The use of carboplatin in malignant germ cell tumours.
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Animals↗
Biomedical subjects
C Bokemeyer
Publications and source records attributed to C Bokemeyer.
Overexpression of the p53 oncoprotein in carcinoma in situ of the testis.
Carcinoma in situ (CIS) is regarded as the precursor lesion of testicular germ cell tumors. In adults CIS cells have also been described within the normal testicular tissue adjacent to mature teratomas with a frequency of 52-88%. These CIS-cells can be identified by immunohistochemical staining for "placental like alkaline phosphatase" (PLAP). In four of eight patients with mature teratomas CIS was identified by immunohistochemistry for "PLAP" in atrophic testicular tubules adjacent to the tumors. In three of these patients cells of CIS were positive for the p53 oncoprotein, indicating a mutational inactivation of the p53 tumor suppressor gene. The malignant potential of mature teratomas, which do occur without histological signs of malignancy, may therefore be associated with the occurrence of CIS within the histologically normal appearing testicular tissue adjacent to the mature tumor. Immunohistochemical positivity for the p53 protein in CIS cells of some patients may indicate that the mutational inactivation of the p53 tumor suppressor gene could be involved early in the development of testicular germ cell tumors.
Adult↗
The anti-tumour activity of ifosfamide on heterotransplanted testicular cancer cell lines remains unaltered by the uroprotector mesna.
Ifosfamide is clinically used in combination chemotherapy regimens for the treatment of patients with high-grade lymphomas, sarcomas and metastatic germ cell tumours. In order to reduce the oxazophosphorine-related urothelial toxicity, sodium mercaptoethane sulphonate (mesna) is used in different schedules following the administration of ifosfamide. The proposed mechanism of mesna activity is the binding of toxic oxazaphosphorine metabolites such as acrolein in the urine of the patients. Since an influence of mesna on ifosfamide anti-tumour activity is controversial, the current study has used xenografts from two human testicular cancer cell lines heterotransplanted into nude mice to study the anti-tumour activity of ifosfamide in combination with different dosages and schedules of mesna. In both human testicular cancer cell lines, H 12.1 and 2102 EP, ifosfamide demonstrated anti-tumour activity as a single agent. No reduction in ifosfamide activity was observed with the application of mesna at a dose range from 50% to 200% of the ifosfamide dose. Furthermore, the application of mesna before and 3 h after ifosfamide, a schedule used in many clinical protocols because of the short half life of mesna, not only maintained high ifosfamide anti-tumour activity but also seemed to be associated with the lower systemic and urothelial toxicity of ifosfamide therapy compared with ifosfamide given alone. In conclusion, the experimental in vivo system using human heterotransplanted testicular cancer cell lines confirms the significant anti-tumour activity of ifosfamide in malignant germ cell tumours and demonstrates that mesna does not impair ifosfamide anti-tumour activity in this model. These results are most likely transferable to the use of mesna in patients with metastatic testicular cancer.
Animals↗
Interaction between Helicobacter pylori and human gastric epithelial cells in culture: effect of antiulcer drugs.
A human in vitro model to study the interaction between Helicobacter pylori and gastric epithelial cells was developed using primary cultures of gastric mucosal cells (isolated from gastric biopsies or operative specimen and maintained in culture for 2 weeks) as well as the well-differentiated human gastric carcinoma cell line HM02, the undifferentiated gastric tumour cell line HM51, and the laryngeal epithelial cell line HEp-2. Primary cultures and all cell lines were exposed to seven isolates of H. pylori isolated from gastritis and duodenal ulcer patients. Microbial adherence was assessed by microscopical evaluation of Giemsa-stained preparations and by culturing the viable bacteria attached to the epithelial cells. All H. pylori isolates adhered to the gastric cells in primary culture, to HM02 cells, and to HEp-2 cells with the greatest binding affinity found in primary gastric cells. No adherence was detected in HM51 cells. H. pylori adherence was dependent on bacterial load, incubation time, and temperature. There was no difference in microbial binding between H. pylori isolates derived from gastritis and duodenal ulcer patients. The effect of antiulcer drugs on H. pylori adherence was investigated by pre-incubating isolates of H. pylori with omeprazole, cimetidine, and bismuth subcitrate. Omeprazole and cimetidine failed to significantly influence microbial adherence. In contrast, bismuth subcitrate already in concentrations below the MIC range decreased H. pylori adherence in gastric epithelial cells and in HEp-2 cells substantially. Our study shows that primary cultured human gastric mucosal cells and the human gastric carcinoma cell line HM02 provide suitable in vitro models for the study of the interactions between H. pylori and the gastric epithelium. This gastric cell model is characterized by a high affinity for H. pylori binding.
Anti-Ulcer Agents↗
High-dose treatment with carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in relapsed or refractory germ cell cancer: a phase I/II study. The German Testicular Cancer Cooperative Study Group.
PURPOSE: This trial evaluated the toxicity and efficacy of high-dose carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in patients with refractory or relapsed germ cell cancer. PATIENTS AND METHODS: Between August 1989 and September 1992, 74 patients with refractory or recurrent germ-cell tumors received one cycle of escalating doses of carboplatin (1,500 to 2,000 mg/m2), etoposide (1,200 to 2,400 mg/m2), and ifosfamide (0 to 10 g/m2). Before high-dose therapy, two cycles of conventional-dose cisplatin, etoposide, and ifosfamide were administered to assess tumor responsiveness. Seventy-four patients were assessable for toxicity and 68 for response. RESULTS: The doses of carboplatin 1,500 mg/m2, etoposide 2,400 mg/m2, and ifosfamide 10 g/m2 appeared to be safe. At this dosage, we treated 20 patients and observed World Health Organization (WHO) grade 3 and 4 hematotoxicity (100%), nausea (100%), diarrhea (30%), and hepatotoxicity (10%). All patients developed granulocytopenic fever. At carboplatin doses of 1,500 mg/m2, kidney toxicity was mild, with a median maximum creatinine level of 1.4 mg/dL (range, 1.1 to 3.0 mg/dL). However, at carboplatin doses of 1,750 and 2,000 mg/m2, we observed nonacceptable nephrotoxicity and neurotoxicity. Two (3%) patients died of treatment-related complications. Six patients required hemodialysis, which was temporary in five patients and permanent in one. Objective responses were obtained in 43 of 68 (63%) patients, including 21 (31%) complete remissions (CRs) and 14 (20%) inoperable partial remissions (PRs) with marker normalization. The median observation time of surviving patients was 12 months (range, 2 to 32). The probabilities of overall survival, event-free survival, and the relapse-free survival at 2 years were 44% (SD 8%), 35% (SD 6%), and 67% (SD 9%), respectively. Patients with disease refractory to conventional-dose pretreatment had a poor prognosis, with only one of 23 patients surviving event-free at 7 months after high-dose chemotherapy (HDT). In contrast, 24 of 45 (53.3%) patients with sensitive disease survive event-free with a probability of event-free survival at 2 years of 50% (SD 8%). CONCLUSION: High-dose carboplatin, etoposide, and ifosfamide plus autologous stem-cell transplantation can be used in refractory and relapsed germ cell cancer with acceptable toxicity, and represents an effective, potentially curative salvage treatment.
Adult↗
The role of granulocyte-macrophage colony-stimulating factor in the treatment of germ cell tumors. German Testicular Cancer Study Group.
Hematopoietic growth factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), may gain increasing importance in the treatment of patients with malignant germ cell tumors. For patients with far advanced testicular cancer, who only have a chance of long-term cure in the range of 40% to 50% by standard induction chemotherapy, the German Testicular Cancer Study Group has shown that the application of GM-CSF after PEI chemotherapy has allowed the increase of dose intensity of this three-drug regimen by a factor of 1.4. In 75 evaluable patients an overall survival rate of 79% after a median follow-up of 27 months was achieved. The dose-limiting toxicity of this stepwise dose escalation protocol of the PEI regimen was severe mucositis/enteritis (World Health Organization [WHO] degrees 3/degrees 4) in 33% of the patients and prolonged thrombocytopenia (< 20,000/microL for more than 10 days). In future trials, hematopoietic growth factors will be used in the treatment of far-advanced testicular cancer to generate peripheral blood stem cells (PBSC) that can be used to overcome both granulocytopenia and thrombocytopenia. This approach with the use of PBSC and hematopoietic growth factors will allow us to apply multiple cycles of up-front dose-intensified PEI chemotherapy in this unfavorable subgroup of patients. However, with the establishment of an optimal hematopoietic support in these studies, the value of dose-intensified chemotherapy in advanced testicular cancer will have to be tested against standard dose regimens in prospective randomized trials.
Antineoplastic Combined Chemotherapy Protocols↗
[Metastatic adult teratoma of the testis. Possibilities of chemotherapy and surgical treatment].
We report on a patient with the diagnosis of an adult teratoma metastasizing as choriocarcinoma. The 49-year-old man died of dysfunction of the liver caused by massive metastatic involvement. This case demonstrates the malignant potential of adult teratoma and emphasizes the need for chemotherapy of the same kind as for other malignant germ cell tumours if undifferentiated metastases of the teratoma are present. The chemotherapeutic modalities and the options for surgical treatment of metastatic adult teratomas of the testis are discussed.
Carcinoma, Squamous Cell↗
Cardiotoxicity of 5-fluorouracil in combination with folinic acid in patients with gastrointestinal cancer.
BACKGROUND: Cardiotoxicity related to the widely used cytotoxic compound 5-fluorouracil (5-FU) is rare compared with the frequency observed with the use of anthracyclines. More effective protocols incorporating active biomodulatory compounds like folinic acid (FA) or combination chemotherapy change type and severity of toxicity as well. The objective of the current study was to assess cardiotoxicity of the combination 5-FU and folinic acid. METHODS: The authors' multicenter experience with 390 patients treated for advanced gastrointestinal cancer with intermediate-dose folinic acid and 5-FU was reviewed. RESULTS: The overall risk of cardiotoxicity was 3%, which is not significantly higher than that reported with 5-FU alone. Eight of 53 patients with a history of cardiac disease reported cardiac symptoms (15.1%), compared with 5 of 337 patients (1.5%) with a no history of cardiac disease. Median time to symptoms was 3 days (range, 2-6). Nine patients had symptoms resembling myocardial ischemia, one patient died due to assumed myocardial infarction related closely to fluorouracil treatment, four patients had supraventricular arrhythmia, and one patient had congestive heart failure. A history of cardiac disease was the only risk factor associated with cardiotoxicity. Relapses were frequent on reinstitution of therapy despite cardiac symptoms in the preceding cycle. Therapeutically or prophylactically administered nitrates had no significant effect. CONCLUSION: Physicians should be aware of the cardiotoxic properties of active fluorouracil treatment. The combination of 5-FU and leucovorin does not differ from single-agent therapy in frequency or type of cardiotoxicity. Close monitoring of patients is mandatory, especially for those patients at high risk for cardiac side effects. Treatment should be discontinued if coronary symptoms develop, because neither effective treatment nor prophylaxis exists for such symptoms.
Adult↗
Single-agent carboplatinum for advanced seminoma. A phase II study.
BACKGROUND: To reduce the side effects of cisplatin-based combination chemotherapy, the activity of carboplatinum was evaluated in patients with advanced seminoma. METHODS: Forty-two evaluable patients with advanced seminoma (defined as abdominal lymph nodes > 5 cm or supradiaphragmatic or visceral disease) received single-agent carboplatinum at a dose of 400 mg/m2 intravenously every 4 weeks for a maximum of six cycles. The median follow-up was 31 months (18-67 months). RESULTS: Thirty patients (71%) achieved a complete remission (CR; 21 chemotherapy alone, 9 with additional surgery), 8 patients (19%) a partial remission (PR), and 4 patients had disease progression (10%). Patients with metastases confined to the lymph nodes had a significantly higher remission rate than patients with visceral metastases (97% versus 50%; P < 0.002). Elevation of lactate dehydrogenase or human chorionic gonadotropin before radiation therapy had no influence on response rate. Eight patients have relapsed (five from CR and three from PR). All 12 patients failing carboplatinum therapy received cisplatin-based combination regimens. Ten patients achieved a stable favorable response (eight CR, two PR), whereas two patients died of their disease. Currently, 30 patients (71%) are continuously free from progression (25 CR, 5 PR), and 40 patients are alive (survival 93%). Toxicity was mild with no neurotoxicity or nephrotoxicity. CONCLUSIONS: The use of up-front carboplatinum therapy appears not to compromise the ultimate curability of patients with advanced seminoma. Randomized trials, however, will have to demonstrate the effectiveness of carboplatinum with regard to survival, and help to identify prognostic subgroups of patients who require up-front cisplatinum-based combination chemotherapy.
Adult↗
Preclinical activity of a new platinum analogue, lobaplatin, in cisplatin-sensitive and -resistant human testicular, ovarian, and gastric carcinoma cell lines.
Lobaplatin [1,2-diamminomethylcyclobutane-platinum(II) lactate] is a new platinum compound with interesting preclinical activity and apparently no nephro- or neurotoxicity that is currently undergoing clinical phase II studies. Little is known about the cross-resistance between cisplatin and lobaplatin. The activity of this new compound in comparison with cisplatin and carboplatin was evaluated in cisplatin-sensitive and cisplatin-resistant human testicular, gastric, and ovarian carcinoma cell lines using 96 h continuous drug exposure in a sulforhodamine-B assay. In three cisplatin-sensitive testicular carcinoma cell lines, lobaplatin and cisplatin showed comparable antitumor activity. The 50% growth-inhibitory concentrations (IC50 values) determined for cisplatin ranged from 0.1 to 0.4 microM, and those found for lobaplatin ranged from 0.25 to 0.5 microM. Carboplatin showed markedly lower cytotoxicity in all cell lines tested. Lobaplatin was not cross-resistant to cisplatin in a 10-fold cisplatin-resistant testicular carcinoma cell line and showed only weak cross-resistance in a 20-fold cisplatin-resistant ovarian carcinoma cell line. In contrast, complete cross-resistance between cisplatin and lobaplatin occurred in two cisplatin-resistant human gastric carcinoma cell lines, which were 3.3- and 9-fold resistant to cisplatin and 3.1- and 6.5-fold resistant to lobaplatin, respectively. Furthermore, lobaplatin showed significant activity against cisplatin-resistant human ovarian and testicular carcinoma xenografts in vivo. These data indicate a high level of activity for lobaplatin at clinically achievable concentrations in ug-sensitive testicular, ovarian, and gastric carcinoma cell lines and a lack of complete cross-resistance to cisplatin. Further clinical development of lobaplatin is clearly warranted.
Antineoplastic Agents↗
Analysis of a non-ras 21-kDa protein in patients with metastatic testicular germ-cell tumors.
A novel protein of 21 kDa (p21) has been detected in the sera of patients with different solid tumors. The serum levels of this p21 protein were measured in seven patients with metastatic testicular germ-cell tumors before and after chemotherapy using an enzyme-linked immunosorbent assay. In five out of six patients who responded to chemotherapy a concomitant decrease of p21 serum levels was found. The decrease of p21 was in accordance with the decline of the established tumor markers alpha-fetoprotein, human chorionic gonadotropin beta-subunit and lactate dehydrogenase in three patients with non-seminomatous tumors and with the decline of lactate dehydrogenase and the clinical response in two patients with seminoma. In one patient the predicted decline of p21 did not occur despite the patient's clinical response to chemotherapy. In the seventh patient, who relapsed directly after chemotherapy, no decline of either p21 levels or tumor markers was observed. The absolute amount of the p21 protein prior to chemotherapy did not correlate with the patients' tumor burden. Elevated levels of p21 were found in patients with seminomatous and non-seminomatous germ-cell tumors. Since seminoma patients do not secrete tumor markers like alpha-fetoprotein or human chorionic gonadotropin beta, the determination of p21 levels may help to evaluate the efficacy of chemotherapy in patients with seminomatous as well as in patients with marker-negative non-seminomatous germ-cell tumors. The biological role of p21 and its clinical significance will be further investigated.
Adult↗
Comparison of 5 vs 10 micrograms/kg per day of GM-CSF following dose-intensified chemotherapy with cisplatin, etoposide, and ifosfamide in patients with advanced testicular cancer.
Despite the increasing use of granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment of chemotherapy-induced neutropenia, few studies have focused on the activity and toxicity of the different clinically used dosages of GM-CSF. Forty-four patients with "poor-risk" (advanced disease, according to the Indiana University classification) testicular cancer were treated with a dose-intensified chemotherapy regimen of cisplatin (30 mg/m2), etoposide (200 mg/m2), and ifosfamide (1.6 g/m2), given on days 1-5 for a total of four cycles at planned intervals of 21 days. Patients (pts) received GM-CSF, either 10 (22 pts; 70 cycles evaluable) or 5 micrograms/kg body wt. daily s.c. (22 pts; 72 cycles evaluable), starting the first day after chemotherapy for 10 consecutive days. Overall, 34 patients (78%) achieved a favorable response (CR or PR with negative tumor markers), six patients (14%) failed this chemotherapy regimen, and four patients (9%) died of therapy-related complications. The durations of both neutropenia and thrombocytopenia increased with the number of treatment cycles given. The duration of granulocytopenia after the fourth PEI cycle was significantly shorter for patients receiving 10 micrograms/kg than for those with 5 micrograms/kg per day of GM-CSF (9 vs 13 days; p < 0.05). The median duration of thrombocytopenia < 20,000/microliters after the fourth cycle of PEI was also significantly reduced in favor of patients receiving 10 micrograms/kg of GM-CSF (4 vs 9 days; p < 0.02). However, there were no differences in the frequency of severe infections or in the achieved dose intensity. Five patients (11%) discontinued GM-CSF due to side effects (three anaphylactoid-type reactions, one myalgia and fever, one cutaneous toxicity). No difference in the frequency of side effects was seen between patients receiving 5 and those receiving 10 micrograms/kg per day of GM-CSF. The dose of 5 micrograms/kg per day of GM-CSF may be sufficient to ameliorate neutropenia following standard-dose chemotherapy, while higher dosages of GM-CSF may be advantageous in patients receiving repetitive cycles of dose-intensified chemotherapy.
Antineoplastic Combined Chemotherapy Protocols↗
A phase I/II study of a stepwise dose-escalated regimen of cisplatin, etoposide and ifosfamide plus granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced germ cell tumours.
In order to improve the survival of patients with metastatic advanced disease germ cell tumours (according to Indiana University classification), 77 patients were treated by a stepwise dose-escalated combination regimen of platinum (P), etoposide (E) and ifosfamide (I) (PEI) followed by application of granulocyte-macrophage colony-stimulating factor (GM-CSF) (10 micrograms/kg subcutaneously per day at levels 2 and 3) starting the first day after chemotherapy for 10 consecutive days. The maximally tolerated dose was reached at the third dose level with P 30 mg/m2, E 200 mg/m2 and I 1.6 g/m2, all given for 5 days, once every 21 days, for a total of four cycles. Sixty-seven per cent of patients had three or more metastatic sites. Twenty-two per cent of patients had extragonadal primary tumours. 49 (65%) patients achieved complete remission, and 9 additional patients (12%) achieved marker normalisation with unresectable residual disease. After a median follow-up of 27 months, the overall survival is 80%, with 67% of patients remaining free from progression. The dose-limiting toxicities were WHO grades 3/4 mucositis/enteritis in 33% of patients and prolonged thrombocytopenia < 20.000/microliters (> 10 days). Adverse reactions to GM-CSF occurred in 13% of patients. The use of a single haematopoietic growth factor allowed only a moderate increase in dose intensity (factor 1.37). Peripheral blood stem cells will be additionally incorporated into the treatment protocol in order to deliver multiple cycles of an upfront dose-intensified PEI regimen in patients with "poor risk" germ cell tumours with less toxicity.
Antineoplastic Combined Chemotherapy Protocols↗
Familial occurrence of Leydig cell tumors: a report of a case in a father and his adult son.
We report on the familial occurrence of nonhormone-secreting Leydig cell tumors in a father and his adult son. No evidence for an underlying endocrinological disorder was found. The father even had metachronous bilateral Leydig cell tumors with an interval of 11 months.
Adult↗
Bilateral testicular tumours: prevalence and clinical implications.
In a series of 773 patients with the diagnosis of a testicular germ cell tumour, treated at Hannover University Medical School between 1972 and 1985 and with a median follow-up of 9 years (60-210 months), bilateral testicular tumours occurred in 27 (3.5%) patients. None of 157 patients receiving chemotherapy for metastatic disease of the first tumour developed a metachronous bilateral tumour. Of 24 patients with metachronous tumours 23 had stage I and 1 patient had stage II at the time of initial diagnosis. The second testicular tumour was stage I in 18 patients, stage II in 5 and stage IV in 1 patient. 3 patients (13%) relapsed after treatment for their second germ cell tumour (surveillance 13 patients, radiotherapy 7 patients, lymph node dissection 2 patients and chemotherapy 2 patients), 1 of which died after refusing further treatment. The cure rate was 96% in patients with bilateral disease. Routine biopsy of the contralateral testis to identify existing carcinoma in situ (CIS) is recommended. Patients with CIS must be informed about their increased risk of a second testicular tumour. Irradiation of CIS or close clinical follow-up might both constitute appropriate strategies for the management of these patients.
Humans↗
Side-effects of GM-CSF treatment in advanced testicular cancer.
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Anaphylaxis↗
Secondary cancer following Hodgkin's disease.
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Adolescent↗
Treatment of advanced germ cell tumours by dose intensified chemotherapy with haematopoietic growth factors or peripheral blood stem cells (PBSC).
Dose intensification of the most active drugs may improve the treatment results of patients (pts.) with far advanced metastatic testicular cancer. At Hannover University pts. with advanced testicular cancer (Indiana University criteria) were entered in a phase I/II study of a step-wise dose-intensified regimen of platinum, etoposide, and ifosfamide (PEI) with s.c. GM-CSF (5-10 micrograms/kg/day). Due to thrombocytopenia and mucositis the MTD was reached at dose level 3 with P 30 mg/m2, E 200 mg/m2, and I 1.6 g/m2 (d 1-5, q 21 d, 4 cycles). Overall, 49 of 75 pts. (65.3%) achieved CR/NED. 11 pts. (14.6%) failed PEI therapy, but 4 of these achieved CR/NED by salvage treatment. After a median follow-up of 22 months 66% of pts. are alive and free of disease. The dose intensity was 1.42 compared to a standard PEI regimen. A further increase of dose-intensity will require additional haematopoietic support, e.g. peripheral blood stem cells (PBSC). PBSC following dose-intensified PEI-chemotherapy plus G- or GM-CSF are used in the current study of the German Testicular Cancer Study Group for the treatment of advanced germ cell tumours.
Antineoplastic Combined Chemotherapy Protocols↗