Treatment strategies in metastatic testicular cancer.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
C Bokemeyer
Publications and source records attributed to C Bokemeyer.
Secondary neoplasms following treatment of malignant germ cell tumors.
PURPOSE: The current study investigates the frequency and outcome of secondary malignancies in patients treated for testicular cancer at Hannover University Medical School between 1970 and 1990. PATIENTS AND METHODS: One thousand twenty-five patients with a median follow-up duration of 61 months (range, 12 to 240) were included in the analysis. Follow-up was complete in 1,018 patients (99%). Histology was seminoma in 324 patients (38.7%) and nonseminomatous germ cell tumor in 624 patients (61.3%). At the time of median follow-up, 814 patients (79.9%) were alive. RESULTS: Fourteen patients developed a secondary neoplasm (cumulative incidence, 1.38%; 95% confidence interval [CI], 0.75 to 2.30); 13 patients had solid tumors and one had secondary lymphoblastic leukemia with a t(4; 11) translocation including band 11q23. None of 224 patients on surveillance strategy (with or without retroperitoneal lymph node dissection [RPLND]) developed a second neoplasm, compared with four of 413 patients (0.97%; 95% CI, 0 to 1.9) after cisplatin-based chemotherapy (not significant) and nine of 332 patients (2.7%; 95% CI, 0.9 to 4.5) after radiotherapy (P = .02). The cumulative incidence of a secondary neoplasia of 1.76% (95% CI, 0.97 to 2.94) in patients treated by radiotherapy and/or chemotherapy was significantly higher compared with patients on surveillance protocols (P = .03). Chemotherapy containing standard-dose etoposide did not increase the risk of occurrence of secondary neoplasms. A significantly elevated relative risk of 7.53 (range, 3.4 to 14.3) compared with the male German population was only found for patients treated by radiotherapy. CONCLUSION: Compared with patients who have other curable malignant tumors, an incidence of 1.38 of secondary neoplasms after a median follow-up duration of 61 months is low. The highest risk for secondary neoplasia after treatment of testicular cancer is associated with the use of radiotherapy. Following chemotherapy, no significantly elevated risk was observed. In conclusion, the benefits of curative treatment far outweigh the risk of secondary cancer in patients with malignant germ cell tumors.
Adolescent↗
Successful treatment of Mucor pneumonia in a patient with relapsed lymphoblastic leukemia after bone marrow transplantation.
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Adult↗
A pilot study of rapidly alternating epirubicin/dacarbazine and ifosfamide as first-line therapy for metastatic soft-tissue sarcoma in adults.
Currently, anthracyclines and ifosfamide are the most effective drugs for the treatment of disseminated soft-tissue sarcoma. We designed a treatment protocol of rapidly alternating epirubicin/dacarbazine and ifosfamide for previously untreated soft-tissue sarcoma, whereby 100 mg/m2 epirubicin was given on day 1, 500 mg/m2 dacarbazine was given on days 1 and 2, and 6,000 mg/m2 ifosfamide given via 24-h infusion was begun on day 15. The entire treatment cycle was scheduled to begin again on day 28 if the leukocyte count had reached 3.0 x 10(9)/l. From June 1988 to May 1991, a total of 28 patients were enrolled in the study. Eight patients (31%) achieved a partial response to therapy. The median duration of partial response was 8.5 months, and the median time to progression for all patients was 5 months. Myelosuppression was dose-limiting (leukocyte nadir, 1.7 x 10(9)/l; platelet nadir, 70 x 10(9)/l). Prolonged myelosuppression forced frequent therapy delays; therefore, only 74% of the planned doses could be given. The nonhematologic toxicity was tolerable. This rapidly alternating treatment protocol was determined to offer no therapeutic advantage over anthracycline therapy either alone or in combination with dacarbazine in terms of response rate or time to disease progression. The inclusion of hematopoietic growth factors, however, might ameliorate the dose-limiting myelosuppression and permit the administration of higher doses.
Adult↗
Pen-based remote data entry system. A pilot clinical trial.
This study assesses the feasibility of pen-based remote data entry and measures the acceptance of such systems by patients and physicians. Three clinical investigators participated in a phase-I/II clinical trial of escalated doses of chemotherapy followed by Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF). The study included 20 patients with testicular cancer who were treated at three university hospitals. The patients' data obtained in this trial were recorded and stored on a pen-based computer system. A total of 798 data points were recorded for each patient using 33 electronic forms resembling the paper forms used during an earlier phase of the study. The data recorded include the past medical history, inclusion/exclusion criteria, disease staging, therapy documentation, laboratory values and side effects. Both physicians and patients were interviewed directly after using the pen-based remote data entry system. Patients accepted that their physician was taking notes on an electronic form rather than on paper. All patients noted that a pen-based system is superior to a desktop computer when used during an interview. For the investigators electronic data entry takes additional effort, but time savings are realized later with less data clearing and increased data quality. These benefits are important for the study sponsor as well. In conclusion, pen-based remote data entry is a feasible new mode of recording clinical data with concrete benefits to both investigators and sponsors.
Data Display↗
[Germ-cell tumors of the testis. The epidemiological and etiological aspects].
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Disease Susceptibility↗
Phase II study of single-agent etoposide in patients with metastatic squamous-cell carcinoma of the esophagus.
A total of 26 evaluable patients presenting with advanced or metastatic squamous-cell carcinoma of the esophagus were entered in a phase II trial to assess the single-agent activity of etoposide. Etoposide was given at a dose of 200 mg/m2 on 3 consecutive days every 3 weeks. Five patients (19%) achieved a partial response and seven (27%) experienced stabilisation of their disease. The median duration of response was 4 months (range 3-8 months). The major toxicity was leukopenia, which reached WHO grade 3 in 46% of patients and grade 4 in 11% of cases, with five instances of leukopenic fever and one therapy-associated death being recorded. Etoposide given at this dose and on this schedule seems to have considerable activity against non-pretreated metastatic esophageal carcinoma.
Adult↗
Antitumour effect and symptomatic control with interferon alpha 2b in patients with endocrine active tumours.
26 patients with progressive neuroendocrine tumours received 3 x 10(6)U/m2 interferon alfa (IFN-alpha 2b) subcutaneously thrice weekly, until progression, as outpatients with moderate toxicity. 4/16 carcinoids and none out of 10 endocrine pancreatic tumours showed objective regression. Another 17 patients (68%) had no change. For a median of 34 weeks symptom control was excellent: 9 of 17 patients had major relief from pain, 11 of 13 from diarrhoea, and 7 of 7 from flushing. Thus, low-dose INF-alpha 2b given thrice weekly might be as effective as daily treatment with higher dosages. Treatment was only administered to patients with progression or major symptoms and this did not seem to adversely affect remission quality and survival.
Adult↗
Epirubicin/dacarbazine rapidly alternated with ifosfamide in the treatment of metastatic soft tissue sarcomas.
Twenty-eight patients with non-pretreated metastatic soft tissue sarcomas were entered on a treatment protocol of rapidly alternating epirubicin/dacarbazine and ifosfamide: Epirubicin 100 mg/m2 d1, dacarbazine 500 mg/m2 d1 + d2, ifosfamide 6000 mg/m2 24-h infusion d15; repeated d29. Eight patients (30%) achieved partial responses, with a median duration of 8.5 months. The median time to progression was 5.5 months. Myelosuppression was the main toxicity. Only 74% of the planned dose intensity could be administered. This rapidly alternating treatment protocol is not superior to anthracycline single agent therapy.
Adolescent↗
Secondary lymphoblastic leukemia following treatment of a malignant germ cell tumour.
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Adult↗
Dose escalation of cisplatin (P), etoposide (E), and ifosfamide (I) with GM-CSF for advanced germ cell tumors.
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Cisplatin↗
The role of schedule dependency of 5-fluorouracil/leucovorin combinations in advanced colorectal cancer.
The dose intensity in cancer monochemotherapy is probably the most important prognostic factor. In combination chemotherapy, in which interactions between agents do occur, response, survival, and toxicity might vary between different schedules. In a literature review of all published data of folinic acid and 5-fluorouracil intravenous bolus therapy in colorectal cancer with comparable dose intensity, an attempt was made to characterize the possible differences of the variations of schedules used. The antitumor activity increased significantly from 19% to 30%-35% when the two drugs were used concomitantly in multiple fractions per cycle rather than on a single day. However, fractionation changed the type of dose-limiting toxicity from hematologic and neurologic to gastrointestinal side effects. The different schedules did not differ significantly in the overall frequency of severe toxicities; however, recommending a certain schedule outside of controlled trials should be done cautiously.
Clinical Trials as Topic↗
Interferon alpha-2b, 5-fluorouracil, and folinic acid combination therapy in advanced colorectal cancer: preliminary results of a phase I/II trial.
We conducted a phase I/II trial of 5-fluorouracil (5-FU)/folinic acid (FA) and alpha-2b interferon (IFN) in 43 previously untreated patients with measurable metastatic colorectal cancer. Patients had disease progression prior to therapy consistent of 5-FU 500 mg/m2 (level A) or 600 mg/m2 (level B) as starting dose administered as a 2-hour infusion, FA 200 mg/m2, and alpha-2b IFN 5MU/m2 subcutaneously. All drugs were given on days 1 to 5 and cycles were repeated after 3 to 4 weeks. The aim of the study was to define the maximal tolerable dose (MTD) of 5-FU for this schedule. In the absence of toxicity above MTD, defined as diarrhea and mucositis of World Health Organization grade 2 and leukopenia of World Health Organization, grade 3 5-FU was increased in increments of 100 mg/m2 for further cycles. Twenty-four patients were started on level A; 18 were started on level B. Forty-two patients were evaluable for toxicity, 32 for response. Three of 32 patients achieved a partial response; in 22 of 32 patients, tumor stabilization occurred. Forty percent of patients started on level A developed grade 2 diarrhea; 28% of patients developed grade 2 or 3 mucositis. Of 18 patients on level B, two patients experienced grade 4 mucositis (11%) and grade 3 or 4 diarrhea (11%). One drug-related death in the presence of sepsis occurred. Due to 11% of patients with grade 4 toxicity when started on 600 mg/m2 5-FU and 40% of patients with grade 2 diarrhea when started on level A, MTD as starting dose for 5-FU is 500 mg/m2 as a 2-hour infusion when used in combination with FA and IFN on a day 1 to 5 active schedule. We observed a wide range of 5-FU dose tolerated by individual patients. While some patients experienced severe, mainly gastrointestinal, toxicity on lower levels of 5-FU, others tolerated much higher 5-FU doses (11 patients, 700 mg/m2; 5 patients, 800 mg/m2; and one patient, 900 mg/m2). Our data suggest that double modulation of 5-FU by FA and IFN may not be superior to modulation of 5-FU with either drug alone.
Adult↗
Cisplatin/etoposide/ifosfamide stepwise dose escalation with concomitant granulocyte/macrophage-colony-stimulating factor for patients with far-advanced testicular carcinoma.
In order to develop a more dose-intensive induction regimen for the treatment of far-advanced testicular tumours, the German Cooperative Group for Testicular Tumours started a dose-escalation trial of cisplatin, etoposide and ifosfamide. At the first dose level 18 patients with advanced testicular cancer (Indiana University classification) received cisplatin 25 mg/m2, etoposide 120-150 mg/m2 and ifosfamide 1.2 g/m2 for 5 days every 3 weeks. Of these, 13 patients (72%) became tumour-free, 2 achieved a stable, marker-negative partial remission, 2 had progressive disease and 1 patient died of Clostridium sepsis. The main toxicity was myelosuppression with a white blood cell nadir of 900/microliters and a thrombocyte nadir of 47,000/microliters. Granulocytopenic fever occurred in 43% of all cycles. At the second dose level 15 patients received cisplatin 30 mg/m2, etoposide 150 mg/m2 and ifosfamide 1.6 g/m2 five times every 3 weeks together with s.c. recombinant granulocyte/macrophage-colony-stimulating factor (GM-CSF) 10 micrograms/kg on days 6-15. Acute toxicity was severe with a white blood cell nadir of 300/microliters and thrombocyte nadir of 11,000/microliters. The duration of the thrombocytopenia increased with cycle number; 63% of all cycles were associated with granulocytopenic fever and in 83% platelet transfusions were required. One patient died from acute renal failure and Aspergillus sepsis; 3 patients experienced adverse reactions to GM-CSF, requiring omission of this drugs in 2; 33% had grade 3 or 4 mucositis. At this dose level 8 patients (53%) became tumour-free, 4 patients (26%) had marker normalization with irresectable residual disease and 2 patients were treatment failures. Though acute toxicity was severe at this dose level, there was no unexpected or unmanageable organ toxicity and thus patients are now entered at dose level 3, which consists of cisplatin 30 mg/m2, etoposide 200 mg/m2 and ifosfamide 1.6 g/m2 for 5 days and GM-CSF 10 micrograms kg-1 day-1 on days 6-15 s.c.
Antineoplastic Combined Chemotherapy Protocols↗
Cisplatin, etoposide, and ifosfamide salvage therapy for refractory or relapsing germ cell carcinoma.
Thirty patients with metastatic progressive germ cell carcinoma who failed to be cured with first-line cisplatin chemotherapy were treated with a salvage regimen consisting of cisplatin 20 mg/m2, etoposide 100 mg/m2, and ifosfamide 1.2 g/m2 (PEI) intravenously (IV), days 1 to 5 every 3 weeks. Ten patients (33%) were tumor-free at the end of therapy. Complete response (CR) was achieved with chemotherapy alone in four patients and with additional surgery in six patients (two necroses, two mature teratomas, two carcinomas). Six patients (20%) had normalization of tumor markers but unresectable residual disease (Rm-), and the remaining 14 patients (46%) failed to respond. Of 10 patients with CR, nine (90%) relapsed again (eight carcinomas, one mature teratoma). The median duration of CR was 3.5 months. The median survival of the whole group was 311 days (range, 110 to 996+). Currently, seven of 30 patients are alive, and five of them are without signs of progressive tumor. The response to prior cisplatin therapy predicted for response and survival after PEI salvage therapy. Of 14 patients with prior CR, eight (57%) achieved a second CR compared with one of 11 (9%) with prior unfavorable response (P = .039). The median survival for patients with prior favorable response was 400 days, compared with 251 days for patients with prior unfavorable response (P less than .001). Myelosuppression was dose-limiting, with leukopenia greater than grade 2 in 84% and thrombocytopenia greater than grade 2 in 51% of all cycles. This three-drug regimen can induce a second CR in one third of patients with relapsed or refractory germ cell carcinoma. Only those patients with prior favorable responses can expect to be cured by this salvage regimen, while patients with prior unfavorable response should be considered for alternative salvage approaches.
Adult↗
Giant aneurysm causing frontal lobe syndrome.
A 67-year-old patient with a completely thrombosed giant aneurysm of the anterior communicating artery is described. The only neurological findings were a disturbance of stance and gait and slight bilateral grasp reflexes. He had had the features of a frontal lobe psychotic syndrome for more than 12 years. Computed tomography demonstrated a primarily hyperdense calcified suprasellar space-occupying lesion. Magnetic resonance imaging proved valuable in establishing the correct diagnosis, which was confirmed post mortem.
Aged↗
High dose epirubicin in refractory or relapsed non-seminomatous testicular cancer: a phase II study.
Sixteen patients with metastatic nonseminomatous testicular cancer refractory to cisplatinum combination chemotherapy, were treated with epirubicin 100-120 mg/m2 q d 22. One partial remission lasting 6 months was achieved. Two additional patients had stabilisation of disease for 3 and 4 months. Median time to progression was 43 days. Myelosuppression was dose-limiting, with a WBC nadir of 1900/microliters. 4/30 cycles (13%) were associated with granulocytopenic fever. One patient developed a decline in cardiac ejection fraction without clinical signs of congestive heart failure. Epirubicin in this dosage and schedule has no major therapeutic activity in heavily pretreated non-seminomatous testicular cancer.
Combined Modality Therapy↗
Growth requirements, growth factor responsiveness, and growth factor secretion of three human embryonal carcinoma cell lines.
The in vitro growth requirements of three human embryonal carcinoma cell lines (H 12.7, 2102 EP, 1428 A) were investigated. The basal medium DME/F12 supplemented with insulin, transferrin, and low-density and high-density lipoproteins was sufficient to support substantial multiplication of all three lines. The most efficient attachment factor was either fibronectin (for 2102 EP and 1428 A) or collagen type I (H 12.7). In a serum-free system the influence of epidermal growth factor (EGF), insulin-like growth factor I, multiplication stimulating activity (MSA), a platelet extract, and the glucocorticoids dexamethasone and hydrocortisone, as determined by the DNA synthesis rate of the cells, was generally minimal. However, the DNA synthesis rate of cell lines H 12.7 and 2102 EP was increased by MSA, and the line with the highest potential to differentiate (H 12.7) was stimulated by EGF. All three cell lines secreted growth factors in a heterologous stimulation assay. Insulin-like growth factors I and II were not part of the growth promoting activity. The inhibitory effect of a monoclonal anti-EGF antibody on the 3H-thymidine incorporation of cell line 2102 EP might indicate autocrine secretion of EGF or an EGF-like factor by this cell line.
Cell Division↗