# Annals of Surgical Oncology

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Bone is the most common site for breast cancer metastases, occurring in up to 70% of those with metastatic disease. In order to effectively manage these patients, it is essential to have consistent, reproducible and validated methods of assessing response to therapy. We present current clinical practice of imaging response assessment of bone metastases. We also review the biology of bone metastases and measures of response assessment including clinical assessment, tumour markers and imaging techniques; bone scans (BSs), computed tomography (CT), positron emission tomography, magnetic resonance imaging (MRI) and whole-body diffusion-weighted MRI (WB DW-MRI). The current standard of care of BSs and CT has significant limitations and are not routinely recommended for the purpose of response assessment in the bones. WB DW-MRI has the potential to address this unmet need and should be evaluated in clinical trials.

Diffuse large B-cell lymphoma (DLBCL) is a treatable and potentially curable malignancy that is increasing in prevalence in the elderly. Until recently, older patients with this malignancy were under-represented on clinical treatment trials, so optimal therapeutic approaches for these patients were generally extrapolated from the treatment of younger patients with this disorder. Because of heightened toxicity concerns, older patients were sometimes given reduced dose therapy, potentially negatively impacting outcome. Geriatric considerations including functional status and comorbidities often were not accounted for in treatment decisions. Because of these issues as well as the lack of treatment guidelines for the elderly population, the International Society of Geriatric Oncology convened an expert panel to review DLBCL treatment in the elderly and develop consensus guidelines for therapeutic approaches in this patient population. The following treatment guidelines address initial DLBCL therapy, in both limited and advanced stage disease, as well as approaches to the relapsed and refractory patient.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults, accounting for 35%–40% of all cases. The combination of the anti-CD20 monoclonal antibody rituximab with anthracycline-based combination chemotherapy (R-CHOP, rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone) lead to complete remission in most and can cure more than half of patients with DLBCL. The diversity in clinical presentation, as well as the pathologic and biologic heterogeneity, suggests that DLBCL comprises several disease entities that might ultimately benefit from different therapeutic approaches. In this review, we summarize the current literature focusing on the genetic lesions identified in DLBCL.

The prevention of chemotherapy-induced nausea and vomiting (CINV) has been revolutionized over the past 25 years. Guideline-based treatment means that vomiting can be prevented in the majority, but not in all patients. Therefore, antiemetic research continues with the goal of optimizing CINV control for all patients. This comprehensive review summarizes the research efforts in this field over the past few years. Emerging from this research are two new antiemetic agents, netupitant/palonosetron, the first antiemetic combination agent and rolapitant, a new NK1RA. In addition, studies have evaluated the benefits of olanzapine and ginger, explored optimal combinations of agents for delayed CINV prevention, confirmed that dexamethasone-sparing regimens are effective, and demonstrated the value of NK1RAs in high-dose chemotherapy settings as well as with certain moderately emetogenic chemotherapies such as carboplatin. Research has also validated the correlation between antiemetic guideline adherence and improved CINV control. Finally, regulatory authorities have utilized extreme caution in retiring some 5-HT3RAs or decreasing their maximum dose.

Background

Frailty is a state of vulnerability to poor resolution of homeostasis following a stressor event, such as chemotherapy or cancer surgery. Better knowledge of the epidemiology of frailty could help drive a global cancer care strategy for older people. The aim of this review was to establish the prevalence and outcomes of frailty and pre-frailty in older cancer patients.

Methods

Observational studies that reported data on the prevalence and/or outcomes of frailty in older cancer patients with any stage of solid or haematological malignancy were considered. We searched Medline, CINAHL, Cochrane Library, EMBASE, Web of Science, Allied and Complementary medicine, Psychinfo and ProQuest (1 January 1996 to 30 June 2013). The primary outcomes were prevalence of frailty, treatment-related side-effects, unplanned hospitalization and mortality. Risk of bias was assessed using the Newcastle–Ottawa checklist.

Results

Data from 20 studies evaluating 2916 participants are included. The median reported prevalence of frailty and pre-frailty was 42% (range 6%–86%) and 43% (range 13%–79%), respectively. A median of 32% (range 11%–78%) of patients were classified as fit. Frailty was independently associated with increased all-cause mortality [adjusted 5-year hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.36–2.57]. There was evidence of increased risk of postoperative mortality for both frailty (adjusted 30-day HR 2.67, 95% CI 1.08–6.62) and pre-frailty (adjusted HR 2.33, 95% CI 1.20–4.52). Treatment complications were more frequent in those with frailty, including intolerance to cancer treatment (adjusted odds ratio 4.86, 95% CI 2.19–10.78) and postoperative complications (adjusted 30-day HR 3.19, 95% CI 1.68–6.04).

Conclusions

More than half of older cancer patients have pre-frailty or frailty and these patients are at increased risk of chemotherapy intolerance, postoperative complications and mortality. The findings of this review support routine assessment of frailty in older cancer patients to guide treatment decisions, and the development of multidisciplinary geriatric oncology services.

Background

Obesity-related hormonal and metabolic perturbations implicated in colorectal carcinogenesis are mainly driven by visceral adipose tissue (VAT) rather than subcutaneous adipose tissue (SAT). Yet, most epidemiologic studies have examined the relationship between excess adiposity and colorectal neoplasia using body mass index (BMI) and waist circumference (WC). Due to the inability of BMI and WC to distinguish VAT from SAT, they are likely to have underestimated the true association.

Patients and methods

We conducted a dose–response meta-analysis to summarize the relationships between VAT and colorectal adenomas and to examine the value of VAT as an independent risk factor beyond BMI, WC, and SAT. PubMed and Embase were searched through September 2014 to identify relevant observational studies. The summary odds ratio (OR) 95% confidence interval (CI) were estimated using a random-effects model.

Results

In linear dose–response meta-analysis, the summary OR for each 25 cm2 increase in VAT area was 1.13 (95% CI 1.05–1.21; I2 = 62%; 6 studies; 2776 cases; range of VAT area = 30–228 cm2). The dose–response curve suggested no evidence of nonlinearity (Pnon-linearity = 0.37). In meta-analysis comparing the highest versus lowest category of VAT based on 12 studies, a positive association between VAT and adenomas remained statistically significant even after adjustment for BMI, WC, and SAT. In contrast, adjustment for VAT substantially attenuated associations of BMI, WC, and SAT with adenomas. Across the studies, VAT was more strongly associated with advanced adenomas than nonadvanced adenomas.

Conclusions

VAT may be the underlying mediator of the observed associations of BMI and WC with adenomas, increasing adenoma risk continuously over a wide range of VAT area. Considering that the joint use of BMI and WC better captures VAT than the use of either one, clinicians are recommended to use both BMI and WC to identify those at high risk for colorectal neoplasia.

Background

Comprehensive molecular profiling led to the recognition of multiple prostate cancer (PCa) molecular subtypes and driving alterations, but translating these findings to clinical practice is challenging.

Patients and methods

We developed a formalin-fixed paraffin-embedded (FFPE) tissue compatible integrative assay for PCa molecular subtyping and interrogation of relevant genetic/transcriptomic alterations (MiPC). We applied MiPC, which combines capture-based next generation sequencing and quantitative reverse transcription PCR (qRT-PCR), to 53 FFPE PCa specimens representing cases not well represented in frozen tissue cohorts, including 8 paired primary tumor and lymph node metastases. Results were validated using multiplexed PCR based NGS and Sanger sequencing.

Results

We identified known and novel potential driving, somatic mutations and copy number alterations, including a novel BRAF T599_V600insHT mutation and CYP11B2 amplification in a patient treated with ketoconazole (a potent CYP11B2 inhibitor). qRT-PCR integration enabled comprehensive molecular subtyping and provided complementary information, such as androgen receptor (AR) target gene module assessment in advanced cases and SPINK1 over-expression. MiPC identified highly concordant profiles for all 8 tumor/lymph node metastasis pairs, consistent with limited heterogeneity amongst driving events. MiPC and exome sequencing were performed on separately isolated conventional acinar PCa and prostatic small cell carcinoma (SCC) components from the same FFPE resection specimen to enable direct comparison of histologically distinct components. While both components showed TMPRSS2:ERG fusions, the SCC component exclusively harbored complete TP53 inactivation (frameshift variant and copy loss) and two CREBBP mutations.

Conclusions

Our results demonstrate the feasibility of integrative profiling of routine PCa specimens, which may have utility for understanding disease biology and enabling personalized medicine applications.

Background

We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC).

Patients and methods

A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome.

Results

We recruited 55 eligible participants from September 2010 to August 2012. Demographics: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5–10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12–undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified.

Conclusions

The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment.

Australian New Zealand Clinical Trials Registry

ACTRN12609000643279.

Background

Papillary renal cell carcinoma (PRCC), type 1 and type 2, represents 10%–15% of renal cell carcinomas (RCC). There is no standard first-line treatment of metastatic PRCC (mPRCC). Anti-angiogenics have shown activity in retrospective studies but no prospective studies in pure papillary histology have been reported, but one with foretinib.

Patients and methods

A prospective phase II study evaluated sunitinib in first-line treatment of mPRCC. The primary end point was overall response rate (ORR). Secondary end points were progression-free survival (PFS) and overall survival (OS).

Results

Fifteen and 46 patients, respectively, with type 1 and type 2 mPRCC were enrolled. Using the MSKCC scoring system: 12 (20%), 33 (55%) and 9 (15%) patients were, respectively, in the favourable, intermediate or poor risk group and 7 undetermined. Median follow-up is 51.4 months. In type 1, 2 patients 13% [95% confidence interval (CI) 0.1–30.5] had a partial response (PR), 10 had stable disease (SD) with 5 (33%) ≥12 weeks. In type 2, 5 patients 11% (95% CI 1.9–20.3) had a PR, 25 had SD with 10(22%) ≥12 weeks. Median PFS was 6.6 months (95% CI 2.8–14.8) in type 1 and 5.5 months (95% CI 3.8–7.1) in type 2. Median OS was 17.8 (95% CI 5.7–26.1) and 12.4 (95% CI 8.2–14.3) months, respectively, in type 1 and 2. Safety was as expected with sunitinib for metastatic RCC.

Conclusion

Sunitinib showed activity in treatment of type 1 and 2 mPRCC but lower than in clear-cell mRCC. Both PFS and OS are longer in type I PRCC. Sunitinib represents an acceptable option in first-line treatment of mPRCC.

Background

To examine the association between hypertension (HTN), angiotensin system inhibitors (ASI) use and survival outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib (SU).

Methods

We retrospectively reviewed all patients with mRCC who received SU as first-line treatment in Gustave Roussy from April 2004 to November 2013. The HTN (either pre-existing or secondary to SU), use of ASI (either before or during SU) were analysed. Overall survival (OS) and progression-free survival (PFS) of different exposures were compared with log-rank test. The associations between exposures and survival outcomes were estimated with hazard ratios (HRs) and 95% confidence interval (CI) through a multivariable Cox model adjusted for age, gender, International mRCC Database Consortium risk group and histology.

Results

Among 213 patients with a 3.6-year median follow-up, 134 were hypertensive and 105 were ASI users with a significant association between the two exposures (P < 0.0001). Hypertensive patients have longer OS (median: 41.6 versus 16.4 months, P < 0.0001) and longer PFS (median: 12.9 versus 5.6 months, P < 0.0001) than non-hypertensive patients (n = 79). ASI users (n = 105) had more HTN_PRE compared with those (n = 108) who did not (65% versus 19%, P < 0.001). Multivariable analysis showed that hypertensive patients were significantly associated with OS (P = 0.05) and marginally with PFS (P = 0.06) while ASI intake was significantly associated with better OS [HR = 0.40; 95% CI (0.24–0.66), P < 0.001] and PFS [HR = 0.55 (0.35–0.86), P = 0.009]. The latter remain statistically significantly associated after controlling for the number of metastases. There is no difference on outcome between patients who receive ASI before starting SU and those who received ASI during SU treatment.

Conclusion

Concomitant use of ASI may significantly improve OS and PFS in mRCC patients receiving SU. HTN is marginally associated with the outcome in these patients.

Background

Tecemotide is a MUC1-antigen-specific cancer immunotherapy. The phase III START study did not meet its primary end point but reported notable survival benefit with tecemotide versus placebo in an exploratory analysis of the predefined patient subgroup treated with concurrent chemoradiotherapy. Here, we attempted to gain further insight into the effects of tecemotide in START.

Patients and methods

START recruited patients who did not progress following frontline chemoradiotherapy for unresectable stage III non-small-cell lung cancer. We present updated overall survival (OS) data and exploratory analyses of OS for baseline biomarkers: soluble MUC1 (sMUC1), antinuclear antibodies (ANA), neutrophil/lymphocyte ratio (NLR), lymphocyte count, and HLA type.

Results

Updated OS data are consistent with the primary analysis: median 25.8 months (tecemotide) versus 22.4 months (placebo) (HR 0.89, 95% CI 0.77–1.03, P = 0.111), with ~20 months additional median follow-up time compared with the primary analysis. Exploratory analysis of the predefined subgroup treated with concurrent chemoradiotherapy revealed clinically relevant prolonged OS with tecemotide versus placebo (29.4 versus 20.8 months; HR 0.81, 95% CI 0.68–0.98, P = 0.026). No improvement was seen with sequential chemoradiotherapy. High sMUC1 and ANA correlated with a possible survival benefit with tecemotide (interaction P = 0.0085 and 0.0022) and might have future value as biomarkers. Interactions between lymphocyte count, NLR, or prespecified HLA alleles and treatment effect were not observed.

Conclusion

Updated OS data support potential treatment benefit with tecemotide in patients treated with concurrent chemoradiotherapy. Exploratory biomarker analyses suggest that elevated sMUC1 or ANA levels correlate with tecemotide benefit.

ClinicalTrials.gov number

NCT00409188.

Background

MicroRNAs (miRNAs) have a key role in carcinogenesis through negative regulation of their target genes. Therefore, genetic variations in miRNAs or their target sites may affect miRNA–mRNA interactions, thereby result in altered expression of target genes. This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) located in the miRNA target sites (poly-miRTSs) and survival of patients with early-stage non-small-cell lung cancer (NSCLC).

Methods

Using public SNP database and miRNA target sites prediction program, 354 poly-miRTSs were selected for genotyping. Among these, 154 SNPs applicable to Sequenom's MassARRAY platform were investigated in 357 patients. A replication study was carried out on an independent patient population (n = 479). Renilla luciferase assay and reverse transcription-polymerase chain reaction were conducted to examine functional relevance of potentially functional poly-miRTSs.

Results

Of the 154 SNPs analyzed in a discovery set, 14 SNPs were significantly associated with survival outcomes. Among these, KRT81 rs3660G>C was found to be associated with survival outcomes in the validation cohort. In the combined analysis, patients with the rs3660 GC + CC genotype had a significantly better overall survival compared with those with GG genotype [adjusted hazard ratio (aHR) for OS, 0.65; 95% confidence interval (CI) 0.50–0.85; P = 0.001]. An increased expression of the reporter gene for the C allele of rs3660 compared with the G allele was observed by luciferase assay. Consistently, the C allele was associated with higher relative expression level of KRT81 in tumor tissues.

Conclusion

The rs3660G>C affects KRT81 expression and thus influences survival in early-stage NSCLC. The analysis of the rs3660G>C polymorphism may be useful to identify patients at high risk of a poor disease outcome.

Background

In published radiotherapy trials, the failure rate in the control arm among patients with one to three positive nodes is high compared with that seen with modern adjuvant treatments. Therefore, the generalizability of the results has been questioned. The aim of the present study was to compare relative survival in breast cancer patients between two Swedish regions with screening mammography programs and adjuvant treatment guidelines similar with the exception of the indication of radiotherapy for patients with one to three positive nodes.

Patients and methods

Between 1989 and 2006, breast cancer patients were managed very similarly in the west and southeast regions, except for indication for postoperative radiotherapy. In patients with one to three positive nodes, postmastectomy radiotherapy was generally given in the southeast region (89% of all cases) and generally not given in the west region (15% of all cases). For patients with one to three positive nodes who underwent breast-conserving surgery, patients in the west region had breast radiotherapy only, while patients in the southeast region had both breast and lymph nodes irradiated.

Results

The 10-year relative survival for patients with one to three positive lymph nodes was 78% in the west region and 77% in the southeast region (P = 0.12). Separate analyses depending on type of surgery, as well as number of examined nodes, also revealed similar relative survival.

Conclusion

Locoregional postoperative radiotherapy has well-known side-effects, but in this population-based study, there was little or no influence of this type of radiotherapy on survival when one to three lymph nodes were involved.

Background

Disseminated tumor cells (DTCs) are detectable in the bone marrow (BM) of patients with primary breast cancer (PBC) and predictive of an impaired prognosis. This large trial aimed to analyze the impact of DTC detection on locoregional relapse (LR).

Patients and methods

Patients with nonmetastatic PBC were eligible for this analysis. BM aspiration (BMA1) was carried out during primary surgery and DTCs were detected by using immunocytochemistry (A45-B/B3 antibody against pancytokeratin) and morphological criteria. At the time of LR, a subgroup of patients with nonmetastatic and operable LR received a secondary BM aspiration (BMA2).

Results

A total of 3072 patients were included into the analysis. Of these, 732 (24%) presented with DTCs at BMA1. One hundred thirty-nine patients experienced LR and 48 of these (35%) were initially DTC positive. DTC detection was significantly associated with an increased risk of LR in univariate (P = 0.002) and multivariate analysis (P = 0.009) with a hazard ratio of 1.65 (95% confidence interval 1.13–2.40). Of the patients with LR, 55 patients were available for BMA2 and 17 of these (32%) were DTC positive. DTC detection at the time of LR was indicative of impaired overall survival (univariate analysis, P = 0.037).

Conclusions

DTC detection in patients with PBC is associated with an increased risk of LR, indicating that tumor cells may have the ability to recirculate from the BM to the site of the primary tumor. The impaired prognosis associated with DTC detection at the time of LR may help to identify patients that are in need for additional or more aggressive treatment.

Background

Recent investigations of breast cancer survival in the United States suggest that patients who receive mastectomy have poorer survival than those who receive breast-conserving surgery (BCS) plus radiotherapy, despite clinically established equivalence. This study investigates breast cancer survival in the publicly funded health care system present in Alberta, Canada.

Patients and methods

Surgically treated stage I–III breast cancer cases diagnosed in Alberta from 2002 to 2010 were included. Demographic, treatment and mortality information were collected from the Alberta Cancer Registry. Unadjusted overall and breast cancer-specific mortality was assessed using Kaplan–Meier and cumulative incidence curves, respectively. Cox proportional hazards models were used to calculate stage-specific mortality hazard estimates associated with surgical treatment received.

Results

A total of 14 939 cases of breast cancer (14 633 patients) were included in this study. The unadjusted 5-year all-cause survival probabilities for patients treated with BCS plus radiotherapy, mastectomy, and BCS alone were 94% (95% CI 93% to 95%), 83% (95% CI 82% to 84%) and 74% (95% CI 70% to 78%), respectively. Stage II and III patients who received mastectomy had a higher all-cause (stage II HR = 1.36, 95% CI 1.13–1.48; stage III HR = 1.74, 95% CI 1.24–2.45) and breast cancer-specific (stage II HR = 1.39, 95% CI 1.09–1.76; stage III HR = 1.79, 95% CI 1.21–2.65) mortality hazard compared with those who received BCS plus radiotherapy, adjusting for patient and clinical characteristics. BCS alone was consistently associated with poor survival.

Conclusions

Stage II and III breast cancer patients diagnosed in Alberta, Canada, who received mastectomy had a significantly higher all-cause and breast cancer-specific mortality hazard compared with those who received BCS plus radiotherapy. We suggest greater efforts toward educating and encouraging patients to receive BCS plus radiotherapy rather than mastectomy when it is medically feasible and appropriate.

Background

Combination chemotherapy ABVD (doxorubicin, bleomycin, vinblastine and dacarabazine) cures ~70% of patients with advanced Hodgkin's lymphoma (aHL, stages IIB, III and IV) while more toxic escalated BEACOPP (EB, combination of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone) increases cure rates to 85%. Patients with a positive interim positron emission tomography–computerized tomography (PET–CT) scan after two cycles (PET-2) of ABVD have very poor outcomes with continued ABVD. Intensifying therapy with EB in PET-2-positive patients (‘response-adapted therapy’) may improve cure rates, whereas the negative patients can continue ABVD alone.

Patients and methods

Eligible patients with newly diagnosed aHL received two cycles of ABVD and underwent PET-2 (scored with semi-quantitative 5-point visual criteria, ‘Deauville score’). PET-2-negative patients continued four additional cycles of ABVD, whereas PET-2-positive patients received four cycles of EB. A phase II sample size of 50 was estimated keeping the lower and higher proportion of rejection of the event-free survival (EFS) as 70% and 85%, respectively.

Results

Fifty patients [median age 28 (12–60) years; male : female: 39 : 11; stages: IIB—3 (6%), III—29 (58%) and IV—18 (36%); International Prognostic Score (IPS): 0–3: 34 (68%); 4–7: 16 (32%)] were enrolled; 49 underwent PET-2. Eight (16%) were PET-2-positive, whereas 41 (84%) were negative. Forty-seven were evaluable for EFS and all 50 for overall survival (OS). The 2-year EFS was 76% (95% CI: 68–83) and OS was 88% (95% CI: 82–94). PET-2 was strongly prognostic-2-year EFS, negative versus positive: 82% versus 50%; P = 0.013.

Conclusion

PET-2 response-adapted strategy could not achieve EFS of 85% in aHL. However, escalated therapy improved outcomes in PET-2-positive patients compared with historical data.

Trial registration

CTRI/2012/06/002741 (http://www.ctri.nic.in) and NCT01304849 (http://www.clinicaltrials.gov).

Background

Although ibrutinib is highly effective in patients with relapsed/refractory mantle cell lymphoma (MCL), a substantial proportion of patients have resistant disease. The subsequent outcomes of such patients are unknown.

Patients and methods

We carried out a retrospective review of all patients with MCL treated with ibrutinib at MD Anderson Cancer Center between January 2011 and January 2014 using pharmacy and clinical databases. Patients who had discontinued ibrutinib for any reason were included in the study.

Results

We identified 42 patients with MCL who discontinued therapy due to disease progression on treatment (n = 28), toxicity (n = 6), elective stem-cell transplant in remission (n = 4) or withdrawn consent (n = 4). The median age was 69 years, 35 (83%) were male; the median number of prior treatments was 2 (range 1–8) and the median time from initial diagnosis of MCL to commencing ibrutinib was 3.0 (range 0.5–15.5) years. Patients had received a median of 6.5 (range 1–43) cycles of ibrutinib. Among 31 patients who experienced disease progression following ibrutinib and underwent salvage therapy, the overall and complete response rates were 32% and 19%, respectively. After a median follow-up of 10.7 (range 2.4–38.9) months from discontinuation of ibrutinib, the median overall survival (OS) among patients with disease progression was 8.4 months. By univariate analysis, elevated serum lactate dehydrogenase at progression was associated with inferior OS.

Conclusion

The outcome of patients with MCL who experience disease progression following ibrutinib therapy is poor, with both low response rates to salvage therapy and short duration of responses. Further studies to better understand and overcome ibrutinib resistance are urgently needed.

Background

Chronic myeloid leukaemia (CML) is characterised by the presence of a fusion driver oncogene, BCR-ABL1, which is a constitutive tyrosine kinase. Tyrosine kinase inhibitors (TKIs) are the central treatment strategy for CML patients and have significantly improved survival rates, but the T315I mutation in the kinase domain of BCR-ABL1 confers resistance to all clinically approved TKIs, except ponatinib. However, compound mutations can mediate resistance even to ponatinib and remain a clinical challenge in CML therapy. Here, we investigated a ponatinib-resistant CML patient through whole-genome sequencing (WGS) to identify the cause of resistance and to find alternative therapeutic targets.

Patients and methods

We carried out WGS on a ponatinib-resistant CML patient and demonstrated an effective combination therapy against the primary CML cells derived from this patient in vitro.

Results

Our findings demonstrate the emergence of compound mutations in the BCR-ABL1 kinase domain following ponatinib treatment, and chromosomal structural variation data predicted amplification of BCL2. The primary CD34+ CML cells from this patient showed increased sensitivity to the combination of ponatinib and ABT-263, a BCL2 inhibitor with a negligible effect against the normal CD34+ cells.

Conclusion

Our results show the potential of personalised medicine approaches in TKI-resistant CML patients and provide a strategy that could improve clinical outcomes for these patients.

Background

Early tumor shrinkage (ETS) and depth of response (DoR) predict overall survival (OS) in first-line trials of chemotherapy ± anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC). These associations and the predictive accuracy of response measurements for survival parameters were investigated in the phase III TRIBE trial of FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev.

Patients and methods

A landmark approach was adopted to define the assessable population. The distribution of RECIST response rate, ETS and DoR was compared in the two arms. Associations between response measurements and progression-free survival (PFS), post-progression survival (PPS) and OS were tested by univariate and multivariate Cox models. Prediction performance of each factor was estimated by C-index.

Results

A significantly higher percentage of patients in the FOLFOXIRI plus bev arm achieved ETS ≥20%, when compared with the control arm (62.7% versus 51.9%, P = 0.025). Also the DoR was significantly higher in the triplet plus bev arm (43.4% versus 37.8%, P = 0.003). Both ETS and DoR were associated with PFS, PPS and OS at the univariate analyses and in the multivariate models stratified for other prognostic variables. Both ETS and DoR were able to predict survival as accurately as RECIST response.

Conclusion

FOLFOXIRI plus bev improves ETS and DoR when compared with FOLFIRI plus bev. Achieving rapid and deep tumor shrinkage consistently delays tumor progression and prolongs survival in patients treated with first-line chemotherapy plus bev. ETS is a promising and valuable end point for clinical trials' design deserving further investigation.

Background

Masitinib is a selective oral tyrosine–kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC).

Patients and methods

Patients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m2) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic.

Results

Three hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl–CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the ‘ACOX1’ subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the ‘pain’ subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable.

Conclusions

The present data warrant initiation of a confirmatory study that may support the use of masitinib plus gemcitabine for treatment of PDAC patients with overexpression of ACOX1 or baseline pain (VAS > 20mm). Masitinib's effect in these subgroups is also supported by biological plausibility and evidence of internal clinical validation.

Trial Registration

ClinicalTrials.gov:NCT00789633.

Background

We report the results from a first-line phase III randomized clinical trial on metastatic colorectal cancer (mCRC) aimed at evaluating the effectiveness of adding bevacizumab (B) to standard first-line chemotherapy (CT).

Patients and methods

mCRC patients were randomized to receive first-line CT (FOLFIRI or FOLFOX4) plus B (arm A) or CT only (arm B). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (ORR) and safety. Three hundred and fifty patients and 310 events were required to have an 80% statistical power to detect a difference in PFS between the groups.

Results

Between November 2007 and March 2012, 376 patients were randomized. About 60% of patients received FOLFOX4 and 40% FOLFIRI. After a median follow-up of 36 months, 343 progressions and 275 deaths had been observed in the overall population. The median PFS was 9.6 [95% confidence interval (CI) 8.2–10.3] and 8.4 (95% CI 7.2–9.0) months for arms A and B, respectively, with a hazard ratio of 0.86 (95% CI 0.70–1.07; P = 0.182). No statistically significant differences in OS or ORR were observed. B-containing regimens were associated with more frequent hypertension, bleeding, proteinuria and asthenia.

Conclusions

The addition of B to standard first-line CT for mCRC did not provide a benefit in terms of PFS, OS or ORR. Further research is warranted to better identify the target population.

Clinical trial number

NCT01878422.

Backgroud

The R98 trial explores the addition of irinotecan to a 5-fluorouracil (5-FU) plus leucovorin (5-FU/LV) adjuvant regimen in optimally resected stages II–III rectal cancers. We report the updated long-term results. Disease-free survival (DFS) was the primary end point.

Patienst and methods

Between March 1999 and December 2005, 357 patients were randomized: 178 in 5-FU/LV and 179 in LV5-FU2 + irinotecan arm. The trial was stratified by control arm: Mayo Clinic regimen or LV5-FU2 regimen.

Results

Three hundred and fifty-seven randomized patients were evaluable for efficacy. With a follow-up of 156 months, the DFS was in favour of experimental arm but did not reach statistical significance [hazard ratio (HR) = 0.80, P = 0.154]. The same was observed for overall survival (OS) (HR = 0.87, P = 0.433). The 5-year DFS was 58% in the control arm and 63% in the experimental arm. The 5-year OS was 74% in the control arm and 75% in the experimental arm. Patients allocated to the experimental arm had more grade 3–4 neutropenia when compared with the LV5-FU2 arm (33% versus 6%, P = 0.03), but not when compared with the Mayo Clinic arm (33% versus 36%, P = 0.84). Grade 3–4 diarrhoea tended to be higher in the experimental arm, but analyses stratified by control arm or by radiotherapy failed to show significant differences across strata (test for interaction P = 0.44).

Conclusion

Even though a benefit of irinotecan in subgroups of patients cannot be excluded, due to early termination and lack of power, the study does not support the addition of irinotecan to 5-FU/LV in routine in patients with resected stage II–III rectal cancer.

Background

To determine genomic alterations in head and neck squamous cell carcinoma (HNSCC) using formalin-fixed, paraffin-embedded (FFPE) tumors obtained through routine clinical practice, selected cancer-related genes were evaluated and compared with alterations seen in frozen tumors obtained through research studies.

Patients and methods

DNA samples obtained from 252 FFPE HNSCC were analyzed using next-generation sequencing-based (NGS) clinical assay to determine sequence and copy number variations in 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. Human papillomavirus (HPV) status was determined by presence of the HPV DNA sequence in all samples and corroborated with high-risk HPV in situ hybridization (ISH) and p16 immunohistochemical (IHC) staining in a subset of tumors. Sequencing data from 399 frozen tumors in The Cancer Genome Atlas and University of Chicago public datasets were analyzed for comparison.

Results

Among 252 FFPE HNSCC, 84 (33%) were HPV positive and 168 (67%) were HPV negative by sequencing. A subset of 40 tumors with HPV ISH and p16 IHC results showed complete concordance with NGS-derived HPV status. The most common genes with genomic alterations were PIK3CA and PTEN in HPV-positive tumors and TP53 and CDKN2A/B in HPV-negative tumors. In the pathway analysis, the PI3K pathway in HPV-positive tumors and DNA repair-p53 and cell cycle pathways in HPV-negative tumors were frequently altered. The HPV-positive oropharynx and HPV-positive nasal cavity/paranasal sinus carcinoma shared similar mutational profiles.

Conclusion

The genomic profile of FFPE HNSCC tumors obtained through routine clinical practice is comparable with frozen tumors studied in research setting, demonstrating the feasibility of comprehensive genomic profiling in a clinical setting. However, the clinical significance of these genomic alterations requires further investigation through application of these genomic profiles as integral biomarkers in clinical trials.

Background

This phase I study evaluated the safety and efficacy of the oral mTOR inhibitor everolimus in combination with thoracic radiotherapy followed by consolidation chemotherapy in locally advanced or oligometastatic untreated non-small-cell lung cancer (NSCLC).

Patients and methods

Everolimus dose was escalated in incremental steps [sequential cohorts of three patients until the occurrence of dose-limiting toxicity (DLT)] and administered orally weekly (weekly group: dose of 10, 20 or 50 mg) or daily (daily group: 2.5, 5 or 10 mg), 1 week before, and during radiotherapy until 3.5 weeks after the end of radiotherapy. Two cycles of chemotherapy (cisplatin–navelbine) were administrated 4.5 weeks after the end of radiotherapy.

Results

Twenty-six patients were included in two centers, 56% had adenocarcinoma and 84% had stage III disease. In the weekly group (12 assessable patients), everolimus could be administered safely up to the maximum planned weekly dose of 50 mg; however, one patient experienced a DLT of interstitial pneumonitis at the weekly dose level of 20 mg. In the daily group (9 assessable patients): one DLT of interstitial pneumonitis with a fatal outcome was observed at the daily dose level of 2.5 mg; two other DLTs (one grade 3 esophagitis and one bilateral interstitial pneumonitis) were found at the daily dose level of 5 mg. Overall there were five patients with G3–4 interstitial pneumonitis related to treatment. Among 22 assessable patients for response, there were 9 (41%) partial response and 7 (32%) stable disease. At a median follow-up of 29 months, the 2-year overall survival and progression-free survival actuarial rates were 31% and 12%, respectively.

Conclusion

In previously untreated and unselected NSCLC patients, the recommended phase II dose of everolimus in combination with thoracic radiotherapy is 50 mg/week. Pulmonary toxicity is of concern and should be carefully monitored to establish the potential role of mTOR inhibitor with concomitant radiotherapy.

EudraCT N

2007-001698-27.

Background

Ramucirumab is a fully human immunoglobulin G1 monoclonal antibody receptor antagonist designed to block the ligand-binding site of vascular endothelial growth factor receptor-2 (VEGFR-2). An initial phase I study evaluated ramucirumab administered weekly in advanced cancer patients. This phase I study of ramucirumab [administered every 2 or 3 weeks (Q2W or Q3W)] examined safety, maximum tolerated dose, pharmacokinetics, immunogenicity, antitumor activity, and pharmacodynamics.

Patients and methods

Patients with advanced solid malignancies were treated with escalating doses of ramucirumab i.v. over 1 h. Blood was sampled for pharmacokinetics studies throughout treatment; levels of circulating vascular endothelial growth factor-A (VEGF-A) and soluble VEGF receptors (R)-1 and -2 were assessed.

Results

Twenty-five patients were treated with ramucirumab: 13 with 6, 8, or 10 mg/kg Q2W, and 12 with 15 or 20 mg/kg Q3W. The median treatment duration was 12 weeks (range 2–81). No dose-limiting toxicities were observed. The most frequently reported adverse events (AEs) included proteinuria and hypertension (n = 6 each), and diarrhea, fatigue and headache (n = 4 each). Treatment-related grade 3/4 AEs were: two grade 3 hypertension (10 and 20 mg/kg), one each grade 3 vomiting, fatigue (20 mg/kg), atrial flutter (15 mg/kg), and one each grade 4 duodenal ulcer hemorrhage (6 mg/kg) and grade 4 pneumothorax (20 mg/kg). Pharmacokinetic analysis revealed low clearance and half-life of ~110–160 h. Analysis of serum biomarkers indicated considerable patient-to-patient variability, but trends toward elevated VEGF-A and a transient decline in soluble VEGFR-2. Fifteen patients (60%) had best response of stable disease, with a median duration of 13 months (range 2–18 months) in tumor types including colorectal, renal, liver, and neuroendocrine cancers.

Conclusion

Ramucirumab was well tolerated. Study results led to recommended phase II doses of 8 mg/kg Q2W and 10 mg/kg Q3W. Prolonged stable disease was observed, suggesting ramucirumab efficacy in various solid tumors.

ClinicalTrials.gov

NCT00786383.

Background

Recent evidence suggests that ionizing radiation may be associated with unexpected side-effects in melanoma patients treated with concomitant BRAF inhibitors. A large multicenter analysis was carried out to generate reliable safety data and elucidate the mechanism.

Methods

A total of 161 melanoma patients from 11 European skin cancer centers were evaluated for acute and late toxicity, of whom 70 consecutive patients received 86 series of radiotherapy with concomitant BRAF inhibitor therapy. To further characterize and quantify a possible radiosensitization by BRAF inhibitors, blood samples of 35 melanoma patients were used for individual radiosensitivity testing by fluorescence in situ hybridization of chromosomal breaks after ex vivo irradiation.

Results

With radiotherapy and concomitant BRAF inhibitor therapy the rate of acute radiodermatitis ≥2° was 36% and follicular cystic proliferation was seen in 13% of all radiotherapies. Non-skin toxicities included hearing disorders (4%) and dysphagia (2%). Following whole-brain radiotherapy, rates of radiodermatitis ≥2° were 44% and 8% (P < 0.001) for patients with and without BRAF inhibitor therapy, respectively. Concomitant treatment with vemurafenib induced acute radiodermatitis ≥2° more frequently than treatment with dabrafenib (40% versus 26%, P = 0.07). In line with these findings, analysis of chromosomal breaks ex vivo indicated significantly increased radiosensitivity for patients under vemurafenib (P = 0.004) and for patients switched from vemurafenib to dabrafenib (P = 0.002), but not for patients on dabrafenib only. No toxicities were reported after stereotactic treatment.

Conclusion

Radiotherapy with concomitant BRAF inhibitor therapy is feasible with an acceptable increase in toxicity. Vemurafenib is a more potent radiosensitizer than dabrafenib.

Background

Docetaxel is a widely used cytotoxic agent. This study evaluates the impact of docetaxel toxicities on patient's health-related quality of life (QoL).

Patients and methods

We conducted a multicenter, prospective, non-interventional trial, in which the QoL was assessed using the EORTC QLQ-C30 questionnaires at baseline and every 4 weeks up to 40 weeks in patients receiving a docetaxel-based chemotherapy for metastatic disease. Treatment-related adverse events were correlated with the corresponding QoL scores. Uni- and multivariate analyses were applied.

Results

From January 2008 to June 2011, a total of 2659 patients were included. The majority of patients (48.1%) had prostate cancer, followed by breast (17.1%) and non-small-cell-lung cancer (15.8%). Patients received a median of 5 docetaxel cycles with the median dose of 75 mg/m2. The presence of grade 3/4 diarrhea showed the strongest effect on global health status/QoL average scores (50.91 versus 33.06), followed by vomiting (50.91 versus 35.17), dyspnea (50.94 versus 35.81), mucositis/stomatitis (50.88 versus 36.41), nausea (50.91 versus 36.68), infection (50.90 versus 37.14), fatigue (50.90 versus 43.82) and anemia (50.91 versus 41.03), P < 0.05 for all comparisons. Grade 3/4 leukopenia/neutropenia, alopecia, constipation, neurotoxicity and nail disorders had no significant impact on the global health status/QoL or other items.

Conclusion

In this large non-interventional trial, docetaxel-associated grade 3 or 4 toxicities were shown to have a strong detrimental effect on patient's QoL. Notably, diarrhea and vomiting had the strongest negative impact on QoL measures. This has to be kept in mind while making therapeutic decisions and providing optimized supportive treatment measures.

Clinical trials number

This study was registered at Deutsches Krebsstudienregister (DKSR, primary registry in the WHO Registry Network) with the ID 527.

Background

A combination of aprepitant, a 5-HT3 receptor antagonist (r.a.), and dexamethasone is recommended for the prophylaxis of cisplatin-induced nausea and vomiting in the acute phase, and aprepitant + dexamethasone (A + D) in the delayed phase. The aim of this study was to verify if A + D is superior to metoclopramide plus dexamethasone (M + D) in preventing delayed emesis in cancer patients receiving the same prophylaxis for acute emesis.

Patients and methods

A randomized double-blind study comparing A + D versus M + D was completed in previously untreated cancer patients. Before chemotherapy, all patients were treated with intravenous palonosetron 0.25 mg and dexamethasone 12 mg, and oral aprepitant 125 mg. On day 2–4, patients randomly received oral dexamethasone 8 mg plus aprepitant 80 mg once daily (days 2–3) or metoclopramide 20 mg four times daily plus dexamethasone 8 mg bid. Primary endpoint was rate of complete response (no vomiting, no rescue treatment) in day 2–5 after chemotherapy.

Results

Due to difficulty in the accrual of patients, 303 of the 480 planned patients were enrolled, 284 were fully evaluable, 147 receiving A + D, 137 M + D. Day 1 results were similar in both arms. On day 2–5, complete response rate was not significantly different (80.3% with A + D versus 82.5% with M + D, P < 0.38, respectively), and all secondary endpoints were also similar (complete protection, total control, no vomiting, no nausea, and score of Functional Living Index-Emesis; P < 0.24). Adverse events incidence was not significantly different between the two treatments.

Conclusions

In cancer patients submitted to cisplatin-based chemotherapy, receiving the same antiemetic prophylaxis for acute emesis, A + D is not superior to M + D in preventing delayed emesis, and both treatments present similar toxicity.

ClinicalTrials.gov number

NCT00869310.

Background

Predictive models are an integral part of current clinical practice and help determine optimal treatment strategies for individual patients. A drawback is that covariates are assumed to have constant effects on overall survival (OS), when in fact, these effects may change during follow-up (FU). Furthermore, breast cancer (BC) patients may experience events that alter their prognosis from that time onwards. We investigated the ‘dynamic’ effects of different covariates on OS and developed a nomogram to calculate 5-year dynamic OS (DOS) probability at different prediction timepoints (tP) during FU.

Methods

Dutch and Belgian postmenopausal, endocrine-sensitive, early BC patients enrolled in the TEAM trial were included. We assessed time-varying effects of specific covariates and obtained 5-year DOS predictions using a proportional baselines landmark supermodel. Covariates included age, histological grade, hormone receptor and HER2 status, T- and N-stage, locoregional recurrence (LRR), distant recurrence, and treatment compliance. A nomogram was designed to calculate 5-year DOS based on individual characteristics.

Results

A total of 2602 patients were included (mean FU 6.2 years). N-stage, LRR, and HER2 status demonstrated time-varying effects on 5-year DOS. Hazard ratio (HR) functions for LRR, high-risk N-stage (N2/3), and HER2 positivity were HR = (8.427 x 0.583$${\hspace{0.17em}}^{{t}_{\mathrm{P}}})$$, HR = (3.621 x 0.816$${\hspace{0.17em}}^{{t}_{\mathrm{P}}})$$, and HR = (1.235 x 0.851$${\hspace{0.17em}}^{{t}_{\mathrm{P}}})$$, respectively. Treatment discontinuation was associated with a higher mortality risk, but without a time-varying effect [HR 1.263 (0.867–1.841)]. All other covariates were time-constant.

Discussion

The current nomogram accounts for elapsed time since starting adjuvant endocrine treatment and optimizes prediction of individual 5-year DOS during FU for postmenopausal, endocrine-sensitive BC patients. The nomogram can facilitate in determining whether further therapy will benefit an individual patient, although validation in an independent dataset is still needed.

Background

Cancer survivorship is an increasingly important issue in cancer control. Life expectancy of patients diagnosed with breast, colon, and testicular cancers, stratified by age at diagnosis and time since diagnosis, is provided as an indicator to evaluate future mortality risks and health care needs of cancer survivors.

Patients and methods

The standard period life table methodology was applied to estimate excess mortality risk for cancer patients diagnosed in 1985–2011 from SEER registries and mortality data of the general US population. The sensitivity of life expectancy estimates on different assumptions was evaluated.

Results

Younger patients with colon cancer showed wider differences in life expectancy compared with that of the general population (11.2 years in women and 10.7 in men at age 45–49 years) than older patients (6.3 and 5.8 at age 60–64 years, respectively). Life expectancy progressively increases in patients surviving the first years, up to 4 years from diagnosis, and then starts to decrease again, approaching that of the general population. For breast cancer, the initial drop in life expectancy is less marked, and again with wider differences in younger patients, varying from 8.7 at age 40–44 years to 2.4 at ages 70–74 years. After diagnosis, life expectancy still decreases with time, but less than that in the general population, slowly approaching that of cancer-free women. Life expectancy of men diagnosed with testicular cancer at age 30 years is estimated as 45.2 years, 2 years less than cancer-free men of the same age. The difference becomes 1.3 years for patients surviving the first year, and then slowly approaches zero with increasing survival time.

Conclusions

Life expectancy provides meaningful information on cancer patients, and can help in assessing when a cancer survivor can be considered as cured.