Proportion Of Complete Remission Research Articles

A Phase I/II Study of Reduced Dose FCR (FCR-lite) in Combination with Lenalidomide Followed By Lenalidomide Maintenance (FCR2) for Initial Therapy of CLL: Final Results and Long-Term Follow-up

A Phase I/II Study of Reduced Dose FCR (FCR-lite) in Combination with Lenalidomide Followed By Lenalidomide Maintenance (FCR2) for Initial Therapy of CLL: Final Results and Long-Term Follow-up

Antitumor evaluation of the new Bcl‐2/Bcl‐xl inhibitor S44563 in primary human uveal melanoma xenografts

AbstractPurpose Nearly half of primary Uveal melanoma (UM) metastasizes in liver, but there are currently no effective therapies. Human UM are characterized by a high expression of Bcl‐2, ranging between 50% and 100%. This observation has been confirmed in our panel of 16 human UM xenografts obtained from patient’s tumors (Némati et al, CCR 2010). We have investigated the efficacy of the new Bcl‐2/Bcl‐XL inhibitor S44563 on 4 primary human UM xenografts.Methods Four well characterized primary human UM xenografts were used. S44563 (50 or 100 mg/kg, days 1‐5/8‐12/22‐26/29‐33) was administered IP alone or combined with fotemustine, concomitantly (15 or 30 mg/kg days 1 and 22), or after chemotherapy (100 mg/kg, days 43‐47/50‐54/64‐68/71‐75). Tumor Growth Inhibition (TGI) was calculated to measure the efficiency of drugs. Bcl‐2, Bcl‐XL, and Mcl‐1 expressions were determined by immunohistochemistry (IHC).Results S44563 administered alone induced a moderate TGI of about 50% in 1 model (MP41). When combined S44563 to fotemustine, we observed a synergistic activity in 2 models (MP77 and MM66), without impact on the proportion of complete remission. Finally, when S44563 was concomitantly and/or administered after fotemustine, we found a delay of tumor growth in 2 among the 3 tested xenografts (MP77, and MM26). IHC analyses showed that Bcl‐2, Bcl‐XL, and Mcl‐1 expressions were not modified after S44563 administration.Conclusion We have shown that S44563 increased the efficacy of chemotherapy in concomitant combination or after fotemustine. Such preliminary results underline the therapeutic potential of this new Bcl‐2/Bcl‐xl inhibitor in human UM.

Abstract B217: Antitumor activity of the new Bcl-2/Bcl-xl inhibitor S44563 in primary human uveal melanoma xenografts.

Abstract Background: Uveal melanoma (UM) is the most common primary malignancy of the eye in adults. Although over 95% of patients have disease limited to the eye at diagnosis, 50% will develop liver metastases and ultimately die of their disease. Because of the limited efficacy of current treatments, new therapeutic strategies need therefore to be developed. Reduced capacity for apoptosis induction is one potential obstacle to therapy but, consequently, regulators of apoptosis may constitute an attractive approach to anticancer therapeutics, such as the Bcl-2 family proteins. Human uveal melanomas are characterized by a high amount of Bcl-2 expression, ranging between 50% and 100% of studied cases. Such an observation has been confirmed in our panel of 16 primary human uveal melanoma xenografts obtained from patient's tumors (Némati et al, CCR 2010). We have therefore investigated the efficacy of the new Bcl-2/Bcl-XL inhibitor S44563 on 4 primary human UM xenografts. Materials and methods: Four well characterized models of primary human UM, obtained from patients after enucleation (MP41 and MP77) or liver metastasis surgery (MM26 and MM66) (Némati et al, CCR 2010), were used for the in vivo experiments. S44563 (50 or 100 mg/kg/day, days 1–5/8–12/22–26/29–33) was administered IP alone or combined with fotemustine, either concomitant (15 or 30 mg/kg days 1 and 22), or after chemotherapy (100 mg/kg) at days 43–47/50–54/64–68/71–75. Tumor Growth Inhibition (TGI) was calculated to measure the efficiency of various tested compounds. Bcl-2, Bcl-XL, and Mcl-1 expressions after S44563 administration were determined by immunohistochemistry (IHC). Results: The expression of Bcl-2, defined by IHC, was highly positive for the 4 models used (75% to 100% of tumor cells). S44563 administered alone at 50 and 100 mg/kg induced a moderate TGI of about 50% in 1 model (MP41) among all without dose effect. When S44563 was combined to fotemustine, we observed a synergistic activity in 2 models (MP77 and MM66) among the 4 tested, without impact on the proportion of complete remission. Finally, when S44563 was concomitantly and/or administered after fotemustine, we found a delay of tumor growth in 2 among the 3 tested xenografts (MP77, and MM26). IHC analyses showed that Bcl-2, Bcl-XL, and Mcl-1 expressions were not modified after S44563 administration. Conclusion: We have shown that S44563, despite a relative low efficacy when administered alone, increased the efficacy of chemotherapy in concomitant combination or after fotemustine. Such preliminary results therefore underline the therapeutic potential of this new Bcl-2/Bcl-xl inhibitor in human uveal melanoma. Némati et al. Clin Cancer Res 2010;16:2352–2362. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B217.

Therapieergebnisse beim Morbus Hodgkin

The results of therapy in 239 patients (161 men, 78 women, median age 33 [13-80] years) who had been treated for Hodgkin's disease between 1972 and 1986 were evaluated retrospectively. The proportion of complete remissions depended on the stage of the disease and was 90% (35 out of 39 patients) for stage IA, 90% (9 out of 10) for stage IB, 84% (40 out of 48) for stage IIA, 88% (22 out of 25) for stage IIB and 86% (37 out of 43) for stage IIIA. At five and ten years, survival rates among patients in stages IA to IIB were 76 and 69%, respectively, and for patients in stage IIIA 81 and 52%, respectively. For patients who enjoyed complete remissions the probability of surviving for 5 or 10 years without recurrence was 62% or 54%, respectively, for stages IA to IIB, and 75 or 43%, respectively, for stage IIIA. There were no statistically significant differences between stages I, II and IIIA as regards remission rate, survival time or recurrence-free survival time. During these stages the patient's age proved to be the only prognostic factor of any statistical significance. For stages IIIB and for IVA and IVB the proportion of complete remissions achieved by combined chemotherapy with COPP was 62%. At 5 and 10 years the proportion of these patients in permanent remission was 63 and 53%, respectively, while survival rates in the entire series were 46% and 40%, respectively. A genuine cure--in the sense of at least 10 years' survival without recurrence after the first complete remission--can be expected in one third of patients in stages IIIB to IVB.

The role of fludarabine in hematological malignancies

Fludarabine monophosphate, a synthetic nucleoside analog, has been shown to have considerable activity in a number of lymphoid malignancies. In chronic lymphocytic leukemia the response rates can exceed 70% with a considerable proportion of complete remissions being attained. These rates are markedly superior to earlier therapies with which complete remission was uncommon. It also has significant activity in previously treated patients for whom effective salvage regimens were unsatisfactory. In addition, fludarabine shows substantial activity in low grade non-Hodgkin's lymphoma, both as initial treatment and as salvage therapy. Fludarabine is effective in Waldenstrom's macroglobulinemia and is active in other low grade lymphoid malignancies. Major toxicities are reversible myelosuppression and depletion of T lymphocytes. The use of fludarabine in hematological malignancies will be reviewed, with reference to its mode of action and future use in combination therapies.

Treatment of Adult Soft-Tissue Sarcomas with Dose-Intensified Chemotherapy and Haematopoietic Growth Factors

Only few cytostatic drugs are used for the treatment of adult soft-tissue sarcoma, with adriamycin and ifosfamide being the most active agents achieving response rates of 20-35%. In addition, for dacarbazine and cyclophosphamide responses have been reported in 10-20% of patients. A dose-response relationship for adriamycin has been suggested based on results from phase II and III studies. 70 mg/m2 single-agent adriamycin every 3 weeks is considered as standard anthracycline treatment for metastatic soft-tissue sarcomas; higher doses have been associated with cardiac and skin toxicity. Clinical studies have also indicated a dose-response relationship for ifosfamide. Tumour responses to high-dose ifosfamide regimens ( > 5 g/m2, given as continuous intravenous infusion) have been achieved in patients relapsing after or resistant to ifosfamide-based regimens at standard doses. Haematopoietic growth factors, particularly G-CSF and GM-CSF, seem to reduce the number of infectious episodes following standard-dose chemotherapy and may allow the application of full doses of chemotherapy cycles on schedule. However, only moderate dose escalations of chemotherapy regimens by factors 1.2-1.4 were possible with the use of G-CSF or GM-CSF due to severe mucositis and cumulative thrombocytopenia. Studies with ultra-high doses of melphalan, ifosfamide or ifosfamide and either carboplatin or adriamycin followed by autologous bone marrow rescue or peripheral blood progenitor cells and growth factors have demonstrated that instead of myelosuppression other toxicities will be dose-limiting. Most studies using escalated doses of active agents in soft-tissue sarcomas followed by haematopoietic support measures have consistently demonstrated response rates of 40-50% compared with 20-30% following standard-dose chemotherapy. However, only a small proportion of complete remissions was achieved, and the overall duration of responses was not longer than for standard therapy. Currently dose-intensified chemotherapy cannot be regarded as standard treatment for soft-tissue sarcomas, and its value must be studied in controlled clinical trials. With the availability of new methods for haematopoietic support, such as myeloid growth factors and peripheral blood progenitor cells, the hypothesis of a dose-response relationship in soft-tissue sarcoma can be clinically tested. Its potential implication for cure should be further studied in a neoadjuvant or adjuvant setting.

RANDOMISED TRIAL COMPARING LOW-DOSE CISPLATIN AND CHLORAMBUCIL WITH LOW-DOSE CISPLATIN, CHLORAMBUCIL, AND DOXORUBICIN IN ADVANCED OVARIAN CARCINOMA

Ninety-eight patients with advanced ovarian cancer took part in a prospective randomised trial comparing low-dose cisplatin and chlorambucil with low-dose cisplatin, chlorambucil, and doxorubicin. After 4 years response rates (>50%) and proportion of complete remissions (28%) were similar in both groups. Median duration of remission was longest in the complete remitters, being 31 months in those having cisplatin and chlorambucil, and 24 months in those having doxorubicin as well.