Primary Central Nervous System Lymphoma: Evolving Biologic Insights and Recent Therapeutic Advances.

Primary central nervous system lymphoma (PCNSL) is a rare and clinically aggressive disease entity associated with poor survival. Though high-dose methotrexate-based immunochemotherapy approaches are effective at inducing responses, few patients experience long-term durable remissions. Recently, novel insights into the biology of this unique disease have been elucidated and have paved the way for the investigation of rational approaches such as Bruton tyrosine kinase inhibition and immunomodulation. Although these strategies can induce high response rates in PCNSL, remissions are short lived, with median progression-free survivals in the range of 6 months or less. Moving forward, understanding the mechanisms of treatment resistance with these and other novel agents is key to developing optimal combinatorial strategies. New approaches such as immune checkpoint inhibition and chimeric antigen receptor T-cell therapy are under investigation for PCNSL and thus far demonstrate activity in anecdotal clinical experiences. Future trials should focus on investigating novel rational combinations designed to optimally target the biology of PCNSL and simultaneously investigate mechanisms of resistance leading to treatment failure.

Inactivation of endothelial cell phosphoinositide 3-kinase ß inhibits tumor angiogenesis and tumor growth.

Angiogenesis inhibitors, such as the receptor tyrosine kinase (RTK) inhibitor sunitinib, target vascular endothelial growth factor (VEGF) signaling in cancers. However, only a fraction of patients respond, and most ultimately develop resistance to current angiogenesis inhibitor therapies. Activity of alternative pro-angiogenic growth factors, acting via RTK or G-protein coupled receptors (GPCR), may mediate VEGF inhibitor resistance. The phosphoinositide 3-kinase (PI3K)ß isoform is uniquely coupled to both RTK and GPCRs. We investigated the role of endothelial cell (EC) PI3Kß in tumor angiogenesis. Pro-angiogenic GPCR ligands were expressed by patient-derived renal cell carcinomas (PD-RCC), and selective inactivation of PI3Kß reduced PD-RCC-stimulated EC spheroid sprouting. EC-specific PI3Kß knockout (ΕC-ßKO) in mice potentiated the sunitinib-induced reduction in subcutaneous growth of LLC1 and B16F10, and lung metastasis of B16F10 tumors. Compared to single-agent sunitinib treatment, tumors in sunitinib-treated ΕC-ßKO mice showed a marked decrease in microvessel density, and reduced new vessel formation. The fraction of perfused mature tumor microvessels was increased in ΕC-ßKO mice suggesting immature microvessels were most sensitive to combined sunitinib and PI3Kß inactivation. Taken together, EC PI3Kß inactivation with sunitinib inhibition reduces microvessel turnover and decreases heterogeneity of the tumor microenvironment, hence PI3Kß inhibition may be a useful adjuvant antiangiogenesis therapy with sunitinib.

The Effect of Treatment Sequence on Overall Survival for Men With Metastatic Castration-resistant Prostate Cancer: A Multicenter Retrospective Study.

INTRODUCTION: We aimed to evaluate the treatment sequence for patients with metastatic castration-resistant prostate cancer (mCRPC) in real-world practice and compare overall survival in each sequential therapy. PATIENTS AND METHODS: We retrospectively evaluated 146 patients with mCRPC who were initially treated with androgen deprivation therapy as metastatic hormone-naive prostate cancer in 14 hospitals between January 2010 and March 2019. The agents for the sequential therapy included new androgen receptor-targeted agents (ART: abiraterone acetate or enzalutamide), docetaxel, and/or cabazitaxel. We evaluated the treatment sequence for mCRPC and the effect of sequence patterns on overall survival. RESULTS: The median age was 71 years. A total of 35 patients received ART-ART, 33 received ART-docetaxel, 68 received docetaxel-ART, and 10 received docetaxel-cabazitaxel sequences. The most prescribed treatment sequence was docetaxel-ART (47%), followed by ART-ART (24%). Overall survival calculated from the initial diagnosis reached 83, 57, 79, and 37 months in the ART-ART, ART-docetaxel, docetaxel-ART, and docetaxel-cabazitaxel, respectively. Multivariate Cox regression analyses showed no significant difference in overall survival between the first-line ART (n = 68) and first-line docetaxel (n = 78) therapies (hazard ratio [HR], 0.84; P = .530), between the ART-ART (n = 35) and docetaxel-mixed (n = 111) sequences (HR, 0.82; P = .650), and between the first-line abiraterone (n = 32) and first-line enzalutamide (n = 36) sequences (HR, 1.58; P = .384). CONCLUSION: The most prescribed treatment sequence was docetaxel followed by ART. No significant difference was observed in overall survival among the treatment sequences in real-world practice.

Protective Effect of Polysaccharides from Tussilago farfara L. on Bone Marrow Cells and Small Intestinal Epithelium Under Conditions of Polychemotherapy Evaluated by DNA Comet Assay.

Using DNA comet assay we found that polysaccharides from Tussilago farfara L. reduced the intensity of polychemotherapy-induced apoptosis and DNA damage in bone marrow cells and small intestinal epithelium of C57Bl/6 mice, which attested to genoprotective properties of these polysaccharides.

Synergetic and Antagonistic Molecular Effects Mediated by the Feedback Loop of p53 and JNK between Saikosaponin D and SP600125 on Lung Cancer A549 Cells.

We jointly analyzed the changes in cell cycle arrest and distribution, the accumulation of subphase cells, apoptosis, and proliferation in A549 cells treated with Saikosaponin D (Ssd) and JNK inhibitor SP600125 alone or in combination. Our results indicated that cell cycle arrest at G0/G1, S, and G2/M phases was coupled with the accumulation of subG1, subS, and subG2 cells, corresponding to early apoptosis, DNA endoreplication, and later inhibitory proliferation, respectively. Analyzing the expression of 18 cell cycle regulatory genes and JNK and phosphorylated JNK (pJNK) levels revealed an enhancement in these factors by Ssd. Additional SP600125 weakened or eliminated the Ssd-induced increase of these factors except that p53/p21 and Rassfia levels were further improved. Ingenuity Pathway Analysis (IPA) of the interactions of these factors revealed a negative synergistic effect on apoptosis while a positive synergistic effect on proliferative inhibition of the two drugs: (1) Ssd induced apoptosis via the activation of two axes, TGFα-JNK-p53 and TGFα-Rassfia-Mst1. By eliminating the Ssd-induced increase of JNK/pJNK, additional SP600125 weakened the Ssd-induced apoptotic axis of TGFα-JNK-p53 and simultaneously abolished Ssd-induced apoptosis; (2) Ssd inhibited proliferation by the activation of two axes, TGFß-p53/p21/p27/p15/p16 and TGFα-Rassfia-cyclin D1. By improving the Ssd-induced increase of p53/p21 and Rassfia, additional SP600125 enhanced the two axes of Ssd-induced inhibitory proliferation. Analyzing JNK/pJNK, p53, phospho-p53, and TNF-α levels revealed an opposite association of JNK/pJNK with p53 while consistent with phospho-p53 and TNF-α, which supported the proposals that JNK/pJNK negatively regulated p53 level, while it mediated p53 phosphorylation to transcriptionally activate TNF-α expression of apoptotic gene and trigger apoptosis. With the multiple roles, JNK/pJNK forms a synergetic and antagonistic feedback loop with phospho-p53/p53. Within the feedback loop, (1) Ssd-induced apoptosis depended on JNK/pJNK activities mediating phospho-p53 that activated TNF-α expression; (2) by weakening the negative regulation of JNK/pJNK in p53, SP600125 enhanced p53 level and the Ssd-induced inhibitory proliferation axes of TGFß-p53/p21/p27/p15/p16. The results indicated the central coordinating roles of the feedback loop in the synergistic and antagonistic effects of the two drugs in A549 cells and provided a rationale for the combination of Ssd with SP600125 in the treatment of lung cancer.

Identification of a novel oxidative stress induced cell death by Sorafenib and oleanolic acid in human hepatocellular carcinoma cells.

The lack of effective chemotherapies in hepatocellular carcinoma (HCC) is still an unsolved problem and underlines the need for new strategies in liver cancer treatment. In this study, we present a novel approach to improve the efficacy of Sorafenib, today's only routinely used chemotherapeutic drug for HCC, in combination with triterpenoid oleanolic acid (OA). Our data show that cotreatment with subtoxic concentrations of Sorafenib and OA leads to highly synergistic induction of cell death. Importantly, Sorafenib/OA cotreatment triggers cell damage in a sustained manner and suppresses long-term clonogenic survival. Sorafenib/OA cotreatment induces DNA fragmentation and caspase-3/7 cleavage and the addition of the pan-caspase inhibitor zVAD.fmk shows the requirement of caspase activation for Sorafenib/OA-triggered cell death. Furthermore, Sorafenib/OA co-treatment stimulates a significant increase in reactive oxygen species (ROS) levels. Most importantly, the accumulation of intracellular ROS is required for cell death induction, since the addition of ROS scavengers (i.e. α-tocopherol, MnTBAP) that prevent the increase of intracellular ROS levels completely rescues cells from Sorafenib/OA-triggered cell death. In conclusion, OA represents a novel approach to increase the sensitivity of HCC cells to Sorafenib via oxidative stress.

Nimotuzumab, a humanized monoclonal antibody specific for the EGFR, in combination with temozolomide and radiation therapy for newly diagnosed glioblastoma multiforme: First results in Chinese patients.

AIM: To evaluate the safety and efficacy of nimotuzumab, a humanized monoclonal antibody specific for the epidermal growth factor receptor (EGFR), in combination with temozolomide (TMZ) and radiation therapy (RT) in the treatment of newly diagnosed glioblastoma (GBM) in Chinese patients. METHODS: Twenty-six patients with newly diagnosed GBM were enrolled. All patients received standard external beam RT after surgery, with a total dose of 60 Gy in 30 fractions. During RT, concurrent TMZ was given daily at 75 mg/m(2) for 40-42 days, combined with six weekly infusions of nimotuzumab at a 200 mg dose. After a 4-week interval upon completion of RT, six cycles of adjuvant TMZ (150 to 200 mg/m(2) for 5 days in each 28-day cycle) were given. The primary end point was 6-month progression-free survival (PFS) rate. EGFR expression in tumor tissues was analyzed by immunohistochemistry. RESULTS: Treatment was well tolerated and no grade III or higher grade toxicity was observed. Median PFS and overall survival (OS) were 10.0 and 15.9 months, respectively, while the 6-month PFS and OS rates were 69.2% and 88.5%, respectively. No correlation between efficacy and EGFR expression was found. CONCLUSIONS: Combination of Nimotuzumab with RT plus concomitant and adjuvant TMZ showed favorable safety and tolerability profiles in newly diagnosed GBM in Chinese patients. The survival times were similar to those seen in historical data of standard therapy.

Aggravated bone density decline following symptomatic osteonecrosis in children with acute lymphoblastic leukemia.

Osteonecrosis and decline of bone density are serious side effects during and after treatment of childhood acute lymphoblastic leukemia. It is unknown whether osteonecrosis and low bone density occur together in the same patients, or whether these two osteogenic side-effects can mutually influence each other's development. Bone density and the incidence of symptomatic osteonecrosis were prospectively assessed in a national cohort of 466 patients with acute lymphoblastic leukemia (4-18 years of age) who were treated according to the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Bone mineral density of the lumbar spine (BMDLS) (n=466) and of the total body (BMDTB) (n=106) was measured by dual X-ray absorptiometry. Bone density was expressed as age- and gender-matched standard deviation scores. Thirty patients (6.4%) suffered from symptomatic osteonecrosis. At baseline, BMDLS and BMDTB did not differ between patients who did or did not develop osteonecrosis. At cessation of treatment, patients with osteonecrosis had lower mean BMDLS and BMDTB than patients without osteonecrosis (respectively, with osteonecrosis: -2.16 versus without osteonecrosis: -1.21, P<0.01 and with osteonecrosis: -1.73 versus without osteonecrosis: -0.57, P<0.01). Multivariate linear models showed that patients with osteonecrosis had steeper BMDLS and BMDTB declines during follow-up than patients without osteonecrosis (interaction group time, P<0.01 and P<0.01). We conclude that bone density status at the diagnosis of acute lymphoblastic leukemia does not seem to influence the occurrence of symptomatic osteonecrosis. Bone density declines from the time that osteonecrosis is diagnosed; this suggests that the already existing decrease in bone density during acute lymphoblastic leukemia therapy is further aggravated by factors such as restriction of weight-bearing activities and destruction of bone architecture due to osteonecrosis. Osteonecrosis can, therefore, be considered a risk factor for low bone density in children with acute lymphoblastic leukemia.

A phase ib study of safety and pharmacokinetics of ramucirumab in combination with paclitaxel in patients with advanced gastric adenocarcinomas.

LESSONS LEARNED: The pharmacokinetic results of this phase Ib study of ramucirumab combined with paclitaxel as second-line therapy in Japanese patients with metastatic gastric or gastro-esophageal junction adenocarcinoma are in line with previous ramucirumab studies.This combination at the doses and schedule given did not result in any dose-limiting toxicities and appeared to be safe and well tolerated. BACKGROUND: This phase Ib study evaluated the tolerability and pharmacokinetics of ramucirumab, an anti-VEGFR-2 antibody, combined with paclitaxel as second-line therapy in Japanese patients with metastatic gastric or gastroesophageal junction adenocarcinoma after first-line therapy with fluoropyrimidines and/or platinum. METHODS: Patients received ramucirumab 8 mg/kg on days 1 and 15 and paclitaxel 80 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. Safety analyses included all patients (n = 6). RESULTS: No dose-limiting toxicities occurred in the first cycle. All patients experienced ≥1 treatment-emergent adverse event (TEAE); 5 patients experienced grade ≥3 TEAEs. There were two deaths caused by disease progression. The best overall responses were stable disease (n = 5) and partial response (n = 1). Patients received ramucirumab and paclitaxel for a median of 12.5 weeks (range: 11.4-42.7 weeks) and 12.2 weeks (range: 11.0-41.0 weeks), respectively. Following a single dose of ramucirumab IV infusion 8 mg/kg, clearance was ∼0.017 L/hour, half-life (t1/2) was 138 to 225 hours, and steady-state volume of distribution (Vss) was ∼3 L. CONCLUSION: The ramucirumab/paclitaxel combination appears to be well-tolerated in Japanese patients with advanced gastric adenocarcinomas. These results are in line with previous ramucirumab pharmacokinetic studies as anticipated.

Phase 1/2 trials of Temozolomide, Motexafin Gadolinium, and 60-Gy fractionated radiation for newly diagnosed supratentorial glioblastoma multiforme: final results of RTOG 0513.

PURPOSE: The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls. METHODS AND MATERIALS: Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5 mg/kg was reached. Once MTD was established, a 1-sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48 months) with 60 deaths over a 12-month accrual period and an additional 18 months of follow-up. OS and PFS were estimated using the Kaplan-Meier method. RESULTS: In phase 1, 24 patients were enrolled. The MTD established was 5 mg/kg, given intravenously 5 days a week for the first 10 RT fractions, then 3 times a week for the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6 months (95% confidence interval [CI]: 12.9-17.6 months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6 months (95% CI: 5.7-9.6 months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy. CONCLUSIONS: Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.

Maintenance or Consolidation Therapy for Non--Small-Cell Lung Cancer: A Meta-Analysis Involving 5841 Subjects.

INTRODUCTION: Maintenance therapy is a new treatment paradigm for advanced non-small-cell lung cancer (NSCLC). We conducted a meta-analysis to evaluate its clinical efficacy in NSCLC and compared the efficacy of chemotherapy, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), and other treatment approaches. MATERIALS AND METHODS: Electronic databases were obtained from published reports of randomized controlled trials (RCTs) that compared maintenance or consolidation therapy with placebo, best supportive care (BSC) or just observation. Hazard ratios for progression-free survival (PFS) and overall survival (OS), with their relative 95% confidence intervals (CIs), were derived. All statistical analyses were conducted with RevMan 5.0 software, and statistical significance was defined as P < .05. RESULTS: A total of 14 RCTs involving 5841 patients were eligible for our analysis, including chemotherapy used in 5 RCTs, EGFR-TKI in 6, and others (eg, biotherapy) in 3. Our study showed that compared with the control, maintenance or consolidation therapy could prolong the OS (odds ratio [OR], 0.84; 95% CI, 0.75-0.95; P = .005) and PFS (OR, 0.63; 95% CI, 0.54-0.73; P < .00001) periods. Subgroup analysis showed that chemotherapy can improve PFS but not OS, EGFR-TKI can improve PFS and OS, and other therapies can improve neither PFS nor OS. CONCLUSION: Our meta-analysis demonstrated that maintenance therapy for advanced NSCLC patients can decrease the PFS risk to 0.63 and OS to 0.84. However, its clinical effect has yet to be confirmed by further studies.

Markedly improved outcomes and acceptable toxicity in adolescents and young adults with acute lymphoblastic leukemia following treatment with a pediatric protocol: a phase II study by the Japan Adult Leukemia Study Group.

The superiority of the pediatric protocol for adolescents with acute lymphoblastic leukemia (ALL) has already been demonstrated, however, its efficacy in young adults remains unclear. The ALL202-U protocol was conducted to examine the efficacy and feasibility of a pediatric protocol in adolescents and young adults (AYAs) with BCR-ABL-negative ALL. Patients aged 15-24 years (n=139) were treated with the same protocol used for pediatric B-ALL. The primary objective of this study was to assess the disease-free survival (DFS) rate and its secondary aims were to assess toxicity, the complete remission (CR) rate and the overall survival (OS) rate. The CR rate was 94%. The 5-year DFS and OS rates were 67% (95% confidence interval (CI) 58-75%) and 73% (95% CI 64-80%), respectively. Severe adverse events were observed at a frequency that was similar to or lower than that in children treated with the same protocol. Only insufficient maintenance therapy significantly worsened the DFS (hazard ratio 5.60, P<0.001). These results indicate that this protocol may be a feasible and highly effective treatment for AYA with BCR-ABL-negative ALL.

Safety and efficacy of decitabine in combination with temozolomide in metastatic melanoma: a phase I/II study and pharmacokinetic analysis.

BACKGROUND: Temozolomide (TMZ) is widely used for chemotherapy of metastatic melanoma. We hypothesized that epigenetic modulators will reverse chemotherapy resistance, and in this article, we report studies that sought to determine the recommended phase 2 dose (RP2D), safety, and efficacy of decitabine (DAC) combined with TMZ. PATIENTS AND METHODS: In phase I, DAC was given at two dose levels: 0.075 and 0.15 mg/kg intravenously daily × 5 days/week for 2 weeks, TMZ orally 75 mg/m(2) qd for weeks 2-5 of a 6-week cycle. The phase II portion used a two-stage Simon design with a primary end point of objective response rate (ORR). RESULTS: The RP2D is DAC 0.15 mg/kg and TMZ 75 mg/m(2). The phase II portion enrolled 35 patients, 88% had M1c disease; 42% had history of brain metastases. The best responses were 2 complete response (CR), 4 partial response (PR), 14 stable disease (SD), and 13 progressive disease (PD); 18% ORR and 61% clinical benefit rate (CR + PR + SD). The median overall survival (OS) was 12.4 months; the 1-year OS rate was 56%. Grade 3/4 neutropenia was common but lasted >7 days in six patients. CONCLUSIONS: The combination of DAC and TMZ is safe, leads to 18% ORR and 12.4-month median OS, suggesting possible superiority over the historical 1-year OS rate, and warrants further evaluation in a randomized setting.

The potential usage of caffeic acid phenethyl ester (CAPE) against chemotherapy-induced and radiotherapy-induced toxicity.

Protection of the patients against the side effects of chemotherapy and radiotherapy regimens has attracted increasing interest of clinicians and practitioners. Caffeic acid phenethyl ester (CAPE), which is extracted from the propolis of honeybee hives as an active component, specifically inhibits nuclear factor κB at micromolar concentrations and show ability to stop 5-lipoxygenase-catalysed oxygenation of linoleic acid and arachidonic acid. CAPE has antiinflammatory, antiproliferative, antioxidant, cytostatic, antiviral, antibacterial, antifungal and antineoplastic properties. The purpose of this review is to summarize in vivo and in vitro usage of CAPE to prevent the chemotherapy-induced and radiotherapy-induced damages and side effects in experimental animals and to develop a new approach for the potential usage of CAPE in clinical trial as a protective agent during chemotherapy and radiotherapy regimens.

Combination treatment with fulvestrant and various cytotoxic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) has a synergistic effect in estrogen receptor-positive breast cancer.

Patients with estrogen receptor (ER)-positive breast cancers have a better prognosis than those with ER-negative breast cancers, but often have low sensitivity to chemotherapy and a limited survival benefit. We have previously shown a combination effect of taxanes and fulvestrant and suggested that this treatment may be useful for ER-positive breast cancer. In this study, we evaluated the effects of combinations of hormone drugs and chemotherapeutic agents. In vitro, the effects of combinations of five chemotherapeutic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) and three hormone drugs (fulvestrant, tamoxifen, and 4-hydroxytamoxifen) were examined in ER-positive breast cancer cell lines using CalcuSyn software. Changes in chemoresistant factors such as Bcl2, multidrug resistance-associated protein 1, and microtubule-associated protein tau were also examined after exposure of the cells to hormone drugs. In vivo, tumor sizes in mice were evaluated after treatment with docetaxel or doxorubicin alone, fulvestrant alone, and combinations of these agents. Combination treatment with fulvestrant and all five chemotherapeutic agents in vitro showed synergistic effects. In contrast, tamoxifen showed an antagonistic effect with all the chemotherapeutic agents. 4-Hydroxytamoxifen showed an antagonistic effect with doxorubicin and 5-fluorouracil, but a synergistic effect with taxanes and vinorelbine. Regarding chemoresistant factors, Bcl2 and microtubule-associated protein tau were downregulated by fulvestrant. In vivo, a combination of fulvestrant and docetaxel had a synergistic effect on tumor growth, but fulvestrant and doxorubicin did not show this effect. In conclusion, fulvestrant showed good compatibility with all the evaluated chemotherapeutic agents, and especially with docetaxel, in vitro and in vivo.

Does dexamethasone inhibit the antineoplastic effect of cisplatin and docetaxel in head and neck cancer cells?

BACKGROUND/AIM: Comedication with glucocorticoids such as dexamethasone is frequently given to head and neck cancer patients treated with chemotherapy. However, an increasing body of evidence suggests that dexamethasone may induce resistance to antineoplastic agents. The present study was the first to investigate the effect of dexamethasone on the antiproliferative activity of cisplatin and docetaxel in vitro in squamous cell carcinoma of the head and neck (SCCHN) cell lines. MATERIALS AND METHODS: The cytotoxic effect of cisplatin and docetaxel on eight SCCHN cell lines was determined for each drug alone or with increasing concentrations of dexamethasone. Cell growth inhibition and viability were measured quantitatively after 24, 48, 72 hours of treatment using water-soluble-tetrazolium-test and lactate dehydrogenase assays. Absolute tumor cell numbers were determined by cell counting in a Rosenthal chamber. RESULTS: Cisplatin and docetaxel alone inhibited the growth of all eight SCCHN cell lines significantly (p=0.012). The antiproliferative activity of both agents was not decreased by the addition of dexamethasone in any of the cell lines (p>0.05). CONCLUSION: Dexamethasone does not interfere with the cytotoxic action of cisplatin or docetaxel in the investigated SCCHN cell lines.

Phase II trial of low-dose gemcitabine in prolonged infusion and cisplatin for advanced non-small cell lung cancer.

PURPOSE: To evaluate the efficacy and safety of the combination of gemcitabine at a low dose of 250 mg/m(2) in 6h prolonged infusion with cisplatin in chemonaive patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-eight chemonaive patients with stage IIIB or IV NSCLC were included, 39 males and 19 females, with a median age 61 years (range 28-73). Thirty-four (58.6%) patients had adenocarcinoma, 18 (31.0%) squamous cell, and 6 (10.4%) others. Seventeen (29.3%) had stage IIIB and 41 (70.7%) stage IV. Treatment consisted of 250 mg/m(2) gemcitabine in a 6h infusion on days 1 and 8, and cisplatin at 75 mg/m(2) on day 2 of a 3-week cycle. A total of 219 chemotherapy cycles were administered, with a median of 4 cycles per patient (range 1-6). RESULTS: Of the 58 patients enrolled, all were evaluated for toxicity and 56 assessed for response. The overall response rate was 39.3% (95% confidence interval, 26.5-52.1%) with complete and partial responses of 3.6 and 35.7%, respectively. The median time to disease progression was 5.5 months (95% CI, 4.3-6.7 months), and median overall survival time was 10.5 months (95% CI, 8.5-12.5 months). One-year survival rate was 41.4%. Hematologic toxicity was fairly mild, and grades 3-4 hematologic toxicities consisted of neutropenia in 18.9% of patients, thrombocytopenia in 10.3%, and anemia in 6.9%. No patients required platelet transfusions, no bleeding episodes were recorded, and three patients received packed red blood cells (RBC) transfusions. The main nonhematologic toxicities included grade 3 nausea/vomiting in 27.6% of patients, grade 1-2 alopecia in 63.8%, and grade 1-2 skin rash in 17.3 %. CONCLUSIONS: Low-dose gemcitabine in 6h prolonged infusion plus cisplatin is effective in NSCLC treatment. Toxicity, especially myelosuppression, is remarkably mild.

Phase I and pharmacologic study of sequential topotecan-carboplatin-etoposide in patients with extensive stage small cell lung cancer.

The inhibition of topoisomerase I by topotecan results in a compensatory increase in topoisomerase II associated with increased in vitro sensitivity of tumors to etoposide. Maximal synergy has been observed for the sequence of topotecan followed by etoposide. Carboplatin has clinical activity when combined with either of these two agents. These interactions were the pharmacologic rationale for topotecan p.o. days 1-5, carboplatin i.v. day 6, and etoposide p.o. days 6-10. Three successive dose levels were explored: (1) topotecan 2mg/day, carboplatin AUC 5, etoposide 150 mg/day; (2) topotecan 3mg/day, carboplatin AUC 5, etoposide 150 mg/day; and (3) topotecan 3mg/day, carboplatin AUC 5, etoposide 200mg/day. Filgrastim 5 microg/kg/day was injected s.c. days 11-18. Up to 6 cycles were administered every 21 days. Eligible patients had measurable or evaluable, extensive disease, small lung cell lung cancer, no prior chemotherapy, ECOG performance status 0-2, and adequate hematologic, renal, and hepatic function. Follow-up was weekly for CBC. Tumor response was assessed after 2 and 6 cycles. Dose limiting toxicity (DLT) was defined as any of the following in cycle 1: grade 3 or 4 non-hematologic toxicity other than nausea and vomiting, grade 4 neutropenia lasting more than 3 days, neutropenic fever or sepsis, grade 4 thrombocytopenia, or failure to recover neutrophils >or=1500/microl or platelets >or=100,000/microl by day 28. Ten patients were enrolled: median age 62 (range, 50-79); female/male 4/6; and performance status 0/1/2 in 2/7/1. Three patients each were treated on dose levels 1 and 2 without DLT. The first 2 patients entered on dose level 3 had no DLT. The third patient on dose level 3 developed grade 4 neutropenia lasting more than 3 days, neutropenic fever, and grade 4 thrombocytopenia on day 15 of cycle 1. The fourth patient on dose level 3 developed grade 4 thrombocytopenia on day 18 of cycle 1. One patient received only 1 cycle and was not evaluable for response. Seven patients completed 6 cycles: 1 had a complete response and 6 achieved a partial response. The third patient on dose level 3 received 2 cycles and had stable disease, but had to be removed from protocol treatment because of grade 4 neutropenia despite dose reduction in cycle 2. The fourth patient on dose level 3 achieved a partial response, but had to be removed from protocol therapy after cycle 5 because of recurrent grade 4 thrombocytopenia. In conclusion, neutropenia and thrombocytopenia were dose-limiting. The maximum tolerated dose (MTD) is topotecan 3mg/day p.o. days 1-5, carboplatin AUC 5i.v. day 6, and etoposide 150 mg/day p.o. days 6-10 with filgrastim.

Augmentation versus inhibition: effects of conjunctional OX-40 receptor monoclonal antibody and IL-2 treatment on adoptive immunotherapy of advanced tumor.

Therapeutic efficacy of adoptive immunotherapy of malignancies is proportional to the number of effector T cells transferred. Traditionally, exogenous IL-2 treatment has been used to promote the survival and function of transferred cells. Recently, we described the therapeutic effects of in vivo ligation of the costimulatory receptor, OX-40R, on activated T cells during early tumor growth. In this study, we examined the effects of IL-2 and OX-40R mAb on adoptive immunotherapy of advanced tumors. For treatment of 10-day 3-methylcholanthrene 205 pulmonary metastases, systemic transfer of 50 x 10(6) activated tumor-draining lymph node T cells resulted in >99% reduction of metastatic nodules. With either IL-2 or OX-40R mAb conjunctional treatment, only 20 x 10(6) cells were required. Advanced 10-day 3-methylcholanthrene 205 intracranial tumors could be cured by the transfer of 15 x 10(6) L-selectin(low) T cells derived from draining lymph nodes. In this situation, IL-2 administration inhibited therapeutic effects of the transferred cells. By contrast, 5 x 10(6) T cells were sufficient to cure all mice if OX-40R mAb was administrated. Studies on trafficking of systemically transferred T cells revealed that IL-2, but not OX-40R mAb, impeded tumor infiltration by T cells. Tumor regression required participation of both CD4 and CD8 T cells. Because only CD4 T cells expressed OX-40R at cell transfer, direct CD4 T cell activation is possible. Alternatively, OX-40R might be up-regulated on transferred T cells at the tumor site, rendering them reactive to the mAb. Our study suggests OX-40R mAb to be a reagent of choice to augment T cell adoptive immunotherapy in clinical trials.

[The clinical significance of MDR-1 gene expression in the hemopoietic cells of patients with acute leukemias in different phases of the disease]. / Klinicheskoe znachenie ékspressii gena MDR-1 v gemopoéticheskikh kletkakh bol'nykh ostrymy leikozami v raznykh fazakh zabolevaniia.

AIM: Analysis of cytostatic therapy effects on expression of gene MDR-1 in hemopoietic cells of patients with acute leukemia (AL) in complete clinicohematological remission (CCHR). MATERIALS AND METHODS: The study included 48 AL patients. 27 of them were untreated, 25 were resistant to or had recurrent AL. 4 patients were followed up. Bone marrow mononuclear fraction was investigated. Expression of MDR-1 gene in the cells was evaluated at hybridization. RESULTS: High expression of MDR-1 gene occurred in leukemic blast cells either upon achievement of CCHR or at least 6 months after its onset. When using schemes of chemotherapy containing two potential inductors of gene MDR-1, expression of this gene was registered significantly more frequently than in using schemes based on one inducing drug (p < 0.05). Frequency of occurrence of enhanced expression of gene MDR-1 in leukemic blasts significantly correlated with frequency of CCHR (p < 0.05). Correlation between occurrence of the gene's expression in normal hemopoietic cells in CCHR and occurrence of early AL recurrences was not found. CONCLUSION: The findings may facilitate design of new AL treatment programs.