Treatment of chronic lymphocytic leukemia in early and stable phase of the disease: Long-term results of a randomized trial

Abstract: In 1982 the IGCI CLL cooperative group decided to investigate the usefulness of treating, at diagnosis B-cell chronic lymphocytic leukemia (CLL) in early and stable phase of the disease. From January 1982 to December 1986, 148 patients were randomized either to receive immediate treatment with chlorambucil (CLB) or to defer therapy to the time of progression. The early and stable phase of the disease was defined by a total tumor mass (TTM) score < 9, the absence of anemia or thrombocytopenia and a doubling time > 12 months. The main end-point of the study was survival. At the last evaluation in April 1993, after a median follow-up of 75 months, no significant difference was found in overall survival between early vs. deferred treatment patients from every cause of death as well as from death due to CLL-related causes only. The same results were obtained when the patients in more favorable stages, such as Binet stage A and TTM < 4.5, were considered. Interestingly, the incidence of epithelial cancer was similar in the two groups. Early treatment was associated with a significantly better response and a lower progression rate. From this long-term experience, it can be concluded that immediate chemotherapy with CLB is not beneficial for CLL patients in early and stable phase of the disease in terms of survival.     

Results of a randomized study of early stage Hodgkin's disease using ABVD,EBVD, or MBVD

From January 1986 to December 1989, 157 previously untreated patients, with Hodgkin's disease stage I or II without bulky disease, were enrolled in a clinical comparative study. The objectives of the study were to compare the efficacy and safety of using epirubicine or mitoxantrone instead of adriamycin in the combination chemotherapy regimen ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine). The complete response rate was better in the patients treated with the ABVD or EBVD regimens compared to the MBVD arm. Also, differences in overall survival and relapse-free survival were better in the patients who received ABVD or EBVD compared to the MBVD regimen. Hematological, gastrointestinal and cardiac toxicity were similar in the three groups. Dose intensity, delays and complications were also similar in the three groups. The mitoxantrone-containing regimen was found to have less efficacy in comparison to the other regimens tested in the present study in patients with favorable stage I or II Hodgkin's disease. © 1995 Wi1ey-Liss Inc.     

Optimal debulking following chemotherapy of advanced-stage epithelial ovarian carcinoma

We reviewed the records of 110 consecutive patients with advanced-stage epithelial ovarian carcinoma treated at the Soroka Medical Center, Beer-Sheva, Israel, from 1961-1987. Twenty patients (18.1%) had optimal debulking at initial laparotomy, 30 patients (27.2%) had nonoptimal debulking at initial laparotomy, 20 patients (18.1%) had an "inoperable" disease at initial laparotomy, and 40 patients (36.3%) had such poorly written records that no information about the degree of resectability at initial laparotomy could be obtained. Four patients, in whom the residual tumor left at initial laparotomy had responded to chemotherapy, had a second laparotomy. In all four patients optimal debulking surgery at second laparotomy was easy to perform and was successful. The value of a second laparotomy after a few cycles of chemotherapy in order to optimally debulk the residual tumor left at initial laparotomy is discussed. It is concluded that a second attempt of debulking surgery after chemotherapy has a respectable place in the management of patients with advanced-state epithelial ovarian carcinoma, but further research is needed.     

Evidence for Classically Conditioned Fatigue Responses in Patients Receiving Chemotherapy Treatment for Breast Cancer

Fatigue is the most common side effect of chemotherapy for cancer. Not yet explored is the possibility that patients may develop conditioned fatigue responses to clinic cues as a result of the repeated pairing of the clinic environment (conditioned stimulus) with infusions of chemotherapy (unconditioned stimulus) that cause fatigue (unconditioned response). As a first critical test of this possibility, breast cancer patients (N = 82) were studied across their first four cycles of chemotherapy. Consistent with conditioning: (1) fatigue levels in the clinic environment significantly increased with repeated pairings of the clinic environment and chemotherapy administration; (2) fatigue responses in the clinic environment prior to the fourth infusion (CR) were predicted by patients’ previous experiences of post-infusion fatigue (UR) above and beyond effects of concurrent emotional distress. These results provide the first evidence in the literature that fatigue can be conditioned. Additional research is warranted to determine the clinical importance of this source of fatigue in chemotherapy patients.     

Increased aneuploidy in spermatozoa from testicular tumour patients after chemotherapy with cisplatin, etoposide and bleomycin

Testicular cancer is the most common neoplasia occurring in the young male population. The PEB (cisplatin, etoposide and bleomycin) adjuvant chemotherapy usually proposed after orchidectomy in non seminomatous tumours, and in metastatic seminomas, has improved the long-term survival of these patients. Following an azoospermic period, sperm cell recovery is generally observed after treatment delivery, but little is known about the genetic consequences on these new spermatozoa. To estimate the chromosomal consequences of this chemotherapy on sperm cells during the period of recovery of spermatogenesis, sperm cell aneuploidy was studied in testicular cancer patients, at 6-18 months after PEB adjuvant chemotherapy delivery, using fluorescence in-situ hybridization (FISH) of chromosomes 7, 16, 18, X and Y with specific DNA probes. A significant increase in the frequency of diploidy and disomy for chromosomes 16, 18 and XY was observed in treated patients compared with a healthy control group. Spermatozoa aneuploidy occurring during the spermatogenesis recovery period might be a possible side effect of the PEB regimen. Thus, practitioners should be advised to provide counselling about the need for an appropriate duration of contraception. Moreover, genetic counselling should be offered in cases of pregnancy occurring soon after the end of chemotherapy.     

After chemotherapy,functional humoral response capacity is restored before complete restoration of lymphoid compartments

Chemotherapy has, besides the beneficial effects, several adverse effects. Suppression of the immune system is one of the most important problems. Infections caused by encapsulated bacteria like Streptococcus pneumoniae are responsible for a major part of infectious problems during and after treatment. The splenic marginal zone is essential in the initiation of an immune response to encapsulated bacteria. In this study, we analysed the effects of three different cytostatic agents on humoral immune responses. We found a reduced, but detectable immune response capacity at two days after treatment although the marginal zone B cell population is severely reduced at this time point. Twenty-four days after cessation of treatment, the immune response capacity was largely restored although lymphoid compartments were still not completely restored at that time point. Apparently, the presence of only few marginal zone B cells is sufficient to evoke a rise in antibody titres and although antibody titre increases are low, even small rises are most likely clinically relevant.     

Fluoropyrimidine chemotherapy in a rat model: comparison of fluorouracil metabolite profiles determined by high-field 19F-NMR spectroscopy of tissues ex vivo with therapy response and toxicity for locoregional vs systemic infusion protocols

A Sprague-Dawley rat model with DS sarcoma transplanted in the thigh was used to compare transcatheter locoregional i.a. and systemic i.v. administration of 5-fluorouracil (FU) at 12 dose-rate schedules: 25, 50 and 100 mg/kg; bolus, 1, 5 and 24 h infusions. In experiment A tumor (62/67 animals) as well as liver and kidney (56/67 animals) were excised 1 h after a single bolus or 1 h infusion or at the end of 5 and 24 h infusions. (19)F-NMR spectroscopy at 11.7 T was used to quantitate FU and its metabolites in ca. 1 g of tissue at 4 degrees C. In experiment B analogous FU treatments were repeated for 5 days (rats 80+11 controls). Tumor volumes vs time, various blood parameters and survival times were recorded, and a log growth rate parameter log GR, a response index RI, and a toxicity index TI were calculated. The i.a. vs i.v. ratios for tumor concentrations of FU and total anabolites (F-Nucl) were >1 for nearly all treatments and increased with infusion time at the higher doses. F-Nucl in tumor correlated linearly with total fluorine concentration (Tot. F range 30-1100 nmol/g) over all treatments (r=0.92, slope=0.45, p<0.0001). For non-bolus i.v. treatments [FU+F-Nucl] decreased linearly with decreasing FU dose rate (r(2)=0.74, zero intercept), while i.a. treatments showed non-linear behavior. For non-bolus treatments the mean log GR per treatment group showed a negative correlation (r=-0.87) with log[F-Nucl]. The most effective non-toxic treatments were 25 mg/kg over 5 or 24 h; the i.a. route was superior to i.v. on the basis of [FU+F-Nucl], RI, the reduction in log GR, and Kaplan-Meier survival statistics. For liver and kidney Tot. F (>83% FU catabolites) reached ca. 3-4 and 6-7 micromol/g, respectively, at the highest dose rates for either route; F-Nucl were detected only for Tot. F>500 nmol/g and increased exponentially as Tot. F increased (toxic treatments). The concentrations of the main catabolite (alpha-fluoro-beta-alanine, FBAL) in tumor did not correlate with Tot. F but rather with FBAL levels in kidney (r=0.90, all treatments), indicating that uptake of liver-derived FBAL from the circulation is the major source of FBAL in tumor.     

Mitoxantrone combined to vincristine,cyclophosphamide and fluorouracil in advanced breast cancer

Summary In our wide experience of treating advanced breast carcinoma with chemotherapy, the combination of doxorubicin (DOX), vincristine (VCR), cyclophosphamide (CPM) and fluorouracil (FU) gave a complete plus partial response rate of over 60%, with 100% alopecia and frequent cardiac toxicity depending on total dose.After the EORTC Clinical Screening Group phase II trial we have conducted an expected difference method comparative phase II trial using the combination DOX, VCR, CPM, FU and the combination of MTX (10mg/m²), VCR, CPM and FU on a population of 50 breast carcinoma patients similar to those taking part in the first study.The reasons for similarity of action will be presented and discussed.     

High resolution real-time B-mode echotomography in the diagnosis of extracranial carotid lesions. Comparison with traditional angiography

Summary Tumour growth essentially requires fibrin formation and fibrinopeptide A (FPA) is liberated into the circulation on fibrin formation. In the present study, a possible elevation of serum FPA level was examined in patients with metastatic brain tumour. A significant elevation of serum FPA level was shown in all 6 patients with metastatic brain tumour, when blood was drawn from the internal jugular vein. It was extremely high in 2 patients with rapidly growing tumour. However, such a significant elevation was not shown in 3 cancer patients without brain metastasis or in 1 patient with a huge meningioma. This suggests the possibility that the presence of metastatic brain tumour could be detected by measuring FPA in blood drawn form the internal jugular vein. This also suggests the tendency that elevation of serum FPA is higher in patients with more rapidly growing tumour.Infusion of urokinase into the internal carotid artery resulted in an elevation of serum fibrinopeptide B (1)15–42 (FPB) in 5 patients with metastatic brain tumour, when blood was drawn from the internal jugular vein. This suggests that urokinase could induce fibrinolysis in the tumour tissue, though this remains in conclusive because of the lack of complete controls.