[Gemcitabine/cisplatin vs. MVAC. 5 year survival outcome of the phase III study of chemotherapy of advanced urothelial carcinoma in Germany]. / Gemcitabin/Cisplatin vs. MVAC. 5-Jahres-Ergebnisse der Phase-III-Studie zur Chemotherapie des fortgeschrittenen Urothelkarzinoms in Deutschland.

Of 405 patients with stage IV transitional cell carcinoma from an international multicenter phase III trial, 70 were randomized in Germany to receive either gemcitabine/cisplatin or standard MVAC systemic chemotherapy for locally advanced or metastatic urothelial cancer. Overall survival as the primary endpoint of the study was similar in both arms (median survival GC 15.4 months vs MVAC 16.1 months), as were tumor-specific survival and time to progressive disease. In the intent-to-treat analysis, the 5-year overall survival rate was 10% for patients randomized to GC and 18% randomized to MVAC. Tumor overall response rates (GC 54%, MVAC 53%) were similar. The toxic death rate was 0% in the GC arm and 3% (one patient) in the MVAC arm. Significantly more GC than MVAC patients experienced grade 3/4 anemia (GC 52%, MVAC 20%) with significantly more red blood cell transfusions in the GC arm.Significantly more GC than MVAC patients had grade 3/4 thrombocytopenia (GC 54%, MVAC 17%) without grade 3/4 hemorrhage or hematuria in either arm. More MVAC patients experienced grade 3/4 neutropenia (GC 56%, MVAC 61%, p=1.000), neutropenic or leukopenic fever (GC 0%, MVAC 10%, p=0.237), mucositis (GC 0%, MVAC 7%, p=0.495), and alopecia (GC 6%, MVAC 36%, p=0.004). GC represents a reasonable alternative for the palliative treatment of patients with locally advanced and metastatic transitional cell carcinoma. Sustained long-term survival was only found for patients with locally advanced cancer, lymphatic metastases, or solitary distant metastasis but not for visceral metastatic disease.

Remission induction therapy: the more intensive the better?

Intensive induction therapy in acute myeloid leukemia (AML) as in some other systemic malignancies is a strategy fundamentally different from post-remission strategies. Approaches such as consolidation treatment, prolonged maintenance, and autologous or allogeneic transplantation in first remission are directed against the minimal residual disease in which a malignant cell population has survived induction treatment and shows resistance due to special genetic or kinetic features. In contrast, induction therapy deals with naive tumor cells possibly different from their counterparts in remission in terms of their kinetic status and sensitivity. Therefore, in AML the introduction of intensification strategies into the induction phase of treatment has been suggested as a new step in addition to intensification in the postremission phase. As expected from the dose effects observed in post-remission treatment with high-dose cytarabine (AraC) or longer treatment, similar dose effects have been found in induction treatment both from the incorporation of high-dose AraC and from the double-induction strategy used in patients up to 60 years of age. As a particular effect, patients with poor-risk AML according to an unfavorable karyotype, high LDH in serum, or a delayed response show longer survival following double induction containing high-dose AraC as compared to standard-dose AraC. A corresponding dose effect in the induction treatment of patients aged 60 years and older has been found with daunorubicin 60 vs 30 mg/m2 as part of the thioguanine/ AraC/daunorubicin (TAD) regimen with the higher dosage significantly increasing the response rate and survival in these older patients who represent a poor-risk group as a whole. Thus we have been able to demonstrate both in younger and older patients that a poor prognosis can be improved by a more intensive induction therapy. High-dose AraC in induction, however, exhibits cumulative toxicity in that repeated courses containing high-dose AraC in the post-remission period lead to long-lasting aplasias of about 6 weeks. Thus after intensive induction treatment, high-dose chemotherapy in remission may be practicable using stem-cell rescue and may contribute to a further improvement in the outcome in poor-risk as well as average-risk patients with AML. These approaches are currently under investigation by the German AML Cooperative Group (AMLCG). "The more intensive the better" is certainly not the way to go in the management of AML and other systemic malignancies but some increase in intensity may be possible and better.

Palliation by intratumoral infiltration with natural interferon-beta.

BACKGROUND: Curative approaches to tumor therapy have achieved greater importance through new developments such as cytostatic agents and their combination with other therapy concepts, but for the majority of tumor patients only palliative therapy is possible. Size or location of tumor manifestations can result in severe discomfort for patients, in some cases even in a reduction of functionality. PATIENTS AND METHODS: For the purpose of this study, a total of 55 patients with a variety of advanced malignant diseases nonresponding or progressive under radio- and/or chemotherapy were treated by intratumoral injection of natural human fibroblast interferon (nIFN-beta). nIFN-beta was administered intralesionally 3 times per week for at least 4 weeks at doses of 2-8 MIU, depending on tumor size. Local tumor response was observed over a median follow-up period of 18 weeks. RESULTS: In 37 patients (67%) a complete or partial remission of the local tumor manifestation was achieved. Survival times of these patients were improved compared with those of patients without local tumor remission. 16 patients without significant change of tumor volume benefited from the palliative (extensive analgesic) effect of the nIFN-beta therapy. During treatment, none of the patients showed a progression of the locally treated tumor, even when the basic malignant disease progressed. The side effects of the nIFN-beta therapy were tolerable, and no patient discontinued therapy. CONCLUSION: From these observations, intralesional nIFN-beta therapy of malignant tumors appears to be a useful palliative addition to radio- and/or chemotherapy with the aim of local control of tumor growth.

[The value of qualitative regression grading as a prognostic factor for survival after preoperative radiochemotherapy in patients with advanced head and neck cancer]. / Wertigkeit eines qualitativen Regressionsgradings als prognostischer Faktor für das Uberleben bei präoperativ radiochemotherapierten Patienten mit fortgeschrittenen Kopf-Hals-Karzinomen.

BACKGROUND: Multimodal therapeutic strategies gain importance in locally advanced squamous cell carcinoma of the head and neck. Quantitative regression grading can be traced as an independent prognostic parameter in the histological examination in many neoadjuvantly treated cancers. Various regression systems have been suggested. We propose an easy to apply and economical score that seems to have a significant prognostic value in squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: 43 patients with Stage IV squamous cell carcinoma of the head and neck have been treated neoadjuvantly with two cycles chemotherapy (ifosfamide 1.5 g/m2 day 1-5 with mesna [300 mg/m2], cisplatin 60 mg/m2 day 5, second cycle day 22). Hyperfractionated accelerated radiotherapy (30 Gy) was given from day 29 on. We divided the resected tumors histologically as follows: Grade I--no tumor cells to be identified, Grade II--necrosis, Grade III--partial destruction of the carcinoma, Grade IV--vital carcinoma. RESULTS: After 1 year the overall survival amounted to 79%, after 2 years 56%. A significant correlation could be established between qualitative tumor regression and survival. The 1-year survival depended on the regression of the primary as follows: 94% in Grade I, 80% in Grade II, 60% in Grade III and 56% in Grade IV. For the 2-year survival: 76%, 40%, 40%, 11% (p < 0.01). The results were similar regarding the neck dissections. CONCLUSIONS: After radiochemotherapy the histological regression is a significant prognostic factor of survival. A simple system with four subgroups is suggested which seems to be of a high prognostic value. We discuss to intensify the treatment for patients with good regression after neoadjuvant therapy for a further reduction of recurrence.

[Pronounced bilateral mammary hypertrophy as a rare manifestation of acute lymphatic leukemia]. / Ausgeprägte bilaterale Mammahypertrophie als ungewöhnliche Manifestation einer akuten lymphatischen Leukämie.

A 33-year-old patient, hitherto healthy, has been admitted for clarification of bilateral mammary hypertrophy. In the course of the usual routine examination a lump of the size of a cherry was identified in the right breast. Within 6 weeks both breasts had become tight and grown symmetrically to three times their original size. A provisionary diagnosis of high malignant non-hodgkin lymphoma was made by multiple high speed needle biopsies and was later confirmed by a surgical tissue specimen of the right breast. For further classification a bone-marrow biopsy was taken from the pelvic bone and an immature acute lymphoblastic leukemia (ALL), known as preB1-ALL, diagnosed. Sonographic examination, computer tomography of the thorax and mammographical findings, as well as symptoms, outcome and differential diagnosis of a proliferative lymphatic disease with first manifestation in both breasts are presented and discussed.

Prognostic value of hemoglobin concentrations in patients with advanced head and neck cancer treated with combined radio-chemotherapy and surgery.

PURPOSE: Hemoglobin levels are currently the focus of interest as prognostic factors in patients with head and neck cancer. Most published clinical trials have confirmed hemoglobin to possess a significant influence on survival in patients treated with radiotherapy. In our study we have investigated the prognostic value of hemoglobin in a combined modality schedule. PATIENTS AND METHODS: Forty-three patients with advanced head and neck tumors were treated with combined radio-chemotherapy. The therapy comprised 2 courses of induction chemotherapy with ifosfamide (1,500 mg/m2, day 1 to 5) and cisplatin (60 mg/m2, day 5) followed by hyperfractionated accelerated radiotherapy with a total dose of only 30 Gy. Surgery involved tumor resection and neck dissection. RESULTS: The 1-year overall survival rate and the 2-year survival rate were 79% and 56%, respectively. The 1- and 2-year recurrence-free survival rates were 68% and 49%, respectively. Prognostic factors with an impact on survival were seen in tumor size (T3 vs T4, p = 0.0088), response to radio-chemotherapy at the primary site (no vital tumor rest vs vital tumor rest, p = 0.045), response to lymph node radio-chemotherapy (no vital tumor cells vs vital tumor cells, p = 0.013) and level of hemoglobin after radio-chemotherapy (Hb > or = 11.5 g/dl vs < 11.5 g/dl, p = 0.0084). CONCLUSION: In our study hemoglobin level after radio-chemotherapy was identified for the first time to be also a significant prognostic factor (univariate analysis) in head and neck cancer patients who underwent combined radio-chemotherapy. Besides chemotherapy plus low-dose irradiation achieved similar results in comparison with radical resection and high-dose radiotherapy at least for the first 2 years after therapy. Relapsing disease could be treated with 1 additional course of radiotherapy which is supposed to be well tolerated.

Modified neoadjuvant therapy regime with low dose irradiation in advanced head and neck cancer patients: preliminary results of a pilot study to minimize side effects.

We analysed the files of 52 patients with advanced head and neck tumors who were treated in a pilot phase. The therapy consisted of two courses of induction chemotherapy with ifosfamide and cisplatin followed by hyperfractionated-accelerated radiotherapy with a total dose of only 30 Gy. Surgery was performed within the following 7 days with tumor resection and neck dissection. Histologically we found in 50% of the specimens total necrosis of the tumor. The median survival time is calculated to be 22 months. The median follow-up time thus far is 36 months. Hence, therapy results are comparable to other therapy schedules. But side effects, especially late side effects had become minor. Therefore, our therapy regime results in augmentation of the quality of life of these patients.

Dexverapamil to overcome epirubicin resistance in advanced breast cancer.

Resistance to cytotoxic chemotherapy is a major problem in the management of patients with metastatic breast cancer. Various data suggest P-glycoprotein-associated multidrug resistance (MDR) to be a relevant resistance mechanism in this tumor. The purpose of this study was to evaluate feasibility and activity of combining oral dexverapamil, a second-generation chemosensitizer currently in clinical development for MDR reversal, with epirubicin in patients with epirubicin-refractory high-risk metastatic breast cancer. Patients first received epirubicin alone at 120 mg/m2. In cases of clinical refractoriness, epirubicin was continued at the same dose and schedule but supplemented with oral dexverapamil. Dexverapamil was given at 300 mg every 6 h for a total of 13 doses and commenced 2 days prior to epirubicin administration. At the time of this interim analysis, 41 patients had received epirubicin alone and 20 proceeded to treatment with epirubicin plus dexverapamil. Of the 20 patients, 14 were considered evaluable for toxicity and activity. Addition of dexverapamil resulted in a significant decrease in mean heart rate and blood pressure as well as prolongation of PQ time as compared to epirubicin alone. However, these cardiovascular effects of dexverapamil were usually mild, and subjective tolerance of treatment was good. In 7/14 patients, dose escalation of dexverapamil was feasible. Dexverapamil had no effect on epirubicin toxicities and did not require reduction of the epirubicin dose. In 2/14 patients, the addition of dexverapamil to epirubicin was able to convert progressive disease and no changes respectively, into partial responses. In 3 patients with progressive disease, addition of dexverapamil temporarily prevented further tumor progression. Analyses of dexverapamil and nor-dexverapamil plasma levels, of in vitro reversal activity of patient sera containing dexverapamil, and of epirubicin pharmacokinetics without and with dexverapamil are currently in progress. Addition of oral dexverapamil to epirubicin 120 mg/m2 proved to be feasible in a multiinstitutional setting. Patient accrual is continuing to determine whether dexverapamil is capable of overcoming epirubicin refractoriness in a significant number of patients with metastatic breast cancer.

Undifferentiated (embryonal) sarcoma of the liver in an adult patient with metastasis of the heart and brain.

A 26-year-old woman with a tumor of the left liver lobe was admitted to the hospital. After incomplete resection of the tumor and histological diagnosis of an undifferentiated (embryonal) sarcoma of the liver a combination chemotherapy with ifosfamide and epidoxorubicine was started. 11 months later brain metastases were diagnosed. Routine ultrasound examination of the heart disclosed a pericardial tumor infiltrating the left atrium of the heart. After radiation therapy of the brain metastases the patient was treated with two cycles of high-dose ifosfamide and epidoxorubicin. Two years after diagnosis the patient developed signs of cardiac failure and died. Postmortem autopsy confirmed the local recurrence of the liver neoplasm and revealed its continuous spread to the pericardium via the diaphragm and infiltration of the left atrium.

[Initial results of in vivo 31P-NMR spectroscopy of the spleen in patients with splenomegaly]. / Erste Ergebnisse der in-vivo-31P-NMR-Spektroskopie der Milz bei Patienten mit Splenomegalie.

In-vivo 31P-NMR spectroscopy of the spleen was carried out in 15 patients with splenomegaly from various causes (Hodgkin's disease, non-Hodgkin lymphoma, polycythaemia vera, chronic lymphatic leukaemia, chronic myeloid leukaemia). Volume selection was with the ISIS technique, voxel size was between 3 x 5 x 5 and 8 x 6 x 7 cm3. There was a markedly elevated (PM+Pi)/beta-NTP quotient (mean 3.41 with a standard deviation of 0.37) (p < 0.001) and raised PDE/beta/NTP quotient as compared with 8 normals, who showed an (PME+Pi)/beta-NTP quotient of 2.32 and a PDE/beta/NTP quotient of 1.11. These raised quotients were interpreted as indicating increased membrane phospholipid metabolism due to increased cell turnover. The data suggest there may be some clinical value in performing 31P-NMR spectroscopy for defining splenic involvement in myeloproliferative diseases but further confirmatory studies will be necessary.

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.

[MR venography in deep venous thromboses of the leg and pelvis. A comparison of 2D single layer images and 3D MIP reconstructions with phlebography]. / MR-Venographie bei tiefen Bein- und Beckenvenenthrombosen. Vergleich von 2D-Einzelschichtbildern und 3D-MIP-Rekonstruktionen mit der Phlebographie.

A total of 22 MR venograms were performed in 7 volunteers and 15 patients suspected of deep vein thrombosis of the lower limb and pelvis. MR findings were compared to conventional venography in all patients. MR venography is a reliable method for the exclusion of thrombosis proximal to the popliteal vein. In the calf veins, diagnosis of thrombosis is not yet reliable. For MR venography 2D-time-of-flight-inflow-technique and secondary 3D-MIP reconstructions were used and compared to each other. With both methods there were no false negative results in comparison to conventional venography. 2D single slice MR venography showed two false positive results in iliac and one in popliteal vein. MIP 3D reconstructions led to seven false positive results (three iliac, two femoral, two popliteal). The exclusive interpretation of MIP-3D reconstruction is not reliable for decision-making in deep venous thrombosis.

[Manganese-DPDP in the MR tomography of malignant liver tumors. The initial results with a new hepatobiliary contrast agent]. / Mangan-DPDP in der MR-Tomographie maligner Lebertumoren. Erste Ergebnisse mit einem neuen hepatobiliären Kontrastmittel.

The new hepatobiliary contrast agent Mangan-DPDP, unlike extracellular Gd-DTPA, leads to a constant increase in signal intensity of normal liver tissue in MR imaging of the liver which lasts at least for 30 minutes. In 19 patients with malignant liver tumors there was no difference in the contrast between tumor and liver when using a dose of 5 or 10 mumol/kg. Contrast enhanced T1-w SE- and T1-w GE sequences show a significant increase in tumor/liver contrast compared with T1-weighted unenhanced sequences. This increase was also significant when compared with T2-w SE sequences. In 16% additional focal lesions were detected on the enhanced scan.

[The palliative treatment of primary hepatocellular carcinoma by chemoembolization]. / Palliative Behandlung des primären Leberzellkarzinoms mit Chemoembolisation.

16 patients (12 men, 4 women; mean age 62.8 +/- 9.8 years) with inoperable advanced hepatocellular carcinoma were treated palliatively by chemoembolization. 50 mg/m2 epirubicin, 30 mg/m2 cisplatin, 8 ml fatty acid ethyl ester of iodinated papaver oil and 10 ml nonionic contrast medium were injected under fluoroscopy into the proper hepatic artery. Partial remission was achieved in 10 patients after a median of 4 months. In 4 patients there was no change in the morphological and biochemical findings, in two others the tumour progressed, i.e. an overall response rate of 62.5%. The median survival time was 9 months. There were no serious complications ascribable to the treatment. Chemoembolization is a palliative treatment with few side effects which can also be effective in prolonging survival time in advanced hepatocellular carcinoma.

[The results of the chemoembolization of advanced hepatocellular carcinomas. The effect on the survival times, morphological findings and tumor markers]. / Ergebnisse der Chemoembolisation fortgeschrittener Leberzellkarzinome. Einfluss auf Uberlebenszeiten, morphologische Befunde und Tumormarker.

Chemoembolization is a well-recognized therapeutic procedure in the treatment of stage I and stage II hepatocellular carcinoma (HCC). Until now it is rarely used in the treatment of stage III HCC. In a prospective study we analysed the efficacy and the side effects of chemoembolization in 16 patients with stage III HCC. Chemoembolization was performed with an emulsion of lipiodol, 4-epirubicin and cisplatinum. All patients tolerated the treatment without remarkable complications. With 9 months the median survival rate was considerable higher than the survival rate of untreated patients and of patients treated with systemic chemotherapy or with local perfusion.

Adjuvant chemotherapy of metastatic stage II nonseminomatous testis tumor.

In a prospective randomized trial, 225 patients with stage IIB nonseminomatous testis tumor after radical retroperitoneal lymph node dissection received 2 versus 4 courses (arms 1 and 2, respectively) of adjuvant chemotherapy with cis-platinum, vinblastine and bleomycin. With a median followup of 43 months, a total of 7 relapses occurred; 6 in arm 1 and 1 in arm 2. Three patients died: 2 during adjuvant chemotherapy and 1 of progressive disease. The difference in relapse rates between arms 1 and 2 is not statistically significant. Patient compliance differed: chemotherapy was administered according to protocol in 83% and 50% of the cases in arms 1 and 2, respectively. Most frequent side effects observed were nausea, vomiting and alopecia. No significant differences regarding these or other side effects were obtained. Patients with stage IIB nonseminomatous testis tumor after retroperitoneal lymph node dissection are treated sufficiently with 2 courses of adjuvant cis-platinum-containing chemotherapy.

Randomized clinical trial comparing mitoxantrone with epirubicin and with doxorubicin, each combined with cyclophosphamide in the first-line treatment of patients with metastatic breast cancer.

Two hundred and twenty-four patients with advanced breast cancer were enrolled in a multicenter prospective randomized clinical study and received either doxorubicin (40 mg/m2), or epirubicin (40 mg/m2) or mitoxantrone (12 mg/m2) each combined with cyclophosphamide (600 mg/m2) i.v. In the patient collective the following response rates were observed: complete response 12.1%; partial response 30.6%; stable disease 40.5%; progressive disease 16.8%. A complete response was observed significantly less often in patients where more than one organ site was involved as compared to those patients with only one metastatic site. The mean time period required to reach a best response was 3.7 months. There was no significant difference between the response rates in the three arms. In comparing the observed toxicities in 1,434 treatment cycles, there was a significant difference with regard to leukocytopenia (mitoxantrone arm exhibiting more than either epirubicin and doxorubicin) although infections did not occur more frequently in the mitoxantrone arm; with regard to alopecia, mitoxantrone and epirubicin arms both exhibited less than doxorubicin. It is noteworthy that no patient who had previously received adjuvant chemotherapy achieved a complete response (p = 0.006). The overall significance of these findings can only be clearly evaluated when survival times can be measured.

Risk/benefit of treating retroperitoneal teratoid bulky tumors.

Inductive polychemotherapy of germinal cell tumors in advanced stages (T0-4N3M0,1) is effective, yet accompanied by serious side effects. Partial remission necessitates resection of the residual tumor. The complications of the salvage operation are tolerable in proportion to its curativity. In a retrospective analysis, we evaluated the occurrence of toxic side effects and the frequency of intra- and postoperative complications in 128 patients with retroperitoneal teratoid bulky tumor. With a follow-up of three to one hundred ten months (means = 43 months), 91 patients (71%) are alive without evidence of disease; 28 patients (22%) died of apparent tumor progression.