Randomised,open-label,phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer

Background:

Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study ({"type":"clinical-trial","attrs":{"text":"NCT01303172","term_id":"NCT01303172"}}NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma.

Methods:

Patients were randomised (2 : 1) to IMM-101 (10 mg ml^−l intradermally)+GEM (1000 mg m⁻² intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected.

Results:

IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44–1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33–0.87, P=0.01).

Conclusions:

IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study.     

Adjuvant chemotherapy for gastric cancer: a randomised phase 3 trial of mitomycin-C plus either short-term doxifluridine or long-term doxifluridine plus cisplatin after curative D2 gastrectomy (AMC0201)

Background:

This phase 3 study evaluated the efficacy of new adjuvant chemotherapy (MFP), which intensified the mitomycin-C (MMC) plus short-term doxifluridine (Mf) for gastric cancer.

Patients and methods:

A total of 855 patients (424 in Mf, 431 in MFP) with pathological stage II–IV (M0) gastric cancer after D2 gastrectomy were randomly assigned to receive either Mf (MMC 20 mg m⁻², followed by oral doxifluridine 460–600 mg m⁻² per day for 3 months) or MFP (MMC 20 mg m⁻², followed by oral doxifluridine 460–600 mg m⁻² per day for 12 months with 6 monthly infusions of 60 mg m⁻² of cisplatin) chemotherapy.

Results:

With a median follow-up of 6.6 years, there was no difference between the two groups in recurrence-free survival (RFS) (5-year RFS 61.1% in Mf and 57.9% in MFP; hazard ratio 1.10 (95% CI 0.89–1.35); P=0.39) and overall survival (OS) (5-year OS 66.5% in Mf and 65.0% in MFP; hazard ratio 1.11 (95% CI 0.89–1.39); P=0.33).

Conclusion:

Intensification of Mf adjuvant chemotherapy by prolonging the duration of oral fluoropyrimidine and adding cisplatin was safe but not effective to improve the survivals in curatively resected gastric cancer patients.     

Phase I/II study of 131I-MIBG with vincristine and 5 days of irinotecan for advanced neuroblastoma

Background:

¹³¹I-metaiodobenzylguanidine (MIBG) is an active radiopharmaceutical in neuroblastoma. A previous study demonstrated that MIBG could be combined with vincristine and prolonged irinotecan, although 25% of first courses had grade 3 diarrhoea. The current phase I/II study evaluated MIBG with vincristine and 5 days of higher-dose irinotecan.

Methods:

Patients 1–30 years old with advanced neuroblastoma were eligible. Patients received cefixime on days −1 to +6, irinotecan (50 mg m⁻² per dose IV) on days 0–4, vincristine (2 mg m⁻²) on day 0, MIBG (555 or 666 MBq kg⁻¹) on day 1, and peripheral blood stem cells on day 13. UGT1A1 genotyping was performed in consenting patients.

Results:

Thirty-two patients (12 phase I ; 20 phase II) received 42 courses. No dose-limiting toxicities were seen during dose escalation and the recommended administered activity was 666 MBq kg⁻¹. Myelosuppression and diarrhoea were the most common toxicities, with grade 3 diarrhoea in 6% of first courses. Patients homozygous for UGT1A1*28 had more grade 4 thrombocytopenia (80% vs 37% P=0.14). Responses (five complete and four partial) occurred in 9 out of 32 (28%) patients.

Conclusions:

MIBG (666 MBq kg⁻¹) with vincristine and this irinotecan schedule is tolerable and active, with less severe diarrhoea compared with a regimen using more protracted irinotecan.     

Tumour-associated CD66b+ neutrophil count is an independent prognostic factor for recurrence in localised cervical cancer

Background:

The prognostic impact of tumour-promoting immune cells in cervical cancer is unclear.

Methods:

Federation of Gynaecology and Obstetrics (FIGO) stage IB and IIA cervical cancer patients (N=101) were assessed for tumour-associated CD66b⁺ neutrophils and CD163⁺ macrophages by immunohistochemistry in whole tissue sections using stereology. Results were correlated with previous results on tumour-infiltrating CD3⁺, CD4⁺, and CD8⁺ lymphocytes in the same cohort with recurrence-free survival (RFS) as end point.

Results:

The highest densities of CD66b⁺ neutrophils and CD163⁺ macrophages were observed in the peritumoural compartment (median 53.1 cells mm⁻² and 1.3% area fraction, respectively). Above median peritumoural and stromal CD66b⁺ neutrophils and peritumoural CD163⁺ macrophages were significantly associated with short RFS. Multivariate analysis identified high peritumoural neutrophils (HR 2.27; 95% CI 1.09–4.75; P=0.03), low peritumoural CD8⁺ lymphocytes (HR 3.67; 95% CI 1.63–8.25; P=0.002), and lymph node metastases (HR 2.70; 95% CI 1.26–5.76; P=0.01) as independent prognostic factors for short RFS, whereas CD163⁺ macrophages were not significant. An index of combined intratumoral and peritumoral CD66b⁺ neutrophils to CD8⁺ lymphocytes had good discriminatory power for each quartile with 5-year RFS of 92%, 80%, 62%, and 44% (P=0.001).

Conclusion:

Tumour-associated neutrophil count is an independent prognostic factor for short RFS in localised cervical cancer. Combining CD66b and CD8 may further improve prognostic stratification. These findings require prospective validation.     

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.     

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.     

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.     

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.     

Androgen receptor expression predicts beneficial tamoxifen response in oestrogen receptor-α-negative breast cancer

Background:

Although the androgen receptor (AR) is frequently expressed in breast cancer, its relevance in the disease is not fully understood. In addition, the relevance of AR in determining tamoxifen treatment efficiency requires evaluation.

Purpose:

To investigate the tamoxifen predictive relevance of the AR protein expression in breast cancer.

Methods

Patients were randomised to tamoxifen 40 mg daily for 2 or 5 years or to no endocrine treatment. Mean follow-up was 15 years. Hazard ratios were calculated with recurrence-free survival as end point.

Results:

In patients with oestrogen receptor (ER)-negative tumours, expression of AR predicted decreased recurrence rate with tamoxifen (hazard ratio (HR)=0.34; 95% confidence interval (CI)=0.14–0.81; P=0.015), whereas the opposite was seen in the AR− group (HR=2.92; 95% CI=1.16–7.31; P=0.022). Interaction test was significant P<0.001. Patients with triple-negative and AR+ tumours benefitted from tamoxifen treatment (HR=0.12; 95% CI=0.014–0.95 P=0.044), whereas patients with AR− tumours had worse outcome when treated with tamoxifen (HR=3.98; 95% CI=1.32–12.03; P=0.014). Interaction test was significant P=0.003. Patients with ER+ tumours showed benefit from tamoxifen treatment regardless of AR expression.

Conclusions:

AR can predict tamoxifen treatment benefit in patients with ER− tumours and triple-negative breast cancer.     

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.     

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.     

Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102)

Background:

A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival.

Methods:

Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1–5, vincristine 0.7 mg m⁻² day 5, mitomycin 7 mg m⁻² day 5, cisplatin 14 mg m⁻² days 1–5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival.

Results:

A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80% P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85).

Conclusion:

Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.     

Sarcopenia and body mass index predict sunitinib-induced early dose-limiting toxicities in renal cancer patients

Background:

Little is known on factors predicting sunitinib toxicity. Recently, the condition of low muscle mass, named sarcopenia, was identified as a significant predictor of toxicity in metastatic renal cell cancer (mRCC) patients treated with sorafenib. We investigated whether sarcopenia could predict early dose-limiting toxicities (DLTs) occurrence in mRCC patients treated with sunitinib.

Methods:

Consecutive mRCC patients treated with sunitinib were retrospectively reviewed. A DLT was defined as any toxicity leading to dose reduction or treatment discontinuation. Body composition was evaluated using CT scan obtained within 1 month before treatment initiation.

Results:

Among 61 patients eligible for analysis, 52.5% were sarcopenic and 32.8% had both sarcopenia and a body mass index (BMI)<25 kg m⁻². Eighteen patients (29.5%) experienced a DLT during the first cycle. Sarcopenic patients with a BMI<25 kg m⁻² experienced more DLTs (P=0.01; odds ratio=4.1; 95% CI: (1.3–13.3)), more cumulative grade 2 or 3 toxicities (P=0.008), more grade 3 toxicities (P=0.04) and more acute vascular toxicities (P=0.009).

Conclusion:

Patients with sarcopenia and a BMI<25 kg m⁻² experienced significantly more DLTs during the first cycle of treatment.     

Body mass index and circulating oestrone sulphate in women treated with adjuvant letrozole

Background:

Obesity is an independent adverse prognostic factor in early breast cancer patients, but it is still controversial whether obesity may affect adjuvant endocrine therapy efficacy. The aim of our study (ancillary to the two clinical trials Gruppo Italiano Mammella (GIM)4 and GIM5) was to investigate whether the circulating oestrogen levels during treatment with the aromatase inhibitor letrozole are related to body mass index (BMI) in postmenopausal women with breast cancer.

Methods:

Plasma concentration of oestrone sulphate (ES) was evaluated by radioimmunoassay in 370 patients. Plasma samples were obtained after at least 6 weeks of letrozole therapy (steady-state time). Patients were divided into four groups according to BMI. Differences among the geometric means (by ANOVA and ANCOVA) and correlation (by Spearman''s rho) between the ES levels and BMI were assessed.

Results:

Picomolar geometric mean values (95% confidence interval, n=patients) of circulating ES during letrozole were 58.6 (51.0–67.2, n=150) when BMI was <25.0 kg m⁻²; 65.6 (57.8–74.6, n=154) when 25.0–29.9 kg m⁻²; 59.3 (47.1–74.6, n=50) when 30.0–34.9 kg m⁻²; and 43.3 (23.0–81.7, n=16) when ⩾35.0 kg m⁻². No statistically significant difference in terms of ES levels among groups and no correlation with BMI were observed.

Conclusions:

Body mass index does not seem to affect circulating oestrogen levels in letrozole-treated patients.     

Pharmacokinetics of concomitant cisplatin and paclitaxel administered by hyperthermic intraperitoneal chemotherapy to patients with peritoneal carcinomatosis from epithelial ovarian cancer

Background:

Hyperthermic intraperitoneal chemotherapy (HIPEC) is advised as a treatment option for epithelial ovarian cancer (EOC) with peritoneal carcinomatosis. This study was designed to define the pharmacokinetics of cisplatin (CDDP) and paclitaxel (PTX) administered together during HIPEC.

Methods:

Thirteen women with EOC underwent cytoreductive surgery (CRS) and HIPEC, with CDDP and PTX. Blood, peritoneal perfusate and tissue samples were harvested to determine drug exposure by high-performance liquid chromatography and matrix-assisted laser desorption ionization imaging mass spectrometry (IMS).

Results:

The mean maximum concentrations of CDDP and PTX in perfusate were, respectively, 24.8±10.4 μg ml⁻¹ and 69.8±14.3 μg ml⁻¹; in plasma were 1.87±0.4 μg ml⁻¹ and 0.055±0.009 μg ml⁻¹. The mean concentrations of CDDP and PTX in peritoneum at the end of HIPEC were 23.3±8.0 μg g⁻¹ and 30.1±18.3 μg⁻¹g⁻¹, respectively. The penetration of PTX into the peritoneal wall, determined by IMS, was about 0.5 mm. Grade 3–4 surgical complications were recorded in four patients, five patients presented grade 3 and two patients presented grade 4 hematological complications.

Conclusions:

HIPEC with CDDP and PTX after CRS is feasible with acceptable morbidity and has a favorable pharmacokinetic profile: high drug concentrations are achieved in peritoneal tissue with low systemic exposure. Larger studies are needed to demonstrate its efficacy in patients with microscopic postsurgical residual tumours in the peritoneal cavity.     

Alpha-1-fucosidase as a prognostic indicator for hepatocellular carcinoma following hepatectomy: a large-scale,long-term study

Background:

Preoperative alpha-L-fucosidase (AFU) has been used as a diagnostic biomarker for hepatocellular carcinoma (HCC), but its role as a prognostic predictor after partial hepatectomy has not been well defined. The study aimed to investigate the prognostic significance of preoperative serum AFU for HCC patients after hepatic resection.

Methods:

A retrospective training data set and a prospective validation data set were used to evaluate the prognosis of HCC after partial hepatectomy. A total of 669 patients with histopathologically confirmed HCC were enrolled. Univariate and multivariate analyses were used to identify the prognostic significance of preoperative serum AFU.

Results:

The retrospective training data set showed a preoperative AFU>35 u l⁻¹ should be used. The prospective validation data set showed preoperative AFU was an independent prognostic factor of overall survival (OS) (P=0.008; hazard ratio: 2.333; 95% confidence interval: 1.249–4.369). Patients with a preoperative AFU>35 u l⁻¹ had a lower recurrence-free survival rate and an OS rate than those with AFU⩽35 u l⁻¹, and they have a higher tendency to form macrovascular invasion. Furthermore, the prognostic significance of AFU>35 u l⁻¹ could also be applied to patients with alpha-fetoprotein levels of ⩽400 ng ml⁻¹.

Conclusions:

Preoperative serum AFU is a prognostic predictor of HCC.     

Phase II multi-institutional prospective randomised trial comparing S-1+paclitaxel with S-1+cisplatin in patients with unresectable and/or recurrent advanced gastric cancer

Background:

A combination of S-1 and cisplatin has been shown to be effective with acceptable safety for the first-line treatment of far-advanced gastric cancer in Japan. This is the first randomised phase II trial to compare S-1+paclitaxel with S-1+cisplatin in this setting.

Methods:

Patients with unresectable and/or recurrent advanced gastric cancer were randomly assigned to receive one of the two regimens: S-1 (40 mg m⁻² twice daily) on days 1–14 plus paclitaxel (60 mg m⁻²) on days 1, 8, and 15 of a 4-week cycle (S-1+paclitaxel) or S-1 (40 mg m⁻² twice daily) on days 1–21 plus cisplatin (60 mg m⁻²) on day 8 of a 5-week cycle (S-1+cisplatin). The primary end point was the response rate (RR). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.

Results:

A total of 83 patients were eligible for safety and efficacy analyses. In the S-1+paclitaxel and S-1+cisplatin groups, RRs (52.3% vs 48.7% P=0.74) and median PFS (9 vs 6 months; P=0.50) were similar. The median OS was similar in the S-1+paclitaxel and S-1+cisplatin groups (16 vs 17 months; P=0.84). The incidence of grade 3 or higher haematological toxicity was 19.0% with S-1+paclitaxel and 19.5% with S-1+cisplatin. The incidence of grade 3 or higher non-haematological toxicity was 14.2% with S-1+paclitaxel and 17.1% with S-1+cisplatin.

Conclusion:

S-1+paclitaxel was suggested to be a feasible and effective non-platinum-based regimen for chemotherapy in patients with advanced gastric cancer. Our results should be confirmed in multicenter, phase III-controlled clinical trials.     

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.     

COX-2 expression is predictive for early relapse and aromatase inhibitor resistance in patients with ductal carcinoma in situ of the breast,and is a target for treatment

Background:

Stratification of patients for treatment of ductal carcinoma in situ (DCIS) is suboptimal, with high systemic overtreatment rates.

Methods:

A training set of 95 tumours from women with pure DCIS were immunostained for proteins involved in cell survival, hypoxia, growth factor and hormone signalling. A generalised linear regression with regularisation and variable selection was applied to a multiple covariate Cox survival analysis with recurrence-free survival 10-fold cross-validation and leave-one-out iterative approach were used to build and test the model that was validated using an independent cohort of 58 patients with pure DCIS. The clinical role of a COX-2-targeting agent was then tested in a proof-of-concept neoadjuvant randomised trial in ER-positive DCIS treated with exemestane 25 mg day⁻¹±celecoxib 800 mg day⁻¹.

Results:

The COX-2 expression was an independent prognostic factor for early relapse in the training (HR 37.47 (95% CI: 5.56–252.74) P=0.0001) and independent validation cohort (HR 3.9 (95% CI: 1.8–8.3) P=0.002). There was no significant interaction with other clinicopathological variables. A statistically significant reduction of Ki-67 expression after treatment with exemestane±celecoxib was observed (P<0.02) with greater reduction in the combination arm (P<0.004). Concomitant reduction in COX-2 expression was statistically significant in the exemestane and celecoxib arm (P<0.03) only.

Conclusions:

In patients with DCIS, COX-2 may predict recurrence, aiding clinical decision making. A combination of an aromatase inhibitor and celecoxib has significant biological effect and may be integrated into treatment of COX2-positive DCIS at high risk of recurrence.