The aim of the study is to demonstrate that intrapatient dose escalation of carboplatin would improve the outcome in ovarian cancer compared with flat dosing.
Patients and methods
Patients with untreated stage IC-IV ovarian cancer received six cycles of carboplatin area under the curve 6 (AUC 6) 3 weekly either with no dose modification except for toxicity (Arm A) or with dose escalations in cycles 2–6 based on nadir neutrophil and platelet counts (Arm B). The primary end-point was progression-free survival (PFS).
Nine hundred and sixty-four patients were recruited from 71 centers. Dose escalation was achieved in 77% of patients who had ≥1 cycle. The median AUCs (cycle 2–6) received were 6.0 (Arm A) and 7.2 (Arm B) (P < 0.001). Grade 3/4 non-hematological toxicity was higher in Arm B (31% versus 22% P = 0.001). The median PFS was 12.1 months in Arm A and B [hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.85–1.15; P = 0.93]. The median overall survival (OS) was 34.1 and 30.7 months in Arms A and B, respectively (HR 0.98; 95% CI 0.81–1.18, P = 0.82). In multivariate analysis, baseline neutrophil (P < 0.001), baseline platelet counts (P < 0.001) and the difference between white blood cell (WBC) and neutrophil count (P = 0.009) had a significant adverse prognostic value.
Intrapatient dose escalation of carboplatin based on nadir blood counts is feasible and safe. However, it provided no improvement in PFS or OS compared with flat dosing. Baseline neutrophils over-ride nadir counts in prognostic significance. These data may have wider implications particularly in respect of the management of chemotherapy-induced neutropenia.
carboplatin; dose escalation; myelosuppresssion; ovarian cancer
Owing to the increasing prevalence of obesity and diabetes in Asia, and the paucity of studies, we examined the influence of raised blood glucose and diabetes on cancer mortality risk.
Thirty-six cohort Asian and Australasian studies provided 367,361 participants (74% from Asia); 6% had diabetes at baseline. Associations between diabetes and site-specific cancer mortality were estimated using time-dependent Cox models, stratified by study and sex, and adjusted for age.
During a median follow-up of 4.0 years, there were 5,992 deaths due to cancer (74% Asian; 41% female). Participants with diabetes had 23% greater risk of mortality from all-cause cancer compared with those without: hazard ratio (HR) 1.23 (95% CI 1.12, 1.35). Diabetes was associated with mortality due to cancer of the liver (HR 1.51, 95% CI 1.19, 1.91), pancreas (HR 1.78, 95% CI 1.20, 2.65), and, less strongly, colorectum (HR 1.32, 95% CI 0.98, 1.78). There was no evidence of sex- or region-specific differences in these associations. The population attributable fractions for cancer mortality due to diabetes were generally higher for Asia compared with non-Asian populations.
Diabetes is associated with increased mortality from selected cancers in Asian and non-Asian populations.
Diabetes Mellitus; Cancer Mortality; Epidemiology; Asia-Pacific
The observation that taller people experience an increased risk of selected cancers is largely restricted to Caucasian cohorts. These associations may plausibly differ in Asian populations. For the first time, we make direct comparison of the associations between height and a series of malignancies in Australasian (Caucasian) and Asian populations.
Analyses were based on the Asia Pacific Cohort Studies Collaboration of 506, 648 male and female study participants (408,381 Asia, 98267 Australasia) drawn from 38 population-based cohort studies. Cox proportional hazards regression was used to estimate the relationship between height and cancer rates.
A total of 3,272,600 person years of follow-up gave rise to 7497 cancer deaths (5232 in men, 2265 in women). After multiple adjustments and left censoring, taller individuals experienced increased rates of carcinoma of the intestine (men and women); all cancers, liver, lung, breast, ‘other’ malignancies (all women); and prostate and bladder (men). No consistent regional (Asia vs. Australasia) or sex-differences were observed.
In the present study, taller men and women had an elevated risk of selected malignancies. These associations did not differ appreciably between Asian and Caucasian populations.
Asia; body height; stature; cancer; malignancy
Patients and methods
We present a retrospective analysis of 99 consecutive patients with relapsed non-Hodgkin’s lymphomas who were older than 65 years at the time of high-dose chemotherapy and autologous progenitor cell transplantation.
Median age at transplant was 68 years (range 65–82). Thirty-six percent of patients had a hematopoietic cell transplantation comorbidity index of >2 at the time of transplantation. The cumulative nonrelapse mortality was 8% [95% confidence interval (CI) 4–17] at 26 months and the 3-year overall survival (OS) was 61% (95% CI 49–71). On multivariate analysis, disease status at transplant and lactate dehydrogenase (LDH) > normal were significant predictors for OS (P = 0.002). Comorbidity index of >2 did not impact OS but did predict for higher risk of developing grade 3–5 toxicity (P = 0.006). Eight patients developed secondary myelodysplastic syndrome/acute myelogenous leukemia after transplantation (cumulative incidence 16%).
Patients with relapsed lymphomas who are >65 years of age should be considered transplant candidates, particularly if they have chemosensitive disease and normal LDH levels at the time of transplantation. Patients with comorbidity index of >2 can also undergo transplantation with acceptable outcomes but may be at higher risk for developing toxicity.
autologous transplant; elderly; non-Hodgkin’s lymphoma
Troxacitabine is a novel L-nucleoside analogue. Preclinical studies showed improved activity with infusions of at least 3 days compared with bolus regimens, especially at concentrations >20 ng/ml. This phase I study tested the feasibility of achieving a troxacitabine steady-state concentration of 20 ng/ml for at least 72 h in patients with solid tumors.
Patients and methods
Patients with solid tumors received troxacitabine as a progressively longer infusion on days 1–4 of a 28-day cycle. The initial length of infusion and infusion rate were 48 h and 3 mg/m2/day.
Twenty-one patients were treated at infusion lengths that increased from 48 to 72 h and then 96 h. The infusion rate was decreased from 3 to 1.88 mg/m2/day due to toxicity. Dose-limiting toxicities consisted of grade 4 neutropenia (three) and grade 3 constipation (one). The maximum tolerated dose of continuous infusion troxacitabine in patients with solid tumors is 7.5 mg/m2 administered over 96 h. This dose level resulted in steady-state drug concentration of at least 20 ng/ml for 72 h.
Administration of troxacitabine by continuous infusion achieved the prospectively defined target plasma concentration. Pharmacokinetics (PK) modeling coupled with real-time PK assessment was an efficient approach to conduct hypothesis-driven phase I trials.
continuous infusion; PK modeling; troxacitabine
Pancreatic carcinoma remains a treatment-refractory cancer with a poor prognosis. Here, we compared anti-EGF receptor and anti-HER2 monoclonal antibodies (2mAbs) injections with standard gemcitabine treatment on human pancreatic carcinoma xenografts.
Materials and Methods
Nude mice, bearing human pancreatic carcinoma, xenografts, were treated with either combined anti-EGFR (cetuximab) and anti-HER2 (trastuzumab), or gemcitabine and tumor growth were observed.
Results and Conclusion
In first-line therapy, mice survival was significantly longer in 2mAbs groups compared to gemcitabine (p<0.0001: BxPC-3; p=0.0679: MiaPaCa-2; p=0.0019: Capan-1) and to controls (p<0.0001). In second-line therapy tumor regressions were observed after replacing gemcitabine by 2mAbs treatment, resulting in significantly longer animal survival, compared with mice receiving continuous gemcitabine injections (p=0.008, BxPC-3; p=0.05; MiaPaCa-2; p<0.001, Capan-1). Therapeutic benefit of 2mAbs was observed, despite K-Ras mutation. Interestingly, concerning the mechanism of action, coinjection of F(ab)′2 fragments from 2mAbs induced significant tumor growth inhibition, compared to controls (p=0.001), indicating that the 2mAbs had an, Fc-independent, direct action on tumor cells.
This pre-clinical study demonstrated a significant improvement of survival and tumour regression in mice treated with anti-EGFR/anti-HER2 2mAbs in first and second-line treatments, compared to gemcitabine, independently of the K-Ras status.
Animals; Antibodies, Monoclonal; administration & dosage; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; therapeutic use; Blotting, Western; Cell Line, Tumor; Deoxycytidine; analogs & derivatives; therapeutic use; Female; Humans; Immunohistochemistry; Mice; Mice, Nude; Pancreatic Neoplasms; drug therapy; Receptor, Epidermal Growth Factor; antagonists & inhibitors; immunology; Receptor, erbB-2; antagonists & inhibitors; immunology; Xenograft Model Antitumor Assays; EGFR; gemcitabine; HER2; monoclonal antibodies; pancreatic carcinoma
The epithelial-mesenchymal transition (EMT) describes a rapid and often reversible modulation of phenotype by epithelial cells. EMT was originally defined in the context of developmental stages, including heart morphogenesis, mesoderm and neural crest formation. Epithelial cells loosen cell-cell adhesion structures throughout EMT. They modulate their polarity, cytoskeleton organization and typically express vimentin filaments and downregulate cytokeratins. They become isolated, mobile and resistant to anoikis. The epithelial-mesenchymal transition at least superficially resembles the evolution from normal to transformed cell phenotype during carcinoma progression. The relevance of the concept of epithelial-mesenchymal transition in this context was suggested by in vitro models using transformed epithelial cells. Transduction pathways typical for embryogenic EMT in vivo were also found to be activated during cancer progression. More recently, it has been found that such pathways suggest an increased plasticity linked to cellular stemness and ability to generate tumors. However, in the absence of direct evidence, a number of oncologists and pathologists remain skeptical about applying the EMT concept to human tumor progression. In fact, EMT concept appears to be fully relevant in some situations, but the concept has to be adjusted in other situations to reflect tumor cell renewal and plasticity during carcinoma progression and metastasis.
Animals; Cell Dedifferentiation; physiology; Epithelial-Mesenchymal Transition; physiology; Female; Humans; Mammary Neoplasms, Experimental; pathology; Mice; Neoplasms; etiology; pathology; Epithelium; differentiation; morphogenesis; invasiveness; apoptosis
Low tumour expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) have been linked with improved outcome for colorectal cancer (CRC) patients treated with 5-fluorouracil (5-FU). It is unclear whether this occurs because such tumours have better prognosis or they are more sensitive to 5-FU treatment.
Patients and methods
Associations between TS, DPD and TP levels, determined by tissue microarrays and immunohistochemistry, and survival was evaluated in 945 CRC patients according to treatment status.
Low TS and DPD expression associated with worse prognosis in stage II [hazard ratio (HR) = 1.69, 95% confidence interval (CI) (1.09–2.63) and HR = 1.92 (95% CI 1.23–2.94), respectively] and stage III CRC patients treated by surgery alone [HR = 1.39 (95% CI 0.92–2.13) and HR = 1.49 (95% CI 1.02–2.17), respectively]. Low TS, DPD and TP associated with trends for better outcome in stage III patients treated with 5-FU [HR = 0.81 (95% CI 0.49–1.33), HR = 0.70 (95% CI 0.42–1.15) and HR = 0.66 (95% CI 0.39–1.12), respectively].
Low TS and DPD expression are prognostic for worse outcome in CRC patients treated by surgery alone, whereas low TS, DPD and TP expression are prognostic for better outcome in patients treated with 5-FU chemotherapy. These results provide indirect evidence that low TS, DPD and TP protein expression are predictive of good response to 5-FU chemotherapy.
colorectal cancer; fluorouracil; predictive; prognostic; thymidylate synthase
Background: To determine the maximum tolerated dose (MTD), safety, potential pharmacokinetic (PK) interactions, and effect on liver histology of trabectedin in combination with pegylated liposomal doxorubicin (PLD) for advanced malignancies.
Patients and methods: Entry criteria for the 36 patients included normal liver function, prior doxorubicin exposure <250 mg/m2, and normal cardiac function. A 1-h PLD (30 mg/m2) infusion was followed immediately by one of six trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m2) infused over 3 h, repeated every 21 days until evidence of complete response (CR), disease progression, or unacceptable toxicity. Plasma samples were obtained to assess PK profiles.
Results: The MTD of trabectedin was 1.1 mg/m2. Drug-related grade 3 and 4 toxic effects were neutropenia (31%) and elevated transaminases (31%). Six patients responded (one CR, five partial responses), with an overall response rate of 16.7%, and 14 had stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) >4 months (39%). Neither drug had its PK affected significantly by concomitant administration compared with trabectedin and PLD each given as a single agent.
Conclusion: Trabectedin combined with PLD is generally well tolerated at therapeutic doses of both drugs in pretreated patients with diverse tumor types and appears to provide clinical benefit. These results support the need for additional studies of this combination in appropriate cancer types.
ET-743; ovarian cancer; pegylated liposomal doxorubicin (PLD); sarcomas; trabectedin
To determine the maximum tolerated dose (MTD), safety, potential pharmacokinetic (PK) interactions, and effect on liver histology of trabectedin in combination with pegylated liposomal doxorubicin (PLD) for advanced malignancies.
Patients and Methods
Entry criteria for the 36 patients included normal liver function, prior doxorubicin exposure <250 mg/m2, and normal cardiac function. A 1-hour PLD (30 mg/m2) infusion was followed immediately by 1 of 6 trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m2) infused over 3 hours, repeated every 21 days until evidence of complete response (CR), disease progression, or unacceptable txicity. Plasma samples were obtained to assess PK profiles.
The MTD of trabectedin was 1.1 mg/m2. Drug-related grade 3 and 4 toxicities were neutropenia (31%) and elevated transaminases (31%). Six patients responded (1 CR, 5 partial responses), with an overall response rate of 16.7%, and 14 had stable disease >4 months (39%). Neither drug had its PK affected significantly by concomitant administration compared to trabectedin and PLD each given as a single agent.
Trabectedin combined with PLD is generally well tolerated at therapeutic doses of both drugs in pretreated patients with diverse tumor types, and appears to provide clinical benefit. These results support the need for additional studies of this combination in appropriate cancer types.
trabectedin; ET-743; pegylated liposomal doxorubicin (PLD); sarcomas; ovarian cancer