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Year of Publication
1.  Addressing overdiagnosis and overtreatment in cancer: a prescription for change 
The Lancet. Oncology  2014;15(6):e234-e242.
A vast range of disorders—from indolent to fast-growing lesions—are labelled as cancer. Therefore, we believe that several changes should be made to the approach to cancer screening and care, such as use of new terminology for indolent and precancerous disorders. We propose the term indolent lesion of epithelial origin, or IDLE, for those lesions (currently labelled as cancers) and their precursors that are unlikely to cause harm if they are left untreated. Furthermore, precursors of cancer or high-risk disorders should not have the term cancer in them. The rationale for this change in approach is that indolent lesions with low malignant potential are common, and screening brings indolent lesions and their precursors to clinical attention, which leads to overdiagnosis and, if unrecognised, possible overtreatment. To minimise that potential, new strategies should be adopted to better define and manage IDLEs. Screening guidelines should be revised to lower the chance of detection of minimal-risk IDLEs and inconsequential cancers with the same energy traditionally used to increase the sensitivity of screening tests. Changing the terminology for some of the lesions currently referred to as cancer will allow physicians to shift medicolegal notions and perceived risk to reflect the evolving understanding of biology, be more judicious about when a biopsy should be done, and organise studies and registries that offer observation or less invasive approaches for indolent disease. Emphasis on avoidance of harm while assuring benefit will improve screening and treatment of patients and will be equally effective in the prevention of death from cancer.
doi:10.1016/S1470-2045(13)70598-9
PMCID: PMC4322920  PMID: 24807866
2.  [No title available] 
PMCID: PMC3954701  PMID: 24439931
3.  [No title available] 
PMCID: PMC3982874  PMID: 24439313
4.  The Addition of Gemtuzumab Ozogamicin to Induction Chemotherapy in Acute Myeloid Leukaemia : An IndividualPatient Data Meta-analysis of Randomised Trials in Adults 
The Lancet. Oncology  2014;15(9):986-996.
Summary
Background
Gemtuzumab Ozogamicin (GO) was the first example of antibody directed chemotherapy in cancer and developed for Acute Myeloid Leukaemia. Its role has been unclear. Five randomised trials where it was combined with standard induction chemotherapy in adults have produced different results. In an effort to clarify the level of benefit, if any, and in which patients outcomes might be improved, an individual patient data meta-analysis of these 5 trials has been undertaken.
Methods
All randomised trials of GO in adults (age >15), given in conjunction with the first course of intensive induction chemotherapy for AML (excluding APL) were identified. In a collaboration between the groups involved, source data concerning demographics, treatment was requested in May 2013 and collected in 3325 randomised patients (median age 58). All trials were centrally randomised and open-label, with survival as primary endpoint. Analyses are presented by standard techniques, and within standardised risk groups
Results
Remission rates were not increased, but by significantly reducing the risk of relapse overall survival at 5 years was improved irrespective of patient age (30.7% vs 34.6%; HR 0.90 (95% CI 0.82-0.98), p=0.01). The survival benefit was particularly clear in those with favourable cytogenetics (55.2% vs 76.3%; HR0.47 (0.31-0.73), p=0.0005), but also observed in intermediate risk patients (34.1% vs 39.4%; HR 0.84 (0.75-0.95), p=0.007) Patients with adverse karyotype did not benefit overall or within any trial. Dose levels of 3mg/m2 were associated with less toxicity and equal efficacy.
Interpretation
GO can be safely added to conventional induction therapy. For patients who do not have adverse cytogenetics there is a significant survival benefit. These data suggest that the use of GO should be re-evaluated and the license status of GO may need to be reviewed.
Role of funding source
There was no funder for this meta-analysis.
doi:10.1016/S1470-2045(14)70281-5
PMCID: PMC4137593  PMID: 25008258
5.  Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis 
The Lancet. Oncology  2009;11(2):136-146.
Summary
Background
Analyses of microRNA expression profiles have shown that many microRNAs are expressed aberrantly and correlate with tumorigenesis, progression, and prognosis of various haematological and solid tumours. We aimed to assess the relation between microRNA expression and progression and prognosis of gastric cancer.
Methods
353 gastric samples from two independent subsets of patients from Japan were analysed by microRNA microarray. MicroRNA expression patterns were compared between non-tumour mucosa and cancer samples, graded by diffuse and intestinal histological types and by progression-related factors (eg, depth of invasion, metastasis, and stage). Disease outcome was calculated by multivariable regression analysis to establish whether microRNAs are independent prognostic factors.
Findings
In 160 paired samples of non-tumour mucosa and cancer, 22 microRNAs were upregulated and 13 were downregulated in gastric cancer; 292 (83%) samples were distinguished correctly by this signature. The two histological subtypes of gastric cancer showed different microRNA signatures: eight microRNAs were upregulated in diffuse-type and four in intestinal-type cancer. In the progression-related signature, miR-125b, miR-199a, and miR-100 were the most important microRNAs involved. Low expression of let-7g (hazard ratio 2·6 [95% CI 1·3–4·9]) and miR-433 (2·1 [1·1–3·9]) and high expression of miR-214 (2·4 [1·2–4·5]) were associated with unfavourable outcome in overall survival independent of clinical covariates, including depth of invasion, lymph-node metastasis, and stage.
Interpretation
MicroRNAs are expressed differentially in gastric cancers, and histological subtypes are characterised by specific microRNA signatures. Unique microRNAs are associated with progression and prognosis of gastric cancer.
Funding
National Cancer Institute.
doi:10.1016/S1470-2045(09)70343-2
PMCID: PMC4299826  PMID: 20022810
6.  [No title available] 
PMCID: PMC4291166  PMID: 25439688
7.  Phase 1/2 trial of vorinostat plus tacrolimus and mycophenolate to prevent graft versus host disease following related donor reduced intensity conditioning allogeneic hematopoietic stem cell transplantation 
The lancet oncology  2013;15(1):87-95.
BACKGROUND
Acute graft-versus-host disease (GVHD) remains a significant barrier to a more widespread application of allogeneic hematopoietic stem cell transplantation (HSCT). Vorinostat (suberoylanilide hydroxamic acid) is a histone deacetylases (HDAC) inhibitor that has been shown to attenuate GVHD in pre-clinical models. We aimed to study the safety and activity of vorinostat in combination with standard immunoprophylaxis for GVHD prevention in patients undergoing related donor reduced intensity conditioning HSCT.
METHODS
In this prospective, single-arm phase 1/2 study of vorinostat, we recruited patients with high-risk hematologic malignances at two centers in the USA. We enrolled patients aged 18 years or older who were candidates for a reduced intensity conditioning HSCT and had an available 8/8- or 7/8-Human Leukocyte Antigen (HLA) matched related donor. Disease status had to be adequately controlled at the time of transplant. All patients received a conditioning regimen consisting of fludarabine 40 mg/m2 daily for four days (total dose 160 mg/m2) and busulfan 3·2 mg/kg daily for two days (total dose 6·4 mg/kg). GVHD prophylaxis consisted of mycophenolate mofetil 1 gram three times daily from day 0 and through day 28 and tacrolimus beginning on day −3 pre-HSCT and tapered beginning on day 56 and discontinued by day 180 post-HSCT in the absence of GVHD. The investigational agent, vorinostat, was initiated on day −10 through day 100 post-HSCT. The primary endpoint of the study was grade 2–4 acute GVHD by day 100. We expected to reduce the incidence to 25% from 42% based on similarly treated patients from the study centers and published literature. Patients were assessed for both toxicity and the primary endpoint if at least 21 days of vorinostat were administered. Patients who received less than 21 days of therapy were still assessed for toxicity and were replaced in accordance to the protocol. The trial is registered with ClinicalTrials.gov, NCT00810602.
FINDINGS
Between March 2008 and February 2013, we enrolled 50 patients evaluable for both toxicity and response. All patients engrafted neutrophils and platelets at expected times post-HSCT. The median percentages of chimerism in whole-blood at day 100 and 1-year were 98% (interquartile range [IQR], 98–100) and 100% (IQR, 100–100), respectively. The primary endpoint of the study was met with a day 100 cumulative incidence of grade 2–4 acute GVHD of 22% (95% cumulative incidence: 13%, 36%). Eight additional patients enrolled were assessed for toxicity only, in accordance with the protocol, because they received less than 21 days of study drug. The most common non-hematologic adverse events were all grade 3 and included electrolyte disturbances (N=15), hyperglycemia (N=10), infections (N=4), mucositis (N=4), and elevated liver enzymes (N=3). There was one grade 4 hypokalemia event and two grade 4 infections. Non-symptomatic thrombocytopenia which occurred after engraftment was the most common hematologic grade 3 or 4 adverse event (N=9), but was transient and all cases resolved swiftly.
INTERPRETATION
Administration of vorinostat in combination with standard GVHD prophylaxis after related donor reduced intensity conditioning HSCT is safe and appears to reduce severe GVHD. Future studies are needed to assess the effect of vorinostat in the prevention of GVHD in broader HSCT settings.
doi:10.1016/S1470-2045(13)70512-6
PMCID: PMC4103793  PMID: 24295572
GVHD; hematopoietic stem cell transplantation; HDAC inhibitor; vorinostat
8.  Abdominal radiation and diabetes: one more piece in the puzzle 
The Lancet. Oncology  2012;13(10):961-962.
doi:10.1016/S1470-2045(12)70340-6
PMCID: PMC4280844  PMID: 22921662
9.  Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial 
The Lancet. Oncology  2013;14(9):893-900.
Background
Bone metastasis is a hallmark of advanced prostate cancer. The endothelin pathway has a mechanistic role in bone metastases. Atrasentan, an endothelin receptor antagonist, has reported activity in prostate cancer. We assessed the survival impact of atrasentan in castration resistant prostate cancer (CRPC) patients with bone metastases being treated with standard-of-care docetaxel.
Methods
Men with metastatic CRPC were stratified for progression type (PSA or radiologic), baseline pain, extra skeletal metastases and bisphosphonate use and randomised using double-blinded methodology on a 1:1 ratio to docetaxel with atrasentan or placebo for up to 12 cycles of 3 weeks and treated until progression or unacceptable toxicity. Non-progressing patients were permitted to continue atrasentan or placebo for up to 52 weeks. Co-primary endpoints were progression-free (PFS) and overall survival (OS) where 930 patients are needed to detect a 25% increase in median overall survival of 18 months with the addition of atrasentan (1-sided log-rank α=0.025, power 87%, 4 years accrual, 2.5 additional years of follow-up).
Results
1038 patents were accrued. Treatment was halted in April 2011, after an independent data safety monitoring committee pre-planned futility interim analysis. There was no significant difference in OS (HR=1.04 (95% CI 0.90,1.19) p=0.64) or PFS (HR=1.02 (95% CI 0.89,1.16) p=0.81). There was no significant difference between arms for RECIST or PSA response, treatment related deaths or grade 3 or more toxicity. Although 370 patients continued on blinded study drug after cessation of docetaxel, atrasentan did not significantly prolong post-chemotherapy OS in this subset.
Interpretation
Atrasentan, when added to docetaxel, does not improve overall or progression-free survival in men with castration-resistant prostate cancer and bone metastases.
doi:10.1016/S1470-2045(13)70294-8
PMCID: PMC4277263  PMID: 23871417
10.  Recommendations for Breast Cancer Surveillance for Female Childhood, Adolescent and Young Adult Cancer Survivors Treated with Chest Radiation: A Report from the International Late Effects of Childhood Cancer Guideline Harmonization Group 
The Lancet. Oncology  2013;14(13):e621-e629.
Summary
Female childhood, adolescent and young adult (CAYA) cancer survivors treated with radiation to fields that include breast tissue (chest radiation) have an increased risk of breast cancer. Clinical practice guidelines are essential to ensure that these survivors receive optimum care, and thereby reduce the detrimental consequences of cancer treatment. However, surveillance recommendations vary among the existing long-term follow-up guidelines. This guideline provides international harmonized breast cancer surveillance recommendations for female CAYA cancer survivors treated with chest radiation prior to age 30 years. We applied evidence-based methods to develop the international harmonized recommendations. The recommendations were formulated by an international multidisciplinary guideline panel and categorized according to a 4-level colour grading schema adapted from existing level of evidence criteria. The harmonized breast cancer surveillance recommendations are based on a transparent process and are intended to be scientifically rigorous, positively influence health outcomes, and facilitate care for CAYA cancer survivors.
doi:10.1016/S1470-2045(13)70303-6
PMCID: PMC4257601  PMID: 24275135
11.  Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial 
The Lancet. Oncology  2013;14(13):1317-1325.
Summary
Background
Neoadjuvant chemotherapy with trastuzumab for patients with HER2-positive breast cancer can produce a pathological complete response in the breast in 30–65% of patients. We investigated the effect of the timing of trastuzumab administration with anthracycline and taxane neoadjuvant chemotherapy.
Methods
This randomised trial was done at 36 centres in the USA and Puerto Rico. Women with operable HER2-positive invasive breast cancer were randomly assigned (1:1) with a biased coin minimisation algorithm, stratified for age, tumour size, and hormone receptor status. Neither patients nor investigators (except for a cardiac safety review panel) were masked to treatment assignment. Patients randomly assigned to sequential treatment received fluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2 (FEC-75) on day 1 of a 21-day cycle for four cycles followed by paclitaxel 80 mg/m2 and trastuzumab 2 mg/kg (after a 4 mg/kg loading dose) once per week for 12 weeks, while those randomly assigned to the concurrent treatment group received paclitaxel and trastuzumab once per week for 12 weeks followed by four cycles of FEC-75 (on day 1 of each 21-day cycle) and once-weekly trastuzumab, in the same doses as the sequential group. Surgery, including evaluation of the axilla, was done within 6 weeks of completion of neoadjuvant treatment. The primary outcome was the percentage of patients who had a pathological complete response in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00513292.
Findings
From Sept 15, 2007, to Dec 15, 2011, 282 women were enrolled (140 in the sequential group, 142 in the concurrent group). Two patients in the sequential group withdrew consent before starting treatment. 78 of 138 (56.5%, 95% CI 47.8–64.9) patients who received sequential treatment had a pathological complete response in the breast versus 77 of 142 (54.2%, 95% CI 45.7–62.6) who received concurrent treatment (difference 2.3%, 95% CI–9.3 to 13.9). No treatment-related deaths occurred. The most common severe toxic effects were neutropenia (35 [25.3%] of 138 patients in the sequential group vs 45 [31.7%] of 142 patients in the concurrent group) and fatigue (six [4.3%] vs 12 [8.5%]). Left ventricular ejection fraction dropped below the institutional lower limit of normal at week 12 in one (0.8%) of 130 patients who received sequential treatment and four (2.9%) of 137 patients who received concurrent treatment; by week 24, it had dropped below this limit in nine (7.1%) of 126 patients and in six (4.6%) of 130 patients, respectively.
Interpretation
Concurrent administration of trastuzumab with anthracyclines off ers no additional benefi t and is not warranted.
doi:10.1016/S1470-2045(13)70502-3
PMCID: PMC4176878  PMID: 24239210
12.  Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis 
The lancet oncology  2013;14(12):1200-1207.
Background
Recurrent medulloblastoma is a daunting therapeutic challenge as it is almost universally fatal. Recent studies confirmed that medulloblastoma comprises four distinct subgroups. We sought to delineate subgroup specific differences in medulloblastoma recurrence patterns.
Methods
We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children between 1994-2012, and performed molecular subgrouping on FFPE tissues using a nanoString-based assay. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence and survival post-recurrence were determined in a subgroup specific fashion. Subgroup specific recurrence patterns were confirmed in two independent, non-overlapping FFPE validation cohorts. Where possible molecular subgrouping was performed on tissue obtained from both the initial surgery and at recurrence.
Results
A screening cohort of 30 recurrent medulloblastomas was assembled; nine with local recurrences, and 21 metastatic. When re-analysed in a subgroup specific manner, local recurrences were more frequent in SHH tumours (8/9, 88%) and metastatic recurrences were more common in Group 3 and 4 (17/20 [85%] with one WNT, p=0.0014, local vs metastatic recurrence, SHH vs Group 3 vs Group 4). The subgroup specific location of recurrence was confirmed in a multicenter validation cohort (p=0·0013 for local vs metastatic recurrence SHH vs Group 3 vs Group 4, n=77), and a second independent validation cohort comprising 96 recurrences (p<0·0001 for local vs metastatic recurrence SHH vs Group 3 vs Group 4, n=96). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival post recurrence was significantly longer in Group 4 patients (p=0·013) as confirmed in a multicenter validation cohort (p=0·0075). Strikingly, subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs.
Conclusions
Medulloblastoma does not switch subgroup at the time of recurrence further highlighting the stability of the four principle medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups were observed which have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of SHH patients. Refinement of therapy for Groups 3 and 4 should focus on the metastatic compartment, as it is the near universal cause of patient deaths.
doi:10.1016/S1470-2045(13)70449-2
PMCID: PMC3953419  PMID: 24140199
13.  Management of adult and paediatric acute lymphoblastic leukaemia in Asia: resource-stratified guidelines from the Asian Oncology Summit 2013 
The lancet oncology  2013;14(12):e508-e523.
The survival rates for both adult and children with acute lymphoblastic leukaemia have improved substantially in recent years with wider use of improved risk-directed therapy and supportive care. In nearly all developed countries, clinical practice guidelines have been formulated by multidisciplinary panels of leukaemia experts, with the goal of providing recommendations on standard treatment approaches based on current evidence. However, those guidelines do not take into account resource limitations in low-income countries, including financial and technical challenges. In Asia, there are huge disparities in economy and infrastructure among the countries, and even among different regions in some large countries. This review summarizes the recommendations developed for Asian countries by a panel of adult and paediatric leukaemia therapists, based on the availability of financial, skill and logistical resources, at a consensus session held as part of the 2013 Asian Oncology Summit in Bangkok, Thailand. The management strategies described here are stratified by a four-tier system (basic, limited, enhanced and maximum) based on the resources available to a particular country or region.
doi:10.1016/S1470-2045(13)70452-2
PMCID: PMC4059516  PMID: 24176570
14.  Triage options for HPV-positive women in cervical cancer screening 
The Lancet. Oncology  2012;14(2):107-109.
doi:10.1016/S1470-2045(12)70568-5
PMCID: PMC4198376  PMID: 23261357
15.  Is cancer gene therapy an empty suit? 
The lancet oncology  2013;14(11):e447-e456.
Gene therapy as a treatment for cancer is regarded as high in promise, but low in delivery, a deficiency that has become more obvious with ever-increasing reports of the successful correction of monogenic disorders by this approach. We review the commercial and scientific obstacles that have led to these delays and describe how they are progressively being overcome. Recent and striking successes and correspondingly increased commercial involvement suggest that gene transfer could finally become a powerful method for development of safe and effective cancer therapeutic drugs.
doi:10.1016/S1470-2045(13)70173-6
PMCID: PMC3916772  PMID: 24079872
16.  Prediction of late distant recurrence in estrogen receptor positive breast cancer patients: prospective comparison of the Breast Cancer Index (BCI), Oncotype DX recurrence score, and IHC4 in TransATAC 
The lancet oncology  2013;14(11):1067-1076.
SUMMARY
BACKGROUND
Greater than 50% of recurrences in estrogen receptor-positive (ER+) breast cancer occur after 5 years of adjuvant endocrine therapy. Biomarkers capable of improving the risk-benefit of extended adjuvant endocrine therapy for these late recurrences would be clinically valuable. We compared the prognostic ability of the Breast Cancer Index (BCI), Oncotype DX Recurrence Score (RS) and IHC4 for both early and late recurrence among patients with ER+, node negative (N0) disease within the ATAC clinical trial.
METHODS
BCI was performed from 1102 primary tumor samples from ER+ patients and two versions (BCI-C (primary) and BCI-L (secondary), based on cubic and linear combinations of the variables) were evaluated. RS and IHC4 values were previously derived. Prognostic discrimination for early (<5y) and late recurrence (5–10y) was assessed. To evaluate the ability of the biomarkers to predict recurrence beyond standard clinicopathological parameters, the likelihood-ratio chi-square (LR-Δχ2) was calculated from Cox proportional hazards models. The primary endpoint was distant recurrence (DR).
FINDINGS
In the primary analysis of 665 ER+ N0 patients, categorical BCI-C demonstrated significant differences in risk of DR over 10 years (P<0·0001). In the secondary analysis, BCI-L proved to be a much stronger predictor, and BCI-L, IHC4 and RS had significant prognostic performance for early DR (BCI-L, p<0·0002), while only BCI-L was significant for late DR (LR-Δχ2: 7·97, p=0·0048). For risk of early DR at 5 years, BCI-L classified 59% (390/665), 25% (166/665) and 16% (109/665) of patients with 1.3% (0.5% – 3.1%), 5.6% (2.9% – 10.5%) and 18.1% (12.0% – 27.0%) for low, intermediate and high risk, respectively. For risk of late DR at 10 years, BCI-L classified 61% (366/596), 25% (146/596) and 14% (84/596) of patients with 3.5% (2.0% – 6.1%), 13.4% (8.5% – 20.8%) and 13.3% (7.4% – 23.4%) for low, intermediate and high, respectively.
INTERPRETATION
While all three biomarkers predicted for early DR, BCI-L was the only significant prognostic for risk of late DR. The three BCI-L groups identified two risk populations for both early and late DR with 84% (556/665) of patients having low risk for early DR, and a smaller population (39%, 230/596) having high risk for late DR who may benefit from extended endocrine or other therapy.
FUNDING
Avon Foundation, National Institutes of Health, Breast Cancer Foundation, DOD Breast Cancer Research Program, Susan G. Komen for the Cure, Breakthrough Breast Cancer through the Mary-Jean Mitchell Green Foundation, Astrazeneca, NIHR Biomedical Research Centre at the Royal Marsden.
doi:10.1016/S1470-2045(13)70387-5
PMCID: PMC3918681  PMID: 24035531
17.  THE CELL OF ORIGIN OF OVARIAN EPITHELIAL TUMORS 
The Lancet. Oncology  2008;9(12):1191-1197.
Although ovarian epithelial tumors are widely believed to arise in the coelomic epithelium that covers the ovarian surface, it was also suggested that they could instead arise from tissues that are embryologically derived from the mullerian ducts. This article revisits this debate based on recent epidemiological and molecular biological observations as well as evidence based on histopathological observations of surgical specimens from individuals with familial ovarian cancer predisposition. Morphological, embryological, and molecular biological characteristics of ovarian epithelial tumors that must be accounted for in formulating a theory about their cell of origin are reviewed, followed by comments about the ability of these two hypotheses to account for each of these characteristics. An argument is made that primary ovarian epithelial tumors fallopian tube carcinomas, and primary peritoneal carcinomas are all mullerian in nature and could therefore be regarded as a single disease entity. Although a significant proportion of cancers presently regarded as of primary ovarian origin arise in the fimbriated end of the fallopian tube, this site cannot account for an equally significant proportion of these tumors, which are most likely derived from components of the secondary mullerian system.
doi:10.1016/S1470-2045(08)70308-5
PMCID: PMC4176875  PMID: 19038766
18.  Phase III trial (EORTC 10994/BIG 1-00) assessing the value of p53 using a functional assay to predict sensitivity to a taxane versus non taxane primary chemotherapy in breast cancer: final analysis 
The Lancet. Oncology  2011;12(6):527-539.
Background
This study tested the hypothesis that docetaxel confers a greater advantage over anthracyclines in p53 mutant compared to p53 wild type breast cancers.
Methods
Patients with locally advanced, inflammatory or large operable breast cancers were randomised to receive neoadjuvant chemotherapy consisting of either a standard anthracycline regimen (FEC 100 or tailored FEC) or a taxane-based regimen (docetaxel for 3 cycles, followed by epirubicin and docetaxel for 3 cycles). In this open label study, randomisation was performed using a minimisation method that stratified by institution and initial tumour stage (large operable versus locally advanced or inflammatory breast cancer). p53 status was assessed with a yeast functional assay on tumour biopsies taken before chemotherapy. The primary endpoint was a comparison of progression-free survival in the two arms according to p53 status and in the entire trial population (by intention to treat). We report the final analysis of the trial. The study is registered in ClinicalTrials.gov, number NCT00017095.
Findings
1856 patients were enrolled and 370 were unassessable for p53 tumour status (the main reason being low tumour cell content in the biopsy). 675 events for the primary endpoint were registered. The hazard ratio (HR) between the two arms for progression-free survival (PFS) was 0.84 (98% CI: 0.63–1.14; p=0.17) in the p53 mutant group and 0.89 (98% CI: 0.68–1.18; p=0.35) in the p53 wild type group. In the entire population, the HR was 0.85 (98% CI: 0.71–1.02; p=0.035) for the use of docetaxel. The most common grade 3 or 4 adverse events were neutropenia in 1598 patients (86.6%), febrile neutropenia in 284 (15.4%), fatigue in 136 (7.4%), infection in 121 (6.6%) and nausea or vomiting in 89 (4.8%). Two patients died of toxicity during or within 30 days of chemotherapy completion and without disease relapse (one in each arm).
Interpretation
Although p53 status is prognostic for overall survival, it was not predictive of preferential sensitivity to taxanes. p53 status tested by yeast assay in this population can not be used to select patients for FEC versus taxane-based chemotherapy.
Funding
National Cancer Institute (USA), “La Ligue Nationale Contre le Cancer”, EU (fp6 Active p53 grant), Pharmacia and Sanofi-Aventis.
doi:10.1016/S1470-2045(11)70094-8
PMCID: PMC4172919  PMID: 21570352
19.  Ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study 
The Lancet. Oncology  2014;15(10):1090-1099.
Summary
Background
Ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), is an effective therapy for patients with relapsed chronic lymphocytic leukemia (CLL). We investigated the activity and safety of the combination of ibrutinib with the monoclonal antibody rituximab (iR) in patients with high-risk CLL.
Methods
In this single-arm, phase 2 studywe enrolled 40 patients with high-risk CLL at MD Anderson Cancer Center, Houston, Texas, USA. Patients with symptomatic CLL requiring therapy received 28 day cycles of once-daily ibrutinib 420 mg , together with rituximab (weekly during cycle 1, then once per cycle until cycle 6), followed by continuous single-agent ibrutinib. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01520519 and is no longer accruing patients.
Findings
Between February 28, 2012 and September 11, 2012, we enrolled 40 CLL patients with high-risk disease features. 20 patients had del17p or TP53 mutations (16 previously treated, 4 untreated), 13 had relapsed CLL with del11q, and 7 patients a PFS < 36 months after frontline chemo-immunotherapy. Toxicity was mainly of mild to moderate severity (grade 1–2). 10 (25%) patients had diarrhea (grade 1 in 9 [22.5%] patients, grade 2 in 1 [2.5%]), bleeding events occurred in 14 (35%) patients (8 [20%] patients with grade 1, 5 [12.5%] patients grade 2, and 1 [2.5%] grade 3), nausea in 15 (37.5) patients (10 [25%] grade 1, 5 [12.5%] grade 2), and fatigue in 7 (17.5%) patients (4 [10%] grade 1, 3 [7.5%] grade 2). Grade 3 infections occurred in 4 patients (10%), no grade 4 or 5 infections occurred. At 18 months, the Kaplan Meier estimate of progression-free survival was 78% (95% CI 60.6–88.5) (del[17p] or TP53 mutation: 72%, 95% CI: 45.6–87.6)
Interpretation
Ibrutinib in combination with rituximab is a well-tolerated regimen for patients with high-risk CLL. It induces high rates of remissions and has positive impact on QOL in this difficult-to-treat patient population. These encouraging data merit further investigation of the added benefit of rituximab as combination partner for ibrutinib in an ongoing randomized trial, in which single-agent ibrutinib is compared to iR combination therapy (NCT02007044).
Funding
Pharmacyclics, Inc., Cancer Prevention and Research Institute of Texas (CPRIT), Leukemia & Lymphoma Society, NCI Grant P30 CA016672, MD Anderson’s Moon Shot Program in CLL, and MD Anderson Cancer Center Support Grant CA016672.
doi:10.1016/S1470-2045(14)70335-3
PMCID: PMC4174348  PMID: 25150798
20.  Obesity, overweight and cancer mortality in the Asia-Pacific Cohort Studies Collaboration: pooled analyses of 424 519 participants 
The Lancet. Oncology  2010;11(8):741-752.
SUMMARY
Background
Excess weight is an established risk factor for several cancers but there are sparse data from Asian populations in whom overweight and obesity is increasing rapidly and adiposity can be substantially greater for the same body mass index (BMI) compared to Caucasians.
Methods
We examined associations of adult BMI with cancer mortality (overall and 20 sites) in geographic populations from Asia and Australia/New Zealand (ANZ) within the Asia Pacific Cohort Studies Collaboration using Cox regression. Pooled data from 39 cohorts (recruitment 1961-99, median follow-up 4 years) were analyzed for 424 519 participants (77% Asian; 41% female; mean recruitment age 48 years) with individual data on BMI.
Findings
After excluding follow-up < 3 years, 4872 cancer deaths occurred in 401 215 participants. Hazard ratios (95% CI) for cancer sites with increased mortality risk in the obese (≥30 kg/m2) relative to the normal weight (18.5-24.9 kg/m2) were: 1.21 (1.09-1.36) for all-cause cancer (excluding lung and upper-aero digestive tract), 1.50 (1.13-1.99) for colon, 1.68 (1.06-2.67) for rectum, 1.63 (1.13-2.35) for breast in women aged ≥ 60 years, 2.62 (1.57-4.37) for ovary, 4.21 (1.89-9.39) for cervix, 1.45 (0.97-2.19) for prostate, and 1.66 (1.03-2.68) for leukaemia with the increased risk associated with a 5-unit increment in BMI ≥ 18.5 kg/m2 ranging from 1.13 (0.91-1.40) for rectum to 1.45 (1.00-2.11) for cervix. There was little evidence of regional differences in relative risk except for oropharynx and larynx where the association was inverse in ANZ but absent in Asia.
Interpretation
Overweight and obese individuals in populations across the Asia-Pacific region are at significantly increased risk of mortality from cancer. Strategies to prevent overweight and obesity across Asia are required to reduce the burden of cancer expected to occur if the obesity epidemic continues.
Funding
The APCSC has been funded by the National Health and Medical Research Council of Australia, the Health Research Council of New Zealand and Pfizer Inc., through an unrestricted medical grant.
doi:10.1016/S1470-2045(10)70141-8
PMCID: PMC4170782  PMID: 20594911
body mass index; obesity; overweight; cancer; mortality; Asia-Pacific
21.  Statins and breast cancer prognosis: evidence and opportunities 
The Lancet. Oncology  2014;15(10):e461-e468.
SUMMARY
Much preclinical and epidemiologic evidence supports anticancer effects of HMG-CoA reductase inhibitors (statins). Epidemiologic evidence does not support an association between statin use and reduced breast cancer incidence, but does support a protective effect of statins—particularly simvastatin—on breast cancer prognosis. We argue that the current evidence base is sufficient to justify a clinical trial of breast cancer adjuvant therapy with statins. We advocate for such a trial to be initiated without delay. If a protective effect of statins on breast cancer recurrence is supported by trial evidence, then the indications for a safe, well-tolerated, and in expensive treatment can be expanded to improve outcomes for breast cancer survivors. We discuss several design opportunities—including candidate predictive biomarkers of statin safety and efficacy—and offer solutions to key challenges to enrolment, follow-up, and analysis of such a trial.
doi:10.1016/S1470-2045(14)70119-6
PMCID: PMC4167822  PMID: 25186049
22.  Sex hormones and breast cancer risk in premenopausal women: collaborative reanalysis of seven prospective studies 
The lancet oncology  2013;14(10):1009-1019.
Background
The relationships of circulating concentrations of oestrogens, progesterone and androgens with breast cancer and related risk factors in premenopausal women are not well understood.
Methods
Individual data on prediagnostic sex hormone and sex hormone binding globulin (SHBG) concentrations were contributed by 7 prospective studies. Analyses were restricted to women who were premenopausal and under age 50 at blood collection, and to breast cancer cases diagnosed before age 50. The odds ratios (ORs) with 95% confidence intervals (95% CIs) for breast cancer associated with hormone concentrations were estimated by conditional logistic regression in up to 767 cases and 1699 controls matched for age, date of blood collection, and day of cycle, with stratification by study and further adjustment for cycle phase. The associations of hormones with risk factors for breast cancer in control women were examined by comparing geometric mean hormone concentrations in categories of these risk factors, adjusted for study, age, phase of menstrual cycle and body mass index (BMI). All statistical tests were two-sided.
Findings
ORs for breast cancer associated with a doubling in hormone concentration were 1.19 (95% CI 1.06–1.35) for oestradiol, 1.17 (1.03–1.33) for calculated free oestradiol, 1.27 (1.05–1.54) for oestrone, 1.30 (1.10–1.55) for androstenedione, 1.17 (1.04–1.32) for dehydroepiandrosterone sulphate, 1.18 (1.03–1.35) for testosterone and 1.08 (0.97–1.21) for calculated free testosterone. Breast cancer risk was not associated with luteal phase progesterone (for a doubling in concentration OR=1.00 (0.92–1.09)), and adjustment for other factors had little effect on any of these ORs. The cross-sectional analyses in control women showed several associations of sex hormones with breast cancer risk factors.
Interpretation
Circulating oestrogens and androgens are positively associated with the risk for breast cancer in premenopausal women.
doi:10.1016/S1470-2045(13)70301-2
PMCID: PMC4056766  PMID: 23890780
Breast cancer; sex hormones; premenopausal
23.  The role and targeting of Aurora kinases in head and neck cancer 
The Lancet. Oncology  2013;14(10):e425-e435.
Summary
Controlled activation of the Aurora kinases regulates mitotic progression in normal cells. Overexpression and hyperactivation of the Aurora-A and -B kinases play a leading role in tumorigenesis, inducing aneuploidy and genomic instability. In squamous cell carcinomas of the head and neck (SCCHN), overexpression of Aurora-A is associated with decreased survival, and reduction of Aurora-A and -B expression inhibits SCCHN cell growth and increases apoptosis. In this article, we provide a basic overview of the biological functions of Aurora kinases in normal cells and in cancer, and review both small studies and high throughput datasets that implicate Aurora-A, particularly, in the pathogenesis of SCCHN. Early phase clinical trials are beginning to evaluate the activity of small molecule inhibitors of the Aurora kinases. We summarize the state of current trials evaluating Aurora inhibitors in SCCHN, and discuss rational directions for future drug combination trials and biomarkers for use with Aurora-inhibiting agents.
doi:10.1016/S1470-2045(13)70128-1
PMCID: PMC4139969  PMID: 23993387
24.  Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial 
The lancet oncology  2013;14(10):999-1008.
Summary
Background
Myeloablative chemoradiotherapy and immunomagnetically purged autologous bone marrow transplantation has been shown to improve outcome for patients with high-risk neuroblastoma. Currently, peripheral blood stem cells (PBSC) are infused after myeloablative therapy, but the effect of purging is unknown. We did a randomised study of tumour-selective PBSC purging in stem-cell transplantation for patients with high-risk neuroblastoma.
Methods
Between March 16, 2001, and Feb 24, 2006, children and young adults (<30 years) with high-risk neuroblastoma were randomly assigned at diagnosis by a web-based system (in a 1:1 ratio) to receive either nonpurged or immunomagnetically purged PBSC. Randomisation was done in blocks stratified by International Neuroblastoma Staging System stage, age, MYCN status, and International Neuroblastoma Pathology classification. Patients and treating physicians were not masked to treatment assignment. All patients were treated with six cycles of induction chemotherapy, myeloablative consolidation, and radiation therapy to the primary tumour site plus metaiodobenzylguanidine avid metastases present before myeloablative therapy, followed by oral isotretinoin. PBSC collection was done after two induction cycles. For purging, PBSC were mixed with carbonyl iron and phagocytic cells removed with samarium cobalt magnets. Remaining cells were mixed with immunomagnetic beads prepared with five monoclonal antibodies targeting neuroblastoma cell surface antigens and attached cells were removed using samarium cobalt magnets. Patients underwent autologous stem-cell transplantation with PBSC as randomly assigned after six cycles of induction therapy. The primary endpoint was event-free survival and was analysed by intention-to-treat. The trial is registered with ClinicalTrials.gov, number NCT00004188.
Findings
495 patients were enrolled, of whom 486 were randomly assigned to treatment: 243 patients to receive non-purged PBSC and 243 to received purged PBSC. PBSC were collected from 229 patients from the purged group and 236 patients from the non-purged group, and 180 patients from the purged group and 192 from the non-purged group received transplant. 5-year event-free survival was 40% (95% CI 33–46) in the purged group versus 36% (30–42) in the non-purged group (p=0·77); 5-year overall survival was 50% (95% CI 43–56) in the purged group compared with 51% (44–57) in the non-purged group (p=0·81). Toxic deaths occurred in 15 patients during induction (eight in the purged group and seven in the non-purged group) and 12 during consolidation (eight in the purged group and four in the non-purged group). The most common adverse event reported was grade 3 or worse stomatitis during both induction (87 of 242 patients in the purged group and 93 of 243 patients in the non-purged group) and consolidation (131 of 177 in the purged group vs 145 of 191 in the non-purged group). Serious adverse events during induction were grade 3 or higher decreased cardiac function (four of 242 in the purged group and five of 243 in the non-purged group) and elevated creatinine (five of 242 in the purged group and six of 243 non-purged group) and during consolidation were sinusoidal obstructive syndrome (12 of 177 in the purged group and 17 of 191 in the non-purged group), acute vascular leak (11 of 177 in the purged group and nine of 191 in the non-purged group), and decreased cardiac function (one of 177 in the purged group and four of 191 in the non-purged group).
Interpretation
Immunomagnetic purging of PBSC for autologous stem-cell transplantation did not improve outcome, perhaps because of incomplete purging or residual tumour in patients. Non-purged PBSC are acceptable for support of myeloablative therapy of high-risk neuroblastoma.
Funding
National Cancer Institute and Alex’s Lemonade Stand Foundation.
doi:10.1016/S1470-2045(13)70309-7
PMCID: PMC3963485  PMID: 23890779
25.  Fertility preservation for girls and young women with cancer: population-based validation of criteria for ovarian tissue cryopreservation 
The Lancet. Oncology  2014;15(10):1129-1136.
Summary
Background
Ovarian tissue cryopreservation with later reimplantation has been shown to preserve fertility in adult women, but this approach remains unproven and experimental in children and adolescents. We aimed to assess the use of the Edinburgh selection criteria for ovarian tissue cryopreservation in girls and young women with cancer to determine whether we are offering this invasive procedure to the patients who are most at risk of premature ovarian insufficiency.
Methods
Cryopreservation of ovarian tissue has been selectively offered to girls and young women with cancer who met the Edinburgh selection criteria since 1996. Between Jan 1, 1996, and June 30, 2012, 410 female patients younger than 18 years at diagnosis were treated for cancer (including leukaemia and brain tumours) at the Edinburgh Children's Cancer Centre, which serves the whole South East of Scotland region. We determined the ovarian status of these patients from review of clinical records and classified them as having premature ovarian insufficiency or not, or as unable to be determined. Patients younger than 12 years at time of data cutoff (Jan 31, 2013) were excluded from the analysis.
Findings
34 (8%) of the 410 patients met the Edinburgh selection criteria and were offered ovarian tissue cryopreservation before starting cancer treatment. 13 patients declined the procedure and 21 consented, and the procedure was completed successfully in 20 patients. Of the 20 patients who had ovarian tissue successfully cryopreserved, 14 were available for assessment of ovarian function. Of the 13 patients who had declined the procedure, six were available for assessment of ovarian function. Median age at the time of follow-up for the 20 assessable patients was 16·9 years (IQR 15·5–21·8). Of the 14 assessable patients who had successfully undergone ovarian cryopreservation, six had developed premature ovarian insufficiency at a median age of 13·4 years (IQR 12·5–14·6), one of whom also had a natural pregnancy. Of the six assessable patients who had declined the procedure, one had developed premature ovarian insufficiency. Assessment of ovarian function was possible for 141 of the 376 patients who were not offered cryopreservation; one of these patients had developed premature ovarian insufficiency. The cumulative probability of developing premature ovarian insufficiency after treatment was completed was significantly higher for patients who met the criteria for ovarian tissue cryopreservation than for those who did not (15-year probability 35% [95% CI 10–53] vs 1% [0–2]; p<0·0001; hazard ratio 56·8 [95% CI 6·2–521·6] at 10 years).
Interpretation
The results of this analysis show that the Edinburgh selection criteria accurately identify the few girls and young women who will develop premature ovarian insufficiency, and validate their use for selection of patients for ovarian tissue cryopreservation. Further follow-up of this cohort of patients is likely to allow refinement of the criteria for this experimental procedure in girls and young women with cancer.
Funding
UK Medical Research Council.
doi:10.1016/S1470-2045(14)70334-1
PMCID: PMC4153375  PMID: 25130994

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