Plasma MIC-1 correlates with systemic inflammation but is not an independent determinant of nutritional status or survival in oesophago-gastric cancer

Background:

Macrophage inhibitory cytokine-1(MIC-1) is a potential modulator of systemic inflammation and nutritional depletion, both of which are adverse prognostic factors in oesophago-gastric cancer (OGC).

Methods:

Plasma MIC-1, systemic inflammation (defined as plasma C-reactive protein (CRP) of ⩾10 mg l^–1 or modified Glasgow prognostic score (mGPS) of ⩾1), and nutritional status were assessed in newly diagnosed OGC patients (n=293). Healthy volunteers (n=35) served as controls.

Results:

MIC-1 was elevated in patients (median=1371 pg ml^–1; range 141–39 053) when compared with controls (median=377 pg ml^–1; range 141–3786; P<0.001). Patients with gastric tumours (median=1592 pg ml^–1; range 141–12 643) showed higher MIC-1 concentrations than patients with junctional (median=1337 pg ml^–1; range 383–39 053) and oesophageal tumours (median=1180 pg ml^–1; range 258–31 184; P=0.015). Patients showed a median weight loss of 6.4% (range 0.0–33.4%), and 42% of patients had an mGPS of ⩾1 or plasma CRP of ⩾10 mg l^–1 (median=9 mg l^–1; range 1–200). MIC-1 correlated positively with disease stage (r²=0.217; P<0.001), age (r²=0.332; P<0.001), CRP (r²=0.314; P<0.001), and mGPS (r²=0.336; P<0.001), and negatively with Karnofsky Performance Score (r²=−0.269; P<0.001). However, although MIC-1 correlated weakly with dietary intake (r²=0.157; P=0.031), it did not correlate with weight loss, BMI, or anthropometry. Patients with MIC-1 levels in the upper quartile showed reduced survival (median=204 days; 95% CI 157–251) when compared with patients with MIC-1 levels in the lower three quartiles (median=316 days; 95% CI 259–373; P=0.036), but MIC-1 was not an independent prognostic indicator.

Conclusions:

There is no independent link between plasma MIC-1 levels and depleted nutritional status or survival in OGC.     

Improving the accuracy of pre-operative survival prediction in renal cell carcinoma with C-reactive protein

Background:

Validated objective biomarkers are needed for patients with renal cell carcinoma (RCC) to guide patient management and define high-risk populations for follow-up or for therapeutic purposes.

Methods:

Patients undergoing nephrectomy for RCC (n=286 all stages, 84% with conventional clear cell type) were included with a median duration follow-up of 5 years. The prognostic significance of pre-operative haematological and biochemical variables, including C-reactive protein (CRP) values were examined and whether they added additional information to a recently published pre-operative scoring system was determined.

Results:

C-reactive protein was the most significant predictor of overall survival (OS; χ²=50.9, P<0.001). Five-year OS for patients with CRP⩽15 mg l⁻¹ vs >15 mg l⁻¹ was 72% (95% CI 65–78%) and 33% (95% CI 23–44%), respectively. Similar results were seen for cancer-specific survival (CSS) and disease-free survival. On multivariate analysis, CRP remained highly significant for CSS (χ²=17.3, P<0.0001) and OS (χ²=9.8, P<0.002), in addition to other pre-operative variables including log of neutrophil/lymphocyte ratio, red blood cell count and white cell count. C-reactive protein was significant in addition to the pre-operative nomogram score (χ²=12.5, P=0.0004 for OS, χ²=16.2, P=0.0001 for CSS and χ²=8.6, P=0.003 for DFS) and was still significant when other pre-operative variables were included.

Conclusion:

C-reactive protein and other haematological and biochemical variables have independent prognostic significance in RCC and may enhance pre-operative scoring systems.     

Phase I dose-escalation study of aflibercept in combination with docetaxel and cisplatin in patients with advanced solid tumours

Background:

This phase I cohort study investigated aflibercept (vascular endothelial growth factor (VEGF) trap) plus docetaxel and cisplatin in patients with advanced solid tumours.

Methods:

Patients received intravenous aflibercept 4, 5, or 6 mg kg⁻¹ with docetaxel and cisplatin (75 mg m⁻² each) on day 1 of a 3-week cycle until progressive disease or unacceptable toxicity. Primary objectives were determining cycle 1 dose-limiting toxicities (DLTs) and the aflibercept recommended phase II trial dose (RP2D) for this combination.

Results:

During the dose-escalation phase (n=16), there were two DLTs of febrile neutropenia (at 4 and 5 mg kg⁻¹). Granulocyte colony-stimulating factor prophylaxis was subsequently recommended. The RP2D of aflibercept was established at 6 mg kg⁻¹ and administered to 14 additional patients. The most frequent grade 3/4 adverse events (AEs) were neutropenia (43.3%), stomatitis (20.0%), asthenia/fatigue (20.0%), and hypertension (16.7%). All-grade AEs associated with VEGF blockade included epistaxis (83.3%), dysphonia (70.0%), proteinuria (53.3%), and hypertension (50.0%). There were five partial responses (16.7%) and 18 cases of stable disease (60.0%) (lasting >3 months in 10 patients). There were no pharmacokinetic (PK) interactions between the three drugs.

Conclusion:

Aflibercept 6 mg kg⁻¹ with docetaxel and cisplatin 75 mg m⁻² every 3 weeks is the RP2D based on tolerability, antitumour activity, and PKs.     

The management and outcome of women with post-hydatidiform mole ‘low-risk' gestational trophoblastic neoplasia,but hCG levels in excess of 100?000?IU?l?1

Background:

Gestational trophoblastic neoplasia (GTN) after a hydatidiform mole is either treated with single- or multi-agent chemotherapy determined by a multifactorial scoring system. Women with human chorionic gonadotrophin (hCG) levels >100 000 IU l⁻¹ can remain within the low-risk/single-agent category and usually choose one drug therapy. Here we compare the success and duration of single- vs multi-agent chemotherapy in this patient group.

Methods:

Between 1980 and 2008, 65 women had a pre-treatment hCG >100 000 IU l⁻¹ and were low risk. The initial hCG level, treatment regimens, changes and duration and overall survival were recorded.

Results:

Of 37 patients starting low-risk/single-agent treatment, 11 (29.7%) were treated successfully, whereas 26 (70.3%) required additional multi-agent chemotherapy to achieve complete remission (CR). Combination chemotherapy was initially commenced in 28 women, and 2 (7%) required additional drugs for CR. The overall duration of therapy for those commencing and completing single- or multi-agent chemotherapy was 130 and 123 days (P=0.78), respectively. The median-treatment duration for patients commencing single-agent but changing to multi-agent chemotherapy was 13 days more than those receiving high-risk treatment alone (136 vs 123 days; P=0.07). All 3 patients with an initial hCG >400 000 IU l⁻¹ and treated with single-agent therapy developed drug resistance. Overall survival for all patients was 100%.

Conclusion:

Low-risk post-molar GTN patients with a pre-treatment hCG >100 000 and <400 000 IU l⁻¹ can be offered low-risk single-agent therapy, as this will cure 30%, is relatively non-toxic and only prolongs treatment by 2 weeks if a change to combination agents is required. Patients whose hCG is >400 000 IU l⁻¹ should receive multi-agent chemotherapy from the outset.     

Randomised, non-comparative phase II study of weekly docetaxel with cisplatin and 5-fluorouracil or with capecitabine in oesophagogastric cancer: the AGITG ATTAX trial

Background:

Docetaxel administered 3-weekly with cisplatin and 5-fluorouracil leads to better survival than does standard therapy in patients with oesophagogastric cancer, but leads to high rates of haematological toxicity. Weekly docetaxel is associated with less haematological toxicity. This randomised phase II study tested weekly docetaxel-based combination chemotherapy regimens, with the aim of maintaining their activity while reducing toxicity.

Methods:

Patients with histologically confirmed metastatic oesophageal or gastric carcinoma were randomised to receive weekly docetaxel (30 mg m⁻²) on days 1 and 8, cisplatin (60 mg m⁻²) on day 1, and 5-fluorouracil (200 mg m⁻² per day) continuously, every 3 weeks (weekly TCF, wTCF); or docetaxel (30 mg m⁻²) on days 1 and 8 and capecitabine (1600 mg m⁻² per day) on days 1–14, every 3 weeks (weekly TX, wTX).

Results:

A total of 106 patients were enrolled (wTCF, n=50; wTX, n=56). Response rates, the primary end point, were 47% with wTCF and 26% with wTX. Rates of febrile neutropenia were low in each arm. Median progression-free and overall survival times were 5.9 and 11.2 months for wTCF and 4.6 and 10.1 months for wTX, respectively.

Conclusion:

Weekly TCF and TX have encouraging activity and less haematological toxicity than TCF administered 3-weekly. Weekly docetaxel-based combination regimens warrant further evaluation in this disease.     

Docetaxel and capecitabine for advanced gastric cancer: investigating dose-dependent efficacy in two patient cohorts

Background:

No comparisons of different doses of docetaxel-capecitabine in patients with advanced gastric cancer have been performed.

Methods:

Patients with previously untreated metastatic/locally advanced gastro-oesophageal or gastric adenocarcinoma were enrolled in a prospective multicentre phase II trial. Two sequential cohorts received docetaxel 75 mg m⁻² (day 1) plus capecitabine 1000 mg m⁻² twice daily (days 1–14) (cohort I) or docetaxel 60 mg m⁻² (day 1) plus capecitabine 800 mg m⁻² twice daily (days 1–14) (cohort II) every 3 weeks. The primary end point was confirmed overall response rate.

Results:

In all, 91 patients were enrolled (cohort I, n=40; cohort II, n=51) and 87 were evaluable for efficacy (n=38, 49, respectively). Overall response rate was 50.0% in cohort I and 23.5% in cohort II (exploratory analysis, P=0.014). Median times to tumour progression and overall survival were 5.6 and 10.1 months in cohort I and 3.7 and 7.2 months in cohort II, respectively. Dose reductions for docetaxel and capecitabine were required in 50.0% and 57.5% of patients in cohort I and 11.8% and 15.7% in cohort II, respectively.

Conclusion:

Starting treatment with full doses and reducing promptly seems to be the more promisingly effective strategy than starting cautiously with lower doses. Docetaxel/capecitabine 75/2000 mg m⁻² is a manageable, convenient outpatient combination with promising efficacy against advanced gastric cancer.     

Cancer risk by combined levels of YKL-40 and C-reactive protein in the general population

Background:

YKL-40 and C-reactive protein (CRP) are biomarkers that may reflect cancer-related subclinical inflammation. We assessed elevated YKL-40 and CRP levels as combined risk predictors for cancer.

Methods:

We measured plasma YKL-40 and CRP at baseline in 8706 individuals from the Danish general population.

Results:

Hazard ratio (HR) of gastrointestinal cancer for a doubling of YKL-40 levels was 1.37 (95% CI: 1.17–1.61) and indifferent to adjustment for CRP levels. Hazard ratio of lung cancer for a doubling of CRP levels was 1.35 (1.17–1.56) and indifferent to adjustment for YKL-40 levels. Compared to individuals with both low CRP (<1.7 mg l⁻¹) and YKL-40 (<154 μg l⁻¹), individuals with high YKL-40 but low CRP had an HR of gastrointestinal cancer of 3.36 (1.70–6.64), whereas individuals with high CRP but low YKL-40 had an HR of lung cancer of 2.19 (1.24–3.87). The area under the receiver operating characteristic (ROC) curve was 0.68 for the ability of YKL-40 to predict gastrointestinal cancer and 0.67 for the ability of CRP to predict lung cancer.

Conclusion:

Elevated YKL-40 levels are associated with increased risk of gastrointestinal cancer, independently of CRP levels, whereas elevated CRP levels are associated with increased risk of lung cancer, independently of YKL-40 levels.     

Phase II and UGT1A1 genotype study of irinotecan dose escalation as salvage therapy for advanced gastric cancer

Background:

To assess the efficacy and safety of individualised dose optimisation of irinotecan monotherapy as salvage treatment for advanced gastric cancer (AGC).

Methods:

A total of 43 patients were enrolled. Intravenous irinotecan (350 mg m⁻²) was administered every 3 weeks. The dose was increased (425 mg m⁻² and 500 mg m⁻²) or decreased (250 mg m⁻²) depending on patient tolerance. UGT1A1 genotypes were determined by direct sequencing of genomic DNA extracted from peripheral blood.

Results:

A total of 183 cycles of irinotecan were administered, with a median of four cycles per patient. The overall response rate was 9.3%, and the disease control rate was 62.8%. Median time to disease progression was 2.8 months, and median overall survival was 8.0 months. Grade 3–4 neutropenia was the most common toxicity (53.5%), and febrile neutropenia was the least common toxicity (4.6%). Compared with defective allele groups, UGT1A1 *1/*1 was associated with a lower incidence of grade 3–4 neutropenia during the first cycle (P=0.018).

Conclusion:

Individualised irinotecan dose escalation based on patient tolerance was not associated with increased toxicity and shows modest activity as salvage chemotherapy for AGC. The role of UGT1A1 genotype in clinical toxicity requires further evaluation.     

Correlation of capecitabine-induced skin toxicity with treatment efficacy in patients with metastatic colorectal cancer: results from the German AIO KRK-0104 trial

Background:

The AIO KRK-0104 randomised phase II trial investigated the efficacy and safety of two capecitabine-based regimens: combination of capecitabine and irinotecan (CAPIRI) plus cetuximab (CAPIRI-C) and combination of capecitabine with oxaliplatin (CAPOX) plus cetuximab (CAPOX-C) in the first-line treatment of metastatic colorectal cancer (mCRC). Treatment-related skin toxicity (ST) was evaluated separately for capecitabine and cetuximab. The present analysis investigates the correlation of capecitabine-attributed ST (Cape-ST) and parameters of treatment efficacy.

Methods:

Patients with mCRC were randomised to cetuximab (400 mg m⁻², day 1, followed by 250 mg m⁻² weekly) plus CAPIRI (irinotecan 200 mg m⁻², day 1; capecitabine 800 mg m⁻², twice daily, days 1–14, every 3 weeks), or cetuximab plus CAPOX (oxaliplatin 130 mg m⁻², day 1; capecitabine 1000 mg m⁻², twice daily, days 1–14, every 3 weeks).

Results:

Of 185 recruited patients, 149 (CAPIRI-C, n=78; CAPOX-C, n=71) received study treatment beyond the first tumour assessment and were evaluable for efficacy. Capecitabine-attributed ST, predominantly hand–foot syndrome, was observed in 32.2% of patients. Capecitabine-attributed ST grade 1–3 was associated with a significantly higher disease control rate (DCR) (97.9 vs 86.1%, P=0.038) compared with grade 0 toxicity. Moreover, Cape-ST grade 1–3 related to a markedly longer progression-free survival (PFS) (9.9 vs 5.6 months, P<0.001) and overall survival (OS) (32.8 vs 22.4 months, P=0.008). Separate analyses of treatment arms indicated that the effect of Cape-ST on PFS remained significant for both arms, whereas the effect on OS remained apparent as a strong trend.

Conclusion:

This analysis supports the hypothesis that for the evaluated regimens, a correlation exists between Cape-ST and treatment efficacy regarding DCR, PFS, and OS.     

Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial

Background:

We assessed the effectiveness of cetuximab plus chronomodulated irinotecan, 5-fluorouracil (5-FU), leucovorin (FA) and oxaliplatin (L-OHP) (chrono-IFLO) administered as neoadjuvant chemotherapy to increase the resectability of colorectal liver metastases.

Methods:

This was a phase II prospective trial with rate of liver metastases resection as primary end point. Forty-three patients with unresectable metastases were enroled: 9 with metastases >5 cm; 29 with multinodular (>4) disease; 1 with hilar location; 4 with extrahepatic lung disease. Treatment consisted of cetuximab at day 1 plus chronomodulated irinotecan 5-FU, FA and L-OHP for 2–6 days every 2 weeks. After the first 17 patients, doses were reduced for irinotecan to 110 mg m⁻², 5-FU to 550 mg m⁻² per day and L-OHP to 15 mg m⁻² per day.

Results:

Macroscopically complete resections were performed in 26 out of 43 patients (60%) after a median of 6 (range 3–15) cycles. Partial response was noticed in 34 patients (79%). Median overall survival was 37 months (95% CI: 21–53 months), with a 2-year survival of 68% in the entire population, 80.6% in resected patients and 47.1% in unresected patients (P=0.01). Grade 3/4 diarrhoea occurred in 93% and 36% of patients before and after dose reduction.

Conclusion:

Cetuximab plus chrono-IFLO achieved 60% complete resectability of colorectal liver metastases.     

A novel, externally validated inflammation-based prognostic algorithm in hepatocellular carcinoma: the prognostic nutritional index (PNI)

Background:

There is increasing evidence that the presence of an ongoing systemic inflammatory response is a stage-independent predictor of poor outcome in patients with cancer. The aim of this study was to investigate whether an inflammation-based prognostic score, the prognostic nutritional index (PNI), is associated with overall survival (OS) in patients with hepatocellular carcinoma (HCC).

Methods:

All patients with a new diagnosis of HCC presenting to the Medical Oncology Department, Hammersmith Hospital between 1993 and 2011 (n=112) were included. Demographic and clinical data were collected. Patients in whom the combined albumin (g l⁻¹) × total lymphocyte count × 10⁹ l⁻¹ was ⩾45, at presentation, were allocated a PNI score of 0. Patients in whom this total score was <45 were allocated a score of 1. Univariate and multivariate analyses were performed to identify clinicopathological variables associated with OS. Independent predictors of survival identified on multivariate analysis were validated in an independent, stage-matched cohort of 68 patients.

Results:

Univariate analyses showed that PNI (P=0.003), intrahepatic spread (P<0.001), the presence of extrahepatic disease (P=0.006), portal vein thrombosis (P=0.02), tumour multifocality (P=0.003), alfa-fetoprotein >400 ng ml⁻¹ (P<0.001) and Barcelona Clinic Liver Cancer score (P<0.01) were all predictors of OS in the training set. Multivariate analysis revealed the PNI (P=0.05), presence of extrahepatic disease (P<0.001) and degree of intrahepatic spread (P<0.001) as independent predictors of worse OS in this population. The PNI retained independent prognostic value in the validation set (P<0.001).

Conclusion:

The presence of a systemic inflammatory response, as measured by the PNI, is an independent and externally validated predictor of poor OS in patients with HCC.     

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.     

A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours

Background:

To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin.

Methods:

Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg⁻¹ in combination with fixed doses of pemetrexed (500 mg m⁻²) plus cisplatin (75 mg m⁻²) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations.

Results:

Eighteen patients were enrolled. One patient dosed at 4 mg kg⁻¹ experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg⁻¹ cohort or the 6 mg kg⁻¹ dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ⩾3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted.

Conclusion:

The results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg⁻¹, to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.     

Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker

Background:

Histone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA.

Methods:

This phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin.

Results:

In total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day⁻¹ on days 1–3, followed by doxorubicin (20 mg m⁻²) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day⁻¹ of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day⁻¹. Non-dose-limiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for ⩾8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression.

Conclusion:

These findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day⁻¹. The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting.     

A Phase I clinical study of cisplatin-incorporated polymeric micelles (NC-6004) in patients with solid tumours

Background:

On the basis of preclinical studies of NC-6004, a cisplatin-incorporated micellar formulation, we hypothesised that NC-6004 could show lower toxicity than cisplatin and show greater anti-tumour activity in phase I study.

Methods:

A total of 17 patients were recruited in a range of advanced solid tumour types. NC-6004 was administered intravenously (i.v.) every 3 weeks. The dose escalation started at 10 mg m⁻² and was increased up to 120 mg m⁻² according to the accelerated titration method and modified Fibonacci method.

Results:

One dose-limiting toxicity (DLT) occurred in a patient who was given 90 mg m⁻² of NC-6004, otherwise any significant cisplatin-related toxicity was not observed or generally mild toxicity was observed. Despite the implementation of post-hydration and pre-medication regimen, renal impairment and hypersensitivity reactions still developed at 120 mg m⁻², which led to the conclusion that the maximum tolerated dose was 120 mg m⁻², and the recommended dose was 90 mg m⁻², although DLT was not defined as per protocol. Stable disease was observed in seven patients. The maximum concentration and area under the concentration–time curve of ultrafilterable platinum at 120 mg m⁻² NC-6004 were 34-fold smaller and 8.5-fold larger, respectively, than those for cisplatin.

Conclusion:

The delayed and sustained release of cisplatin after i.v. administration contributes to the low toxicity of NC-6004.     

Phase I trial of docetaxel, cisplatin and concurrent radical radiotherapy in locally advanced oesophageal cancer

Background:

Locally advanced oesophageal cancer (LAEC) is associated with poor survival and more effective treatments are needed. The aim of this phase I trial was to assess the maximum tolerated dose (MTD) of a novel weekly docetaxel and cisplatin regimen concurrent with radical radiotherapy.

Methods:

Patients with unresectable, non-metastatic LAEC were eligible. Treatment comprised docetaxel 15–30 mg m⁻² per week and cisplatin 15–30 mg m⁻² per week in six planned dose levels (DLs) in 3–6 patient cohorts with 50 Gy radiotherapy in 25 fractions. Maximum tolerated dose was based on defined dose-limiting toxicities (DLTs) during therapy and 2 weeks post therapy.

Results:

A total of 24 patients were enrolled. There were two DLTs: grade 3 fever in DL1 (docetaxel 15 mg m⁻², cisplatin 15 mg m⁻²) and grade 3 nausea in DL2 (20 mg m⁻², 15 mg m⁻²). These DLs were each expanded to six patients without further DLTs. The most common acute toxicity was grade 3 radiation oesophagitis (37.5%). There were no grade 4 toxicities, and haematologic toxicity was minimal. Cisplatin and docetaxel dose intensity was 100% at the highest dose level (DL6). A MTD was not reached in this trial. Tumour overall response rate was 50% (33% complete, 17% partial).

Conclusion:

Cisplatin and docetaxel each 30 mg m⁻² per week concurrent with 50 Gy radiotherapy is recommended for use in phase II clinical trials in oesophageal cancer.     

Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study

Background:

Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer.

Methods:

Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m⁻² plus irinotecan 250 mg m⁻² (Day 1)) or 3-weekly DF (docetaxel 85 mg m⁻² (Day 1) followed by 5-fluorouracil 750 mg m⁻² per day as a continuous infusion (Days 1–5)).

Results:

A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3–4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively).

Conclusion:

Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.     

Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

Background:

Cetuximab enhances the efficacy of chemotherapy in several cancer types. This trial assessed the activity of cetuximab and chemotherapy in advanced gastric cancer.

Methods:

Patients with previously untreated, metastatic, gastric cancer received cetuximab 400 mg m⁻² at first infusion followed by weekly infusions of 250 mg m⁻² combined with FUFOX (oxaliplatin 50 mg m⁻², 5-FU 2000 mg m⁻², and DL-folinic acid 200 mg m⁻² d1, 8, 15 and 22 qd36). The primary endpoint was tumour response.

Results:

Overall, 52 patients were enrolled. The most common grade 3/4 toxicities were diarrhoea (33%), and skin toxicity (24%). Efficacy was evaluable in 46 patients who showed a response rate of 65% (CI 95%: 50–79%) including four complete responses. Time to progression (TTP) was 7.6 months (CI 95%: 5.0–10.1 months) and overall survival (OS) was 9.5 months (CI 95%: 7.9–11.1 months). Epidermal growth factor receptor (EGFR) was detectable in 60% of tumours but showed no correlation with treatment outcome. A KRAS mutation was found in only 1 of 32 (3%) tumour samples analysed.

Conclusion:

Cetuximab plus FUFOX showed an interesting high response rate in metastatic gastric cancer. Cetuximab plus platinum–fluoropyrimidine chemotherapy is at present being investigated in a phase III randomised controlled trial.     

Phase I study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours

Background:

Preclinical studies suggest that histone deacetylase (HDAC) inhibitors may restore tumour sensitivity to retinoids. The objective of this study was to determine the safety, tolerability, and the pharmacokinetic (PK)/pharmacodynamic (PD) profiles of the HDAC inhibitor entinostat in combination with 13-cis retinoic acid (CRA) in patients with solid tumours.

Methods:

Patients with advanced solid tumours were treated with entinostat orally once weekly and with CRA orally twice daily × 3 weeks every 4 weeks. The starting dose for entinostat was 4 mg m⁻² with a fixed dose of CRA at 1 mg kg⁻¹ per day. Entinostat dose was escalated by 1 mg m⁻² increments. Pharmacokinetic concentrations of entinostat and CRA were determined by LC/MS/MS. Western blot analysis of peripheral blood mononuclear cells and tumour samples were performed to evaluate target inhibition.

Results:

A total of 19 patients were enroled. The maximum tolerated dose (MTD) was exceeded at the entinostat 5 mg m⁻² dose level (G3 hyponatremia, neutropenia, and anaemia). Fatigue (G1 or G2) was a common side effect. Entinostat exhibited substantial variability in clearance (147%) and exposure. CRA trough concentrations were consistent with prior reports. No objective responses were observed, however, prolonged stable disease occurred in patients with prostate, pancreatic, and kidney cancer. Data further showed increased tumour histone acetylation and decreased phosphorylated ERK protein expression.

Conclusion:

The combination of entinostat with CRA was reasonably well tolerated. The recommended phase II doses are entinostat 4 mg m⁻² once weekly and CRA 1 mg kg⁻¹ per day. Although no tumour responses were seen, further evaluation of this combination is warranted.     

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.