[Lymphedema in patients with breast cancer--a consensus regarding diagnostics and therapy in patients with postoperative lymphedema after primary breast cancer]. / Lymphödem bei Mammakarzinom--Konsensus zur Sektoren übergreifenden Diagnostik und Therapie des postoperativen Lymphödems bei Patientinnen mit primärem Mammakarzinom.

UNLABELLED: Secondary lymphedema is one of the most frequent long-term side effects affecting up to 30% of all breast cancer patients after local surgical and radiation treatment. Destruction of the lymphatic system causes a progressive and chronic condition with functional impairments and disabilities limiting patients in their daily activities and involving nearly all aspects of their quality of life. Also, problems in the occupational area may be caused by lymphedema. The need for improving oncological management for early diagnosis and referral for effective treatment of lymphedema is a major goal of breast cancer heath care while survival improves. METHOD: A systematic consensus process was performed involving all relevant partners and providers of lymphedema health care to develop a practical documentation concept and make recommendations according to the evidence of clinical studies and currently available guidelines. RESULTS: A practical concept of documentation with defined assessment points was developed for evaluation and monitoring of lymphedema, which included the assessment of quality of life parameters with recognised instruments by the patient themselves. Consensus recommendations for the postoperative management, prevention, treatment and follow-up of breast cancer patients along a clinical algorithm for in- and outpatient care were finalized. CONCLUSION: With improved survival, long-term side effects with major impact on quality of life become a most important end point criteria of oncological treatment. The clearly defined documentation concept and the comprehensive recommendations for lymphedema management may assist clinicians and patients to make timely decisions about in- and outpatient health care practice to optimize the interface between acute medicine and rehabilitation. Patients' compliance with treatment and prevention routines will be as important as ensuring the continuity of care. A longitudinal prospective study evaluating the effectiveness and efficacy of the consensus recommendation is currently being implemented.

Effects of inpatient rehabilitation on health-related quality of life in breast cancer patients.

BACKGROUND: Major endpoint for the assessment of a complex inpatient rehabilitation program is the health-related quality of life. In a prospective longitudinal study we evaluated the subjective well-being of breast cancer patients by different methods. PATIENTS AND METHODS: 183 breast cancer patients were asked to complete six different questionnaires at three different time points: t1: start of treatment, t2: end of treatment, t3: 3 months after t2. RESULTS: In the Hospital Anxiety and Depression Scale (HADS-D) we observed high mean scores for anxiety (8.73) and depression (5.55), as compared to a healthy control population (5.8 and 3.34, respectively). There was a significant improvement for both scores at t2 (6.84 and 4.77, respectively) and for anxiety at t3 (7.68). This was confirmed by the FBK questionnaire showing a significant decrease of the psychological distress in the t1/t2 and t1/t3 time periods as well. The global health score of the QLQ-C30 instrument increased significantly at the end of the rehabilitation and was maintained at the 3-month follow-up. This was true for most of the functional subscales as well. Older widowed women with 3-4 accompanying diseases had the most profit from the program. Using the Perceived Adjustment to Chronic Illness Scale (PACIS), we observed significantly less effort of coping with the illness at t2 and t3. CONCLUSIONS: At the end of a complex rehabilitation program for breast cancer patients, the health-related quality of life improved in several domains. While after a 3-month follow-up the scores were still better than before the treatment, anxiety and depression increased again. Therefore, the good results of the rehabilitation program should be maintained by continuous ambulatory treatment.

Rehabilitation in women with breast cancer-special problems in hereditary diseases.

A rehabilitation program for women with high risk for breast cancer or known hereditary breast carcinoma is described. The rehabilitation uses complex and interdisciplinary therapeutic interventions to improve symptoms, functional deficits and disease and treatment related psychologic distress. An essential component of the rehabilitation is an educational program with up-to-date information about the possibilities and limitations of genetic testing and recommendations about primary and secondary prevention. Suggestions for risk reduction as primary prevention are discussed. This rehabilitation program should be implemented in an effective follow-up care for women genetically susceptible to breast cancer.

Clinical phase I and pharmacokinetic trial of the new titanium complex budotitane.

Budotitane [cis-diethoxybis(1-phenylbutane-1,3-dionato)titanium (IV)] is a novel inorganic metal complex. Preclinical studies in established screening models indicate considerable antitumor activity. We have performed a clinical Phase I and pharmacokinetic trial with budotitane administered as i.v. infusion twice weekly. The starting dose of 100 mg/m2 was derived from a prior single dose Phase I study. Eighteen patients with solid tumors refractory to all other known treatment modalities were entered. 17 patients had received prior chemotherapy. Dose levels ranged from 100 mg/m2 to 230 mg/m2, with a total of 122 budotitane infusions administered. Neither leuko- nor thrombocytopenia were observed. 2/5 pts at 180 mg/m2 and 2/4 pts at 230 mg/m2 developed a 3-fold increase of reticulocytes without signs of hemolysis or bleeding. Nonhematologic toxicity was moderate at doses of < or = 180 mg/m2. Fifteen patients reported loss of taste at the day of infusion. At 230 mg/m2, 2/4 pts developed WHO grade 3 cardiac arrhythmias with polytope premature ventricular beats and nonsustained ventricular tachycardia. A limited pharmacokinetic analysis was performed at dose levels 180 mg/m2 and 230 mg/m2. At 180 mg/m2, Cmax was 2.9 +/- 1.2 microg/ml, t1/2 78.7 +/- 24.4 h, Cltot 25.3 +/- 4.6 ml/min and AUC 203 +/- 71.5 h x microg/ml. At 230 mg/m2, Cmax was 2.2 +/- 0.8 microg/ml, t1/2 59.3 +/- 12.1 h, Cltot 44.9 +/- 23.6 ml/min and AUC was 183 +/- 90.4 h x microg/ml. No objective tumor response was observed. We conclude that the maximum tolerated dose of budotitane administered twice weekly is 230 mg/m2, the dose limiting toxicity is cardiac arrhythmia. Further evaluation of the nature of the cardiac toxicities observed is warranted. Using this schedule, 180 mg/m2 is a safe dose for subsequent clinical studies.

Tumor necrosis factor for the treatment of malignancies.

Tumor necrosis factor (TNF) is a cytokine produced in vivo by activated macrophages and monocytes with pleiotropic effects on normal and malignant cells. TNF is cytotoxic to several tumor cell lines in vitro and in vivo. Phase I and phase II trials have been conducted to determine toxicity to humans and to evaluate responses. Recent investigations will be reviewed. Despite promising results in vitro and in vivo, data from systemic administration in the treatment of malignancies have been disappointing. Local administration has been successful. Therefore, we suggest that future efforts concerning TNF administration in the treatment of malignancies should aim at local treatment.

Multiple myeloma: effect of daily dichloromethylene bisphosphonate on skeletal complications.

In 1989, a prospective randomized multicenter study was initiated in order to determine the safety and efficacy of oral clodronate in myeloma patients. The primary objective of this long-term trial is to evaluate whether supportive clodronate is able to prevent or retard the progression of bone disease and reduce the occurrence of characteristic complications: pain, pathologic fractures, and hypercalcemia. We now report first results as an interim analysis, including data obtained from 26 patients (total number of Tübingen patients n = 36) who entered the study at the Medizinische Universitätsklinik Tübingen. Patients were randomized to receive either chemotherapy alone (melphalan 15 mg/m2 i.v. on day 1 and prednisolone 60 mg/m2 orally on days 1-4 every 4 weeks (control group) or in combination with 1600 mg clodronate/day orally as a single dose for a period of at least 1 year. Repeated radiologic examinations in addition to hematologic and biochemical analysis were performed in order to evaluate the skeletal status with respect to lytic bone lesions and osteoporosis and the course of serum M protein and light chain excretion into urine. Clodronate treatment resulted in a significant decrease of serum calcium concentrations and of biochemical indices for bone resorption. No clodronate-related toxicity or hypocalcemia was observed. In patients treated with chemotherapy alone, this effect was less marked and discontinuous. Clodronate-treated patients developed fewer progressive bone lesions (significant for lytic, not for osteoporotic lesions). No hypercalcemic episodes occurred in the clodronate-treated patients, but there were six episodes in the control group. Whereas the number of vertebral fractures was evidently less is clodronate-treated patients, three of those patients suffered from multiple fractures of long bones and ribs. All together, 12 pathologic fractures occurred in five clodronate-treated patients, whereas in the control group 23 pathologic fractures occurred in the same number of patients during the whole observation period. The final analysis of all multicenter included patients should clarify these findings. There was a significant finding that clodronate proved to have an analgesic effect.

Cyclic alternating chemotherapy of high-grade malignant non-Hodgkin lymphomas with VIM-Bleo and CHOP.

Between 1986 and 1988, 81 patients with high grade malignant non-Hodgkin lymphoma according to the Kiel classification were treated with the VIM-Bleo/CHOP-regimen: etoposide 100 mg/m2 intravenously on days 1-3, ifosfamide 1.5 g/m2 intravenously days 1-5 with mesna for prophylaxis of cystitis, methotrexate 30 mg/m2 intravenously on days 3, bleomycin 10 mg intravenously on days 8 and 15, cyclophosphamide 750 mg/m2 day 22, doxorubicin 50 mg/m2 day 22, vincristine 1.4 mg/m2 on day 22, and prednisolone 100 mg postoperatively on days 1-5 and 22-26. Cycles were repeated four times beginning on day 43. Regions with bulky disease were irradiated after chemotherapy. 36 patients (44%) had stage II, 12 (15%) stage III and 33 (41%) stage IV disease. B-symptoms were present in 49% of patients. Serum lactate dehydrogenase activity was elevated in 53%. Overall, 59 patients (73%) achieved a complete and 14 (17%) a partial remission. 8 (9%) had stable or progressive disease. After a median follow up of 30 months thus far, probability of long-term relapse free survival is 66% for patients in complete remission. Overall survival is 72% at 24 months. Toxicity from treatment was very low with leukopenia being the main side effect. Major infections were observed in only 2% of cycles with one treatment related death. VIM-Bleo/CHOP is a well tolerated regimen with remission rates in the range of other, more toxic regimens. However, cyclic alternating treatment did not improve results as compared with repeated treatment with a single standard protocol.

Tumor necrosis factor in advanced colorectal cancer: a phase II study. A trial of the phase I/II study group of the Association for Medical Oncology of the German Cancer Society.

In a phase II study, the efficacy and toxicity of human recombinant tumor necrosis factor (rh TNF-alpha) were evaluated in patients with advanced colorectal carcinoma. Rh TNF-alpha was given as short term infusion at a dose of 3 x 10(5) U/m2 on three successive days. Treatment was repeated after a two week interval. The response was evaluated after four treatment cycles. In 15 patients entering the study, we found one partial response, one stable disease, 9 progressive diseases, and four patients who were not evaluable for tumor remission. There were numerous side effects of the treatment, mainly fever, chills, loss of appetite, leukopenia, and hepatotoxicity. In this regimen, rh TNF-alpha does not suggest a therapeutic advantage for treatment of advanced colorectal carcinoma.

[Combination of recombinant interferon alpha-2A and vinblastine in advanced renal cell cancer].

Experimental results suggest synergistic activity of interferon with different cytotoxic agents, including vinblastine. Both interferon and vinblastine have shown synergistic activity against renal cell carcinoma in the human stem cell assay. In this multicenter phase II study, patients with documented advanced renal cell carcinoma were treated with interferon alpha-2a at a dose of 18 x 10(6) IU i.m. 3 days per week and vinblastine 0.1 mg/kg body weight i.v. every 3 weeks. Combination therapy was given for 6 months except patients with progressive disease. We observed 6/34 (17.6%) partial remissions and 16/34 (47%) no changes. Five out of six responses were seen in pulmonary metastases with a median response duration of 10 months and a median survival for the responders of 17 months. A dose reduction because of interferon toxicity was necessary in 60% of the treated patients. The main side effects were fever and influenza-like symptoms of different intensity in 70% of the patients, which decreased during the treatment periods. This trial demonstrates modest but definite antitumor activity of the combination of interferon alpha-2a/vinblastine. In comparison with single agent therapy we did not observe improved remission rates for the combination treatment.

[Metastatic C-cell carcinoma with bone marrow carcinosis in type IIa multiple endocrine neoplasia (MEN). Diagnostic and therapeutic problems]. / Metastasierendes C-Zellkarzinom mit Knochenmarkkarzinose bei multipler endokriner Neoplasie (MEN) Typ IIa. Diagnostische und therapeutische Probleme.

The course of the disease in a patient with multiple endocrine neoplasia type IIa over a period of seven years is described. In spite of multiple diagnostic procedures, only a bone marrow biopsy was able to prove metastatic disease. All therapeutic measures, such as combination chemotherapy, sandostatin, bromocriptine, and 131Iodinemethylendiphosphonate-therapy were not effective in reducing tumor load or symptoms.

[Treatment of advanced pancreatic cancer with 5-fluorouracil, 4-epidoxorubicin and mitomycin C (FEM II). From the Chemotherapy of Gastrointestinal Tumors Group]. / Behandlung des fortgeschrittenen Pankreaskarzinoms mit 5-Fluorouracil, 4-Epidoxorubicin und Mitomycin C (FEM II). Aus der Chemotherapiegruppe gastrointestinaler Tumoren (CGT).

In a multicentre phase II trial, 20 patients with advanced pancreatic carcinoma were treated with 5-fluorouracil, 4-epidoxorubicin and mitomycin C, in which 4-epidoxorubicin was administered by escalated dose and split course (FEM II). From among 12 patients evaluable for response, 2 partial and 1 minimal remission were observed, suggesting a response rate of 25%. Four patients (30%) showed a no change and 5 progression. The median survival of all patients was 3.4 months, of the responders 8.4 months, of those with no change 5.2, and of those showing progression 3.4 months. Considerable nausea/vomiting and leukopenia was observed. The preliminary data suggest that the FEM II regimen does not offer any progress in terms of efficacy, survival and toxicity for advanced pancreatic carcinoma.

Phase I-II trial of doxifluridine (5'DFUR) administered as long-term continuous infusion using a portable infusion pump for advanced colorectal cancer.

Doxifluridine, a new fluoropyrimidine analog, was administered to 21 patients with advanced colorectal carcinoma. The starting dose was 1.0 g/m2 given over 24 h for 90 consecutive days as a continuous infusion. Due to severe skin reactions (hand-foot syndrome), the dose was reduced stepwise to 0.75 g/m2/day. Twenty patients were evaluable for efficacy, one had an early non-toxic death. Seven out of 20 (35%) showed a partial response; disease stabilization was observed in 10 patients (50%) and three showed progressive disease after 3 months of treatment. All 17 patients who achieved a partial response or a stabilization of disease were treated until progressive disease was documented and some had therapy up to 46 weeks. Toxicity was minimal and mainly defined as hand-foot syndrome which occurred in 50% of the patients of whom three experienced severe reaction. There was no myelosuppression, renal or liver dysfunction, no cardiac alterations and only one patient experienced severe dizziness. Doxifluridine is active in advanced colorectal carcinoma when the drug is given as a continuous infusion for 90 consecutive days at a daily dose of 0.75 g/m2.

Dose escalation and split course of 4-epidoxorubicin in combination chemotherapy (FEM II) of advanced gastric carcinoma. A phase-II trail of the 'Chemotherapiegruppe Gastrointestinaler Tumoren (CGT)'.

In a phase II trial 46 patients with advanced gastric carcinoma were treated with FEM combination chemotherapy (5-fluorouracil, 4-epidoxorubicin and mitomycin C) in which 4-epidoxorubicin was administered by escalated dose and split course (FEM II). Twenty-nine patients with measurable disease were evaluable for response. One complete remission and 7 partial remissions were achieved, suggesting an overall response rate of 28%; 2 minimal responses (7%) and 9 patients with no change were observed (31%); 10 patients had tumor progression (34%). Median survival time for all patients was 6.2 months, for patients with CR + PR + MR 16.2 months, for patients with no change 8.4 months, and with tumor progression 3.5 months. WHO grade 2 and 3 leukopenia appeared in 6%, thrombocytopenia in 0% and alopecia in 27% of the patients after the first cycle. Nausea and vomiting grade 2 and 3 were seen in 21%. Comparing these results with our earlier data achieved with FEM I, FEM II showed a tendency towards better response and survival, and subjective toxicity (nausea/vomiting) was significantly reduced. Therefore, in our opinion FEM II is preferable for practical use.

Combined modality of radiation and chemotherapy for the treatment of gastric carcinoma. A review.

The results of combined radiation and chemotherapy for the treatment of gastric carcinoma are reviewed. A small amount of postoperative adjuvant combined treatments of the curatively resected gastric carcinoma was performed which do not suggest any advantage of treatment compared to observation. For locally advanced and unresectable gastric carcinoma 5-fluorouracil or ftorafur was administered simultaneously to local irradiation in several phase-II studies. The response rates of 37%-58% and one year survival of 45%-72% do not suggest an advantage of combined modality compared to the one way treatment. The FAM, FAMe or FAB regimen was also used and obviously do not improve the results of combined modality treatment. A small but well conducted prospective randomized trials compared radiotherapy with and without chemotherapy or chemotherapy with and without radiotherapy. Recent results from different cooperative groups failed to improve the treatment results in terms of response and survival.

Sequential high dose methotrexate, 5-fluorouracil and folinic acid does not improve response rates in advanced colorectal cancer.

27 patients with advanced colorectal cancer were treated in a phase-II trial with high dose sequential methotrexate (MTX), 5-fluorouracil (5-FU), and folinic acid (FA). Following a 4 h infusion of 800 mg/m2 MTX and a 4 h interval, 1,500 mg/m2 5-FU and 200 mg/m2 FA were given as a 24 h infusion. Out of 23 evaluable patients we observed one partial remission and 9 disease stabilizations. Median survival time of all patients was 10.4 months. Overall toxicity was low. In comparison to a previous trial we did not observe better treatment results by adding high dose FA to a sequential MTX/5-FU schedule.

Assessment of the preclinical activity of budotitane in three different transplantable tumor systems, its lack of mutagenicity, and first results of clinical phase I studies.

The antitumor activity of budotitane was investigated in three different tumor systems--the transplantable murine ascitic-colon-adenocarcinoma MAC 15A, the TD-osteosarcoma of the rat, and the intramuscularly transplanted murine sarcoma 180. Marked inhibition of tumor growth was observed in the intramuscularly transplanted sarcoma 180, and cure rates of 50-80% were achieved in the colon adenocarcinoma MAC 15A. In contrast to these findings, bulotitane was inactive in the transplantable TD-osteosarcoma of the rat. Preliminary mutagenicity studies with the Salmonella typhimurium/mammalian microsome assay of Ames did not show any evidence of mutagenicity for the compound. The first results of the phase I clinical trials showed mild hepatotoxicity at a dose level of 15 mg/kg, dose-limiting nephrotoxicity at 21 mg/kg, and a reversible impairment of the sense of taste, beginning at a dose of 9 mg/kg.