Sequential methotrexate and 5-fluorouracil: improved response rate in metastatic colorectal cancer.

The efficacy of chemotherapy with sequential methotrexate (MTX) and 5-fluorouracil (5-FU) in metastatic colorectal cancer was studied in a multicenter phase II trial using a seven-hour time interval. Forty-two patients were evaluable for response and 16 achieved objective tumor regression (greater than 50%). Median survival of all patients was 12.5 months. The result of this study indicates that MTX and 5-FU are synergistic in human colorectal cancer if given sequentially with a seven-hour time interval. This is supported by a review of the literature that reveals a significantly higher response rate in patients treated with a four-hour or more MTX/5-FU interval as compared to a one-hour interval.

Resistance of tumour cells to chemotherapy: importance of host defence factors.

The arguments favouring the hypothesis that chemotherapeutic agents might act in cooperation with host defence mechanisms are reviewed briefly. In patients with far advanced solid tumours plasma factors blocking in vitro immune reactions have been identified and successfully removed by immune adsorption or plasma exchange. By plasmapheresis performed in patients with metastatic malignancies resistant to chemotherapy it was possible to induce tumour regressions. In 25/28 patients responding to the combined plasmapheresis/chemotherapy procedure a positive correlation was found to clinical results and patterns of plasma-blocking factor activities.

Intra-arterial perfusion therapy with 5-fluorouracil in patients with metastatic colorectal carcinoma and intractable pelvic pain.

In a phase-II trial, 18 patients with intractable pelvic and perineal pain caused by local recurrent and/or metastatic colorectal carcinoma resistant to combinations of analgesics, systemic cytostatic chemotherapy and/or radiation were treated with intra-arterial perfusion therapy using 15-30 mg 5-FU/kg body wt./day for 1-5 days. Of 18 patients, ten achieved complete pain relief for 3-32 weeks (mean, 15.7 weeks); after the perfusion therapy eight used less than 50% of the amount of analgesics required before treatment; one patient had only a minor response; two patients were treated unsuccessfully. Side effects were mild and controllable. One patient died subsequent to arterial embolism in the leg where the catheter was placed; pelvic perfusion therefore appears risky in patients with severe arteriosclerosis.

The efficacy of large volume plasma exchange in chemotherapy resistant malignancies.

Chemotherapy resistance in cancer patients may be due to serum blocking factors, which can be diminished or eliminated by large volume plasma exchange (PE). This procedure was performed with the IBM blood cell separator in 69 patients resistant to chemotherapy. Immediately after PE the chemotherapy was given but it was reinstituted, if clinical evaluation revealed partial remission, minor response or no change. 37 out of 69 patients (53.6%) responded again, 32 (46.4%) did not. Response duration ranged from 2 to 45 weeks. Best clinical results were obtained in patients with colorectal cancer, 15 out of 23 showed improvement between 4 to 45 weeks. Serum blocking activity was measured using a modified mixed lymphocyte culture assay (MLC). There was a 80% positive correlation between clinical course of patients and MLC levels, if basic activity before the first PE was compared to MLC inhibition before the following PE's.

The use of RA 233 in the preparation of platelets, with the blood cell separator.

The intravenous administration of the inhibitor of platelet adhesiveness RA 233 to blood donors before and during cell separation did not increase the yield of platelets in the final concentrate.

[The protective effect of hydroxyethylstarch (HES) in the cryoconservation of bone marrow of the mouse and of man (author's transl)]. / Die protektive Wirkung von Hydroxyäthylstärke bei der Kryokonservierung von Knochenmark der Maus und des Menschen

The cryoprotective effect of hydroxyethylstarch has been tested in mice and in man using the spleen colony technique (CFU-S test) or the agar colony technique (CFU-C test) as viability assays for the haemopoietic stem cell. In mice we found a mean CFU-S recovery of 88.7%+/-3.9% when a rapid, and 77.8%+/-3.2% when a slow, stepwise dilution method was applied to remove the protective medium (17.5-20% hydroxyethylstarch+20% calf serum) after thawing. In man the rapid dilution after thawing gave a mean CFU-C recovery of 80% but a wide scatter.

The growth capacity of hematopoietic progenitor cells in severe neutropenia induced by famotidine.

In four cases of severe neutropenia of unknown origin we found a strong inhibition of the growth of granulocyte-macrophage (GM) progenitor cells. The development of GM colonies in culture (GM-CFU-c) was more than 80% reduced in comparison to the control group. In particular, the interleukin 3-(IL-3) and granulocyte macrophage colony-stimulating factor-(GM-CSF) dependent growth was affected; a combination of growth factors (IL-3, GM-CSF, and G-CSF, the granulocyte colony-stimulating factor) resulted in a less reduced growth. The findings were primarily compatible with drug-induced bone marrow failure. Among the medications given to the patients, famotidine, an H2-receptor blocker, was discussed as an agent which possibly triggers off this process. After the withdrawal of famotidine, in three cases a continual increase of the growth of GM precursors was detected, reaching the normal level 7-17 days later. In one case, further investigations of the progenitor cells could not be carried out due to the death of the patient, but the rapid increase of neutrophils in the peripheral blood after withdrawal of famotidine pointed to the recovery of hematopoiesis. In vitro studies showed that famotidine, depending on the dose, inhibits the single growth factor-dependent colony growth (IL-3, GM-CSF, or G-CSF) of bone marrow progenitors from a concentration as low as 10 micrograms/ml. With the combination of all three growth factors only slight inhibitory effects were detectable (up to 150 micrograms/ml famotidine). These results indicate that famotidine, in common with other H2-receptor antagonists, can affect hematopoietic progenitor cells. However, the plasma concentration of famotidine normally used in ulcer therapy does not seem to influence the hematopoiesis. Apparently, the progenitor cells of only a few patients possess a higher sensitivity to the blockade of H2-receptors at this concentration of famotidine. This was demonstrated in one case (patient 3) 2 years after the patient had recovered from famotidine-induced neutropenia. The growth of peripheral myeloid, erythroid, and multilineage progenitor cells of this patient was remarkably reduced even at famotidine concentrations of 0.1-5.0 micron/ml whereas in the control group no inhibition was detected at these famotidine concentrations. Again, the IL-3-dependent colony formation was more affected than in the case of the combination of IL-3, GM-CSF, and G-CSF. After the removal of accessory cells the inhibitory effect of famotidine persisted, demonstrating that accessory cells do not play a major role in this process.

High-dose epirubicin in combination with cyclophosphamide (HD-EC) in advanced breast cancer: final results of a dose finding study and phase II trial.

In the dose finding study we were able to demonstrate that an increase of the epirubicin dose to 120 mg/m2 in combination with cyclophosphamide (600 mg/m2) is possible. The phase II trial had to check the efficacy and the toxicity of this combination with a therapy interval of 21 days. 34 patients with metastatic breast cancer previously not treated with chemotherapy for metastatic disease entered this phase II trial, which tested the efficacy and toxicity of the chemotherapy combination epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 (HD-EC regimen) i.v. every three weeks. Excluded from the trial were patients at risk of anthracycline toxicity and those with bone or brain metastases. Results compare favourably with best data reported in the literature for chemotherapy of metastatic breast cancer: overall remission rates of 73% (35% CR, 38% PR), median TTP of 58 weeks for CR (range 32-168 weeks) and 52 weeks for the PR group (range 24-110 weeks); median survival time for CR 71+ weeks (range 52-196+), for PR 74+ weeks (range 40-134+ weeks). No therapy was given for remission maintenance after a stable remission was obtained. This results in a very favourable ratio of time with chemotherapy to maintenance time without chemotherapy, which is 10 weeks/62 weeks for CR and 12 weeks/49 weeks for PR. Evidence of tumor remission was found in 80% of the patients who already responded to chemotherapy after the first cycle. The early onset of tumor response as well as the short induction chemotherapy period necessary to obtain best response are considered major advantages of the HD-EC regimen.

Tumor-associated antigens in effusions of malignant and benign origin.

We determined the concentration and effusion/serum ratio of mucin-like carcinoma-associated antigen (MCA) in comparison to carcinoembryonic antigen, carbohydrate antigen 19-9, cancer antigen 125, and cancer antigen 15-3 in 80 sera and 99 effusions from 64 patients with histologically confirmed malignancies (4 patients out of this group showed various effusions simultaneously, which were analyzed separately) and 31 patients with various nonneoplastic diseases. Tumor cells were detected by cytological examination in 41 effusions (60.3%) from patients with neoplastic diseases, while in another 27 cases this method failed to demonstrate the malignant origin of the effusion. Of the cytological "positive" malignant effusions 90% were also correctly identified by an elevated MCA concentration at a cutoff level of 10 U/ml, whereas only one effusion of benign origin (3%) showed a slightly elevated MCA concentration of 10.5 U/ml. In 33% of cytologically "negative" effusions of patients with neoplastic diseases, the MCA concentration was also elevated, with a maximum of 453 U/ml. Increased MCA levels in cytologically confirmed malignant effusions were not restricted to metastatic breast cancer. All 17 cytologically "positive" "non-breast cancer" effusions were correctly identified by their MCA concentrations. None of the other tumor markers reached this high sensitivity at the same level of specificity. The ratio of effusion/serum concentration of all tumor markers as well as the concentration of cancer antigen 125 in effusions was of little diagnostic value. Our results indicate that the MCA concentration in an effusion correlates very closely with its malignant origin and is superior to all the other antigens tested.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro adsorption of colon cancer sera over staphylococcus protein A: lymphocyte stimulation by leakage of adsorbance.

Serum factors may be responsible for reduced host-anti-tumor defence. Although there is still confusion about their origin, attempts have been made to immobilize serum components by Protein A columns as a therapeutic modality. In our study the in vitro adsorption of 90% of the IgG from cancer sera on "immobilized protein A" did not influence the inhibitory serum activity as measured in a mixed lymphocyte culture. Therefore, IgG or immune complexes do not seem to be the suppressive serum factor in patients with advanced colorectal carcinoma. There is evidence for leakage of small amounts of protein A from the columns which have immunostimulatory activity. Perhaps this may explain necrosis after a therapeutic immunoadsorption.

Glycoprotein-adsorption from cancer sera--influence on a mixed lymphocyte culture.

The nature of the inhibitory activity of sera of patients with metastatic cancer on in vitro immunoassays remains unclear. Serum glycoprotein levels in cancer patients show a reasonable correlation with the clinical status, especially with progressive metastatic disease. Glycoproteins like acute phase reactants have been connected with immunosuppressive activity in cancer patients' sera. In this study, we examined the influence of glycoprotein fractions of normal and cancer sera, separated by Con A immunoadsorption, on the mixed lymphocyte culture as a reference system for suppressive activity. Glycoprotein rich fractions with the utmost recovery of the acute phase reactants inhibited the mixed lymphocyte culture in a dose-dependent manner. This effect was more pronounced in patients sera as compared to control sera. But there is evidence of additional blocking activity in the glycoprotein poor serum fraction, indicating blocking factors still to be identified.

[Preliminary results of a chemotherapy study of patients with squamous cell carcinoma in the head and neck region. Comparison of 2 therapeutic regimens: cis-diamminodichloroplatinum (II) and bleomycin compared to methotrexate and vindesine]. / Zwischenauswertung einer Chemotherapie-Studie and Patienten mit Plattenepithelkarzinomen im Kopf-Hals-Bereich. Vergleich zweier Therapieregime: Cis-Diaminodichloroplatinum (II) (cis-DIP) und Pleomycin gegen Methotrexat und Vindesin.

The preliminary results of a controlled study for treatment of 33 patients with squamous cell carcinoma of the head and neck region with regimen A: cis-DDP (3 mg/M2 dl) plus Bleomycin (15 mg/m2 i.v. continuously d2-6) against regimen B: Methotrexate (30 mg/m2 i.v. dl + 6) and vindesine (3 mg/m2 i.v. dl + 7) were as follows: complete remission (cr): 1 X A, 0 X B; partial remission (pr): 6 X A, 4 X B; minor response (mr): 3 X A, 7 X B; no change (nc): 2 X A, 0 X B; progression (pg): 5 X A, 5 X B. Due to progressive disease 8 patients were further treated with the alternative regimen with following results: cr: 1 X A; mr: 1 X A, 2 X B; nc: 1 X B; pg: 3 X A. Considering prognostic factors it could be demonstrated that primary chemotherapy (pc) was more effective that applied after operation and/or radiotherapy (secondary chemotherapy = sc): cr + pr: (= 53%), 4 X sc (= 22%); nc + pg: 1 X pc (= 7%), 7 X sc (= 39%).

[Treatment of epidermoid head and neck cancer with cisplatinum/bleomycin vs methotrexate/vindesine]. / Zytostatische Therapie von Plattenepithelkarzinomen im Kopf-Hals-Bereich mit Cisplatin/Bleomycin oder Methotrexat/Vindesin.

Treatment of patients with advanced squamous head and neck tumors demonstrates even with best surgical and x-ray techniques only five year survival rats between 10 and 30%. Chemotherapy in addition seems to improve these results. From July 79 to January 80 21 patients with advanced squamous-cell carcinoma at the head and neck region were treated in a controlled pilot study with Cisplatinum/Bleomycin or Methotrexate/vindesine. 6 patients were primarily treated with chemotherapy, all other secondary progressive disease after surgical and x-ray procedure. Without respect to the generally cell tolerated therapy modality on overall remission induction rate of 50 and 70% was observed. In a subsequent randomized controlled multicentric study both regimes will be compared concerning remission, survival and toxicity.

Immune complex-like material in the serum and plasma exchange in patients with metastatic cancer.

Clinical significance of immune complex-like material in the serum was investigated in tumour patients undergoing plasma exchange with albumin-saline solution and subsequent chemotherapy. Immune complexes were detected by the Clq binding assay or the Raji cell radioimmunoassay in nine out of forty-five patients before this therapy. Levels of immune complexes were decreased to 10-30% of the initial value by plasma exchange depending on exchanged plasma volume. In contrast to other serum proteins like alpha 1-antitrypsin and alpha 2-macroglobulin, which showed protein specific increase during follow up after plasma exchange in all patients, recovery rates of immune complexes and IgG were highly individual but parallel in each patient. Clinical response to this protocol did not correlate with immune complex status, suggesting that removal of the measured immune complex like material had little clinical significance or was not longlasting enough to provide therapeutic benefit.

Phase II evaluation of carboplatin in advanced esophageal carcinoma. A trial of the Phase I/II Study Group of the Association for Medical Oncology of the German Cancer Society.

Eighteen patients with advanced squamous cell carcinoma of the esophagus without prior chemotherapy were treated with carboplatin. Based on experimental data a split dose of carboplatin of 130 mg/m2 given on days 1, 3 and 5 was administered. In cases showing no WBC and platelet suppression, an escalated dose of 160 mg/m2 was proposed. Out of 18 evaluable patients no complete and partial responses were observed and there were only 5 patients with stable disease (27.8%) lasting 2-7 months. Therefore, carboplatin in the regimen used shows no meaningful antitumor activity in patients with advanced esophageal carcinoma. The escalated dose (mean 107-123% of the starting dose) was well tolerated and was followed by only minor gastrointestinal and hematological toxicity. Therefore, this regimen can be recommended for future trials.

Treatment of polycythemia vera by isovolemic large-volume erythrocytapheresis.

Excess red blood cells (RBC) in patients with polycythemia vera (PV) are usually removed by repeated phlebotomy. In order to improve the efficacy of this treatment, we used isovolemic large-volume erythrocytapheresis (EA) by a cell separator. A retrospective analysis of our experience with 69 PV patients (206 EA procedures) is reported. EA induced a rapid, well-tolerated, and long-lasting reduction of Hct, Hb, and RBC counts, as well as an immediate disappearance or reduction of clinical symptoms of PV, while tissue oxygen tension - as measured in 8 patients - increased. Hct was reduced by EA from 56.8% +/- 5.6% to 41.9% +/- 6.6%, Hb from 17.5 +/- 2.3 to 12.7 +/- 2.4 g%, RBC counts from 7.4 +/- 0.9 to 5.4 +/- 0.9 x 10(6)/mm3. The mean volume of the apherisate was 1410 +/- 418 ml, (mean Hct 79.7% +/- 9.3%), and the actual RBC volume removed 1113 +/- 367 ml. The isovolemic procedure was well tolerated and the acceptance by patients seemed to be better than with repeated phlebotomy. In 21 patients whose Hct values (Hct before and after EA 58% +/- 5.7% and 41.5% +/- 4.9%) were regularly followed after EA the mean period with Hct less than 50% after a single EA procedure was 6.1 +/- 4.1 months (median, 6); in 14 out of these 21 patients a Hct of less than 43% after EA was reached and their mean period with Hct less than 50% after EA was 7.6 +/- 4.0 months (median, 7.5). For three patients this period was 11, 13, and 15 months, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of large-volume plasma exchange in patients with chemotherapy-resistant metastatic colorectal cancer.

23 patients with advanced metastatic colorectal adenocarcinoma and measurable metastases were treated with chemotherapy until resistance to chemotherapy was evident. Chemotherapy was then not discontinued but administered for at least a further cycle combined with large-volume plasma exchange (PE). 15 of 23 patients responded again for 4-45 weeks, an average of 13. This effect was thought to be due to dilution or elimination of serum-blocking factors, which could be measured by mixed lymphocyte culture (MLC) assay. 16 of 20 patients showed a positive correlation between the clinical course and MLC activity, if the basic MLC reactivity was compared with the MLC levels at the start of each subsequent PE in each patient. It is postulated that in some tumors there is a resistance to chemotherapy mediated by plasma-blocking factors.

[Determination of the carcinoembryonic antigen (CEA) for predicting the success of therapy in metastatic breast cancer]. / Bestimmung des carcinoembryonalen Antigens (CEA) zur Voraussage des Therapieerfolges beim metastasierenden Mammakarzinom.

In 53 patients with metastatic breast cancer and increased CEA serum levels (greater than 10 micrograms/l) the CEA titer within the first 8 weeks after commencement of chemotherapy was compared with results of therapy. Among 30 patients in whom CEA values had decreased by at least 30% of pretreatment values 12 showed remission, 15 no change and 3 progression of the malignancy. Among 23 patients with unchanged or increasing CEA values during therapy 19 had progression, 3 an arrest and one a remission of the disease. In the one patient with remission the course of the disease was unusual inasmuch as the CEA value increased to 240 micrograms/l serum and liver metastases regressed excessively at the same time. This lead to the assumption of CEA release by tumour necrosis during therapy. The results suggest that in metastatic breast cancer and increased CEA values remission generally cannot be expected should the CEA value remain unchanged or rise within the first 8 weeks after initiation of treatment. In contrast, a decrease of CEA within that time may be considered a prognostically favourable sign which, however, does not mean clinically relevant reduction of tumour size in every case. For evaluation of treatment sufficient precision of CEA determinations must be guaranteed.