Effect of alternative temozolomide schedules on glioblastoma O6-methylguanine-DNA methyltransferase activity and survival

Background:

O⁶-methylguanine-DNA methyltransferase (MGMT) expression in glioblastoma correlates with temozolomide resistance. Dose-intense temozolomide schedules deplete MGMT activity in peripheral blood mononuclear cells; however, no published data exist evaluating the effect of temozolomide schedules on intracranial tumour MGMT activity.

Methods:

Human glioblastoma cells (GBM43) with an unmethylated MGMT promoter were implanted intracranially in immunodeficient rodents. Three weeks later, animals received temozolomide 200 mg m⁻² for 5 days (schedule A, standard dose) or 100 mg m⁻² for 21 days (schedule B, dose intense).

Results:

Tumour MGMT activity was depleted by day 6 in both treatment groups compared with baseline. O⁶-methylguanine-DNA methyltransferase activity returned to baseline by day 22 in the schedule A group, but remained suppressed in the schedule B group. By day 29, MGMT activity had returned to baseline in both groups. Mean tumour volume was significantly decreased compared with untreated controls with either schedule (P<0.01), although neither schedule was superior (P=0.60). Median survival was 64, 42, and 28 days for schedule A, schedule B, and no drug, respectively (P<0.001 A or B vs control, P=NS A vs B).

Conclusions:

Dose-intense temozolomide prolongs tumour MGMT activity depletion compared with standard dosing, however, survival was not improved in this model.     

Optimizing CIGB-300 intralesional delivery in locally advanced cervical cancer

Background:

We conducted a phase 1 trial in patients with locally advanced cervical cancer by injecting 0.5 ml of the CK2-antagonist CIGB-300 in two different sites on tumours to assess tumour uptake, safety, pharmacodynamic activity and identify the recommended dose.

Methods:

Fourteen patients were treated with intralesional injections containing 35 or 70 mg of CIGB-300 in three alternate cycles of three consecutive days each before standard chemoradiotherapy. Tumour uptake was determined using ⁹⁹Tc-radiolabelled peptide. In situ B23/nucleophosmin was determined by immunohistochemistry.

Results:

Maximum tumour uptake for CIGB-300 70-mg dose was significantly higher than the one observed for 35 mg: 16.1±8.9 vs 31.3±12.9 mg (P=0.01). Both, AUC_24h and biological half-life were also significantly higher using 70 mg of CIGB-300 (P<0.001). Unincorporated CIGB-300 diffused rapidly to blood and was mainly distributed towards kidneys, and marginally in liver, lungs, heart and spleen. There was no DLT and moderate allergic-like reactions were the most common systemic side effect with strong correlation between unincorporated CIGB-300 and histamine levels in blood. CIGB-300, 70 mg, downregulated B23/nucleophosmin (P=0.03) in tumour specimens.

Conclusion:

Intralesional injections of 70 mg CIGB-300 in two sites (0.5 ml per injection) and this treatment plan are recommended to be evaluated in phase 2 studies.     

Influencing surgical management in patients with carcinoma of the cervix using a T2- and ZOOM-diffusion-weighted endovaginal MRI technique

Background:

Endovaginal MRI (evMRI) at 3.0-T with T2-weighted (T2-W) and ZOnal Oblique Multislice (ZOOM)-diffusion-weighted imaging (DWI) potentially improves the detection of stage Ia/Ib1 cervical cancer. We aimed to determine its sensitivity/specificity, document tumour-to-stromal contrast and establish the effect of imaging on surgical management.

Methods:

Following ethical approval and written informed consent, 57 consecutive patients with suspected stage Ia/Ib1 cervical cancer underwent evMRI at 3.0-T using T2-W and ZOOM-DWI. Sensitivity/specificity were calculated against histopathology for two independent observers. Tumour-to-stromal contrast was determined on T2-W, and diffusion-weighted (b=800 s mm⁻²) images and apparent diffusion coefficients (ADCs) were recorded. In patients due for radical vaginal trachelectomy (RVT), change of surgical management based on imaging findings was documented.

Results:

Sensitivity/specificity for detecting tumour was the following: reporting read 88.0/81.8%, anonymised read 92.0/81.8% (observer 1); 84.0/72.7% (observer2; median tumour volume=1.7 cm³). Intraobserver agreement was excellent (kappa=0.89) and the interobserver agreement was good (kappa=0.65). Tumour-to-stromal contrast was greater on ZOOM-DWI compared with T2-W images (3.35±2.36 vs 1.39±0.95; P<0.0004). Tumour and stromal ADCs were significantly different (P<0.00001). In 31 patients due for RVT, evMRI altered surgical management in 12 (38.7%) cases (10 cone-biopsy, 2 chemoradiotherapy).

Conclusion:

T2-W+ZOOM-DWI evMRI has high sensitivity/specificity for detecting stage Ia/Ib1 cervical tumours; in patients due for RVT, the surgical management was altered in ∼39%.     

Dual inhibition of epidermal growth factor and insulin-like 1 growth factor receptors reduce intestinal adenoma burden in the Apc(min/+) mouse

Background:

Identification of early molecular pathway changes may be useful as biomarkers for tumour response/resistance prediction, and here we provide direct in vivo proof of this concept. The type 1 insulin-like growth factor receptor (IGF1R) has been implicated in various aspects of adenoma development and metastasis. We show here that, in murine intestinal adenomas acutely exposed to a small molecular inhibitor of EGFR (gefitinib), there is concurrent suppression of EGFR downstream signalling and induction of IGF signalling. We therefore tested the hypothesis that blockade of EGFR signalling was being tempered by compensatory activation of the IGF pathway by examining the effect of chronic suppression of IGF1R using AZ12253801, a small molecular tyrosine kinase inhibitor of IGF1R.

Methods:

Male Apc^min/+ mice with an intestinal tumour burden were exposed to a single dose of an inhibitor against EGFR (gefitinib), IGF1R (AZ12253801), 0.5% Tween 80 or combined EGFR/IGF1R inhibitor and culled 4 h post dosing. Tumour tissue was analysed to detect the early molecular pathways induced and anti-tumour phenotypic changes. Cohorts of male Apc^min/+ mice (n=15–17) were subsequently treated with gefitinib for a period of 8 weeks and subsequently exposed to single (either gefitinib or AZ12253801) or combined (gefitinib and AZ12253801) therapy. We also included a vehicle-treated cohort, which was never exposed to gefitinib and became symptomatic of the disease by day 150.

Results:

Both single treatments delayed the onset of disease symptoms. Combined dosing with gefitinib and AZ12253801 similarly delayed the onset of symptoms, and at 200 days suppressed small intestinal tumourigenesis more effectively than either treatment alone (median small intestinal adenoma volume (47 mm³ (comb) vs 248 mm³ (AZ12253801), P=0.0003 and 47 mm³ (comb) vs 123 mm³ (gefitinib), P=0.0042, Mann–Whitney (two-sided) test).

Conclusion:

Our data provide evidence in support of the use of combinatorial therapy, and establishes the need to further define the precise benefit in vivo.     

Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma

Background:

Sorafenib is the only drug approved for the treatment of hepatocellular carcinoma (HCC). The bioenergetic propensity of cancer cells has been correlated to anticancer drug resistance, but such correlation is unclear in sorafenib resistance of HCC.

Methods:

Six sorafenib-naive HCC cell lines and one sorafenib-resistant HCC cell line (Huh-7R; derived from sorafenib-sensitive Huh-7) were used. The bioenergetic propensity was calculated by measurement of lactate in the presence or absence of oligomycin. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, and siRNA of hexokinase 2 (HK2) were used to target relevant pathways of cancer metabolism. Cell viability, mitochondrial membrane potential, and sub-G1 fraction were measured for in vitro efficacy. Reactive oxygen species (ROS), adenosine triphosphate (ATP) and glucose uptake were also measured. A subcutaneous xenograft mouse model was used for in vivo efficacy.

Results:

The bioenergetic propensity for using glycolysis correlated with decreased sorafenib sensitivity (R²=0.9067, among sorafenib-naive cell lines; P=0.003, compared between Huh-7 and Huh-7 R). DCA reduced lactate production and increased ROS and ATP, indicating activation of oxidative phosphorylation (OXPHOS). DCA markedly sensitised sorafenib-resistant HCC cells to sorafenib-induced apoptosis (sub-G1 (combination vs sorafenib): Hep3B, 65.4±8.4% vs 13±2.9% Huh-7 R, 25.3± 5.7% vs 4.3±1.5% each P<0.0001), whereas siRNA of HK2 did not. Sorafenib (10 mg kg⁻¹ per day) plus DCA (100 mg kg⁻¹ per day) also resulted in superior tumour regression than sorafenib alone in mice (tumour size: −87% vs −36%, P<0.001).

Conclusion:

The bioenergetic propensity is a potentially useful predictive biomarker of sorafenib sensitivity, and activation of OXPHOS by PDK inhibitors may overcome sorafenib resistance of HCC.     

Early expression of the fractalkine receptor CX3CR1 in pancreatic carcinogenesis

Background:

In pancreatic ductal adenocarcinoma (PDAC), fractalkine receptor CX3CR1 contributes to perineural invasion (PNI). We investigated whether CX3CR1 expression occurs early in PDAC and correlates with tumour features other than PNI.

Methods:

We studied CX3CR1 and CX3CL1 expression by immunohistochemistry in 104 human PDAC and coexisting Pancreatic Intraepithelial Neoplasia (PanIN), and in PdxCre/LSL-Kras^G12D mouse model of PDAC. CX3CR1 expression in vitro was studied by a spheroid model, and in vivo by syngenic mouse graft of tumour cells.

Results:

In total, 56 (53.9%) PDAC expressed CX3CR1, 70 (67.3%) CX3CL1, and 45 (43.3%) both. CX3CR1 expression was independently associated with tumour glandular differentiation (P=0.005) and PNI (P=0.01). Pancreatic Intraepithelial Neoplasias were more frequently CX3CR1+ (80.3%, P<0.001) and CX3CL1+ (86.8%, P=0.002) than matched cancers. The survival of PDAC patients was better in those with CX3CR1+ tumour (P=0.05). Mouse PanINs were also CX3CR1⁺ and -CL1⁺. In vitro, cytokines significantly increased CX3CL1 but not CX3CR1 expression. Differently, CX3CR1 was upregulated in tumour spheroids, and in vivo only in well-differentiated tumours.

Conclusion:

Tumour differentiation, rather than inflammatory signalling, modulates CX3CR1 expression in PanINs and PDAC. CX3CR1 expression pattern suggests its early involvement in PDAC progression, outlining a potential target for interfering with the PanIN transition to invasive cancer.     

Insulin-like growth factors and liver cancer risk in male smokers

Background:

The liver is the primary source of circulating insulin-like growth factor (IGF)-I, yet the relation between IGFs and liver cancer is uncertain.

Methods:

In a case–cohort study within a cohort of 29 133 male smokers we examined associations of serum IGF-I and IGF binding protein (IGFBP)-3 with liver cancer (50 cases).

Results:

Nonlinear associations between liver cancer and IGF-I and IGFBP-3 were observed (P=0.04 and P<0.01, respectively), strongest association at lowest levels (odds ratio (OR)=0.2, 95% confidence interval (CI)=0.1–0.7 for 80 vs 30 ng ml⁻¹ of IGF-I; OR=0.2, 95% CI=0.1–0.6 for 1400 vs 700 ng ml⁻¹ of IGFBP-3).

Conclusions:

Low IGF-I and IGFBP-3 levels in male smokers are associated with increased risk of liver cancer.     

Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results

Background:

Radiolabelled antibody targeting of cancer is limited by slow blood clearance. Pretargeting with a non-radiolabelled bispecific monoclonal antibody (bsMAb) followed by a rapidly clearing radiolabelled hapten peptide improves tumour localisation. The primary goals of this first pretargeting study in patients with the anti-CEACAM5 × anti-hapten (HSG) bsMAb, TF2, and the radiolabelled hapten-peptide, IMP288, were to assess optimal pretargeting conditions and safety in patients with metastatic colorectal cancer (CRC).

Methods:

Different dose schedules were studied in four cohorts of five patients: (1) shortening the interval between the bsMAb and peptide administration (5 days vs 1 day), (2) escalating the TF2 dose (from 75 to 150 mg), and (3) reducing the peptide dose (from 100 to 25 μg). After confirmation of tumour targeting by ¹¹¹In-IMP288, patients were treated with a bsMAb/¹⁷⁷Lu-IMP288 cycle.

Results:

Rapid and selective tumour targeting of the radiolabelled peptide was visualised within 1 h, with high tumour-to-tissue ratios (>20 at 24 h). Improved tumour targeting was achieved with a 1-day interval between the administration of the bsMAb and the peptide and with the 25-μg peptide dose. High ¹⁷⁷Lu-IMP288 doses (2.5–7.4 GBq) were well tolerated, with some manageable TF2 infusion reactions, and transient grades 3–4 thrombocytopaenia in 10% of the patients who received ¹⁷⁷Lu-IMP288.

Conclusion:

This phase I study demonstrates for the first time that pretargeting with bsMAb TF2 and radiolabelled IMP288 in patients with CEA-expressing CRC is feasible and safe. With this pretargeting method, tumours are specifically and rapidly targeted.     

Comparisons of vaginal and abdominal radical trachelectomy for early-stage cervical cancer: preliminary results of a multi-center research in China

Background:

There are limited data comparing the prognosis and fertility outcomes of the patients with early cervical cancer treated by trans-vaginal radical trachelectomy (VRT) or abdominal radical trachelectomy (ART).The objective of this study was to compare the surgical and pathologic characteristics, the prognosis and fertility outcomes of the patients treated by VRT or ART.

Methods:

Matched-case study based on a prospectively maintained database of patients underwent radical trachelectomy in 10 centres of China was designed to compare the prognosis and fertility outcomes of the patients treated by VRT or ART.

Results:

Totally 150 cases, 77 in the VRT and 73 in the ART group, were included. VRT and ART provide similar surgical and pathological outcomes except larger specimens obtained by ART. In the ART group, no patient developed recurrent diseases, but, in the VRT group, 7 (9.8%) patients developed recurrent diseases and 2 (1.6%) patients died of the tumours (P=0.035). The rate of pregnancy in the VRT group was significantly higher than those of ART (39.5% vs 8.8% P=0.003). The patients with tumour size >2 cm showed significant higher recurrent rate (11.6% vs 2.4%, P<0.05) and lower pregnant rate (12.5% vs 32.1%, P=0.094) compared with the patients with tumour size <2 cm.

Conclusion:

Patients treated by ART obtained better oncology results, but their fertility outcomes were unfavourable compared with VRT. Tumour size <2 cm should be emphasised as an indication for radical trachelectomy for improving the outcome of fertility and prognosis.     

Prediction of vascular invasion in hepatocellular carcinoma by next-generation des-r-carboxy prothrombin

Background:

In hepatocellular carcinoma (HCC), des-r-carboxy prothrombin (DCP) more accurately reflects the malignant potential than alpha-fetoprotein (AFP). Next-generation DCP (NX-DCP) was created to overcome some of the limitations of conventional DCP. This study assessed the predictive value of NX-DCP for vascular invasion in HCC.

Methods:

We prospectively studied 82 consecutive patients who were scheduled to undergo resection for HCC. Patients were divided into two groups according to the presence or absence of pathological vascular invasion. The predictive powers of AFP, conventional DCP, and NX-DCP for vascular invasion were compared by receiver operating characteristic curve analysis, and correlations with tumour markers and the presence of vascular invasion were assessed.

Results:

Vascular invasion was pathologically confirmed in 21 patients (positive group) and absent in 61 patients (negative group). The NX-DCP level was significantly higher in the positive group than in the negative group (510.0 mAU ml⁻¹ (10–98 450) vs 34.0 mAU ml⁻¹ (12–541), P<0.0001), while the AFP level did not differ significantly between the groups (9.7 ng ml⁻¹ (1.6–43 960.0) vs 11.0 ng ml⁻¹ (1.6–1650.0), P=0.49). The area under the curve (AUC) of NX-DCP (AUC=0.813, sensitivity=71.4%, 1−specificity=13.1%) had good sensitivity for the prediction of vascular invasion, while the AUC of AFP was 0.550 (sensitivity=28.6%, 1−specificity=1.60%). The suitable cutoff value for identifying pathological vascular invasion in HCC was 33 mm (AUC: 0.783, sensitivity=71.43%, 1−specificity=11.48%).

Conclusions:

The NX-DCP level can be used to predict the presence of vascular invasion in HCC.     

Prognostic and predictive value of plasma testosterone levels in patients receiving first-line chemotherapy for metastatic castrate-resistant prostate cancer

Background:

Biomarkers for metastatic castration-resistant prostatic cancer (mCRPC) are an unmet medical need.

Methods:

The prognostic and predictive value for survival and response to salvage hormonal therapy (SHT) of baseline testosterone level (TL) was analysed in a cohort of 101 mCRPC patients participating in 9 non-hormonal first-line chemotherapy phase II–III trials. Inclusion criteria in all trials required a TL of <50 ng dl⁻¹.

Results:

Median age: 70 years; visceral metastases: 19.8% median prostate-specific antigen (PSA): 50.7 ng ml⁻¹; median TL: 11.5 ng dl⁻¹. Median overall survival (OS; 24.5 months) was significantly longer if baseline TL was above (High TL; n=52) than under (Low TL; n=49) the TL median value (32.7 vs 22.4 months, respectively; P=0.0162, hazard ratio (HR)=0.6). The presence of anaemia was an unfavourable prognostic factor (median OS: 20.6 vs 28.4 months; P=0.0025, HR=1.88 (CI95%: 1.01–3.48)). Patients presenting both anaemia and low testosterone had a worse outcome compared to those with one or none of them (median OS: 17.9 vs 22.4 vs 38.1 months; P=0.0024). High vs Low TL was associated with PSA response rate (55.6% vs 21.7%) in 41 patients receiving SHT.

Conclusion:

Testosterone level under castration range was a prognostic factor for survival mCRPC patients. The PSA response to SHT differed depending on TLs. Testosterone levels might help in treatment decision.     

Randomised phase II study comparing dose-escalated weekly paclitaxel vs standard-dose weekly paclitaxel for patients with previously treated advanced gastric cancer

Background:

This randomised phase II trial compared dose-escalated weekly paclitaxel (wPTX) vs standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC).

Methods:

Ninety patients were randomised to a standard dose of wPTX (80 mg m⁻²) or an escalated dose of wPTX (80–120 mg m⁻²) to assess the superiority of overall survival (OS) with a one-sided alpha error of 0.3 and a power of 0.8.

Results:

The median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs 9.6 months; hazard ratio (HR), 0.75; one-sided P=0.12), although it was statistically not significant. The median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs 2.5 months, HR, 0.55; P=0.017). Objective response rate was 30.3% with dose escalation and 17.1% with standard dose (P=0.2). The frequency of all grades of neutropenia was significantly higher with dose escalation (88.7% vs 60.0%, P=0.002); however, no significant difference was observed in the proportion of patients experiencing grade 3 or more (40.9% vs 31.1%, P=0.34).

Conclusion:

Dose-escalated wPTX in patients with pretreated AGC met our predefined threshold of primary end point, OS (P<0.3); however, it did not show a significantly longer OS. Progression-free survival was significantly better with dose escalation.     

Intake of coffee,caffeine and other methylxanthines and risk of Type I vs Type II endometrial cancer

Background:

Coffee and other sources of methylxanthines and risk of Type I vs Type II endometrial cancer (EC) have not been evaluated previously.

Methods:

Prospective cohort of 23 356 postmenopausal women with 471 Type I and 71 Type II EC cases.

Results:

Type I EC was statistically significantly associated with caffeinated (relative risk (RR)=0.65 for 4+ cups per day vs ⩽1 cup per month: 95% confidence interval (CI): 0.47–0.89) but not decaffeinated (RR=0.76; 95% CI: 0.50–1.15) coffee intake; there were no associations with tea, cola or chocolate, or for Type II EC. The inverse association with caffeinated coffee intake was specific to women with a body mass index 30+ kg m⁻² (RR=0.56; 95% CI: 0.36–0.89).

Conclusion:

Coffee may protect against Type I EC in obese postmenopausal women.     

Randomised phase II trial of S-1 plus oxaliplatin vs S-1 in patients with gemcitabine-refractory pancreatic cancer

Background:

This randomised, open-label, multicenter phase II study compared progression-free survival (PFS) of S-1 plus oxaliplatin (SOX) with that of S-1 alone in patients with gemcitabine-refractory pancreatic cancer.

Methods:

Patients with confirmed progressive disease following the first-line treatment with a gemcitabine-based regimen were randomised to receive either S-1 (80/100/120 mg day⁻¹ based on body surface area (BSA), orally, days 1–28, every 6 weeks) or SOX (S-1 80/100/120 mg day⁻¹ based on BSA, orally, days 1–14, plus oxaliplatin 100 mg m⁻², intravenously, day 1, every 3 weeks). The primary end point was PFS.

Results:

Between January 2009 and July 2010, 271 patients were randomly allocated to either S-1 (n=135) or SOX (n=136). Median PFS for S-1 and SOX were 2.8 and 3.0 months, respectively (hazard ratio (HR)=0.84; 95% confidence interval (CI), 0.65–1.08; stratified log-rank test P=0.18). Median overall survival (OS) was 6.9 vs 7.4 months (HR=1.03; 95% CI, 0.79–1.34; stratified log-rank test P=0.82). The response rate (RR) was 11.5% vs 20.9% (P=0.04). The major grade 3/4 toxicities (S-1 and SOX) were neutropenia (11.4% and 8.1%), thrombocytopenia (4.5% and 10.3%) and anorexia (12.9% and 14.7%).

Conclusions:

Although SOX showed an advantage in RR, it provided no significant improvement in PFS or OS compared with S-1 alone.     

Diffusion-weighted MRI for imaging cell death after cytotoxic or apoptosis-inducing therapy

Background:

Non-invasive serial imaging is desirable to detect processes such as necrotic and apoptotic cell death in cancer patients undergoing treatment. This study investigated the use of diffusion-weighted (DW-) magnetic resonance imaging (MRI) for imaging cell death induced by either a cytotoxic drug (irinotecan), or the apoptosis-inducing agent birinapant, in human tumour xenografts in vivo.

Methods:

Nude mice bearing human SW620 colon carcinoma xenografts were treated with vehicle, irinotecan (50 mg kg⁻¹) or birinapant (30 mg kg⁻¹) for up to 5 days. DW-MRI was performed prior to and on days 1, 3 and 5 during treatment. Assessment of tumour apoptosis and necrosis ex vivo was used to validate the imaging findings.

Results:

Both irinotecan and birinapant induced significant tumour growth delay. Irinotecan induced a small increase in the tumour apparent diffusion coefficient (ADC) after 1 day, with a 20 and 30% increase at days 3 and 5 respectively. ADC was unchanged in the vehicle- and birinapant-treated tumours despite a growth delay in the latter. Histological analysis showed that irinotecan increased necrosis at days 3 and 5, and induced apoptosis after 1 day, compared with vehicle. Birinapant induced apoptosis after day 3, but had no effect on tumour necrosis.

Conclusions:

Tumour ADC changes after irinotecan treatment were associated with the induction of a mixture of necrotic and apoptotic cell death, whereas induction of apoptosis alone with birinapant was not sufficient to induce changes in tissue microstructure that were detectable with DW-MRI. ADC is a useful non-invasive biomarker for early detection of response to cytotoxic drugs, but false negatives may arise while detecting apoptotic response to birinapant.     

Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan

Background:

A British randomised study of gemcitabine plus cisplatin (GC) combination showed promising results in biliary tract cancer (BTC) patients. In our study, we evaluated the efficacy and safety of this combination compared with gemcitabine alone (G) in Japanese BTC patients.

Methods:

Overall, 84 advanced BTC patients were randomised to either cisplatin 25 mg m⁻² plus gemcitabine 1000 mg m⁻² on days 1, 8 of a 21-day cycle (GC-arm), or single-agent gemcitabine 1000 mg m⁻² on days 1, 8 and 15 of a 28-day cycle (G-arm). Treatments were repeated for at least 12 weeks until disease progression or unacceptable toxicity occurred, up to a maximum of 48 weeks.

Results:

A total of 83 patients were included in the analysis. For the GC and G-arms, respectively, the 1-year survival rate was 39.0 vs 31.0%, median survival time 11.2 vs 7.7 months, median progression-free survival time 5.8 vs 3.7 months and overall response rate 19.5 vs 11.9%. The most common grade 3 or 4 toxicities (GC-arm/G-arm) were neutropenia (56.1%/38.1%), thrombocytopenia (39.0%/7.1%), leukopenia (29.3%/19.0%), haemoglobin decrease (36.6%/16.7%) and γ-GTP increase (29.3%/35.7%).

Conclusions:

Gemcitabine plus cisplatin combination therapy was found to be effective and well tolerated, suggesting that it could also be a standard regimen for Japanese patients.     

A randomised,double-blind,placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer

Background:

The purpose of this randomised phase III trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3methyglutaryl coenzyme A reductase inhibitor, to XELIRI/FOLFIRI chemotherapy regimens confers a clinical benefit to patients with previously treated metastatic colorectal cancer.

Methods:

We undertook a double-blind, placebo-controlled phase III trial of 269 patients previously treated for metastatic colorectal cancer and enrolled in 5 centres in South Korea. Patients were randomly assigned (1 : 1) to one of the following groups: FOLFIRI/XELIRI plus simvastatin (40 mg) or FOLFIRI/XELIRI plus placebo. The FOLFIRI regimen consisted of irinotecan at 180 mg m⁻² as a 90-min infusion, leucovorin at 200 mg m⁻² as a 2-h infusion, and a bolus injection of 5-FU 400 mg m⁻² followed by a 46-h continuous infusion of 5-FU at 2400 mg m⁻². The XELIRI regimen consisted of irinotecan at 250 mg m⁻² as a 90-min infusion with capecitabine 1000 mg m⁻² twice daily for 14 days. The primary end point was progression-free survival (PFS). Secondary end points included response rate, duration of response, overall survival (OS), time to progression, and toxicity.

Results:

Between April 2010 and July 2013, 269 patients were enrolled and assigned to treatment groups (134 simvastatin, 135 placebo). The median PFS was 5.9 months (95% CI, 4.5–7.3) in the XELIRI/FOLFIRI plus simvastatin group and 7.0 months (95% CI, 5.4–8.6) in the XELIRI/FOLFIRI plus placebo group (P=0.937). No significant difference was observed between the two groups with respect to OS (median, 15.9 months (simvastatin) vs 19.9 months (placebo), P=0.826). Grade ⩾3 nausea and anorexia were noted slightly more often in patients in the simvastatin arm compared with with the placebo arm (4.5% vs 0.7%, 3.0% vs 0%, respectively).

Conclusions:

The addition of 40 mg simvastatin to the XELIRI/FOLFIRI regimens did not improve PFS in patients with previously treated metastatic colorectal cancer nor did it increase toxicity.     

Cediranib with mFOLFOX6 vs bevacizumab with mFOLFOX6 in previously treated metastatic colorectal cancer

Background:

Cediranib is a highly potent inhibitor of vascular endothelial growth factor (VEGF) signalling with activity against all three VEGF receptors. Bevacizumab is an anti-VEGF-A monoclonal antibody with clinical benefit in previously treated metastatic colorectal cancer (mCRC).

Methods:

Patients with mCRC who had progressed following first-line therapy were randomised 1 : 1 : 1 to modified (m)FOLFOX6 plus cediranib (20 or 30 mg day⁻¹) or bevacizumab (10 mg kg⁻¹ every 2 weeks). The primary objective was to compare progression-free survival (PFS) between treatment arms.

Results:

A total of 210 patients were included in the intent-to-treat (ITT) analysis (cediranib 20 mg, n=71; cediranib 30 mg, n=73; bevacizumab, n=66). Median PFS in the cediranib 20 mg, cediranib 30 mg and bevacizumab groups was 5.8, 7.2 and 7.8 months, respectively. There were no statistically significant differences between treatment arms for PFS (cediranib 20 mg vs bevacizumab: HR=1.28 (95% CI, 0.85–1.95; P=0.29); cediranib 30 mg vs bevacizumab: HR=1.17 (95% CI, 0.77–1.76; P=0.79)) or overall survival (OS). Grade ⩾3 adverse events were more common with cediranib 30 mg (91.8%) vs cediranib 20 mg (81.4%) or bevacizumab (84.8%).

Conclusion:

There were no statistically significant differences between treatment arms for PFS or OS. When combined with mFOLFOX6, the 20 mg day⁻¹ dose of cediranib was better tolerated than the 30 mg day⁻¹ dose.     

Combined treatment of the experimental human papilloma virus-16-positive cervical and head and neck cancers with cisplatin and radioimmunotherapy targeting viral E6 oncoprotein

Background:

Human papilloma virus (HPV) is implicated in >99% of cervical cancers and ∼40% of head and neck squamous cell carcinoma (HNSCC). We previously targeted E6 oncogene with ¹⁸⁸Rhenium-labelled monoclonal antibody (mAb) C1P5 to HPV16 E6 in cervical cancer and HNSCC. Intranuclear E6 can be accessed by mAbs in non-viable cells with leaky membranes. As radioimmunotherapy (RIT) efficacy depends on the availability of target protein—we hypothesised that pretreatment with cisplatin will kill some tumour cells and increase E6 availability for RIT.

Methods

Mice with subcutaneous HPV16+ cervical (CasKi) and HNSCC (2A3) tumours were pretreated with 0–7.5 mg kg⁻¹ per day cisplatin for 3 days followed by ¹⁸⁸Re-C1P5 and biodistribution was performed 24 h later. For RIT, the animals were treated with: 5 mg kg⁻¹ per day cisplatin for 3 days; or 5 mg kg⁻¹ per day cisplatin for 3 days followed 200 or 400μCi ¹⁸⁸Re-C1P5 mAb; or 200 or 400μCi ¹⁸⁸Re-C1P5 mAb; or left untreated, and observed for tumour growth for 24 days.

Results:

Pretreatment with cisplatin increased the uptake of ¹⁸⁸Re-C1P5 in the tumours 2.5 to 3.5-fold and caused significant retardation in tumour growth for CasKi and 2A3 tumours in both RIT alone and cisplatin, and RIT groups in comparison with the untreated control and cisplatin alone groups (P<0.05). The combined treatment was more effective than either modality alone (P<0.05).

Conclusion:

Our study demonstrates that preceding RIT targeting E6 oncogene with chemotherapy is effective in suppressing tumour growth in mouse models of HPV16+ cancers.