Elevated preoperative CEA is associated with worse survival in stage I-III rectal cancer patients

Background:

The objective of this investigation was to assess whether preoperative carcinoembryonic antigen (CEA) level is an independent predictor of overall survival in rectal cancer patients.

Methods:

All patients (n=504) undergoing a resection for stage I–III rectal cancer at the Kantonsspital St Gallen were included into a database between 1991 and 2008. The impact of preoperative CEA level on overall survival was assessed using risk-adjusted Cox proportional hazard regression models and propensity score methods.

Results:

In risk-adjusted Cox proportional hazard regression analyses, preoperative CEA level (hazard ratio (HR): 1.98, 95% confidence interval (CI): 1.36–2.90, P<0.001), distance from anal verge (<5 cm: HR: 1.93, 95% CI: 1.11–3.37; P=0.039), older age (HR: 1.07, 95% CI: 1.05–1.09; P<0.001), lower body mass index (HR: 0.94, 95% CI: 0.89–0.98; P=0.006), advanced tumour stage (stage II HR: 1.41, 95% CI: 0.85–2.32; stage III HR: 2.08, 95% CI: 1.31–3.31; P=0.004), R 1 resection (HR: 5.65, 95% CI: 1.59–20.1; P=0.005) and chronic kidney disease (HR: 2.28, 95% CI: 1.03–5.04; P=0.049) were all predictors for poor overall survival.

Conclusion:

This is one of the first investigations based on a large cohort of exclusively rectal cancer patients demonstrating that preoperative CEA level is a strong predictor of decreased overall survival. Preoperative CEA should be used as a prognostic factor in the preoperative assessment of rectal cancer patients.     

Correlation of BRCA1, TXR1 and TSP1 mRNA expression with treatment outcome to docetaxel-based first-line chemotherapy in patients with advanced/metastatic non-small-cell lung cancer

Background:

We explored the predictive significance of BRCA1, TXR1 and TSP1 expression in non-small-cell lung cancer (NSCLC) patients treated with docetaxel in association with cisplatin or gemcitabine.

Methods:

To analyse BRCA1, TXR1 and TSP1 mRNA expression from microdissected primary tumours of 131 patients with stage IIIB (wet) and IV NSCLC, RT–qPCR was used.

Results:

The mRNA levels of TXR1/TSP1 were inversely correlated (Spearman''s test: −0.37; P=0.001). Low TXR1 mRNA levels were associated with higher response rate (RR; P=0.018), longer median progression-free survival (PFS; P=0.029) and median overall survival (mOS P=0.003), whereas high TSP1 expression was correlated with higher RR (P=0.035), longer PFS (P<0.001) and mOS (P<0.001). Higher BRCA1 mRNA expression was associated with higher RR (P=0.028) and increased PFS (P=0.021), but not mOS (P=0.4). Multivariate analysis demonstrated that low TXR1/high TSP1 expression was an independent factor for increased PFS (HR 0.49; 95% CI 0.32–0.76; P<0.001) and mOS (HR 0.37; 95% CI 0.2–0.58; P<0.001), whereas high BRCA1 expression was correlated with increased PFS (HR 0.53; 95% CI 0.37–0.78; P=0.001).

Conclusions:

These data indicate that TXR1/TSP1 and BRCA1 expression could be used for the prediction of taxanes'' resistance in the treatment of NSCLC.     

Enzastaurin before and concomitant with radiation therapy,followed by enzastaurin maintenance therapy,in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation

Background

This study''s primary objective was evaluation of the progression-free survival rate at 6 months (PFS-6) in patients with newly diagnosed glioblastoma without O⁶-methylguanine-DNA-methyltransferase (MGMT) promoter hypermethylation postsurgically treated with enzastaurin before and concomitantly with radiation therapy, followed by enzastaurin maintenance therapy. PFS-6 of at least 55% was set to be relevant compared with the data of the EORTC 26981/22981 NCIC CE.3 trial.

Methods

Adult patients with a life expectancy of at least 12 weeks who were newly diagnosed with a histologically proven supratentorial glioblastoma without MGMT promoter hypermethylation were eligible. Patients were treated with enzastaurin prior to, concomitantly with, and after standard partial brain radiotherapy. Here we report on a multicenter, open-label, uncontrolled phase II study of patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation treated with enzastaurin and radiation therapy within 4 study periods.

Results

PFS-6 was 53.6% (95% confidence interval [CI]: 39.8–65.6). The median overall survival was 15.0 months (95% CI: 11.9–17.9) for all patients, 3.9 months (95% CI: 0.8–9.0) for patients with biopsy, 15.4 months (95% CI: 10.1–17.9) for patients with partial resection, and 18.9 months (95% CI: 13.9–28.5) for patients with complete resection. The safety profile in this study was as expected from previous trials, and the therapy was well tolerated.

Conclusions

PFS-6 missed the primary planned outcome of 55%. The secondary exploratory analysis according to resection status of the different subgroups of patients with biopsies, partial resection, and complete resection demonstrates the strong prognostic influence of resection on overall survival.     

Docetaxel and epirubicin compared with docetaxel and prednisone in advanced castrate-resistant prostate cancer: a randomised phase II study

Background:

This randomised phase II study compared the activity and safety of the combination docetaxel (D)/epirubicin (EPI) with the conventional treatment D/prednisone (P) in advanced castrate-resistant prostate cancer (CRPC) patients.

Materials and methods:

Patients were randomly assigned to D 30 mg m⁻² as intravenous infusion (i.v.) and EPI 30 mg m⁻² i.v. every week (D/EPI arm), or D 70 mg m⁻² i.v. every 3 weeks and oral P 5 mg twice daily (D/P arm). Chemotherapy was administered until disease progression or unacceptable toxicity.

Results:

A total of 72 patients were enrolled in the study and randomly assigned to treatment: 37 to D/EPI and 35 to D/P. The median progression-free survival (PFS) was 11.1 months (95% CI 9.2–12.6 months) in the D/EPI arm and 7.7 months (95% CI 5.7–9.4 months) in the D/P arm (P=0.0002). The median survival was 27.3 months (95% CI 22.1–30.8 months) in the D/EPI arm and 19.8 months (95% CI 14.4–24.8 months) in the D/P arm (P=0.003). Both regimens were generally well tolerated.

Conclusion:

The treatment of advanced CRPC with weekly D combined with weekly EPI was feasible and tolerable, and led to superior PFS than the treatment with 3-weekly D and oral P.     

A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer

Background:

This multicentre randomised phase III trial was designed to determine whether adjuvant chemotherapy with gemcitabine improves the outcomes of patients with resected pancreatic cancer.

Methods:

Eligibility criteria included macroscopically curative resection of invasive ductal carcinoma of the pancreas and no earlier radiation or chemotherapy. Patients were randomly assigned at a 1 : 1 ratio to either the gemcitabine group or the surgery-only group. Patients assigned to the gemcitabine group received gemcitabine at a dose of 1000 mg m⁻² over 30 min on days 1, 8 and 15, every 4 weeks for 3 cycles.

Results:

Between April 2002 and March 2005, 119 patients were enrolled in this study. Among them, 118 were eligible and analysable (58 in the gemcitabine group and 60 in the surgery-only group). Both groups were well balanced in terms of baseline characteristics. Although heamatological toxicity was frequently observed in the gemcitabine group, most toxicities were transient, and grade 3 or 4 non-heamatological toxicity was rare. Patients in the gemcitabine group showed significantly longer disease-free survival (DFS) than those in the surgery-only group (median DFS, 11.4versus 5.0 months; hazard ratio=0.60 (95% confidence interval (CI): 0.40–0.89); P=0.01), although overall survival did not differ significantly between the gemcitabine and surgery-only groups (median overall survival, 22.3 versus 18.4 months; hazard ratio=0.77 (95% CI: 0.51–1.14); P=0.19).

Conclusion:

The current results suggest that adjuvant gemcitabine contributes to prolonged DFS in patients undergoing macroscopically curative resection of pancreatic cancer.     

Gemcitabine, oxaliplatin and 5-FU in advanced bile duct and gallbladder carcinoma: two parallel, multicentre phase-II trials

Background:

Gemcitabine, oxaliplatin and 5-fluorouracil (5-FU) are active in biliary tract cancer and have a potentially synergistic mode of action and non-overlapping toxicity. The objective of these trials was to determine response, survival and toxicity separately in patients with bile duct cancer (BDC) and gallbladder cancer (GBC) treated with gemcitabine/oxaliplatin/5-FU chemotherapy.

Methods:

Eligible patients with histologically proven, advanced or metastatic BDC (n=37) or GBC (n=35) were treated with gemcitabine (900 mg m⁻² over 30 min), oxaliplatin (65 mg m⁻²) and 5-FU (1500 mg m⁻² over 24 h) on days 1 and 8 of a 21-day cycle. Tumour response was the primary outcome measure.

Results:

Response rates were 19% (95% CI: 6–32%) and 23% (95% CI: 9–37%) for BDC and GBC, respectively. Median survivals were 10.0 months (95% CI: 8.6–12.4) and 9.9 months (95% CI: 7.5–12.2) for BDC and GBC, respectively, and 1- and 2-year survival rates were 40 and 23% in BDC and 34 and 6% in GBC (intention-to-treat analysis). Major grade III and IV adverse events were neutropenia, thrombocytopenia, elevated bilirubin and anorexia.

Conclusion:

Triple-drug chemotherapy achieves comparable results for response and survival to previously reported regimens, but with more toxicity.     

Clinical utility of the Glasgow Prognostic Score in patients undergoing curative nephrectomy for renal clear cell cancer: basis of new prognostic scoring systems

Background:

Measurement of the systemic inflammatory response in malignancy has been recently refined using a selective combination of C-reactive protein and albumin (modified Glasgow Prognostic Score, mGPS). This has prognostic value in patients with metastatic kidney cancer. This study examines the prognostic value of the mGPS in patients undergoing curative nephrectomy for clear cell cancer.

Methods:

Patients with localised renal cell carcinoma undergoing potentially curative resection between March 1997 and July 2007 in a single institution were prospectively studied. The mGPS, University of California Los Angeles Integrated Staging System (UISS), ‘Stage Size Grade Necrosis'' (SSIGN), Kattan and Leibovich scores were constructed.

Results:

A total of 169 patients were studied. The minimum follow-up was 49 months; the median follow-up of the survivors was 98 months. During this period, 35 patients died of their cancer; a further 24 patients died of intercurrent disease. On univariate survival analysis of the scoring systems, Kattan (P<0.05), UISS (P<0.001), SSIGN (P<0.001) and Leibovich (P<0.001) were significantly associated with cancer-specific survival. Using cancer-specific mortality at 4 years as an endpoint, the area under the receiver operator curve was 0.726 (95% CI 0.629–0.822; P=0.001) for Kattan, 0.776 (95% CI 0.671–0.880; P<0.001) for UISS, 0.812 (95% CI 0.733–0.892; P<0.001) for SSIGN, 0.778 (95% CI 0.666–0.889; P<0.001) for Leibovich and 0.800 (95% CI 0.687–0.912; P<0.001) for the mGPS scoring system. On multivariate analysis of significant independent scoring systems and mGPS, UISS (HR 3.08, 95% CI 1.54–6.19, P=0.002) and mGPS (HR 5.13, 95% CI 2.89–9.11, P<0.001) were significant independent predictors of cancer-specific survival.

Conclusions:

The present prospective study shows that the mGPS, an inflammation-based prognostic score, is at least equivalent to and independent of other current validated prognostic scoring systems for patients undergoing curative nephrectomy for renal clear cell cancer. The mGPS is simple, measured preoperatively, based on well-standardised, widely available protein assays, and therefore provides an objective and rational basis before treatment for future staging systems in patients with operable renal cancer.     

The relationship between tumour necrosis, tumour proliferation, local and systemic inflammation, microvessel density and survival in patients undergoing potentially curative resection of oesophageal adenocarcinoma

Background:

There is increasing evidence that the local and systemic inflammatory responses are associated with survival in oesophageal cancer. The aim of this study was to examine the relationship between tumour necrosis, tumour proliferation, local and systemic inflammation and microvessel density and survival in patients undergoing potentially curative resection of oesophageal adenocarcinoma.

Methods:

The interrelationship between tumour necrosis, tumour proliferation, local inflammatory response (Klintrup–Makinen criteria, intra-tumoural CD8+ lymphocyte and macrophage infiltration), systemic inflammatory response (modified Glasgow Prognostic score (mGPS)), and microvessel density was examined in 121 patients undergoing potentially curative resection for oesophageal adenocarcinoma (including type I and II tumours of the gastro-oesophageal junction).

Results:

Tumour necrosis was not significantly associated with any tumour measure other than the degree of differentiation. On multivariate analysis, only age (HR 1.93, 95% CI 1.23–3.04, P=0.004), mGPS (HR 2.91, 95% CI 1.51–5.62, P=0.001), positive to total lymph node ratio (HR 2.38, 95% CI 1.60–3.52, P<0.001) and macrophage infiltration (HR 1.49, 95% CI 1.02–2.18, P=0.041) were independently associated with cancer-specific survival in oesophageal adenocarcinoma. Intra-tumoural macrophages were associated with tumour proliferation (P<0.001) and CD8+ lymphocytes infiltration (P<0.01).

Conclusion:

The results of this study suggest that tumour necrosis does not link local and systemic inflammatory responses and is not significantly associated with survival. In contrast, tumour macrophage infiltration appears to have a central role in the proliferative activity and the coordination of the inflammatory cell infiltrate and is independently associated with poorer survival in patients with oesophageal adenocarcinoma.     

RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs

Background:

Bone metastases (BMs) are associated with poor outcome in metastatic clear-cell renal carcinoma (m-ccRCC) treated with anti-vascular endothelial growth factor tyrosine kinase inhibitors (anti-VEGFR-TKIs). We aimed to investigate whether expression in the primary tumour of genes involved in the development of BM is associated with outcome in m-ccRCC patients treated with anti-VEGFR-TKIs.

Methods:

Metastatic clear-cell renal cell carcinoma patients with available fresh-frozen tumour and treated with anti-VEGFR-TKIs. Quantitative real-time PCR (qRT–PCR) for receptor activator of NF-kB (RANK), RANK-ligand (RANKL), osteoprotegerin (OPG), the proto-oncogene SRC and DKK1 (Dickkopf WNT signalling pathway inhibitor-1). Time-to-event analysis by Kaplan–Meier estimates and Cox regression.

Results:

We included 129 m-ccRCC patients treated between 2005 and 2013. An elevated RANK/OPG ratio was associated with shorter median time to metastasis (HR 0.50 (95% CI 0.29–0.87); P=0.014), shorter time to BM (HR 0.54 (95% CI 0.31–0.97); P=0.037), shorter median overall survival (mOS) since initial diagnosis (HR 2.27 (95% CI 1.44–3.60); P=0.0001), shorter median progression-free survival (HR 0.44 (95% CI 0.28–0.71); P=0.001) and mOS (HR 0.31 (95% CI 0.19–0.52); P<0.0001) on first-line anti-VEGFR-TKIs in the metastatic setting. Higher RANK expression was associated with shorter mOS on first-line anti-VEGFR-TKIs (HR 0.46 (95% CI 0.29–0.73); P=0.001).

Conclusions:

RANK/OPG ratio of expression in primary ccRCC is associated with BM and prognosis in patients treated with anti-VEGFR-TKIs. Prospective validation is warranted.     

Chemotherapy increases long-term survival in patients with adult medulloblastoma—a literature-based meta-analysis

Background

Adult medulloblastoma is a potentially curable malignant entity with an incidence of 0.5–1 per million. Valid data on prognosis, treatment, and demographics are lacking, as most current knowledge stems from retrospective studies. Surgical resection followed by radiotherapy are accepted parts of treatment regimes; however, established prognostic factors and data clarifying the role of chemotherapy are missing.

Methods

We investigated 227 publications from 1969–2013, with 907 identifiable, individual patients being available for meta-analysis. Demographic data, risk stratification, and treatment of these patients were similar to previous cohorts.

Results

The median overall survival (mOS) was 65 months (95% CI: 54.6–75.3) , the 5-year overall survival was 50.9% with 16% of the patients dying more than 5 years after diagnosis. Incomplete resection, clinical and radiological signs for brainstem infiltration, and abstinence from radiotherapy were predictive of worse outcome. Metastatic disease at tumor recurrence was identified as a new prognostic factor, while neither metastasis at initial diagnosis nor desmoplastic/classic histology was correlated with survival. Patients receiving chemotherapy first-line survived significantly longer (mOS: 108 mo, 95% CI: 68.6–148.4) than patients treated with radiation alone (mOS: 57 mo, 95% CI: 39.6–74.4) or patients who received chemotherapy at tumor recurrence. This effect was not biased by tumor stage or decade of treatment. Importantly, (neo)adjuvant chemotherapy also significantly increased the chance for long-term survival (>5 y) compared with radiotherapy alone or chemotherapy at tumor recurrence.

Conclusions

This meta-analysis clarifies relevant prognostic factors and suggests that chemotherapy as part of first-line therapy improves overall survival and increases the proportion of patients with long-term survival.     

Bevacizumab in Combination With Radiotherapy and Temozolomide for Patients With Newly Diagnosed Glioblastoma Multiforme

Background.

Patients with a newly diagnosed glioblastoma multiforme (GBM) have a high risk of recurrent disease with a dismal outcome despite intensive treatment of sequential surgery and chemoradiotherapy with temozolomide (TMZ), followed by TMZ as a single agent. Bevacizumab (BV) may increase response rates to chemotherapy in the recurrent treatment setting of GBM. We hypothesized that a neoadjuvant treatment strategy for patients with newly diagnosed GBM using chemoradiotherapy plus BV would improve resectability and thus survival. We performed a phase II trial of the treatment strategy of BV plus chemoradiation to determine the safety of this combination in patients who had already undergone primary surgery for their GBM.

Methods.

After a biopsy (6 patients) or a resection (13 patients) of a newly diagnosed GBM, 19 patients received radiotherapy (30 fractions of 2 Gy) in combination with daily TMZ 75 mg/m² and BV 10 mg/kg on days 1, 14, and 28, followed by 6 monthly cycles of TMZ 150–200 mg/m² on days 1–5.

Results.

The overall response rate was 26%. Three patients had a complete response after resection, and in two patients, a complete response after resection followed by chemoradiation plus BV was seen. No grade 3–4 toxicities were observed during combination treatment. The median progression-free survival was 9.6 months (95% confidence interval [CI]: 4.3–14.4 months). The median overall survival was 16 months (95% CI: 8.1–26.3 months), similar to a matched control group that received standard chemoradiotherapy from our institution.

Conclusion.

Combination of bevacizumab with radiotherapy and TMZ is safe and feasible in patients with newly diagnosed GBM, but because of low response rates, this treatment strategy does not favor a neoadjuvant approach.     

Comparison of Carboplatin‐ and Cisplatin‐Based Concurrent Chemoradiotherapy in Locally Advanced Cervical Cancer Patients With Morbidity Risks

Purpose.

The aim of this study was to assess the activity and toxicity of primary carboplatin-based chemoradiotherapy (CarboRT) and to compare CarboRT with cisplatin-based chemoradiotherapy (CisRT) in patients with locally advanced cervical cancer and poor general condition.

Patients and Methods.

Fifty-one locally advanced cervical cancer patients with morbidity risks were prospectively enrolled between January 2007 and April 2010. Eligible patients received weekly intravenous CarboRT with carboplatin 100 mg/m², and a comparison was made with a historical patient group that received weekly CisRT with cisplatin 40 mg/m².

Results.

Median follow-up was 36 months (range: 4–66 months) in the CarboRT group and 53 months (range: 4–121 months) in the CisRT group. Compared with the historical CisRT group, the CarboRT group showed no statistically significant differences in recurrence (hazard ratio [HR], 1.21; 95% confidence interval [CI], 0.52–2.81) and survival (HR, 1.80; 95% CI, 0.49–6.54). The mean numbers of received cycles of CarboRT and CisRT were 7.5 ± 1.4 and 6.0 ± 1.8, respectively (p < .001). The rates of grade 3–4 toxicity were similar in the two groups.

Conclusions.

CarboRT was better tolerated than CisRT without compromising tumor response and survival in patients with locally advanced cervical cancer and poor general condition.     

Lower treatment intensity and poorer survival in metastatic colorectal cancer patients who live alone

Background:

Socioeconomic status (SES) and social support influences cancer survival. If SES and social support affects cancer treatment has not been thoroughly explored.

Methods:

A cohort consisting of all patients who were initially diagnosed with or who developed metastatic colorectal cancer (mCRC, n=781) in three Scandinavian university hospitals from October 2003 to August 2006 was set up. Clinical and socioeconomic data were registered prospectively.

Results:

Patients living alone more often had synchronous metastases at presentation and were less often treated with combination chemotherapy than those cohabitating (HR 0.19, 95% CI 0.04–0.85, P=0.03). Surgical removal of metastases was less common in patients living alone (HR 0.29, 95% CI 0.10–0.86, P=0.02) but more common among university-educated patients (HR 2.22, 95% CI 1.10–4.49, P=0.02). Smoking, being married and having children did not influence treatment or survival. Median survival was 7.7 months in patients living alone and 11.7 months in patients living with someone (P<0.001). Living alone remained a prognostic factor for survival after correction for age and comorbidity.

Conclusion:

Patients living alone received less combination chemotherapy and less secondary surgery. Living alone is a strong independent risk factor for poor survival in mCRC.     

Brain metastases free survival differs between breast cancer subtypes

Background:

Brain metastases (BM) are frequently diagnosed in patients with HER-2-positive metastatic breast cancer; in addition, an increasing incidence was reported for triple-negative tumours. We aimed to compare brain metastases free survival (BMFS) of breast cancer subtypes in patients treated between 1996 until 2010.

Methods:

Brain metastases free survival was measured as the interval from diagnosis of extracranial breast cancer metastases until diagnosis of BM. HER-2 status was analysed by immunohistochemistry and reanalysed by fluorescent in situ hybridisation if a score of 2+ was gained. Oestrogen-receptor (ER) and progesterone-receptor (PgR) status was analysed by immunohistochemistry. Brain metastases free survival curves were estimated with the Kaplan–Meier method and compared with the log-rank test.

Results:

Data of 213 patients (46 luminal/124 HER-2/43 triple-negative subtype) with BM from breast cancer were available for the analysis. Brain metastases free survival differed significantly between breast cancer subtypes. Median BMFS in triple-negative tumours was 14 months (95% CI: 11.34–16.66) compared with 18 months (95% CI: 14.46–21.54) in HER-2-positive tumours (P=0.001) and 34 months (95% CI: 23.71–44.29) in luminal tumours (P=0.001), respectively. In HER-2-positive patients, co-positivity for ER and HER-2 prolonged BMFS (26 vs 15 m; P=0.033); in luminal tumours, co-expression of ER and PgR was not significantly associated with BMFS. Brain metastases free survival in patients with lung metastases was significantly shorter (17 vs 21 months; P=0.014).

Conclusion:

Brain metastases free survival in triple-negative breast cancer, as well as in HER-2-positive/ER-negative, is significantly shorter compared with HER-2/ER co-positive or luminal tumours, mirroring the aggressiveness of these breast cancer subtypes.     

Phase II study of NGR-hTNF in combination with doxorubicin in relapsed ovarian cancer patients

Background:

The NGR-hTNF (asparagine–glycine–arginine–human tumour necrosis factor) is able to promote antitumour immune responses and to improve the intratumoural doxorubicin uptake by selectively damaging tumour blood vessels.

Methods:

Patients progressing after ⩾1 platinum/taxane-based regimen received NGR-hTNF 0.8 μg m⁻² and doxorubicin 60 mg m⁻² every 3 weeks. Primary endpoint was a Response Evaluation Criteria in Solid Tumors-defined response rate with a target of more than 6 out of 37 responding patients.

Results:

A total of 37 patients with platinum-free interval lower than 6 months (PFI<6; n=25), or between 6 and 12 months (PFI=6–12; n=12) were enrolled. Median baseline peripheral blood lymphocyte count (PBLC) was 1.6 per ml (interquartile range, 1.2–2.1). In all, 18 patients (49%) received more than 6 cycles. Febrile neutropaenia was registered in one patient (3%). Among 35 assessable patients, 8 (23% 95% CI 12–39%) had partial response (2 with PFI<6; 6 with PFI=6–12) and 15 (43%) had stable disease (10 with PFI<6; 5 with PFI=6–12). Median progression-free survival (PFS) was 5.0 months for all patients, 3.8 months for patients with PFI<6, and 7.8 months for patients with PFI=6–12. Median overall survival (OS) was 17.0 months. Patients with baseline PBLC higher than the first quartile had improved PFS (P=0.01) and OS (P=0.001).

Conclusion:

Tolerability and activity of this combination warrant further randomised testing in patients with PFI<6. The role of PBLC as a blood-based biomarker deserves further investigation.     

Venous thromboembolism is a relevant and underestimated adverse event in cancer patients treated in phase I studies

Background:

To investigate, retrospectively, the role of tumour histotype and antiangiogenic drugs for venous thromboembolism (VTE) development in advanced cancer patients treated in phase I studies.

Methods:

Patients enrolled and treated in phase I studies conducted by SENDO (Southern Europe New Drugs Organisation) were considered.

Results:

Data of 1415 patients were included in the analysis: 526 (37.2%) patients were males, median age was 57.3 years (range: 13–85). Fifty-six (3.96%) patients developed a VTE. At multivariate analysis gynaecologic (hazard ratio (HR): 2.8, 95% confidence interval (CI): 1.29–6.23, P=0.009) and gastrointestinal tumours (HR: 3.23, 95% CI: 1.18–8.87, P=0.023) as well as combination regimens of cytotoxic and antiangiogenic agents (HR: 2.6, 95% CI: 1.11–6.30, P=0.028), white blood cell >11 000 μl⁻¹ (HR: 2.59, 95% CI: 1.10–6.09, P=0.028) and haemoglobin<10 g dl⁻¹ (HR: 3.1, 95% CI: 1.07–8.94, P=0.037) were statistically correlated with VTE development. Venous thromboembolism was the fourth most common cause of drug discontinuation. The median time from first drug administration to discontinuation was 1.4 for VTE and 2.3 months for the other adverse events (P=0.02).

Conclusion:

Venous thromboembolism is a relatively common complication among patients treated in the context of phase I studies, and may lead to early drug discontinuation. A greater risk of developing VTE is associated with the diagnosis of gynaecologic and gastrointestinal tumours and the combined use of chemotherapy and antiangiogenic drugs.     

The role of Cathepsin S as a marker of prognosis and predictor of chemotherapy benefit in adjuvant CRC: a pilot study

Background:

The aim of this pilot retrospective study was to investigate the immunohistochemical expression of Cathepsin S (CatS) in three cohorts of colorectal cancer (CRC) patients (n=560).

Methods:

Prevalence and association with histopathological variables were assessed across all cohorts. Association with clinical outcomes was investigated in the Northern Ireland Adjuvant Chemotherapy Trial cohort (n=211), where stage II/III CRC patients were randomised between surgery-alone or surgery with adjuvant fluorouracil/folinic acid (FU/FA) treatment.

Results:

Greater than 95% of tumours had detectable CatS expression with significantly increased staining in tumours compared with matched normal colon (P>0.001). Increasing CatS was associated with reduced recurrence-free survival (RFS; P=0.03) among patients treated with surgery alone. Adjuvant FU/FA significantly improved RFS (hazard ratio (HR), 0.33; 95% CI, 0.12–0.89) and overall survival (OS; HR, 0.25; 95% CI, 0.08–0.81) among 36 patients with high CatS. Treatment did not benefit the 66 patients with low CatS, with a RFS HR of 1.34 (95% CI, 0.60–3.19) and OS HR of 1.33 (95% CI, 0.56–3.15). Interaction between CatS and treatment status was significant for RFS (P=0.02) and OS (P=0.04) in a multivariate model adjusted for known prognostic markers.

Conclusion:

These results signify that CatS may be an important prognostic biomarker and predictive of response to adjuvant FU/FA in CRC.     

Meta-analysis of immunohistochemical prognostic markers in resected pancreatic cancer

Background:

The potential prognostic value of several commonly investigated immunohistochemical markers in resected pancreatic cancer is variably reported. The objective of this study was to conduct a systematic review of literature evaluating p53, p16, smad4, bcl-2, bax, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression as prognostic factors in resected pancreatic adenocarcinoma and to conduct a subsequent meta-analysis to quantify the overall prognostic effect.

Methods:

Relevant literature was identified using Medline, EMBASE and ISI Web of Science. The primary end point was overall survival assessed on univariate analysis. Only studies analysing resected pancreatic adenocarcinoma were eligible for inclusion and the summary log_e hazard ratio (logHR) and variance were pooled using an inverse variance approach. Evidence of heterogeneity was evaluated using the χ² test for heterogeneity and its impact on the meta-analysis was assessed by the I² statisic. Hazard ratios greater than one reflect adverse survival associated with positive immunostaining.

Results:

Vascular endothelial growth factor emerged as the most potentially informative prognostic marker (11 eligible studies, n=767, HR=1.51 (95% confidence interval, CI=1.18–1.92)) with no evidence of any significant publication bias (Egger''s test, P=0.269). Bcl-2 (5 eligible studies, n=314, HR=0.51 (95% CI=0.38–0.68)), bax (5 studies, n=274, HR=0.63 (95% CI=0.48–0.83)) and p16 (3 studies, n=229, HR=0.63 (95% CI=0.43–0.92)) also returned significant overall survival differences, but in smaller patient series due to a lack of evaluable literature. Neither p53 (17 studies, n=925, HR=1.22 (95% CI=0.96–1.56)), smad4 (5 studies, n=540, HR=0.88 (95% CI=0.61–1.27)) nor EGFR (4 studies, n=250, HR=1.35 (95% CI=0.80–2.27)) was found to represent significant prognostic factors when analysing the pooled patient data. There was evidence of significant heterogeneity in four of the seven study groups.

Conclusion:

These results support the case for immunohistochemical expression of VEGF representing a significant and reproducible marker of adverse prognosis in resected pancreatic cancer.     

A randomised,double-blind,placebo-controlled phase 2 study of trebananib (AMG 386) in combination with FOLFIRI in patients with previously treated metastatic colorectal carcinoma

Background:

This phase 2 study evaluated trebananib (AMG 386), an investigational peptide-Fc fusion protein that neutralises the interaction between angiopoietins-1/2 and the Tie2 receptor, plus FOLFIRI as second-line treatment for patients with metastatic colorectal cancer.

Methods:

Patients had adenocarcinoma of the colon or rectum with progression within 6 months of receiving only one prior fluoropyrimidine/oxaliplatin-based chemotherapy regimen for metastatic disease. All patients received FOLFIRI and were randomised 2 : 1 to also receive intravenous trebananib 10 mg kg⁻¹ once weekly (QW) (Arm A) or placebo QW (Arm B). The primary end point was investigator-assessed progression-free survival (PFS).

Results:

One hundred and forty-four patients were randomised (Arms A/B, n=95/49). Median PFS in Arms A and B was 3.5 and 5.2 months (hazard ratio (HR) 1.23; 95% CI, 0.81–1.86; P=0.33) and median overall survival (OS) was 11.9 and 8.8 months, respectively (HR 0.90; 95% CI; 0.53–1.54; P=0.70). Objective response rate (ORR) was 14% and 0% in Arms A and B, respectively. Incidence of grade ⩾3 adverse events was similar between treatment arms (Arm A, 61% Arm B, 65%) and included pulmonary embolism (1%/4%), deep vein thrombosis (5%/2%), and hypertension (1%/0%).

Conclusion:

Administration of trebananib plus FOLFIRI did not prolong PFS compared with placebo plus FOLFIRI. Toxicities were manageable and consistent with those known for FOLFIRI and trebananib.