Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab na?ve, recurrent glioblastoma

We evaluated the efficacy of carboplatin, irinotecan, and bevacizumab among bevacizumab-na?ve, recurrent glioblastoma (GBM) patients in a phase 2, open-label, single arm trial. Forty eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml-min) on day one, while bevacizumab (10 mg/kg) and irinotecan (340 mg/m(2) for patients on CYP3A-enzyme-inducing anti-epileptics [EIAEDs] and 125 mg/m(2) for patients not on EIAEDs) were administered on days 1 and 14 of every 28-day cycle. Patients were evaluated after each of the first two cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, non-compliance, or voluntary withdrawal. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints included safety and median overall survival (OS). All patients had progression after standard therapy. The median age was 51 years. Sixteen patients (40%) had a KPS of 90-100, while 27 (68%) were at first progression. The median time from original diagnosis was 11.4 months. The PFS-6 rate was 46.5% (95% CI: 30.4, 61.0%) and the median OS was 8.3 months [95% confidence interval (CI): 5.9, and 10.7 months]. Grade 4 events were primarily hematologic and included neutropenia and thrombocytopenia in 20 and 10%, respectively. The most common grade 3 events were neutropenia, thrombocytopenia, fatigue, and infection in 25, 20, 13, and 10%, respectively. Eleven patients (28%) discontinued study therapy due to toxicity and 17 patients (43%) required dose modification. One patient died due to treatment-related intestinal perforation. The addition of carboplatin and irinotecan to bevacizumab significantly increases toxicity but does not improve anti-tumor activity to that achieved historically with single-agent bevacizumab among bevacizumab-na?ve, recurrent GBM patients. (ClinicalTrials.gov number NCT00953121).     

Expression of E-cadherin, β-catenin and topoisomerase IIα in leiomyosarcomas

Introduction  

The expression of E-cadherin, β-catenin and topoisomerase II has been associated with clinical outcome of several cancers including sarcomas. We aimed to evaluate the expression of these markers in leiomyosarcomas (LMS).     

“Two-route chemotherapy” using cis-diamminedichloroplatinum(II) and its antidote,sodium thiosulfate,combined with angiotensin II is effective against peritoneally disseminated cancer in rats

Summary Two-route chemotherapy (TRC) using cis-diamminedichloroplatinum(II) (DDP) and its antidote, sodium thiosulfate (STS), combined with the angiotensin II (AT-II)-induced hypertension method was evaluated for its efficacy against peritoneally disseminated tumors in rats. A bolus i.p. injection of DDP (15 mg/kg) was given 1 min after the initiation of an AT-II (16.5 g/kg) i.v. infusion lasting 11 min. Immediately after the termination of the AT-II infusion, 1,580 mg/kg STS was injected i.v. over a further 5 min. This modified TRC significantly improved the antitumor effect, evaluated by survival (increase in life span, 273%), compared with that achieved with other treatments, as follows: 15 mg/kg DDP i.p. and the concomitant i.v. infusion of 1,580 mg/kg STS (conventional TRC), 153% increase in life span; 5 mg/kg DDP i.p. with or without AT-II i.v. (167% and 107% increases in life span, respectively). As an index of nephrotoxicity, blood urea nitrogen (BUN) levels seen after modified TRC (21.1 mg/dl) were as low as those observed after conventional TRC (19.1 mg/dl), despite the postadministration of STS, and were much lower than those seen after DDP alone or DDP plus AT-II (35.6 and 35.7 mg/dl, respectively). Further evaluation of the effectiveness of modified TRC using various doses of DDP gave similar results. The feasibility of the administration of STS 10 min after DDP treatment was explained by the significant inhibition of DDP delivery to the kidney during the AT-II-induced hypertension. Thus, TRC combined with AT-II has a superior therapeutic effect against peritonitis carcinomatosa induced in rats.Supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Education, Science and Culture, Japan     

Phase II Trial of Dose-dense Pemetrexed,Gemcitabine, and Bevacizumab in Patients With Advanced,Non–Small-cell Lung Cancer

Introduction

Platinum-based chemotherapy is standard for untreated, advanced non-small-cell lung cancer (NSCLC). We investigated the activity and tolerability of the novel combination of dose-dense pemetrexed, gemcitabine, and bevacizumab in patients with advanced NSCLC.

食管细胞学的定量研究：II.食管鳞状上皮正常,增生,癌变细胞...

The relative DNA contents of normal esophageal squamous epithelial cells, hyperplastic, dysplastic (grade I and II), nearly malignant and early malignant squamous epithelial cells of the esophagus were measured in 74 cases by microspectrophotometric technique. The results showed that from normal cells to early stage of malignancy, the DNA contents gradually increased with the increase in severity. In addition, the distribution of DNA values became broader; the peak DNA values shifted to the right, reduced and disappeared. In the meantime, aneuploid cells appeared. There was a definite positive correlation between DNA content and nuclear area in precancerous dysplasia (r greater than 0.9). The results indicate that the current grading of esophageal cytology has its quantitative biochemical basis.     

Predictive value of apoptosis,proliferation, HER-2, and topoisomerase IIα for anthracycline chemotherapy in locally advanced breast cancer

Purpose.Laboratory evidence indicates that tumor growth depends on the balance between cell proliferation and cell death, and many anticancer agents may exert their therapeutic effect by decreasing proliferation and increasing apoptosis. Additionally, clinical observations indicate that overexpression of HER-2 or topoisomerase IIα (topo IIα) may be predictors of better response to anthracyclines in breast cancer. The objective of this study was to determine if proliferation (Ki-67), apoptosis (TUNEL), and expression of HER-2 and topo IIα are affected by anthracycline treatment, and if these molecular markers predict anthracycline responsiveness.Experimental design.Thirty-three women with primary breast tumors ≥3 cm received either doxorubicin (75 mg/m²) or epirubicin (120 mg/m²) for 4 cycles before surgery. Clinical response was evaluated after 4 cycles of treatment. Changes in molecular markers were assessed from core needle taken before treatment (D0), at 24–48 h (Dl) and on day 7 (D7) while on treatment, and from the surgical specimen excised on day 84 (D84) after the fourth cycle of chemotherapy.Results.The overall response rate was 51% (17 of 33 patients), with a 12% complete clinical response rate (4 of 33 patients). There were trends for tumors with higher apoptosis and topo IIα at baseline (D0) to be more responsive to anthracyclines, p = 0.1 and p = 0.08, respectively. Median apoptosis increased from D0 to Dl (p = 0.06) while median Ki-67 decreased (p = 0.07). Overall, expression of HER-2 remained stable throughout the chemotherapy administration. By Day 84, topo IIα had significantly decreased from baseline in responders, while it increased in non-responders, p = 0.03.Conclusions.In human primary breast cancer, anthracycline treatment causes an early increase in apoptosis and a decrease in proliferation. In this pilot study, higher apoptosis and topo IIαa levels in primary tumors were associated with greater responsiveness to anthracyclines, and topo IIα levels declined in responsive tumors.     

Phase II study of MEDI-575, an anti-platelet-derived growth factor-α antibody,in patients with recurrent glioblastoma

MEDI-575, an immunoglobulin G2κ monoclonal antibody, selectively binds to platelet-derived growth factor-α receptor (PDGFR-α) with high specificity. This multicenter, single-arm, open-label, phase II study evaluated the efficacy and safety of MEDI-575 in patients with recurrent glioblastoma. Adults with first recurrence of glioblastoma following surgery, temozolomide, and radiation received MEDI-575 25 mg/kg intravenously over 60 min every 21 days until disease progression or unacceptable toxicity. Six-month progression-free survival rate (PFS-6) was the primary end point; secondary measures included response rate, overall survival (OS), and safety/tolerability. PDGFR-α expression was evaluated by immunohistochemistry. Fifty-six patients were enrolled; median age was 56.5 years (range 23–79), 66?% were male, and 66?% were aged ≥65 years. PFS-6 was 15.4?% [90?% confidence interval (CI) 8.1–24.9]. No complete or partial responses were observed; 23 (41.1?%) patients had stable disease as best response. Median PFS was 1.4 months (90?% CI 1.4, 1.8); median OS was 9.7 months (90?% CI 6.5, 11.8). The most common treatment-related adverse events (AEs) were diarrhea (16?%), nausea (13?%), and fatigue (13?%). Twelve (21?%) patients reported grade ≥3 AEs, with hydrocephalus (n?=?3), dysphagia (n?=?2), and convulsion (n?=?2) reported in more than 1 patient. Two patients had treatment-related Grade ≥3 AEs of decreased lymphocyte count and asthenia (n?=?1 each). Seven patients (13?%) discontinued MEDI-575 owing to AEs. Labeling of PDGFRα in glioblastoma cells and tumor-associated stromal cells was highly variable, with no correlation with PFS. MEDI-575, although well tolerated, had limited clinical activity in recurrent glioblastoma.     

A randomised, phase II study of intetumumab, an anti-αv-integrin mAb, alone and with dacarbazine in stage IV melanoma

Background:

α_v integrins are involved in angiogenesis and melanoma tumourigenesis. Intetumumab (CNTO 95) is a fully human anti-α_v-integrin monoclonal antibody.

Methods:

In a multicentre, randomised, phase II study, stage IV melanoma patients were randomised 1 : 1 : 1 : 1 to 1000 mg m⁻² dacarbazine+placebo (n=32), 1000 mg m⁻² dacarbazine+10 mg kg⁻¹ intetumumab (n=32), 10 mg kg⁻¹ intetumumab (n=33), or 5 mg kg⁻¹ intetumumab (n=32) q3w. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), adverse events, and pharmacokinetics.

Results:

No statistically significant differences in efficacy were observed between groups. In the dacarbazine+placebo, dacarbazine+intetumumab, 10 mg kg⁻¹ intetumumab, and 5 mg kg⁻¹ intetumumab groups, median PFS was 1.8, 2.5, 1.4, and 1.4 months; median OS was 8, 11, 15, and 9.8 months; and ORR of complete+partial response was 10, 3, 6, and 0%. Nonlinear intetumumab pharmacokinetics and potential intetumumab–dacarbazine interactions were observed. Transient, asymptomatic, nonrecurring, grade 1–2, uveitic reactions that resolved spontaneously or with topical steroids were seen in 22–30% of intetumumab-treated patients. Low-grade infusion-reaction symptoms (headache, fatigue, nausea, vomiting, fever, chills) were observed, as expected, in 16–73% of dacarbazine-treated patients. No intetumumab-related myelosuppression, laboratory/electrocardiogram abnormalities, or deaths occurred.

Conclusion:

With its favourable safety profile and a nonsignificant trend towards improved OS, intetumumab merits further investigation in advanced melanoma.     

Pioglitazone, etoricoxib, interferon-α, and metronomic capecitabine for metastatic renal cell carcinoma: final results of a prospective phase II trial

We enrolled 45 patients with metastatic renal cell carcinoma (RCC) at a progressive disease between March 2003 and April 2008 to assess the impact of an anti-inflammatory treatment regime in combination with metronomic low-dose chemotherapy. 42% of the patients had been systemically pre-treated. Therapy consisted of etoricoxib 60 mg daily plus pioglitazone 60 mg daily, day 1+, low-dose interferon-α 4.5 MU sc three times a week, week 1+ and low-dose capecitabine 1 g/m(2) twice daily orally for 14 days, every 3 weeks, day 1+, until disease progression. Objective response was observed in 35% of the patients (PR 27, CR 9%), which was paralleled by strong CRP decline for all patients with initially elevated CRP levels (n = 32). CRP values decreased from mean 42.3 mg/L (range 9.1-236), to 11.1 mg/L, (range 1.1-35.6), P = 0.006. Median overall survival and progression-free survival for the total cohort were 26.9 and 7.2 months for patients with elevated CRP 24.4 and 11.3 months (95% CI, 22.8-31.0/5.7-16.9) and 13.8-2.6 months (95% CI, 6.5-21.1/0.4-4.8) for the non-elevated CRP group, respectively (P = 0.082/0.017). Median observation time: 26.1 months; Overall survival at 5 years: 18%. Toxicity>WHO grade 3 was reported: Hand-foot syndrome in 16 patients (36%), diarrhea in 4, and pneumonia in 2 patients. Our data allow us to conclude that the control of tumor-associated inflammation is an important therapeutic principle in patients with metastatic RCC.     

Phase II Study of Cetuximab,Docetaxel, and Gemcitabine in Patients With Previously Untreated Advanced Non–Small-Cell Lung Cancer

BackgroundTargeting epidermal growth factor receptors (EGFRs) has been a novel strategy in treating non–small-cell lung cancer (NSCLC). This multicenter, community-based trial was designed to examine the role of cetuximab in combination with a nonplatinum regimen.Patients and MethodsEligibility criteria were newly diagnosed unresectable stage III/IV NSCLC, all histologies, measurable disease, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Treatment premedication included dexamethasone 20 mg orally 12 and 6 hours before treatment, and 4 mg 12 hours following treatment; diphenhydramine 50 mg intravenously (I.V.) and cimetidine 300 mg I.V. before cetuximab. Treatment medication included docetaxel 30 mg/m² I.V. days 1 and 8; gemcitabine 1000 mg/m² I.V. days 1 and 8; and cetuximab 400 mg/m² I.V. day 1, then 250 mg/m² I.V. weekly. Patients received up to 6 cycles with restaging every 6 weeks. The primary endpoint was an overall response rate (ORR) ≥ 25%.ResultsSixty-nine patients enrolled from July 2005 to October 2007. Patients had a median age of 69 years; 70% were male and 30% were female; ECOG PS was 0 in 42%, 1 in 51%, and 2 in 7%; patients had adenocarcinoma (42%), squamous cell (30%), large cell (6%), mixed (1%), and not otherwise specified (20%) disease. The ORR was 17% (95% CI, 9%-29%). Thirty-five patients (54%) had stable disease; 14 patients (22%) had progressive disease. With a median follow-up of 17.8 months, the median progression-free and overall survivals were 4 months and 9.4 months, respectively. The most common (> 10%) grade 3/4 toxicities were neutropenia (25%), rash (22%), and fatigue (12%). Accrual in our middle Tennessee offices was temporarily suspended and ultimately stopped because of a higher-than-anticipated rate of cetuximab-related severe hypersensitivity reactions (HSRs) in 4 patients among the first 12 enrolled, including 1 fatal event.ConclusionCetuximab/docetaxel/gemcitabine was relatively well-tolerated and associated with efficacy similar to chemotherapy alone. Additional study with cetuximab/chemotherapy in NSCLC should focus on new potentially predictive biomarkers. Also, additional study is needed to better understand and prevent the severe HSRs that appear to be endemic to specific regions of the United States.     

Reduced levels of topoisomerase IIα and IIβ in a multidrug-resistant lung-cancer cell line

We have previously shown that the doxorubicinselected multidrug-resistant small-cell lung-cancer cell line H69AR is resistant to VP-16-induced single-strand DNA breaks as compared with its parental H69 cell line. Levels of immunoreactive topoisomerase II are also reduced in H69AR cells. In the present study, we found that cleaved complex formation in the presence of VP-16 was decreased in H69AR cells as compared with H69 cells. In addition, the resistant cells contained lower levels of both topoisomerase II and topoisomerase II protein and mRNA. However, these changes were not accompanied by a decrease in the P4-unknotting (strand-passing) activity of 0.67M NaCl nuclear extracts of H69AR cells, nor was there any difference in VP-16 inhibition of unknotting activity in the H69 and H69AR nuclear extracts. These data suggest that reduced levels of topoisomerase II and II may contribute to the resistance of H69AR cells to VP-16 and other drugs that target these isoenzymes.This work was supported by a grant from the National Cancer Institute of Canada (to S. P. C. C.). One of the authors (C. D. E.) was supported in part by a Queen's University graduate fellowship, and another (S. P. C. C.) is a Career Scientist of the Ontario Cancer Treatment and Research Foundation     

Phase II Study of Topotecan and Bevacizumab in Advanced,Refractory Non–Small-Cell Lung Cancer

BackgroundThis clinical trial evaluated whether topotecan in combination with bevacizumab improved progression-free survival (PFS) in patients with advanced, refractory non–small-cell lung cancer in a second-line setting.Patient and MethodsPatients aged 18 years old and older received topotecan (4.0 mg/m²) on days 1, 8, and 15, and bevacizumab (10 mg/kg) on days 1 and 15 as intravenous infusions on a 28-day treatment cycle. Available tumor specimens were analyzed for ISG15 gene expression as a biomarker of response to topotecan.ResultsForty-two patients were enrolled in the study, with a median age of 62.5 years and a median of 3 (range, 1-7) prior treatment regimens. Almost half (n = 18, 42.9%) of the patients received prior bevacizumab therapy. PFS was 5.1 months (95% CI, 3.7-7.8 months), and overall survival was 11.5 months (95% CI, 6.8-15.5 months). Response rates were as follows: 14.3% partial response, 54.8% stable disease, and 28.6% progressive disease. Hematologic toxicities included grade 3 thrombocytopenia (n = 7, 16.7%), neutropenia (n = 4, 9.5%), and anemia (n = 2, 4.8%). One toxic death occurred due to pulmonary hemorrhage, and one patient experienced a grade 4 pulmonary embolism. Grade 3 nonhematologic adverse events were uncommon (< 8%). There was a trend for improved median PFS, 3.5 months vs. 1.8 months (P = .26), in patients with high ISG15 expression.ConclusionBevacizumab in combination with topotecan as a salvage therapy for metastatic non–small-cell lung cancer is well tolerated and is worthy of further investigation.     

Primary treatment of low-grade non-Hodgkin's lymphoma using an all oral anthracycline-containing regimen, chlorambucil, idarubicin, dexamethasone (CID) – a phase II study

Purpose: The alkylating cytostatic prodrug cyclophosphamide is bioactivated by the human cytochrome P450 enzyme system. Since these enzymes are not only expressed in human liver, but also in extrahepatic tissue, local bioactivation of this drug may play an important role in its antineoplastic effects, e.g., chemotherapy of lung tumors. This would require uptake of significant amounts of cyclophosphamide into tumor tissue, which has not yet been demonstrated. Methods: We used a recently developed, ex vivo isolated, ventilated and perfused human lung model to study cyclophosphamide uptake into bronchial carcinoma and healthy lung tissue. Following a standard lobectomy, lung samples containing the tumor were perfused with buffer containing 2 mM cyclophosphamide for 2 h. Cyclophosphamide concentrations in perfusate and healthy peripheral tissue were measured during the perfusion and in tumors at the end of perfusion. Results: In all tissue samples, cyclophosphamide uptake was relatively poor, indicated by a tissue to perfusate ratio of 0.021. Moreover, in tumor samples, cyclophosphamide concentrations were significantly lower (P < 0.05) than in healthy lung tissue and showed pronounced interindividual variability. Median concentrations were 36.8 μg/g (26.9–44.2 μg/g) in healthy tissue and 5.1 μg/g (0.0–26.8 μg/g) in tumor samples. Tumor cyclophosphamide concentrations varied between 0 and 75% of those reached in healthy tissue. Conclusions: Our results indicate that CP tumor concentrations are modulated by factors different from dose and that expression of bioactivating enzymes in human lung or transfection of genes encoding these enzymes into tumor cells does not necessarily lead to local bioactivation of cyclophosphamide. Received: 4 March 1999 / Accepted: 8 June 1999     

培洛霉素II期临床研究

为观察国产培洛霉素（ＰＥＰ）的疗效和毒副作用，对１３７例晚期癌症患者采用前瞻性多中心Ⅱ期临床研究。培洛霉素对头颈部肿瘤、恶性淋巴瘤和肺癌疗效较好，有效率分别为６６．７％、５０．０％和３０．０％。主要的毒副作用为发热、轻度胃肠道反应。联合用药采用与日本进口的同类产品对比研究，治疗组与对照组疗效相近，有效率分别为７１．６％和６６．７％（Ｐ〉０．０５），均高于单一用药。两药的疗效、毒副作用相似，国产培洛     

Who gets adjuvant treatment for stage II and III rectal cancer? Insight from surveillance, epidemiology, and end results--Medicare.

PURPOSE: To examine the relationship between patient characteristics and the use of adjuvant pelvic radiation with and without chemotherapy among patients aged 65 years and older with stage II and III rectal cancer. PATIENTS AND METHODS: A retrospective cohort study using the Surveillance, Epidemiology, and End Results-Medicare linked database identified 1,411 patients aged 65 and older with resected stage II and III rectal cancers diagnosed between 1992 and 1996. From claims submitted to Medicare, we measured the use of pelvic radiation therapy with or without chemotherapy and pre- or postoperatively. RESULTS: Fifty-seven percent of patients received radiation, 42% received chemotherapy and radiation, and 7% had treatment delivered preoperatively. Age was the strongest determinant of treatment: 73% of patients aged 65 to 69, 66% aged 70 to 75, 52% aged 75 to 79, 39% aged 80 to 84, and 21% aged 85 to 89 received radiation. The age trend remained strong after adjusting for other factors that predict receipt of treatment and after exclusion of patients with any evident comorbidity (P <.001). Patients were more likely to receive radiation treatment if they had an abdominal perineal resection, stage III disease, or a T4 tumor. CONCLUSION: Because pelvic recurrences are a substantial cause of morbidity, further efforts are needed to ensure that elderly patients have the opportunity to make informed decisions regarding adjuvant treatment.