Chemoimmunotherapy with low dose vinorelbine and interleukin-2 in treatment of patients with metastatic renal cell carcinoma.

Systemic therapies employed in patients with metastatic renal cell carcinoma (MRCC) include chemotherapy to immunomodulatory cytokines (interleukin 2 [IL-2], interferon alpha [INFalpha]), chemoimmunotherapy, adoptive immune therapy and anti-angiogenic therapy. Despite this range of treatment alternatives, the optimal therapy for MRCC patients is far from being established. Thus, attempts with novel therapeutic approaches implementing new drug combinations are justified. We conducted a phase II evaluation of a combination of vinorelbine and IL-2, both at low doses, in 30 patients with MRCC. The rationale of the combination was to damage the tumor tissue to the extent necessary to make it more immunogenic while, at the same time, to obtain an efficient immune response through the concomitant administration of IL-2. The treatment, given in different dose combinations and administration times, resulted feasible, with no renal, neurological or hematological toxicity. The overall survival of the whole group of patients is higher than that usually observed following treatment with immunotherapies (18.2 versus 13.3 months, respectively). While the limited number of treated patients does not allow advancing conclusions on the effective activity of the adopted protocol, the results observed are encouraging.

Dexamethazone-induced acute tumor lysis syndrome in a T-cell malignant lymphoma.

We report a case of steroid-induced acute tumor lysis syndrome and review the literature. A 60-year-old woman was started on steroid therapy for dyspnea due to bilateral pleural effusion and a large mass involving the anterior mediastinum. The final diagnosis was precursor T-lymphoblastic lymphoma-leukemia. Following steroid therapy, the patient developed acute renal failure and laboratory evidence of metabolic changes induced by massive cytolysis. She received vigorous hydration, diuretic and allopurinol therapy, and haemodialysis. Her diuresis, renal function and laboratory data returned to normal within 2 weeks. A review of the medical literature on T-cell lymphoma revealed only one similar case of steroid-induced acute tumor lysis syndrome, a life-threatening metabolic emergency. This risk should be kept into account in the management of patients with lymphoproliferative disorders.

Effects of retinoic acid and amifostine on in vitro growth of normal hemopoietic progenitor cells.

Association of all-trans retinoic acid (ATRA) and amifostine (AMF) might be an alternative in treatment of myelodisplatic syndromes. In this study we undertook a preliminary in vitro research on the effects of a combination of ATRA and AMF on normal hemopoietic progenitors. Mononuclear, non-adherent cells from peripheral blood of normal volunteers, were incubated with AMF, at a the concentration of 500 microM and then cultured for CFU-GM and BFU-E growth adding to culture dishes before gelling ATRA at the concentration 10(-6) and 10(-12)M. Controls were cultures not pre-incubated with AMF, cultures incubated with AMF without addition of ATRA and cultures without addition of any drug. ATRA addition did not have significant effects on hemopoietic progenitors growth. Association of ATRA and AMF do not appear to synergize to stimulate in vitro growth of hemopoietic progenitors.

Advanced colorectal cancer: quality of life and toxicity in patients after weekly 24-hour continuous infusions of biomodulated 5-fluorouracil.

It is generally agreed that chemotherapy prolongs survival and relieves symptoms more than the best supportive care in advanced colorectal cancer. Since its introduction over 35 years ago, 5-fluorouracil (5-FU) has been the only effective chemotherapeutic option available for the treatment of advanced colorectal cancer. Efforts have focused on the use of various 5-FU-based regimens. A commonly used regimen, frequently extolled as the "gold standard" for clinical trials in advanced colorectal cancer, is the Mayo Clinic regimen; this option has, however, been associated with considerable dose-limiting toxicity. Another approach has involved 5-FU administration by continuous intravenous infusion. In this paper we present our experience on 10 Dukes D colorectal cancer patients treated with 24-hour continuous infusion of biomodulated 5-FU delivered in an ambulatory setting with an intravenous infusional pump. The number of treated patients was admittedly not sufficient to evaluate the clinical response of this 5-FU chemotherapeutic regimen. This is not the goal of our work; however, other rationale for adopting this approach is justified: the regimen has a favourable toxicity profile and can provide considerable benefit in terms of improved quality of life while at the same time the health care costs are alleviated since hospitalization is generally not required.

Effects of docetaxel on the in vitro growth of human myeloid progenitors.

Haemotoxicity is usually the primary and dose-limiting side-effect of docetaxel (TXT) a semysyntetic analogue of paclitaxel which has acquired an important role in anticancer treatment. This research presents the results of an in vitro toxicity study of TXT on myeloid progenitors obtained from healthy volunteers and assayed as CFU-GM. Peripheral blood mononucleated non-adherent cells (MNAC) were incubated for 24 h at standard conditions with increasing concentrations of TXT and then cultured for CFU-GM assay. At every concentration severe CFU-GM growth inhibition was observed. In a second set of experiments MNAC were sequentially exposed to TXT and then to doxorubicin or cisplatin or vinorelbine or etoposide at appropriate concentrations. In a third set the sequence of exposure was reversed. No difference of CFU-GM growth inhibition was observed between the alternate sequences. These findings suggest that the toxicity on CFU-GM in vitro growth of TXT combinations with other anticancer drugs is sequence-independent.

In vitro toxicity of taxol based anticancer drug combinations on human hemopoietic progenitors.

The sequence dependency of the interaction of taxol with other anticancer drugs is of clinical importance, and may be due to pharmacokinetic changes and/or to inherent differences in the sensitivity of target normal or cancer cells. This study presents results on the in vitro interaction of taxol with doxorubicin, cisplatin, etoposide and vinorelbine in alternate sequences on human hemopoietic progenitors (CFU-GM). Peripheral blood mononuclear non adherent cells were exposed to IC50 of Taxol for 24 hours and then, for 1 hour to IC50 of each of the other drugs. In a second set of experiments the reverse sequence was applied. The cell suspension was subsequently cultured to assay the growth of CFU-GM. A strong sequence dependency characterizes the combination taxol-vinorelbine, while for the other combinations the order of sequence appears to have little impact on in vitro toxicity on CFU-GM. Comparing results on CFU-GM with that obtained in vitro with the same combination sequences on cancer cell lines some remarkable differences show up. Studies on a normal human myeloid line may therefore have a place in preclinical evaluation of sequence of anticancer drug combinations.

Splenectomy induced complete remission in a patient with multicentric Castleman's disease and autoimmune hemolytic anemia.

Castleman's disease (CD) is a rare disorder of the lymphoid tissue in which the clinical manifestations often mimic a malignant lymphoma. Despite the absence of monoclonality of the lymphoid proliferation, the multicentric variant of the disease (MCD) is characterized by severe symptoms and poor prognosis. Etiologic, pathogenetic, and therapeutic aspects of MCD are still uncertain. We report the case of a 57-year-old patient affected by MCD complicated by severe immunohemolytic anemia. Whereas the clinical and laboratory response to steroids and chemotherapeutic agents was only partial, splenectomy induced a complete remission of hemolysis and disappearance of the constitutional symptoms and of all generalized lymphadenopathies.

In vitro toxicity of A 3'-azido-3'-deoxythymidine and hydroxyurea combination on normal myeloid progenitors.

Hydroxyurea (HU) appears to increase 3'-azido-3'-deoxythymidine (AZT) antiretroviral activity and cytotoxicity by inhibiting thymidilate synthesis. The combination of AZT and HU may therefore be of clinical usefulness. We evaluated the in vitro hemotoxicities of different combinations of AZT and HU in comparison with the hemotoxicities exerted by either of the two drugs alone. Peripheral blood granulocyte macrophage committed progenitors (CFU-GM) of healthy donors were selected as targets of hemotoxicity. Both AZT and HU separately had a dose-dependent inhibitory effect on the in vitro growth of normal circulating CFU-GM. The combination of the two drugs induced a statistically significant synergistic cytotoxicity. In fact, addition of HU induced a remarkable reduction of AZT ID50. Thus, future clinical application of AZT, HU combination should take into account the greater hemosuppressive action of the combination in respect to that observed following administration of either drug alone.

Cisplatin inhibits erythroid committed progenitor (BFU-E) mobilization in peripheral blood.

Circulating myeloid (CFU-GM) and erythroid (BFU-E) progenitor levels were evaluated weekly throughout 3 courses of treatment with vinorelbine (VNB) ifosfamide (IFO) and filgrastim (G-CSF) with or without addition of cisplatin (DDP) in 20 stage IIIB or IV non small-cell lung cancer patients. In IFO, VNB, DDP-treated patients, BFU-E mobilization in peripheral blood following chemotherapy and G-CSF was completely lacking, in contrast with the patients treated with IFO, VNB plus G-CSF. CFU-GM release, however, was of the same order in the 2 groups of patients. Further investigations are needed to explain why presence of DDP in this chemotherapeutic protocol hinders erythroid progenitor release in peripheral blood.

Toxicity on human hemopoietic progenitors of 2'-2'-difluoro-2'deoxycytidine (gemcitabine).

This study presents results on 2'-2'-difluoro-2'deoxycytidine's (dFdC: gemcitabine) in vitro toxicity on peripheral blood CFU-GM and BFU-E obtained from healthy volunteers. Peripheral blood mononucleated non-adherent cells were cultured according to standard methods with continuous exposure (13 days) to dFdC (4,40 and 400 pmol/L) or following 1 hour's, incubation with increasing drug concentrations (1, 10, 100 mumol/L). The results indicate that dFdC has a marked dose-dependent inhibitory effect on the in vitro growth of peripheral blood hemopoietic progenitors., No significant differences were observed for the growth inhibition induced on CFU-GM and BFU-E. Continuous exposure to dFdC gave an IC50 of 4 pmol/L for both CFU-GM and BFU-E. In four chemotherapy naive patients affected by tumors of different type treated with three standard courses of dFdC the variations in the peripheral blood of hemopoietic progenitor level were determined. Patterns of changes were different, but a marked and sustained decrease of both CFU-GM and BFU-E was observed in one case only. The contrast between the apparently rather mild clinical hemotoxicity of dFdC and its in vitro dramatically potent inhibitory activity on hemopoietic progenitors is discussed.

Feasibility and toxicity of combination chemotherapy with ifosfamide, vinorelbine, cisplatin versus ifosfamide, vinorelbine in patients with advanced non small cell lung cancer.

Vinorelbine (VNB) and Ifosfamide (IFO) have recently been proposed for treatment of non small cell lung cancer (NSCLC). The two drugs separately induce response rates in excess of 20% and, when combined, of 32.56%. Cisplatin (DDP) is considered a standard in chemotherapy of NSCLC affected patients. We report data on the feasibility and the toxicity of an IFO, VNB and DDP combination in comparison with IFO, VNB association. Results obtained show that the IFO, VNB, DDP combination has a more severe toxicity profile than the IFO, VNB combination although not to a degree precluding its feasibility. Responses, however, appear somewhat more favorable than in the group treated with the combination IFO, VNB. It is therefore necessary to ascertain if clinical advantages in survival and symptom palliation offered by IFO, VNB, DDP combination outweigh impairment in quality of life due to its significant toxicity.

Carboplatin and cisplatin pharmacokinetics after intrapleural combination treatment in patients with malignant pleural effusion.

BACKGROUND: Cisplatin (DDP) and carboplatin (CBDCA) are two of the most effective drugs in a locoregional approach. Since simultaneous combined treatment with intrapleural DDP and CBDCA has not been reported in humans, we investigated its use in patients with malignant effusions, focusing on pharmacokinetics. PATIENTS AND METHODS: The pharmacokinetics of DDP and CBDCA were studied in 10 patients with malignant pleural effusion treated intrapleurally with a combination of DDP (60 mg/m2) and CBDCA (270 mg/m2) and in additional patients who received the same doses of drugs administered intravenously as single agents or in combination. Platinum (Pt) species originating from DDP (metabolites plus unchanged DDP) and intact CBDCA in plasma and pleural fluid ultrafiltrates were measured by means of high performance liquid chromatography and atomic absorption spectrometry. RESULTS: Both in the plasma and pleural fluid, the total levels of free Pt represented the additive result of the individual concentrations of CBDCA and Pt-species derived from DDP. After intrapleural combination, high pleural-plasma ratios of the peak concentrations and AUCs were observed both for CBDCA and DDP-derived Pt species, highlighting a distinct local pharmacological advantage. However, the Pt species originating from DDP were absorbed more rapidly from the pleural cavity than CBDCA (Ka = 86 x 10(-3) vs. 37 x 10(-3) min-1, P < 0.05). Intrapleural combination of CBDCA and DDP produced therapeutic plasma levels of reactive (free) DDP species and increased the extent of their residence time (MRT) compared with single intravenous DDP treatment [peak concentration: 1.1 +/- 0.1 (SD) vs. 1.6 +/- 0.2 microgram/ml; MRT: 5.2 +/- 1.9 vs. 0.5 +/- 0.06 h]. Furthermore, the plasma AUC of free CBDCA after intrapleural combined treatment (2.1 +/- 0.5 mg/ ml x min) was similar to that after intravenous administration of CBDCA alone (2.1 +/- 0.2 mg/ml x min). The intrapleural treatment was well tolerated by all patients. Toxicity consisted of mild nausea and vomiting (grade 1-2 according to the WHO scale) in four patients. Myelosuppression (grade 1-2) was remarkable only in two heavily pretreated patients. No evidence of recurrence of the pleural effusion was observed in six patients (complete response), while an asymptomatic minimal fluid reaccumulation not requiring drainage (partial response) was observed in four patients. CONCLUSIONS: The pharmacologic results seem to exclude a pharmacokinetic interaction between CBDCA and DDP and suggest that a dose of CBDCA 2-fold higher than that used in this study associated intrapleurally with 60 mg/m2 DDP could induce an acceptable and predictable myelosuppression.

In vitro synergistic inhibition of human bone marrow hemopoietic progenitor growth by a 3'-azido-3'-deoxy-thymidine, 2',3'-dideoxycytidine combination.

In vitro growth of human normal bone marrow granulocyte-macrophage colony forming units (CFU-GMs) and erythroid burst forming units (BFU-Es) was dose-dependently inhibited by 3'-azido-3'deoxythymidine (AZT) (from 0.1 microM to 4 microM) and 2',3'-dideoxycytidine (ddC) (from 0.01 microM to 1.0 microM). These ranges included minimum in vitro inhibitory concentrations to HIV-1 and concentrations corresponding to plasma level achievable in vivo. A synergistic inhibitory effect, statistically highly significant, was observed when combinations of the two drugs were added to cultures. This severe in vitro toxicity of ddC and the synergistic toxicity of AZT-ddC combinations on hemopoietic progenitor cells should be considered when the two drugs are administered in concurrent or alternating regimens.

Interferon-alpha inhibits CFU-GM mobilization following chemotherapy and G-CSF administration.

Changes in routine hematologic data and in circulating granulocyte-macrophage colony-forming units (CFU-GM) during granulocyte colony-stimulating factor (G-CSF) administration were evaluated in non-small cell lung carcinoma (NSCLC) patients treated with a combination of 5-fluorouracil (5-FU) and cisplatin (DDP) with and without the addition of interferon-alpha (IFN-alpha). The patterns of leukocyte changes following chemotherapy plus G-CSF were similar in both the IFN-alpha-inclusive and the IFN-alpha-devoid courses. However, the twofold increase in CFU-GM observed in patients receiving chemotherapy plus G-CSF was completely absent following the course including IFN-alpha. The activity of G-CSF on the hematologic pattern is seemingly affected by its combination with IFN-alpha treatment. Mechanisms of the possible in vivo interaction among IFNs and hematopoietic growth factors remain to be elucidated.

In vitro activity on myeloid progenitors of a combination of 2-chloro-2'-deoxyadenosine and interferon alpha: the effects of IL-1 and GM-CSF.

The toxic effects of a combination of 2-chloro-2'-deoxyadenosine (CDA) and interferon alpha (IFN-alpha), with and without addition of interleukin 1 (IL-1) and/or granulocyte macrophage colony stimulating factor (GM-CSF), on the in vitro growth of peripheral blood granulocyte macrophage committed progenitors (CFU-GM) from 10 normal subjects were investigated. CDA concentration ranged from 15.6 nmol/l to 1 mumol/l, IFN-alpha sole concentration was 10 IU/ml. IL-1 and/or GM-CSF were added at concentrations of 2000 pg/ml and 10 ng/ml, respectively. CDA induced a dose dependent inhibitory effect on CFU-GM growth. Addition of IFN-alpha increased CFU-GM inhibition induced by CDA only at lower concentrations of the latter. IL-1 and GM-CSF, separately or in combination, did not counteract the inhibitory activity of the CDA-IFN-alpha combination.

Producton of tumor necrosis factor and granulocyte colony stimulating factor by bone marrow accessory cells in myelodysplastic patients.

This paper reports on the production of tumor necrosis factor (TNF) and granulocyte macrophage colony-stimulating factor (GM-CSF) by cultured mononuclear adherent cells derived from bone marrow of 25 patients affected by myelodysplastic syndrome (MDS) of different FAB subtypes. Mean production of GM-CSF was much lower than in controls, without significant differences among different subtypes. Mean production of TNF was similar in MDS patients and in controls, but noteworthy differences were observed between patients with RA, RAEB and RAEB-t and patients with RARS and CMML. Growth of bone marrow granulocyte macrophage and erythroid progenitors did not correlate with TNF and GM-CSF production, although in MDS subtypes with higher GM-CSF levels, colony growth was slightly higher than in subtypes with lower GM-CSF production.

[Alpha interferon in the therapy of polycythemia vera]. / L'interferone alfa nella terapia della policitemia vera.

In previous researches recombinant interferon alpha (IFN-alpha) has been demonstrated to significantly control red cell mass and thrombocytemia in patients with polycythemia vera (PV). Further evaluation of drug effectiveness and of modalities of maintenance therapy is warranted. We treated four patients with PV according to PVSG criteria with IFN-alpha (3 MU subcutaneously three times a week) for five months. Thereafter the starting dose was reduced to 1.5 MU three times a week. Treatment with IFN-alpha at the higher dosage induced regression in sizes of the spleen and a return to normal levels of peripheral blood platelets and leukocytes. Phlebotomies, previously performed to keep under control hematocrit values, were no more needed. During maintenance treatment with IFN-alpha reduced dose platelet level remained in the normal range, spleen size did not show further variation but hematocrit slowly rose and phlebotomies had to be resumed. These results confirm IFN-alpha effectiveness in PV, but suggest the need of relatively high dosages of the drug and difficulties in switching to a maintenance treatment.

Circulating hematopoietic progenitor cells in polycythemia vera: the in vivo effect of hydroxyurea.

The in vivo effects of hydroxyurea (HU) on circulating erythroid (BFU-E) and granulocyte-macrophage progenitors (CFU-GM) in patients with polycythemia vera (PV) have been evaluated. HU induced a strong decrease of both BFU-E and CFU-GM in the first month of treatment. During the following 4 months of treatment the level of circulating progenitors remained at very low values, until the end of the period of observation. HU activity involved both erythroid and myeloid committed progenitors and both erythropoietin-stimulated (normal) and endogenous (derived from the abnormal PV clone) BFU-E.

Serum erythropoietin increase in patients receiving adjuvant therapy with 5-fluorouracil and leucovorin.

High-dose anticancer drugs have been shown to induce an increase in serum erythropoietin (sEpo) levels not mediated by hypoxia. In this study, sEpo was assessed in seven patients who had been administered a course of 5-day leucovorin-modulated 5-fluorouracil (5-FU-LV) as an adjuvant therapy after the removal of colon cancer. During this study, the mean hemoglobin (Hb) concentration stayed at a constant level, peripheral blood (PB) reticulocytes showed an early, sharp decline, and sEpo levels progressively increased for 15 days after the start of chemotherapy. These results appear to indicate that the increase in sEpo, which was not related to anemia, may have followed from the administration of a cytotoxic drug at doses used in routine, clinical practice.

Hematotoxicity of 5-fluorouracil-leucovorin in a setting of adjuvant chemotherapy.

Changes of granulocyte macrophage colony forming units (CFU-GM) were assessed in peripheral blood of patients treated with 5-Fluorouracil-Leucovorin adjuvant chemotherapy after removal of colon cancer. The clinical and hematological state of the patients was steady and as far normal as possible. Leucocyte counts did not show significant changes. The mean peripheral blood level of CFU-GM significantly decreased following 5FU-LV infusion, reaching nadir by day 15. These changes of hemopoietic progenitors, not detected by routine hematic cell counts, point to a perturbation of the granulopoietic system by the 5FU-LV association also at doses used in adjuvant chemotherapy.