Stage B (P2/3A/N0) transitional cell carcinoma of bladder highly curable by radical cystectomy.
Seventy-one patients with pathologic Stage B (P2/3a/N0) transitional cell carcinoma (TCC) of the bladder underwent radical cystectomy alone without preoperative radiotherapy or perioperative chemotherapy between 1983 and 1987 and have been followed a median of fifty months. The five-year actuarial survival and disease-free survival rates were 82 percent and 77 percent, respectively, and only 13 patients (18%) have relapsed. Histologic parameters were evaluated as to prognostic impact; none correlated with disease-free survival rates although the presence of vessel involvement portended a worse disease-free survival rate (68% versus 80%). During this same period, an additional 15 patients underwent radical cystectomy for pathologic Stage B disease but received adjuvant chemotherapy on the basis of vessel invasion. Their disease-free survival rate at five years was 80 percent, comparable to the disease-free survival rate for patients with vessel invasion treated by surgery alone (68%). Although the role of systemic chemotherapy in the management of invasive bladder cancer remains under investigation, it would appear that patients with Stage B TCC are best treated with radical cystectomy alone. Continued analysis of modern surgical results grouped by current pathologic staging criteria is needed to identify patients who have a relatively low risk of relapse and thus little need for additional therapeutic intervention. These results demonstrate that Stage P2/3a/N0 TCC of the bladder is highly curable by surgery.
Adult↗
Phase II study of interferon-alpha and chemotherapy (5-fluorouracil and mitomycin C) in metastatic renal cell cancer.
A total of 49 patients with metastatic renal cell cancer underwent recombinant interferon-alpha 2a therapy combined with chemotherapy. Before therapy the patients without nephrectomy underwent angioinfarction of the primary renal tumor. Combined treatment included interferon at 5 x 10(6) units per m.2 intramuscularly daily, 5-fluorouracil at 750 mg./m.2 daily by continuous infusion intravenously (days 1 to 5) and mitomycin C at 5 mg./m.2 per day intravenously (days 1 and 2) repeated every 28 days. Of the patients 17 (35%, 95% confidence interval 22 to 49%) responded, and all 17 had partial remission that lasted a median of 7.1 months (range 4.2 to 20.9+ months). Response rate differed by metastatic sites: lung 46% (18 of 39 patients), lymph nodes 46% (6 of 13), mediastinum 20% (2 of 10) and liver 18% (2 of 11). Grade 3 to 4 toxicity (World Health Organization) included neutropenia (79% of the patients), thrombocytopenia (45%), stomatitis (34%), diarrhea (8%), nausea (18%) and central nervous system disorders (18%). The overall 35% response rate suggests that the combination of interferon-alpha 2a, 5-fluorouracil and mitomycin C is synergistic. Future studies are needed to confirm this finding and to assess the role of mitomycin C.
Antineoplastic Combined Chemotherapy Protocols↗
Chemotherapy for small cell carcinoma of prostatic origin.
A total of 21 patients with metastatic small cell carcinoma of the prostate was treated with combination chemotherapy, either following initial hormonal therapy (15) or as initial therapy (6). Of the patients 13 (62%) had pure small cell carcinoma, whereas 8 (38%) had mixed histology of small cell carcinoma and adenocarcinoma. Patients presented with a characteristic clinical picture of a large primary mass (16 cases) with a high frequency of visceral metastases to the liver (9), lungs (7) and brain (2). The majority of the patients did not have an elevated serum prostate specific antigen (1 of 14, 7%) or prostatic acid phosphatase (2 of 21, 10%). Serum carcinoembryonic antigen was elevated in 13 patients (62%). Of the 21 patients 13 (62%) responded to chemotherapy. Survival after the diagnosis of small cell carcinoma of the prostate resulted in a median of 9.4 months with a range of 1 to 25 months. The regimens used were those considered active in the treatment of small cell carcinoma of the lung (vincristine, doxorubicin and cyclophosphamide, or etoposide and cisplatin with or without doxorubicin). Small cell carcinoma of the prostate has a characteristic clinical picture and a high response rate to cytotoxic therapy. Early introduction of chemotherapy in the treatment of small cell carcinoma of the prostate may increase the survival rate.
Aged↗
Fluorouracil and recombinant human interferon alfa-2a in the treatment of metastatic chemotherapy-refractory urothelial tumors.
Thirty patients with advanced metastatic and chemotherapy-refractory urothelial tumors received a combination of fluorouracil (5-FU) and recombinant human interferon alfa-2a. Thirty-six sites of metastases were present in the 30 study patients, and the median Eastern Cooperative Oncology Group performance status was 3 (range, 1 to 4). All patients had failed to respond to primary combined methotrexate/cisplatin-based chemotherapy. Nine (30%; confidence interval, 15% to 47%) of the patients achieved a partial response. The mean duration of response was more than 5.2 months (median, 6 months; range, 3 to 8 months). Two patients who achieved a partial response of 5 and 7 months' duration, respectively, had control of residual disease (one with radiation and one with surgical excision) and have remained disease-free for an additional period of more than 7 and 13 months, respectively. These data suggest that the combination of 5-FU and recombinant human interferon alfa-2a is synergistic, with clinical significance for the treatment of urothelial tumors. The response rate for this combination of drugs is higher than that anticipated for either of these agents used alone. Additional confirmatory trials are needed to evaluate the significance of these findings.
Antineoplastic Combined Chemotherapy Protocols↗
Serum biomarkers in metastatic renal cell carcinoma.
To identify possible clinically valuable markers of metastatic renal cell carcinoma, we measured the serum concentrations of several commercially available biomarkers in 117 patients with this disease. The alpha-fetoprotein level was measured in 75 patients and was elevated in 8 (11%); elevation did not correlate with the presence of liver metastasis. Beta subunit of human chorionic gonadotropin levels increased in 8 of 83 patients tested (10%). C-terminal parathyroid hormone levels were measured in 79 patients and were elevated in 15 (19%); their serum creatinine level was normal. Thirteen of this group had normal serum calcium levels, whereas 7 patients with hypercalcemia and no clinically evident bone metastasis had normal parathyroid hormone levels. In only 2 of 72 patients, serum lactate dehydrogenase and its isoenzyme 1 were elevated. Only 1 of 85 patients had mildly elevated serum carcinoembryonic antigen, in contrast to 3 of 7 patients with metastatic transitional cell carcinoma of the renal pelvis who had moderately elevated carcinoembryonic antigen. Elevations in alpha-fetoprotein, human chorionic gonadotropin, and parathyroid hormone correlated with the course of the disease in 13 patients for whom follow-up measurements were available; measurement of these markers, however, is only useful in a small proportion of patients with metastatic renal cell carcinoma.
Biomarkers, Tumor↗
Predictive factors for effective salvage therapy of nonseminomatous germ cell tumors of testis.
Twenty-four patients with metastatic and chemotherapy-refractory nonseminomatous germ cell tumors of the testis were treated with various chemotherapy regimens upon failure. Eight of the 24 patients (33%) are alive and disease-free after salvage therapy with a median follow-up of sixteen months. Prognostic factors tested included those known to be predictive for initial response to therapy (clinical stage and degree of elevation of the biomarkers). In addition, time to initiation of salvage therapy and response to initial chemotherapy were assessed as variables. Our data suggest that patients with solitary organ metastases following relapse, and response to initial chemotherapy are favorable predictors for response to salvage treatment. All the patients with solitary organ metastases (5/5 [100%]) but only 3/19 (16%) of the patients with multiple metastatic sites were salvaged. Patients with delayed initiation of salvage therapy had a reduced likelihood of achieving a complete remission but this was not statistically significant. The variables identified need to be incorporated into future trials testing the efficacy of salvage therapy for patients with nonseminomatous tumors of the testis.
Antineoplastic Combined Chemotherapy Protocols↗
Association of germ cell tumors and Hodgkin's disease.
Two patients presented with synchronous Hodgkin's disease and testicular germ cell neoplasms. Both patients are in complete remission following treatment with multidrug chemotherapy and radiation therapy. Despite epidemiologic similarities between Hodgkin's disease and testicular cancer, only 13 cases of their association in the same patient have been reported in the literature, and in all those instances the tumors occurred metachronously. However, the very rare occurrence of synchronous presentation suggests a possible common pathogenetic factor in our 2 patients.
Adult↗
Circadian infusion of floxuridine in patients with metastatic renal cell carcinoma.
A total of 42 patients with metastatic renal cell carcinoma received floxuridine infusion for 14 days at monthly intervals. The drug was delivered via an external programmable pump on a time-modified or circadian schedule; the highest dose of 68% was given between 3 and 9 p.m. Of the 42 patients 25 (60%) had undergone prior nephrectomy. Of the 40 evaluable patients 4 (10%, 95% confidential interval 3 to 24%) achieved a partial response: 3 of the 4 had undergone prior nephrectomy, while 1 had undergone renal angioinfarction. Another 4 patients (10%) had responses at metastatic sites but no response in the primary kidney tumor. The median duration of response for these 2 groups of patients was 65 and 27 weeks, respectively, and the most responsive site was the lungs. The treatment was generally well tolerated and could be administered on an outpatient basis. Our study confirms the limited but definite activity of floxuridine infused on a circadian schedule in patients with metastatic renal cell carcinoma. We observed responses in metastasis equally in patients with or without prior nephrectomy.
Adult↗
Evidence of malignant features in histologically mature teratoma.
A total of 33 specimens from 29 patients with residual stable teratoma and mature growing teratoma after chemotherapy was analyzed for clinicopathological and deoxyribonucleic acid (DNA) flow cytometric variables, as well as the presence of proliferative antigen and tumor marker levels in an attempt to explain their clinical behavior. We compared the flow cytometric and histological data of these stable and growing teratomas, and of nonseminomatous germ cell tumors before chemotherapy. The DNA content of residual teratoma did not differ significantly from that of the primary testicular tumors (1.38 versus 1.48). Histological analysis of stable and growing teratomas revealed no significant difference but proliferative cellular nuclear antigen was expressed mainly in the epithelial component of the growing teratoma. alpha-Fetoprotein, beta-human chorionic gonadotropin and carcinoembryonic antigen were elevated in the fluid of 6 excised teratomas, while concomitant serum levels were normal. The aneuploidy and elevated cystic fluid tumor markers confirm the malignant phenotype of post-chemotherapy residual teratomas. Therefore, complete surgical removal is essential despite the benign histological appearance.
Antigens, Neoplasm↗
Combination chemotherapy with methotrexate, bleomycin and cisplatin for advanced squamous cell carcinoma of the male genital tract.
A total of 14 men with inoperable or metastatic squamous cell carcinoma of the genital tract received methotrexate, bleomycin and cisplatin. In 12 patients the penis was the primary site. Metastases were usually advanced, and 4 patients had ulceration and infection in the inguinal region or perineum secondary to tumor. Two patients had tumor-related hypercalcemia. Of the patients 11 received the 3 drugs intravenously, whereas 3 received methotrexate intravenously, and bleomycin and cisplatin intra-arterially for large unilateral nodal metastasis. Of the 14 patients 10 responded, for a response rate of 72% (95% confidence interval 57 to 92%) and the median response duration was 6 months (range 4 to 24 months). Two patients (14%) who were treated intravenously achieved complete responses lasting 6 and 24+ months. Responses occurred in 3 patients with infection and in both patients with hypercalcemia. The combination of methotrexate, bleomycin and cisplatin has significant activity in patients with advanced squamous cell carcinoma of the male genital tract. This chemotherapy regimen should be evaluated in earlier disease in the adjuvant or neoadjuvant setting.
Antineoplastic Combined Chemotherapy Protocols↗
Cisplatin combination chemotherapy for elderly patients with urothelial tumours.
The proportion of cancer patients who receive potentially curative therapy declines with increasing chronological age. Between January 1979 and January 1988, 36 patients aged from 76 to 84 years (median 78) consented to cisplatin combination chemotherapy. Eighteen patients received 1 to 7 cycles of adjuvant chemotherapy (median 5). This resulted in a drop in creatinine clearance rate from 70 +/- 28.5 ml/min to 49 +/- 20 ml/min. Eight patients (44%) are alive without evidence of disease, with a whole group median survival of 23 months. The dose intensity of cisplatin was found to predict recurrence. Eighteen other patients were treated for metastatic disease; 39% had an objective response after receiving 2 to 9 cycles (median 7). Only 2 patients (11%) are alive and free of disease. In this group no significant kidney damage occurred and the dose intensity of cisplatin did not predict response. Treatment resulted in a significant sepsis rate (39%) and 6 patients (17%) withdrew from treatment because of toxicity. It was concluded that cisplatin combination chemotherapy can be administered without treatment-related death and its efficacy is similar to that in younger patients. Age should not exclude patients from the potential benefit of such therapy. An important cause of reduced benefit from chemotherapy among elderly patients may be the reduced dosage of cisplatin.
Aged↗
Organ preservation in bladder carcinoma: a matter of selection.
Explore the source record for details and available documents.
Humans↗
Escalated therapy for refractory urothelial tumors: methotrexate-vinblastine-doxorubicin-cisplatin plus unglycosylated recombinant human granulocyte-macrophage colony-stimulating factor.
Thirty-two assessable patients with metastatic urothelial tumors refractory to standard chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were treated with escalated doses of MVAC plus unglycosylated recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Results of this phase I trial revealed that escalated MVAC (30 mg of methotrexate/m2, 4 mg of vinblastine/m2, 60 mg of doxorubicin/m2, and 100 mg of cisplatin/m2) can be tolerated by heavily pretreated patients. The side effects of rhGM-CSF are dose- and schedule-dependent. The maximum tolerated dose is 250 micrograms/m2 per day as a single dose administered subcutaneously (SC) for 10 consecutive days. This dose is well tolerated in outpatients, resulting in only modest fever and few side effects. The same dose delivered as a continuous infusion or a higher dose delivered either as a continuous infusion or SC caused significant side effects. For phase II trials, the starting dose of rhGM-CSF when combined with escalated MVAC is 120 micrograms/m2 per day SC for 10 consecutive days. forty percent of the treated patients responded, seven (23%) with complete remission and five (17%) with partial remission. This response rate is higher than anticipated from such a modest dosage escalation in chemotherapy-refractory patients.
Agranulocytosis↗