Homeopathic treatment of radiation-induced itching in breast cancer patients. A prospective observational study.

Following surgery for carcinoma of the breast, patients receive local radiotherapy. This can cause itching, which may be severe, in the radiation field. The affected skin usually is dry, rough and red. Twenty-five patients were treated homeopathically for radiation-induced itching. Fourteen patients developed itching during their course of post-operative radiation at 27 days median (range: 14-40). Eleven patients experienced itching in the radiation field after completion of treatment (median 21 days) after the end of their radiation treatment. A single dose of an individually selected homeopathic medicine in 30C dilution was given in the clinic, on the basis of repertorisation. Patients were asked to record a visual analogue scale (VAS) before prescription of the homeopathic medicine and at follow-up. Patients were evaluated at median 3 days (range: 1-27 days) after administration of the homeopathic medicine. In total, 14 of 25 patients (56%) responded to the first medicine. Nine patients had a second medicine, seven responded. Altogether 21 of 25 (84%) patients were successfully treated. The following medicines were employed successfully: Fl-ac 9/13, Rhus-t 3/5, Caust 2/3, Ign 2/2, Psor 2/2, gamma-ray 2/2 and Kali-bi 1/1. The VAS measurements before and after homeopathic treatment showed a reduction of the median value of 64mm (range: 20-100mm) to 34mm (median; range: 0-84mm). Homeopathic treatment of radiation-induced itching appears quite successful. The most frequently indicated and most frequently effective medicine was Fluoric acid. An approach that allows greater understanding of the patient as a whole in the short time available in a busy clinic may be required.

Prognostic significance of liver metastases as first site of generalisation in patients with breast cancer--a retrospective analysis.

Of 672 patients with metastatic breast cancer, 24 evaluable patients with primary liver metastases were analysed with regard to their prognostic variables and survival. In 50% of these patients, liver metastases were found within the first 8.5 months after the diagnosis of breast cancer. The median survival of 10 months (range 0-60+ months) was extremely unfavourable. The median survival of hormone-receptor-positive patients (11 months) was significantly longer than that of patients with hormone-receptor-negative tumours (4 months) (P = 0.025). Patients with elevated lactate dehydrogenase (LDH), glutamic-oxaloacetic transaminase (GOT) (> 50 U/I), or bilirubin levels at diagnosis had a significantly shorter median survival than patients with normal laboratory parameters (P = 0.001, P = 0.047, and P = 0.056, respectively). This retrospective study confirms the short survival time for breast cancer patients with liver metastases as initial site of relapse. Hormone-receptor status and the laboratory parameters LDH, GOT, and bilirubin were identified as important prognostic factors for survival.

Modulation of invasive properties of murine squamous carcinoma cells by heterologous expression of cathepsin B and cystatin C.

Murine SCC-VII squamous carcinoma cells have the capacity to penetrate reconstituted basement membranes (Matrigel) in vitro. The invasion of Matrigel layers by SCC-VII cells was significantly reduced by E-64, a specific inhibitor of lysosomal cysteine proteinases. The cathepsin-B-selective E-64 derivative, CA-074, inhibited penetration of Matrigel by SCC-VII cells to the same extent, indicating a major role for this particular lysosomal enzyme in extracellular-matrix degradation during squamous-carcinoma-cell invasion. SCC-VII cells were stably transfected with a cDNA encoding human procathepsin B, in an attempt to modulate the invasive properties of the cell line. The transfected cells expressed the heterologous gene, secreted increased amounts of procathepsin B and displayed enhanced invasive potential. In vivo, the activity of cathepsin B is strictly regulated by endogenous inhibitors. SCC-VII cells were therefore also stably transfected with a cDNA encoding human cystatin C, the most potent cysteine-proteinase inhibitor in mammalian tissues. The expression of this transgene resulted in the production of active recombinant cystatin C and a pronounced reduction in Matrigel invasion. These studies demonstrate that the invasive properties of squamous-cell carcinomas can be changed by modulation of the balance between cathepsin B and its endogenous inhibitors, and provide further evidence for the involvement of this lysosomal cysteine proteinase in tumour invasion and metastasis.

Pharmacokinetics of 4'-O-tetrahydropyranyladriamycin given on a weekly schedule in patients with advanced breast cancer.

Improved quality of life has gained importance over shortly lasting remissions in yet incurable metastatic breast cancer. Fractionation of drug administration is one of the possible approaches to reduce the concentration-dependent toxicity of anthracyclines. We evaluated the pharmacokinetics of 4'-O-tetrahydropyranyladriamycin (THP-ADM) under weekly administration in patients with advanced breast cancer (dose escalation, from 20 to 27 mg/m2 THP-ADM). The concentration-time curves of THP-ADM in plasma were best described by an open three-compartment model [half-life of the first disposition phase (t1/2 alpha), 3.15 min; terminal elimination half-life (t1/2 gamma), 13.9 h] with a mean area under the curve (AUC) of 12.2 ng h ml-1mg-1 m-2, resulting in a mean plasma clearance of 86.9 1h-1 m-2. Metabolism included the formation of Adriamycin (ADM), Adriamycinol (ADM-OH), 13-dihydro-4'-O-tetrahydropyranyladriamycin (THP-OH), 7-deoxyadriamycinone (7H-ADn), and 7-deoxy-13-dihydroadriamycinone (7H-ADn-OH), with maximal plasma concentrations ranging from 2.8 to 5.5 ng/ml. The mean total amount of cytotoxic anthracyclines excreted into urine, mainly as the parent drug, was 5% of the delivered dose. ADM and ADM-OH, but not the parent drug, were observed in urine at up to 4 weeks after the last therapeutic cycle. There was a significant correlation between the leukocyte nadir under therapy and the AUC of ADM-OH (r = 0.800, P < 0.05). Since no shift in the plasma kinetics was observed from the first to the sixth cycle, the favorable ratio of the AUCs of THP-ADM and ADM after fractionation of THP-ADM suggests lower toxic side effects attributable to ADM. This hypothesis was confirmed in a clinical study, where no severe cardiotoxicity and only mild alopecia were observed in 19 patients. Thus, pharmacokinetics studies might be helpful in both individualization of therapy with THP-ADM and optimization of the administration schedule.

[A critical consideration of the combined radiochemotherapy of head and neck tumors]. / Kritische Betrachtung der kombinierten Radiochemotherapie von Kopf-Hals-Tumoren.

PURPOSE: Advanced tumors of the head and neck are often treated with combined radiochemotherapy. The chemotherapeutic agents used should be active in this tumor type and its adverse effects should not overlap with those of the radiation treatment. METHODS: Published studies were reviewed and discussed on the basis of these principles. RESULTS: Initially, single agents such as 5-fluorouracil (5-FU) and methotrexate were used in combination with radiotherapy. These combinations caused an improved local tumor control but also an increased mucosal reaction. For mitomycin C it has been shown in a randomized trial that local tumor control was improved without concomitant increased normal tissue toxicity. Also cisplatin and carboplatin were studied in combination with radiotherapy. Unfortunately, there are no results of randomized studies available but these agents do not seem to increase mucosal toxicity. The standard chemotherapy of squamous cell carcinomas of the head and neck is cisplatin and 5-FU. Many studies have been conducted with this chemotherapy in combination with radiotherapy. To this day it has not been shown that the results of an effective radiation treatment or an effective chemotherapy can be improved by these experiments. The explanation for that is that either the chemotherapy or the radiotherapy cannot be given at full dose because the regimen would become too toxic. CONCLUSION: 5-FU containing polychemotherapy regimens should not be combined with radiation any more because it is known that 5-FU increases the mucosal reaction. Agents that could be studied in the future either alone or in combination with cisplatin or carboplatin are etoposide and taxol.

[Differential prognosis of patients with breast cancer with pleuritis carcinomatosa and with pulmonary lymphangiosis carcinomatosa]. / Unterschiedliche Prognose von Patientinnen mit Mammakarzinom mit Pleuritis carcinomatosa und mit pulmonaler Lymphangiosis carcinomatosa.

The retrospective analysis of 672 consecutive patients with breast cancer revealed malignant pleural effusion and lymphangitic carcinomatosis of the lung to be the sites of first relapse of the disease in only 2% and 1%, respectively. In half of the 10 patients with malignant pleural effusions evaluable for survival, generalization of the disease was recorded at 51 months (range 0-197 months); the corresponding data for patients with lymphangitic carcinomatosis of the lung (n = 7) were 19 months (range 9-44 months). This difference was statistically significant (p < 0.05). The median survival of patients with pleural effusions and with lymphangitic carcinomatosis of the lung was 22 and 8 months, respectively (n.s.).

Glucose starvation and acidosis: effect on experimental metastatic potential, DNA content and MTX resistance of murine tumour cells.

Exposure to oxygen deprivation in vitro has been reported to cause drug resistance in CHO cells (Rice et al., 1986; PNAS 83, 5978) and enhancement of experimental metastatic (colonisation) ability of murine tumour cells (Young et al., 1988; PNAS 85, 9533). Both these studies also demonstrated the induction of a subpopulation of cells with excess DNA content. Since the micromilieu in tumours results in exposure of the tumour cells to conditions of acid pH and nutrient deprivation, as well as hypoxia, we have examined the effect of exposure to acidosis (pH 6.5) and glucose starvation on drug resistance, cellular DNA content and the experimental metastatic ability of KHT sarcoma and B16F1 melanoma cells. Cells were exposed to these conditions for 24 and 48 h and tested for resistance to methotrexate (MTX) or experimental metastatic ability either immediately following these exposures or after 24 or 48 h of recovery in normal growth medium. Both cell lines demonstrated an enhancement of colonisation potential, which was most marked when cells were injected after 48 h of exposure followed by a 24 or 48 h recovery period. Flow cytometric analysis demonstrated an increase in the fraction of KHT cells with excess DNA following both glucose starvation and acidosis we observed only a small increase in MTX resistance following acidic exposure of cells and no change following glucose starvation. Since both acidosis and glucose starvation are known to induce glucose regulated proteins (grp), a subset of the stress protein family, we studied the effect of treatment with another known inducer, 2-deoxyglucose. We found that this agent affected the metastatic efficiency of KHT cells in a manner similar to that observed following exposure to glucose starvation and acidosis. However, further studies are required to establish what role, if any, grp play in this effect. In conclusion this study shows that transient exposure of murine tumour cells to an acidic or glucose deprived environment can cause progression in terms of metastatic potential.

[5-Fluorouracil (5-FU)/leucovorin in comparison to other current chemotherapy protocols in metastasizing colorectal carcinoma]. / 5-Fluorouracil(5-FU)/Leucovorin im Vergleich zu anderen aktuellen Chemotherapieschemata beim metastasierten kolorektalen Karzinom.

17 patients with metastasizing colorectal cancer were treated in a phase II-study with systemic intravenous chemotherapy (Petrelli N, Proc ASCO 286, 1987) consisting of leucovorin 500 mg/m2 in a 2 hr infusion and 5-fluorouracil (5-FU) 600 mg/m2 bolus one hour after the commencement of the leucovorin infusion. Limiting toxicities were gastrointestinal, in form of nausea/vomiting of WHO grade 3 (n = 1) and of diarrhoea of maximal grade 4 (n = 5), as well as haematological with a maximal nadir of leucocytes of WHO grade 4 (n = 1) and of thrombocytes of WHO grade 1 (n = 1). Of the 14 evaluable patients an objective response was achieved in 21% of cases (CR: n = 1, PR: n = 2). 64% of the patients showed no change and 14% showed progression of their disease, 7 out of the 17 patients have died; the median survival was 24 months. With respect to objective remission, our result of 21% response rate is lower than the median of 32% of 24 different studies comprising 695 patients; nevertheless, the present response rate is within the range observed in the published studies of between 0% and 67%. In order to estimate the antitumoral efficacy of the new regimen 5-FU/leucovorin more objectively, a retrospective comparison of the therapy regimens used most frequently in disseminated colorectal cancer (5-FU monotherapy, 5-FU/methotrexate (MTX), 5-FU/MTX/low dose leucovorin, 5-FU/cisplatin, 5-FU/leucovorin) has been performed. The continuous administration of 5-FU monotherapy, with an objective response rate of 26%, was superior to standard 5-FU monotherapy as a bolus injection or short-term infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Complete remission of metastasised clear cell sarcoma of tendons and aponeuroses.

Clear cell sarcoma of tendons and aponeuroses is a rare disorder which originates from migrated neural crest cells. It tends to local recurrences and dissemination and the prognosis has to be considered as poor. Based on a small series of patients, a wide surgical excision of the primary tumour or amputation are the therapies of choice. Radiotherapy might be of some value as an adjuvant treatment but radiotherapy and chemotherapy are of little value in the treatment of the advanced disease. Because of the lack of treatment alternatives we treated a 40-year-old female patient with disseminated clear cell sarcoma with interferon-alpha 2b (IFN-alpha 2b) perilesionally after several courses of systemic chemotherapy and radiotherapy had failed. After 4 months of therapy the patient came into a complete pathological remission which lasted for 17 months. A relapse of round cell sarcoma on both tumour sites was then noted. This outcome shows that IFN-alpha 2b was able to induce a complete remission in clear cell sarcoma and might have altered the natural course of the disease. IFN-alpha should be studied as adjuvant therapy after surgery of primary clear cell sarcoma and as a first-line palliative treatment in disseminated disease.

Phase I-II study on weekly administration of pirarubicin in patients with metastatic breast cancer.

A phase I-II study of weekly low-dose pirarubicin was performed in 19 patients with advanced breast cancer. The goal was to establish the optimal dose intensity, i.e., the maximal dose applicable at tolerable toxicity within the intended schedule. Each of the four different dose groups used (20, 24, 25, and 27 mg/m2) comprised 4-5 patients. In over 47% of patients, objective remissions were obtained (confidence interval 26%; 71%) including one complete and eight partial remissions; the median duration of remission was 41 weeks (range 16-72), and the median time to reach remission was 12 weeks (range 6-36). Efficacy of treatment was more dependent on prior chemotherapy than on pirarubicin dosage. The weekly i.v. push injection of the drug was easily applicable at an outpatient clinic and well tolerated. WHO grade 3 was the highest toxicity observed for leukopenia (3/19), leukopenia associated with infection (1/19), nausea/vomiting (2/19) and alopecia (6/19). More severe myelosuppression was avoided by interrupting the weekly application until recovery of leukocytes to greater than or equal to 3.5 x 10(3)/mm3. No clinical signs of cardiotoxicity were observed. Generally, mild to moderate signs of cardiac dysfunction acquired during therapy were detected by special cardiac monitoring. Only in 3 of 19 patients was a cumulative dose of more than 550 mg/m2 surpassed. This was accepted as the upper limit for conventional anthracycline therapy. The median cumulative dose applied was 325 mg/m2/week (range 58.2-800.0). Because of maldistribution of prognostic factors, no dose-response relationship could be established. With respect to the total time for which each patient was studied, the dose group of 27 mg/m2 achieved the highest dose intensity with a median of 17.4 mg/m2/week (range 13.5-22.4). Therefore, the dosage of 27 mg/m2/week is recommended to be used in further phase II-III trials of weekly applied pirarubicin.

Small bowel function after surgery for chronic radiation enteritis.

The retention of the gamma-emitting 75Se-homotaurocholic acid (SeHCAT) after 72 and 168 h was assessed in 10 patients after ileal resection for radiation injury (group I). 6 patients suffering from chronic postirradiation diarrhea (group II) and 6 patients in whom the ileum had been resected for other indications (group III) were also examined. The retention of SeHCAT was abnormally low (less than 50%) in all cases after 72 h and below 20% in 19 out of 21 cases after 168 h. The length of resected small bowel (groups I and III) was inversely related with SeHCAT retention after 72 h (r = 0.63; p = 0.015), but not after 168 h. There was no correlation between the diarrhea score and the extent of bowel resection, SeHCAT retention or xylose absorption. Hydrogen breath test with lactulose revealed a significantly shortened orocecal transit time in group I, compared to groups II and III. Xylose absorption was significantly reduced in patients with positive 5 g xylose-H2 breath test. In groups I and III, however, xylose absorption tended to improve with increasing time interval following resection (r = 0.79; p = 0.003). It is concluded that radiation injury in addition to small-bowel resection contributes significantly to malabsorption and diarrhea in patients after ileal resection for radiation sequelae. The chronic radiation damage seems to act mainly through impaired motility.

Lack of radiosensitization in Lewis lung carcinoma and a murine plasmacytoma by MTDQ and MTDQ-DA.

MTDQ, and its watersoluble derivative MTDQ-DA, have been tested in combination with radiation using the murine plasmacytoma X5563 and the Lewis lung carcinoma. Neither of the two compounds showed any effect on the single dose radiation response as measured by tumour growth delay. In addition no effect of MTDQ-DA on the response of the X5563 plasmacytoma to fractionated radiation was observed. As a control, studies with the established hypoxic cell sensitizer Misonidazole showed that both tumours could be sensitized to radiation by that drug, in the case of Lewis lung carcinoma the use of the excision cell survival assay showed that this was due to hypoxic cell sensitization.

Response of the seminiferous epithelium to scattered radiation in seminoma patients.

Semen and blood samples were obtained, at 3-month intervals over 12 to 28 months, from patients who underwent subdiaphragmal radiation after orchidectomy for seminoma testis. Before radiotherapy a mean (+/- SE) semen volume of 4.7 +/- 0.5 ml, a mean sperm count of 44.4 +/- 13.5 x 10(6)/ml, a mean percentage of motile cells of 20.3 +/- 5.2, a mean percentage of morphologically normal spermatozoa of 13.4 +/- 5.4, a mean percentage of swollen sperm of 39.6 +/- 7.4, and a mean serum follicle-stimulating hormone (FSH) value of 8.3 +/- 1.2 mIU/ml was found. The mean testicular dose from scatter was 62 +/- 5 cGy (range, 34 to 95 cGy). Sperm counts between 0 and 2.75 x 10(6)/ml were seen at 6.8 +/- 0.6 months and recovery to values greater than 2.25 x 10(6)/ml at 11.8 +/- 0.8 months after the start of radiation. Peak FSH values of 19.2 +/- 1.6 mIU/ml were obtained at 6.7 +/- 0.9 months after the start of irradiation. After recovery mean semen volume was 3.9 +/- 0.4 ml, mean sperm count 34.6 +/- 5.6 x 10(6)/ml, the mean percentage of motile cells 42.5 +/- 6.0, the mean percentage of swollen sperm 58.7 +/- 6.8, and the mean percentage of spermatozoa with normal morphology 23.4 +/- 5.1. Only motility was significantly different (P less than 0.01) from pretreatment values. The elevation of FSH values with time after start of radiotherapy reflected the toxicity to spermatogenesis but no correlation was found between peak FSH levels and scattered radiation dose. Also, neither the time from start of radiotherapy to sperm count nadir or recovery nor the time to peak FSH levels was significantly correlated with radiation dose.

The clinical course of lung metastases from breast cancer.

The clinical course of 50 breast cancer patients whose first metastases were found in the lungs was investigated. 18 months after the start of primary treatment 50% of the patients had developed pulmonary metastases (range: 0-81 months). In 23% of patients a solitary, and in 68% more than one, lung metastases were detected. After a median time of 4 months, in 56% of patients the disease had spread to further organs with bone (25%) and liver (17%) being the most frequent sites. First line management of lung metastases employed surgery, endocrine treatment, chemotherapy or a combination of these modalities. In 24% of patients a complete response was achieved, and in 11% a partial response, with an overall response rate of 35%. Median survival from detection of lung metastases was 13 months (range 4-123+). Patients with only a solitary lung metastasis survived for a median of 11.5 months as compared to 10.5 months for patients with more than one pulmonary metastases. Patients with a disease-free interval of more than 18 months survived significantly longer than patients with a disease-free survival of 18 months or less.

[High dosage and intermediate dosage cytosine arabinoside in the treatment of secondary leukemias]. / Hochdosiertes und mittelhochdosiertes Cytosinarabinosid zur Behandlung von sekundären Leukämien.

Patients with secondary acute myeloid leukaemia (AML) following treatment with alkylating agents and/or radiation show a poor response to standard induction therapy. Between 1983-1987 8 consecutive patients were treated with high-dose cytosine arabinoside (HD-ARA C; 3 g/sqm twice daily for 6 days) or intermediate-dose cytosine arabinoside (ID-ARA C; 0.5 g/sqm twice daily for 6 days). Complete remission was achieved in 3 patients (HD-ARA C: 2/3l; ID-ARA C: 1/5) and partial remission in 3 patients (ID-ARA C: 3/5). One patient (HD-ARA C) died during prolonged aplasia, one patient (ID-ARA C) proved refractory to treatment. The respective duration of remission in the 3 responsive patients was 3, 7 and 8 months. The probability of survival of the whole group was 50% after 12 months and 25% after 24 months. Our results confirm the efficacy of monotherapy with ARA C in the treatment of secondary AML. Consolidation therapy with ID-ARA C for 4 days seems to prolong remission.

Protection from radiation-induced damage to spermatogenesis in the androgen pretreated rat.

Protection of spermatogenesis from radiation-induced damage has been investigated in the adult Wistar rat. Silastic tubing containing either cholesterol or testosterone was implanted subcutaneously 7 weeks before 4 equal daily fractions of either 1, 1.5, 2, and 2.5 Gy of 230 kVp X-rays locally to the testes. Implants were removed on the day following the last fraction and 8 weeks after irradiation 88.6%, 83.8%, 63.6% and 28.9% tubule cross-sections respectively were found regenerating in rats pretreated with testosterone. In contrast, 68.45%, 58.6%, 38.2% and 17.3% tubule cross-sections regenerating were obtained in rats pretreated with cholesterol. Changes in testis weight however were found to show the reverse trend (i.e. a greater weight loss was observed following androgen pretreatment). These results show that protection of spermatogenesis from fractionated irradiation may be achieved in rat testis by androgen pretreatment.

Growth and chemotherapy of a human germ-cell tumour line (GCT 27).

The human germ-cell tumour cell line GCT 27 growing as subcutaneous xenograft tumours in male nude mice was used in the 4th and 5th passage to study chemotherapeutic drug responses. Recipient mice received 5 Gy whole body irradiation immediately before tumour transplantation. The median take rate was 62% (range 39-73%) and the median volume doubling time 14 days (range 7-28 days). For bleomycin, cisplatin and carboplatin a clear dose response for growth delay was observed. Bleomycin caused substantial weight loss at doses above 75 mg/kg whereas good response to cisplatin was obtained without serious toxic effects. Vinblastine and etoposide exerted no effect when given in non-toxic doses. The response to etoposide was not improved either by fractionated treatment or by combination with verapamil. However, the combination of 20 mg/kg etoposide and 2 mg/kg cisplatin, which when given alone were ineffective, led to a growth delay that was equal to that observed following the administration of higher cisplatin doses. This effect may be explained by the fact that etoposide, as an inhibitor of DNA-topoisomerase II, may interfere with the repair of DNA interstrand cross-links caused by cisplatin.

[Diagnostic imaging of hemangiopericytomas]. / Bildgebende Diagnostik bei Hämangioperizytomen.

Eight patients with histologically verified hemangiopericytomas were examined by conventional radiographic techniques (plain films, angiography including cavography) as well as by duplex sonography, CT and MRI. These imaging techniques detected solid tumors with cystic compartments. A typical computed tomographic finding was intensive contrast enhancement within the tumor. Duplex sonography revealed blood flow in the periphery of the tumor. In contrast to reports by other authors no tumor calcification was found by plain film radiography.