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Annals of Surgical Oncology

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Introduction

There is an urgent need for biomarkers to help predict prognosis and guide management of esophageal cancer. This review identifies, evaluates and meta-analyses the evidence for reported somatic and germline DNA sequence biomarkers of outcome and stage.

Methods

A systematic review was carried out of the PubMed, EMBASE and Cochrane databases (20 August 2014), in conjunction with the ASCO Level of Evidence scale for biomarker research. Meta-analyses were carried out for all reported markers associated with outcome measures by more than one study.

Results

Four thousand and four articles were identified, 762 retrieved and 182 studies included. There were 65 reported markers of survival or recurrence 12 (18.5%) were excluded due to multiple comparisons. Following meta-analysis, significant associations were seen for six tumor variants (mutant TP53 and PIK3CA, copy number gain of ERBB2/HER2, CCND1 and FGF3, and chromosomal instability/ploidy) and seven germline polymorphisms: ERCC1 rs3212986, ERCC2 rs1799793, TP53 rs1042522, MDM2 rs2279744, TYMS rs34743033, ABCB1 rs1045642 and MTHFR rs1801133. Twelve germline markers of treatment complications were reported; 10 were excluded. Two tumor and 15 germline markers (11 excluded) of chemo (radio)therapy response were reported. Following meta-analysis, associations were demonstrated for mutant TP53, ERCC1 rs11615 and XRCC1 rs25487. There were 41 tumor/germline reported markers of stage; 27 (65.9%) were excluded.

Conclusions

Numerous DNA markers of outcome and stage have been reported, yet few are backed by high-quality evidence. Despite this, a small number of variants appear reliable. These merit evaluation in prospective trials, within the context of high-throughput sequencing and gene expression.


Background

A wide variety of follow-up strategies are used for patients with colorectal cancer (CRC) after curative surgery. The aim of this study is to review the evidence of the impact of different follow-up strategies in patients with nonmetastatic CRC after curative surgery, in relation to overall survival and other outcomes.

Patients and methods

A systematic search of PubMed, EMBASE, SCOPUS and ISI Web of Knowledge up to June 2014 was carried out. Eligible studies were all randomized clinical trials comparing the effectiveness of different follow-up strategies after curative resection in nonmetastatic CRC.

Results

Eleven studies with n = 4055 participants were included in a meta-analysis. A significant improvement in overall survival was observed in patients with more intensive follow-up strategies [hazard ratio = 0.75; 95% confidence interval (CI) 0.66–0.86]. A higher probability of detection of asymptomatic recurrences [relative risk (RR) = 2.59; 95% CI 1.66–4.06], curative surgery attempted at recurrences (RR = 1.98; 95% CI 1.51–2.60), survival after recurrences (RR = 2.13; 95% CI 1.24–3.69), and a shorter time in detecting recurrences (mean difference = –5.23 months; 95% CI –9.58 to –0.88) was observed in the intervention group. There were no significant differences in the total tumor recurrences, nor in the mortality related to disease.

Conclusion

Intensive follow-up strategies improve overall survival, increase the detection of asymptomatic recurrences and curative surgery attempted at recurrence, and are associated with a shorter time in detecting recurrences. This more intensive follow-up could not be associated with an improvement in cancer-specific survival nor with an increased detection of total tumor recurrences. Follow-up with serum carcinoembryonic antigen and colonoscopies are related to an increase in overall survival.


Background

Outcomes of radiotherapy (RT) compared with chemotherapy (CT) remain poorly defined for clinical stage (CS) IIA and IIB seminoma. We aimed to evaluate the current role of the two treatment modalities in this setting of testicular seminoma.

Patients and methods

A systematic review and meta-analysis (MA) was carried out to identify all evaluable studies. Search was limited to studies published after 1990 and included the Medline, Embase databases, and abstracts from ASCO (GU), ESMO, AUA, and ASTRO meetings up to April 2014. Sensitivity analyses were applied including the following: CSIIA and CSIIB, paraortic + iliac RT only in both stages, RT dose (≥30 versus <30 Gy), and PEB/EP regimens only.

Results

Thirteen studies have been selected for MA on relapse outcome. No randomized trials compared RT and CT. There were 4 prospective and 9 retrospective studies, with a total of 607 patients receiving RT and 283 patients CT. The pooled relapse rate (RR) was similar between the RT [0.11, 95% confidence interval (CI) 0.08–0.14, P for heterogeneity = 0.096, I 2 = 38%] and CT groups (0.08, 95% CI 0.01–0.15, P for heterogeneity <0.001, I 2 = 82.5%). However, in the sensitivity analysis, the pooled RR for RT in CSIIB was 0.12 (95% CI 0.06–0.17) while it was 0.05 (95% CI 0–0.11) for CT. Long-term side-effects and incidence of second cancers were more frequently reported following RT. The overall incidence of nontesticular second malignancies was 0.04 (95% CI 0.01–0.02) in the RT group and 0.02 (95% CI 0.003–0.04) in the CT group.

Conclusions

Although RT and CT appeared to be equal options in CSIIA and IIB seminoma, a trend in favor of CT for a lower incidence of side-effects and RR in CSIIB was found. This evidence is limited by the retrospective quality of studies and their small sample size.


Background

Combining several anticancer agents can increase the overall antitumor action, but at the same time, it can also increase the overall observed toxicity. Adaptive dose-escalation designs for drug combinations have recently emerged as an attractive alternative to algorithm-based designs, and they seem more effective in combination recommendations. These methods are not used in practice currently. Our aim is to describe international scientific practices in the setting of phase I drug combinations in oncology.

Material and methods

A bibliometric study on phase I dose-finding combination trials was conducted using the Medline® PubMed database between 1 January, 2011, and 31 December 2013. Sorting by abstract, we selected all papers involving a minimum of two agents and then retained only those in which at least two agents were dose-escalated.

Results

Among the 847 references retrieved, 162 papers reported drug-combination phase I trials in which at least two agents were dose-escalated. In 88% of trials, a traditional or modified 3 + 3 dose-escalation design was used. All except one trial used a design developed for single-agent evaluation. Our study suggests that drug-combination phase I trials in oncology are very safe, as revealed by the calculated median dose-limiting toxicity rate of 6% at the recommended dose, which is far below the target rate in these trials (33%). We also examined requirements of phase I clinical trials in oncology with drug combinations and the potential advantages of novel approaches in early phases.

Conclusion

Efforts to promote novel and innovative approaches among statisticians and clinicians appear valuable. Adaptive designs have an important role to play in early phase development.


Background

Evidence on adjuvant chemotherapy in older women with breast cancer is poor. We tested whether weekly docetaxel is more effective than standard chemotherapy.

Patients and methods

We carried out a multicenter, randomized phase III study. Women aged 65–79, operated for breast cancer, with average to high risk of recurrence, were allocated 1 : 1 to CMF (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², fluorouracil 600 mg/m², days 1, 8) or docetaxel (35 mg/m2 days 1, 8, 15) every 4 weeks, for four or six cycles according to hormone receptor status. Primary end point was disease-free survival (DFS). A geriatric assessment was carried out. Quality of life (QoL) was assessed with EORTC C-30 and BR-23 questionnaires.

Results

From July 2003 to April 2011, 302 patients were randomized and 299 (152 allocated CMF and 147 docetaxel) were eligible. After 70-month median follow-up, 109 DFS events were observed. Unadjusted hazard ratio (HR) of DFS for docetaxel versus CMF was 1.21 [95% confidence interval (CI) 0.83–1.76, P = 0.32]; DFS estimate at 5 years was 0.69 with CMF and 0.65 with docetaxel. HR of death was 1.34 (95% CI 0.80–2.22, P = 0.26). There was no interaction between treatment arms and geriatric scales measuring patients' ability or comorbidities. Hematological toxicity, mucositis and nausea were worse with CMF; allergy, fatigue, hair loss, onychopathy, dysgeusia, diarrhea, abdominal pain, neuropathy, cardiac and skin toxicity were worse with docetaxel. One death was attributed to CMF and two to docetaxel. Increasing age, impairment in instrumental daily living activities, number of comorbidities and docetaxel treatment were independently associated with severe nonhematological toxicity. QoL was worse with docetaxel for nausea-vomiting, appetite loss, diarrhea, body image, future perspective, treatment side-effects and hair loss items.

Conclusions

Weekly docetaxel is not more effective than standard CMF as adjuvant treatment of older women with breast cancer and worsens QoL and toxicity.

ClinicalTrials.gov

NCT00331097.


Background

To assess the prognostic role of human epidermal growth factor receptor 2 (HER2) overexpression in patients with ductal carcinoma in situ (DCIS).

Patients and methods

We identified patients with HER2-positive DCIS among a population of 1667 cases, prospectively diagnosed and surgically treated at the European Institute of Oncology from 1996 to 2008. Rates of subsequent DCIS or invasive cancer in HER2-positive disease were estimated. We evaluated Cumulative Incidence of In Situ Breast Cancer Recurrence (isBCR), INvasive Breast Cancer Recurrence (IBCR) and any Breast Cancer Recurrence (BCR). isBCR, IBCR and BCR were defined as the time from surgery to breast cancer recurrence as first event (in situ, invasive or both, respectively) or last visit in case of no events.

Results

We identified 560 (33.5%) patients with HER2-positive DCIS. The median follow-up was 7.6 years (interquartile range 5.9–9.5). We observed 422 events out of 1667 patients, with 141 in situ recurrences, 201 invasive recurrences and 80 other events (64 second primaries and 16 deaths). The 10-year isBCR proportions were 11.8% [95% confidence interval (CI) 9.0% to 15.4%] in the HER2-positive group and 8.8% (95% CI 6.9% to 11.0%) in the HER2-negative group (Gray test, P = 0.010). At multivariable analysis, the adjusted risk of isBCR was higher in the HER2-positive group than in the HER2-negative group [hazard ratio (HR) HER2 positive versus negative: 1.59 (95% CI 1.06–2.39)]. We observed significant differences both in BCR and isBCR for patients treated by quadrantectomy without radiotherapy versus patients treated with radiotherapy [adjusted HR HER2 positive versus negative: 1.53 (95% CI 1.07–2.18) and adjusted HR HER2 positive versus negative: 2.18 (95% CI 2.18–3.69), respectively].

Conclusion

HER2 overexpression predicts an increased risk of isBCR. Radiotherapy reduces local failure rates in HER2-positive DCIS.


Background

New data on erythropoiesis-stimulating agents (ESAs) regarding overall survival and disease progression-related outcomes in patients with breast cancer receiving chemotherapy are presented in a meta-analysis of controlled trials of ESA use (epoetin α, epoetin β, darbepoetin α, biosimilars).

Patients and methods

A literature search identified reports from January 1997 through March 2014. We used company databases for Amgen, Inc., or Janssen studies and published data for other studies. Random-effects odds ratios (ORs) were calculated to compare results for patients randomized to ESA with those randomized to control.

Results

Deaths were reported for 571 of 2346 patients (24%) in the ESA groups and 523 of 2367 patients (22%) in the control groups [OR, 1.20; 95% confidence interval (CI) 1.03–1.40]. Sensitivity analyses were conducted to explore the effects of individual studies and exclusion of one study (BEST) resulted in an OR for death of 1.12 (95% CI 0.94–1.34). In seven studies reporting progression-related end points (N = 4197; ESA n = 2088; control n = 2109), the OR was 1.01 (95% CI 0.87–1.16) for ESA compared with control.

Conclusions

After incorporating recent results of ESA use in patients with breast cancer, risks of survival and progression-free survival remain consistent with previously published data.


Background

The discussion on the role of adjuvant chemotherapy for rectal cancer patients treated according to current guidelines is still ongoing. A multicentre, randomized phase III trial, PROCTOR-SCRIPT, was conducted to compare adjuvant chemotherapy with observation for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision (TME).

Patients and methods

The PROCTOR-SCRIPT trial recruited patients from 52 hospitals. Patients with histologically proven stage II or III rectal adenocarcinoma were randomly assigned (1:1) to observation or adjuvant chemotherapy after preoperative (chemo)radiotherapy and TME. Radiotherapy consisted of 5 x 5 Gy. Chemoradiotherapy consisted of 25 x 1.8–2 Gy combined with 5-FU-based chemotherapy. Adjuvant chemotherapy consisted of 5-FU/LV (PROCTOR) or eight courses capecitabine (SCRIPT). Randomization was based on permuted blocks of six, stratified according to centre, residual tumour, time between last irradiation and surgery, and preoperative treatment. The primary end point was overall survival.

Results

Of 470 enrolled patients, 437 were eligible. The trial closed prematurely because of slow patient accrual. Patients were randomly assigned to observation (n = 221) or adjuvant chemotherapy (n = 216). After a median follow-up of 5.0 years, 5-year overall survival was 79.2% in the observation group and 80.4% in the chemotherapy group [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.62–1.39; P = 0.73]. The HR for disease-free survival was 0.80 (95% CI 0.60–1.07; P = 0.13). Five-year cumulative incidence for locoregional recurrences was 7.8% in both groups. Five-year cumulative incidence for distant recurrences was 38.5% and 34.7%, respectively (P = 0.39).

Conclusion

The PROCTOR-SCRIPT trial could not demonstrate a significant benefit of adjuvant chemotherapy with fluoropyrimidine monotherapy after preoperative (chemo)radiotherapy and TME on overall survival, disease-free survival, and recurrence rate. However, this trial did not complete planned accrual.

Registration number

Dutch Colorectal Cancer group, CKTO 2003-16, ISRCTN36266738.


Background

For patients with initially unresectable liver metastases from colorectal cancer, chemotherapy can downsize metastases and facilitate secondary resection. We assessed the efficacy of bevacizumab plus modified FOLFOX-6 (5-fluorouracil/folinic acid, oxaliplatin) or FOLFOXIRI (5-fluorouracil/folinic acid, oxaliplatin, irinotecan) in this setting.

Patients and methods

OLIVIA was a multinational open-label phase II study conducted at 16 centres in Austria, France, Spain, and the UK. Patients with unresectable liver metastases were randomised to bevacizumab (5 mg/kg) plus mFOLFOX-6 [oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, 5-fluorouracil 400 mg/m2 (bolus) then 2400 mg/m2 (46-h infusion)] or FOLFOXIRI [oxaliplatin 85 mg/m2, irinotecan 165 mg/m2, folinic acid 200 mg/m2, 5-fluorouracil 3200 mg/m2 (46-h infusion)] every 2 weeks. Unresectability was defined as ≥1 of the following criteria: no possibility of upfront R0/R1 resection of all lesions; <30% residual liver volume after resection; metastases in contact with major vessels of the remnant liver. Resectability was evaluated by multidisciplinary review. The primary end point was overall resection rate (R0/R1/R2). Efficacy end points were analysed by intention-to-treat analysis.

Results

In patients assigned to bevacizumab–FOLFOXIRI (n = 41) or bevacizumab–mFOLFOX-6 (n = 39), the overall resection rate was 61% [95% confidence interval (CI) 45% to 76%] and 49% (95% CI 32% to 65%), respectively (difference 12%; 95% CI –11% to 36%). R0 resection rates were 49% and 23%, respectively. Overall tumour response rates were 81% (95% CI 65% to 91%) with bevacizumab–FOLFOXIRI and 62% (95% CI 45% to 77%) with bevacizumab–mFOLFOX-6. Median progression-free survival (PFS) was 18·6 (95% CI 12.9–22.3) months and 11·5 (95% CI 9.6–13.6) months, respectively. The most common grade 3–5 adverse events were neutropenia (bevacizumab–FOLFOXIRI, 50%; bevacizumab–mFOLFOX-6, 35%) and diarrhoea (30% and 14%, respectively).

Conclusions

Bevacizumab–FOLFOXIRI was associated with higher response and resection rates and prolonged PFS versus bevacizumab–mFOLFOX-6 in patients with initially unresectable liver metastases from colorectal cancer. Toxicity was increased but manageable with bevacizumab–FOLFOXIRI.

ClinicalTrials.gov

NCT00778102.


Background

Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy.

Patients and methods

In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4–6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%.

Results

The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1–5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8–3.8) months for no continuation; HR 0.74 (95% CI 0.58–0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63–1.1; P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ~30 000 USD per patient.

Conclusions

Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4–6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy.

Clinical trial registration:

ClinicalTrials.gov, number NCT00544700.


Background

Adjuvant oxaliplatin plus capecitabine or leucovorin/5-fluorouracil (LV/5-FU) (XELOX/FOLFOX) is the standard of care for stage III colon cancer (CC); however, there is disagreement regarding oxaliplatin benefit in patients aged >70. In most analyses, the impact of medical comorbidity (MC) has not been assessed. Efficacy and safety of adjuvant XELOX/FOLFOX versus LV/5-FU were compared with respect to age and MC using pooled data from four randomized, controlled trials, selected for access to patient-level MC data and including commonly endorsed and utilized regimens.

Patients and methods

Individual data from patients with stage III CC in NSABP C-08, XELOXA, X-ACT, and AVANT were pooled, excluding bevacizumab-treated patients. Patients were grouped by treatment, MC (low versus high), or age (<70 versus ≥70), and compared for disease-free survival (DFS), overall survival (OS), and adverse events (AEs). Multivariable Cox proportional hazards regression controlled for gender, T stage, and N stage.

Results

DFS benefits were shown for XELOX/FOLFOX versus LV/5-FU regardless of age or MC, although benefits were modestly attenuated for patients aged ≥70. Hazard ratios were 0.68 (P < 0.0001) and 0.77 (P < 0.014) for <70 and ≥70 age groups; 0.69 (P < 0.0001) and 0.59 (P < 0.0001) for Charlson Comorbidity Index ≤1 and >1 groups; and 0.70 (P < 0.0001) and 0.58 (P < 0.0001) for National Cancer Institute Combined Index ≤1 and >1 groups. OS was also significantly improved in all groups. Grade 3/4 serious AE rates were comparable across cohorts and MC scores and higher in patients aged ≥70. Oxaliplatin-relevant grade 3/4 AEs, including neuropathy, were comparable across ages and MC scores.

Conclusions

Results further support consideration of XELOX or FOLFOX as standard treatment options for the adjuvant management of stage III CC in all age groups and in patients with comorbidities, consistent with those who were eligible for these clinical trials.


Background

The combination of bevacizumab with fluorouracil-based chemotherapy is a standard first-line treatment option in metastatic colorectal cancer (mCRC). We studied the efficacy of continuing or reintroducing bevacizumab in combination with second-line chemotherapy after progression to bevacizumab-based first-line therapy.

Patients and methods

In this phase III study, patients with mCRC treated with fluoropyrimidine-based first-line chemotherapy plus bevacizumab were randomized to receive in second-line mFOLFOX-6 or FOLFIRI (depending on first-line regimen) with or without bevacizumab. The primary end point was progression-free survival. To detect a hazard ratio (HR) for progression of 0.70 with an α and β error of 0.05 and 0.20, respectively, 262 patients were required.

Results

In consideration of the results of the ML18147 trial, the study was prematurely stopped. Between April 2008 and May 2012, a total of 185 patients were randomized. Bevacizumab-free interval was longer than 3 months in 43% of patients in chemotherapy alone arm and in 50% of patients in the bevacizumab arm. At a median follow-up of 45.3 months, the median progression-free survival was 5.0 months in the chemotherapy group and 6.8 months in the bevacizumab group [adjusted HR = 0.70; 95% confidence interval (CI) 0.52–0.95; stratified log-rank P = 0.010]. Subgroup analyses showed a consistent benefit in all subgroups analyzed and in particular in patients who had continued or reintroduced bevacizumab. An improved overall survival was also observed in the bevacizumab arm (adjusted HR = 0.77; 95% CI 0.56–1.06; stratified log-rank P = 0.043). Responses (RECIST 1.0) were similar in the chemotherapy and bevacizumab groups (17% and 21%; P = 0.573). Toxicity profile was consistent with previously reported data.

Conclusions

This study demonstrates that the continuation or the reintroduction of bevacizumab with second-line chemotherapy beyond first progression improves the outcome and supports the use of this strategy in the treatment of mCRC.

Clinical Trials.gov number

NCT00720512.


Introduction

KRAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs). We investigated the frequency, co-occurrence, and distribution of acquired KRAS and EGFR mutations in patients with mCRC refractory to anti-EGFR mAbs using circulating tumor DNA (ctDNA).

Patients and methods

Sixty-two post-treatment plasma and 20 matching pretreatment archival tissue samples from KRAS wt mCRC patients refractory to anti-EGFR mAbs were evaluated by high-sensitivity emulsion polymerase chain reaction for KRAS codon 12, 13, 61, and 146 and EGFR 492 mutations.

Results

Plasma analyses showed newly detectable EGFR and KRAS mutations in 5/62 [8%; 95% confidence interval (CI) 0.02–0.18] and 27/62 (44%; 95% CI 0.3–0.56) samples, respectively. KRAS codon 61 and 146 mutations were predominant (33% and 11%, respectively), and multiple EGFR and/or KRAS mutations were detected in 11/27 (41%) cases. The percentage of mutant allele reads was inversely correlated with time since last treatment with EGFR mAbs (P = 0.038). In the matching archival tissue, these mutations were detectable as low-allele-frequency clones in 35% of patients with plasma mutations after treatment with anti-EGFR mAbs and correlated with shorter progression-free survival (PFS) compared with the cases with no new mutations (3.0 versus 8.0 months, P = 0.0004).

Conclusion

Newly detected KRAS and/or EGFR mutations in plasma ctDNA from patients refractory to anti-EGFR treatment appear to derive from rare, pre-existing clones in the primary tumors. These rare clones were associated with shorter PFS in patients receiving anti-EGFR treatment. Multiple simultaneous mutations in KRAS and EGFR in the ctDNA and the decline in allele frequency after discontinuation of anti-EGFR therapy in a subset of patients suggest that several resistance mechanisms can co-exist and that relative clonal burdens may change over time. Monitoring treatment-induced genetic alterations by sequencing ctDNA could identify biomarkers for treatment screening in anti-EGFR-refractory patients.


Background

Screening programmes for contralateral carcinoma in situ (CIS) testis in patients with unilateral germ-cell cancer (GCC) have never been evaluated. We investigated the effect of screening for contralateral CIS in a large nation-wide, population-based study.

Patients and methods

A contralateral single-site biopsy was offered to 4130 patients in whom GCC had been diagnosed in 1984–2007 (screened cohort); 462 patients in whom GCC was diagnosed in 1984–1988 comprised the unscreened cohort. Cases with CIS were offered radiotherapy. Initially CIS-negative biopsies in patients with metachronous GCC were revised according to today's standards. Risk for metachronous GCC was estimated using cumulative incidence and the Cox proportional hazards model.

Results

In the screened cohort, contralateral CIS was found in 181 (4.4%) patients. The cumulative incidence of metachronous GCC after 20 years was 1.9% in the screened cohort and 3.1% in the unscreened cohort (P = 0.097), hazard ratio (HR) for the unscreened cohort: 1.59 (P = 0.144). Expert revision with contemporary methodology of CIS-negative biopsy samples from patients with metachronous cancer revealed CIS in 17 out of 45 (38%) cases. Decreased risks for metachronous GCC were related to older age at diagnosis (HR 0.52 per 10 years, P < 0.001) and chemotherapy (HR 0.35, P = 0.002). Limitations include the small number of patients in the unscreened cohort and the retrospective study design.

Conclusions

Our evaluation of a national population-based screening programme for contralateral CIS in patients with testicular cancer showed no significant difference in the risk for metachronous GCC between a screened and an unscreened cohort. Single-site biopsy including modern immunohistochemistry does not identify all cases of CIS.


Background

The neutrophil-to-lymphocyte ratio (NLR), a marker of host inflammation, has been associated with poor outcome in several solid tumors. Here, we investigated associations of the derived NLR (dNLR) and duration of initial androgen deprivation therapy (ADT) with survival of men with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line chemotherapy.

Patients and methods

Data from the multinational randomized phase III studies VENICE and TAX327 included a total of 2230 men with mCRPC randomized to receive first-line chemotherapy, and were used as training and validation sets, respectively. Associations of dNLR and duration of initial ADT with overall survival (OS) were evaluated by multivariable Cox regression analysis in the training set stratified for performance status and treatment arm. The model was then tested in the validation set. Subsequently, we investigated the treatment effect of docetaxel on OS in subgroups according to dNLR and duration of initial ADT.

Results

In the training set, both dNLR ≥median (2) and duration of initial ADT <median (15 months) were associated with increased risk of death [hazard ratio (HR) 1.29; 95% confidence interval (CI) 1.11–1.50, P < 0.001 and HR 1.41; 95% CI 1.21–1.64, P < 0.001, respectively] after adjustment for age, alkaline phosphatase, hemoglobin, and pain at baseline. In the validation set, dNLR remained an independent prognostic factor for OS (HR 1.43; 95% CI 1.20–1.70, P < 0.001), whereas duration of initial ADT was not (HR 1.16; 95% CI 0.97–1.37, P = 0.10). In subgroup analyses of the TAX327 study, docetaxel improved OS irrespective of dNLR and duration of initial ADT.

Conclusion

The dNLR was prognostic for OS in men with mCRPC receiving first-line chemotherapy in two randomized phase III trials. A high dNLR (≥2) was associated with shorter survival irrespective of the received treatment. This readily available biomarker may serve for risk stratification in future clinical trials and could be incorporated into prognostic nomograms.

Clinical Trials number

NCT00519285.


Background

The neutrophil–lymphocyte ratio (NLR), proposed as an indicator of cancer-related inflammation, has known prognostic value in prostate cancer. We examine its association with survival (OS) and response in patients treated with second-line chemotherapy.

Methods

We analysed patients with metastatic castration-resistant prostate cancer (mCRPC) treated in the TROPIC trial, evaluating cabazitaxel versus mitoxantrone. Cox regression models were used to investigate the association of baseline NLR (BLNLR) with OS and the significance of a change in NLR count with treatment. Logistic regression models were used to determine the association of BLNLR counts with prostate specific antigen (PSA) and RECIST responses. The optimal NLR cut-off was established based on the concordance index of different values.

Results

Data from 755, 654 and 405 patients was available for OS, PSA and RECIST response analysis respectively. Median OS was 14.0 months [95% confidence interval (CI) 13.2–14.8]. Median NLR was 2.9 (IQR: 1.9–5.1). BLNLR was associated with survival (HR 1.5, 95% CI 1.1–2.1, P = 0.011) in multivariable analysis (MVA) independently of variables included in the Halabi nomogram, treatment arm and corticosteroid use. The optimal cut-off for a dichotomous NLR was selected at 3.0 based on its higher c-index related to survival. BLNLR ≥3.0 was associated with lower PSA response (40.1% versus 59.9%; P < 0.001) and RECIST response (7.7% versus 15.6%, P = 0.022) in MVA. Conversion from high (≥3) to low (<3) NLR was associated with improved survival (HR 0.66; 95% CI 0.51–0.85; P = 0.001) and higher PSA response rates (66.4% versus 33.6%; P = 0.000). Use of corticosteroids at baseline did not modify the association between NLR and survival.

Conclusions

NLR is a valid prognostic biomarker in CRPC and is associated with survival, PSA and RECIST responses in patients treated with second-line chemotherapy. Changes in NLR counts with treatment may indicate benefit. NLR prognostic value is independent of prior use of corticosteroids.

ClinicalTrials.gov

NCT00417079.


Background

A rare recurrent missense variant in HOXB13 (rs138213197/G84E) was recently reported to be associated with hereditary prostate cancer. Population-based studies have established that, since the frequency of this single-nucleotide polymorphism (SNP) varies between geographic regions, the associated proportion of prostate cancer (PrCa) risk contribution is also highly variable by country.

Patients and methods

This is the largest comprehensive case–control study assessing the prevalence of the HOXB13 G84E variant to date and is the first in the UK population. We genotyped 8652 men diagnosed with PrCa within the UK Genetic Prostate Cancer Study (UKGPCS) and 5252 healthy men from the UK ProtecT study.

Results

HOXB13 G84E was identified in 0.5% of the healthy controls and 1.5% of the PrCa cases, and it was associated with a 2.93-fold increased risk of PrCa [95% confidence interval (CI) 1.94–4.59; P = 6.27 x 10–8]. The risk was even higher among men with family history of PrCa [odds ratio (OR) = 4.53, 95% CI 2.86–7.34; P = 3.1 x 10–8] and in young-onset PrCa (diagnosed up to the age of 55 years; OR = 3.11, 95% CI 1.98–5.00; P = 6.1 x 10–7). There was no significant association between Gleason Score, presenting prostate specific antigen, tumour–node–metastasis (TNM) stage or NCCN risk group and carrier status. HOXB13 G84E was not associated with overall or cancer-specific survival. We found that the polygenic PrCa risk score (PR score), calculated using the 71 known single-nucleotide polymorphisms (SNPs) associated with PrCa and the HOXB13 G84E variant act multiplicatively on PrCa risk. Based on the estimated prevalence and risk, this rare variant explains ~1% of the familial risk of PrCa in the UK population.

Conclusions

The clinical importance of HOXB13 G84E in PrCa management has not been established. This variant was found to have no effect on prognostic implications but could be used for stratifying screening, by identifying men at high risk.

Clinical Trials Numbers

Prostate Testing for Cancer and Treatment (ProtecT): NCT02044172.

UK Genetic Prostate Cancer Study

Epidemiology and Molecular Genetics Studies (UKGPCS): NCT01737242.


Background

It is unclear whether treating brain metastasis before starting systemic chemotherapy can improve survival compared with upfront chemotherapy in non-small-cell lung cancer (NSCLC) with asymptomatic cerebral oligo-metastases.

Patients and methods

We undertook a randomized, controlled trial of 105 patients with one to four brain metastases, admitted to Samsung Medical Center between 2008 and 2013. Patients were randomly assigned to receive stereotactic radiosurgery (SRS) (49 patients) followed by chemotherapy or upfront chemotherapy (49 patients). The primary end point was overall survival (OS) and secondary end points included central nervous system (CNS) progression-free survival, progression to symptomatic brain metastasis and brain functional outcome.

Results

The median age was 58 years (range, 29–85) with ECOG 0–1 performance status, and 40% of patients were never smokers. Most patients had adenocarcinoma, and about half of patients had only one brain metastasis, while the rest had multiple cerebral metastases. The median OS time was 14.6 months [95% confidence interval (CI), 9.2–20.0] in the SRS group and 15.3 months (95% CI, 7.2–23.4) for the upfront chemotherapy group (P = 0.418). There was no significant difference in time to CNS disease progression [median, 9.4 months (SRS) versus 6.6 months (upfront chemotherapy), P = 0.248]. Symptomatic progression of brain metastases was observed more frequently in the upfront chemotherapy group (26.5%) than the SRS group (18.4%) but without statistical significance.

Conclusions

Although this study included smaller sample size than initially anticipated due to early termination, SRS followed by chemotherapy did not improve OS in oligo-brain metastases NSCLC patients compared with upfront chemotherapy. Further study with large number of patients should be needed to confirm the use of upfront chemotherapy alone in this subgroup of patients.

Clinical trials number

NCT01301560.


Background

The role of adjuvant chemotherapy for non-small-cell lung cancer (NSCLC) stage I patients with tumors size ≥4 cm is not well established in the elderly.

Patients and methods

We identified 3289 patients with stage I NSCLC (T2N0M0 and tumor size ≥4 cm) who underwent lobectomy from the Surveillance, Epidemiology and End Results (SEER)–Medicare linked database diagnosed from 1992 to 2009. Overall survival and rates of serious adverse events (defined as those requiring admission to hospital) were compared between patients treated with resection alone, platinum-based adjuvant chemotherapy, or postoperative radiation (PORT) with or without adjuvant chemotherapy. Propensity scores for receiving each treatment were calculated and survival analyses were conducted using inverse probability weights based on the propensity score.

Results

Overall, 84% patients were treated with resection alone, 9% received platinum-based adjuvant chemotherapy, and 7% underwent PORT with or without adjuvant chemotherapy. Adjusted analysis showed that adjuvant chemotherapy [hazard ratio (HR), 0.82; 95% confidence interval (CI) 0.68–0.98] was associated with improved survival compared with resection alone. Conversely, the use of PORT with or without adjuvant chemotherapy (HR 1.91; 95% CI 1.64–2.23) was associated with worse outcomes. Patients receiving adjuvant chemotherapy had more serious adverse events compared with those treated with resection alone, with neutropenia (odds ratio, 21.2; 95% CI 5.8–76.6) being most significant. No significant difference was observed in rates of fever, cytopenias, nausea, and renal dysfunction.

Conclusions

Platinum-based adjuvant chemotherapy is associated with reduced mortality and increased serious adverse events in elderly patients with stage I NSCLC and tumor size ≥4 cm.


Background

For patients with peripheral T-cell lymphoma (PTCL), the value of 18fluoro-deoxyglucose positron emission tomography (FDG-PET) scans for assessing prognosis and response to treatment remains unclear. The utility of FDG-PET, in addition to conventional radiology, was examined as a planned exploratory end point in the pivotal phase 2 trial of romidepsin for the treatment of relapsed/refractory PTCL.

Patients and methods

Patients received romidepsin at a dose of 14 mg/m2 on days 1, 8, and 15 of 28-day cycles. The primary end point was the rate of confirmed/unconfirmed complete response (CR/CRu) as assessed by International Workshop Criteria (IWC) using conventional radiology. For the exploratory PET end point, patients with at least baseline FDG-PET scans were assessed by IWC + PET criteria.

Results

Of 130 patients, 110 had baseline FDG-PET scans, and 105 were PET positive at baseline. The use of IWC + PET criteria increased the objective response rate to 30% compared with 26% by conventional radiology. Durations of response were well differentiated by both conventional radiology response criteria [CR/CRu versus partial response (PR), P = 0.0001] and PET status (negative versus positive, P < 0.0001). Patients who achieved CR/CRu had prolonged progression-free survival (PFS, median 25.9 months) compared with other response groups (P = 0.0007). Patients who achieved PR or stable disease (SD) had similar PFS (median 7.2 and 6.3 months, respectively, P = 0.6427). When grouping PR and SD patients by PET status, patients with PET-negative versus PET-positive disease had a median PFS of 18.2 versus 7.1 months (P = 0.0923).

Conclusion(s)

Routine use of FDG-PET does not obviate conventional staging, but may aid in determining prognosis and refine response assessments for patients with PTCL, particularly for those who do not achieve CR/CRu by conventional staging. The optimal way to incorporate FDG-PET scans for patients with PTCL remains to be determined.

Trial registration

NCT00426764.


Background

Cancer mortality statistics for 2015 were projected from the most recent available data for the European Union (EU) and its six more populous countries. Prostate cancer was analysed in detail.

Patients and methods

Population and death certification data from stomach, colorectum, pancreas, lung, breast, uterus, prostate, leukaemias and total cancers were obtained from the World Health Organisation database and Eurostat. Figures were derived for the EU, France, Germany, Italy, Poland, Spain and the UK. Projected 2015 numbers of deaths by age group were obtained by linear regression on estimated numbers of deaths over the most recent time period identified by a joinpoint regression model.

Results

A total of 1 359 100 cancer deaths are predicted in the EU in 2015 (766 200 men and 592 900 women), corresponding to standardised death rates of 138.4/100 000 men and 83.9/100 000 women, falling 7.5% and 6%, respectively, since 2009. In men, predicted rates for the three major cancers (lung, colorectum and prostate) are lower than in 2009, falling 9%, 5% and 12%. Prostate cancer showed predicted falls of 14%, 17% and 9% in the 35–64, 65–74 and 75+ age groups. In women, breast and colorectal cancers had favourable trends (–10% and –8%), but predicted lung cancer rates rise 9% to 14.24/100 000 becoming the cancer with the highest rate, reaching and possibly overtaking breast cancer rates—though the total number of deaths remain higher for breast (90 800) than lung (87 500). Pancreatic cancer has a negative outlook in both sexes, rising 4% in men and 5% in women between 2009 and 2015.

Conclusions

Cancer mortality predictions for 2015 confirm the overall favourable cancer mortality trend in the EU, translating to an overall 26% fall in men since its peak in 1988, and 21% in women, and the avoidance of over 325 000 deaths in 2015 compared with the peak rate.


Background

A comprehensive body of evidence has shown that aspirin has cancer-preventive effects, particularly against gastrointestinal cancer, but its effects on the risk of ovarian cancer are less well established. This nationwide case–control study examined the association between low-dose aspirin and the risk of ovarian cancer.

Patients and methods

We identified all patients in the Danish Cancer Registry aged 30–84 years old with a histologically verified first diagnosis of epithelial ovarian cancer during 2000–2011. Each patient was sex- and age-matched to 15 population controls using risk-set sampling. Prescription use, comorbidity, reproductive history, and demographic characteristics data were obtained from nationwide registries. The use of low-dose (75–150 mg) aspirin was defined according to the dose as well as the duration and consistency of use. Conditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between low-dose aspirin use and the risk of epithelial ovarian cancer, both overall and for specific histological types.

Results

For 4103 ovarian cancer cases and 58 706 population controls, the adjusted OR for epithelial ovarian cancer associated with ever use (≥2 prescriptions) of low-dose aspirin was 0.94 (95% CI 0.85–1.05). ORs for epithelial ovarian cancer were lower with the use of 150 mg aspirin tablets (OR = 0.82; 95% CI 0.68–0.99) and with long-term use (≥5 years) of low-dose aspirin (OR = 0.77; 95% CI 0.55–1.08). Continuous long-term use of low-dose aspirin, defined as close consecutive prescriptions, was associated with a further reduction in OR (0.56; 95% CI 0.32–0.97). For histological types of epithelial ovarian cancer, the strongest inverse associations with low-dose aspirin use were seen for mucinous and endometrioid tumours.

Conclusion

This nationwide case–control study indicates that low-dose aspirin use may be associated with a reduced risk of epithelial ovarian cancer.


Background

Several studies have reported that the insulin-like growth factor 1 (IGF-1) is positively associated with estrogen receptor-positive [ER(+)] breast cancer risk, whereas there is little or no association with respect to ER(–) breast cancer. All comparisons of ER(+) breast cancer cases, however, have been made versus healthy controls, for whom there is no information about the ER expression in their mammary gland.

Patients and methods

In the context of a case–control investigation conducted in Athens, Greece, we studied 102 women with incident ERα(+) breast cancer and compared their IGF-1 blood levels with those of 178 ERα(+) and 83 ERα(–) women with benign breast disease (BBD) who underwent biopsies in the context of their standard medical care. Data were analysed using multiple logistic regression and controlling for potential confounding variables.

Results

ERα(+) breast cancer patients had higher IGF-1 levels compared with women with BBD [odds ratio (OR) 1.36, 95% confidence interval (CI): 0.95–1.94, per 1 standard deviation (SD) increase in IGF-1 levels]. When ERα status of women with BBD was taken into account, the difference in IGF-1 levels between ERα(+) breast cancer patients and women with BBD was clearly driven by the comparison with BBD women who were ERα(+) (OR = 1.95, 95% CI: 1.31–2.89 per 1 SD increase in IGF-1 levels), whereas there was essentially no association with IGF-1 levels when ERα(+) breast cancer patients were compared with ERα(–) BBD women. These contrasts were particularly evident among post/peri-menopausal women.

Conclusion(s)

We found evidence in support of an interaction of IGF-1 with the expression of ERα in the non-malignant mammary tissue in the context of breast cancer pathogenesis. This is in line with previous evidence suggesting that IGF-1 increases the risk of ER(+) breast cancer.


Background

In the NIBIT-M1 study, we reported a promising activity of ipilimumab combined with fotemustine in metastatic melanoma (MM) patients with or without brain metastases. To corroborate these initial findings, we now investigated the long-term efficacy of this combination.

Patients and methods

This analysis captured the 3-year outcome of MM patients who received ipilimumab combined with fotemustine as first- or second-line treatment. Median overall survival (OS), 3-year survival rates, immune-related (ir) progression-free survival (irPFS), brain PFS, and ir duration of response (irDOR) for the entire population and for patients with brain metastases were assessed. Clinical results were correlated with circulating CD3+CD4+ICOS+CD45RO+ or CD45RA+ T cells, neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status.

Results

Eighty-six MM patients, including 20 with asymptomatic brain metastases that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the study. With a median follow-up of 39.9 months, median OS and 3-year survival rates were 12.9 months [95% confidence interval (CI) 7.1–18.7 months] and 28.5% for the whole study population, and 12.7 months (95% CI 2.7–22.7 months) and 27.8% for patients with brain metastases, respectively. Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. The absolute increase from baseline to week 12 in ‘memory’ but not in ‘naïve’ T cells identified patients with a better survival (P = 0.002). The N/L ratio correlated with a significantly better survival at early time points. BRAF status did not correlate with clinical outcome.

Conclusions

Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of ipilimumab combined with fotemustine in MM patients. Fotemustine does not seem to impair the immunologic activity of ipilimumab.

EudraCT number

2010-019356-50.

CinicalTrials.gov

NCT01654692.


Background

Olaparib (Lynparza™) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that induces synthetic lethality in cancers with homologous recombination defects.

Patients and methods

In this phase I, dose-escalation trial, patients with advanced solid tumours received olaparib (50–200 mg capsules b.i.d.) continuously or intermittently (days 1–14, per 28-day cycle) plus gemcitabine [i.v. 600–800 mg/m2; days 1, 8, 15, and 22 (cycle 1), days 1, 8, and 15 (subsequent cycles)] to establish the maximum tolerated dose. A separate dose-escalation phase evaluated olaparib in tablet formulation (100 mg o.d./b.i.d.; days 1–14) plus gemcitabine (600 mg/m2). In an expansion phase, patients with genetically unselected locally advanced or metastatic pancreatic cancer were randomised 2 : 1 to the tolerated olaparib capsule combination dose or gemcitabine alone (1000 mg/m2).

Results

Sixty-six patients were treated [dose-escalation phase, n = 44 (tablet cohort, n = 12); dose-expansion phase, n = 22 (olaparib plus gemcitabine, n = 15; gemcitabine alone, n = 7)]. In the dose-escalation phase, four patients (6%) experienced dose-limiting toxicities (raised alanine aminotransferase, n = 2; neutropenia, n = 1; febrile neutropenia, n = 1). Grade ≥3 adverse events were reported in 38/47 patients (81%) treated with olaparib capsules plus gemcitabine; most common were haematological toxicities (55%). Tolerated combinations were olaparib 100 mg b.i.d. capsule (intermittently, days 1–14) plus gemcitabine 600 mg/m2 and olaparib 100 mg o.d. tablet (intermittently, days 1–14) plus gemcitabine 600 mg/m2. There were no differences in efficacy observed during the dose-expansion phase.

Conclusions

Olaparib 100 mg b.i.d. (intermittent dosing; capsules) plus gemcitabine 600 mg/m2 is tolerated in advanced solid tumour patients, with no unmanageable/unexpected toxicities. Continuous dosing of olaparib or combination with gemcitabine at doses >600 mg/m2 was not considered to have an acceptable tolerability profile for further study.

ClinicalTrials.gov

NCT00515866.


Background

Programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) pathway negatively regulates T-cell-mediated responses. The prognostic impact of PD-L1 expression needs to be defined in urothelial carcinoma (UC).

Patients and methods

Formalin-fixed paraffin-embedded tumor samples from 160 patients with UC were retrieved. PD-L1 expression was evaluated by immunohistochemistry using a mouse monoclonal anti-PD-L1 antibody (405.9A11). PD-L1 positivity on tumor cell membrane was defined as ≥5% of tumor cell membrane staining. The extent of tumor-infiltrating mononuclear cells (TIMCs) as well as PD-L1 expression on TIMCs was scored from 0 to 4. A score of 2, 3, or 4 was considered PD-L1-positive. Clinico-pathological variables were documented. The Cox regression model was used to assess the association of PD-L1 expression with overall survival (OS) in patients who developed metastases.

Results

TIMCs were present in 143 of the 160 patient samples. Out of 160 samples, 32 (20%) had positive PD-L1 expression in tumor cell membrane. Out of 143 samples with TIMCs, 58 (40%) had positive PD-L1 expression in TIMCs. Smoking history, prior BCG use and chromosome 9 loss did not correlate with PD-L1 expression in either tumor cell membrane or TIMCs. PD-L1 positivity was not different between non-invasive or invasive UC. In patients who developed metastases (M1) and were treated with systemic therapy (n = 100), PD-L1 positivity on tumor cell membrane was seen in 14% of patients and did not correlate with OS (P = 0.45). Out of 89 M1 patients who had evaluable PD-L1 on TIMCs, PD-L1 expression was seen in 33% of patients and was significantly associated with longer OS on multivariate analysis (P = 0.0007).

Conclusion

PD-L1 is widely expressed in tumor cell membrane and TIMCs in UC. PD-L1 in tumor cells was not predictive of OS. However, positive PD-L1 expression in TIMCs was significantly associated with longer survival in those patients who developed metastases.