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2.  Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials 
Annals of Oncology  2014;25(1):149-154.
This study focuses on the outcomes of a large international cohort of patients with metastatic RCC who would not have met the eligibility criteria for clinical trials and compares these to those that would have eligible. The proportion of patients who would have been ineligible and the reason for ineligibility are also discussed.
Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown.
Patients and Methods
mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 103/uL, or neutrophil count <1500/mm3.
Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378–1.751, P < 0.0001).
The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.
PMCID: PMC4155479  PMID: 24356626
metastatic renal cell cancer; outcomes; clinical trials; ineligible
3.  Immunological off-target effects of standard treatments in gastrointestinal cancers 
Annals of Oncology  2013;25(1):24-32.
The effects on immune cells of standard cancer treatments (chemotherapeutic or biologic agents, interventional radiologic procedures) have become better appreciated. Likewise the contribution of the immune system towards the effectiveness of these treatments. This knowledge can potentially lead to novel applications of existing standard of care therapies in addition to potentiating their effect.
The effects on immune cells and the inflammatory microenvironment of commonly applied cancer treatments (chemotherapeutic or biologic agents, interventional radiologic procedures) have become better appreciated. Likewise, the contribution of the immune system toward the effectiveness of these treatments is clearer. The relevance of immune evasion by developing tumors is endorsed by its inclusion as one of the (updated) hallmarks of cancer. A greater understanding of this dimension can potentially lead to novel applications of existing standard of care therapies, in addition to potentiating their effect. This review summarizes the immune aspects of currently employed therapies—cytotoxic chemotherapeutics, biologic agents and interventional radiologic procedures—in solid tumor malignancies with a particular focus on those agents used in gastrointestinal cancers.
PMCID: PMC3868318  PMID: 24201974
pancreatic; immune; myeloid-derived suppressor cells; colorectal; CTLA4
4.  Potential increased risk of cancer from commonly used medications: an umbrella review of meta-analyses 
Annals of Oncology  2013;25(1):16-23.
An umbrella review evaluated 74 meta-analyses addressing the association of commonly used medications with cancer risk. Eleven meta-analyses found some increased risk, but no medication or class had substantial and consistent evidence for increased risk of malignancy. Very large studies with standardized analyses and no selective reporting are needed to detect reliable modest cancer risks in pharmacoepidemiology, if any such exist.
Several commonly used medications have been associated with increased cancer risk in the literature. Here, we evaluated the strength and consistency of these claims in published meta-analyses. We carried out an umbrella review of 74 meta-analysis articles addressing the association of commonly used medications (antidiabetics, antihyperlipidemics, antihypertensives, antirheumatics, drugs for osteoporosis, and others) with cancer risk where at least one meta-analysis in the medication class included some data from randomized trials. Overall, 51 articles found no statistically significant differences, 13 found some decreased cancer risk, and 11 found some increased risk (one reported both increased and decreased risks). The 11 meta-analyses that found some increased risks reported 16 increased risk estimates, of which 5 pertained to overall cancer and 11 to site-specific cancer. Six of the 16 estimates were derived from randomized trials and 10 from observational data. Estimates of increased risk were strongly inversely correlated with the amount of evidence (number of cancer cases) (Spearman's correlation coefficient = −0.77, P < 0.001). In 4 of the 16 topics, another meta-analysis existed that was larger (n = 2) or included better controlled data (n = 2) and in all 4 cases there was no statistically significantly increased risk of malignancy. No medication or class had substantial and consistent evidence for increased risk of malignancy. However, for most medications we cannot exclude small risks or risks in population subsets. Such risks are unlikely to be possible to document robustly unless very large, collaborative studies with standardized analyses and no selective reporting are carried out.
PMCID: PMC3868319  PMID: 24310915
cancer; meta-analysis; pharmacoepidemiology; randomized trials; review
5.  PARP Inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies 
Annals of Oncology  2013;25(1):32-40.
PARP inhibitors have shown promising activity in patients with BRCA1/2 mutation-associated ovarian and breast cancers. Accumulating evidence suggests that PARPi may have a wider application in the cancers defective in DNA repair pathways. Understanding more about the molecular abnormalities, exploring novel therapeutic trial strategies and defining potential predictive biomarkers, is critical to rapidly advancing the field of PARPi therapy.
Poly(ADP-ribose)polymerase inhibitors (PARPis) have shown promising activity in patients with BRCA1/2 mutation-associated (BRCA1/2MUT+) ovarian and breast cancers. Accumulating evidence suggests that PARPi may have a wider application in the treatment of sporadic high-grade serous ovarian cancer, and cancers defective in DNA repair pathways, such as prostate, endometrial, and pancreatic cancers. Several PARPis are currently in phase 1/2 clinical investigation, with registration trials now being designed. Olaparib, one of the most studied PARPis, has demonstrated activity in BRCA1/2MUT+ and BRCA-like sporadic ovarian and breast cancers, and looks promising in prostate and pancreatic cancers. Understanding more about the molecular abnormalities involved in BRCA-like tumors, exploring novel therapeutic trial strategies and drug combinations, and defining potential predictive biomarkers, is critical to rapidly advancing the field of PARPi therapy and improve clinical outcomes.
PMCID: PMC3868320  PMID: 24225019
parp inhibitor; brca-like cancers; brca1/2 mutation; brca1/2 mutation-associated cancers
6.  Adherence to consensus-based diagnosis and treatment guidelines in adult soft-tissue sarcoma patients: a French prospective population-based study† 
Annals of Oncology  2013;25(1):225-231.
The present patient-based prospective study evaluates soft-tissue sarcoma care management. Adherence to clinical guidelines was assessed through 23 criteria defined by consensus. Although practices were found to be relatively compliant overall, initial diagnosis and treatment across all stages need improving, particularly outside specialized centers. Standardized incidence rates are also reported.
Soft-tissue sarcomas (STSs) are rare tumors with varied histological presentations. Management and treatment are thus complex, but crucial for patient outcomes. We assess adherence to adult STS management guidelines across two French regions (10% of the French population). We also report standardized incidence.
Patients and methods
STS patients diagnosed from 1 November 2006 to 31 December 2007 were identified from pathology reports, medical hospital records, and cancer registries. Guideline adherence was assessed by 23 criteria (validated by Delphi consensus method), and age and sex-standardized incidence rates estimated. Associations between patient, treatment, and institutional factors and adherence with three major composite criteria relating to diagnostic imaging and biopsy as well as multidisciplinary team (MDT) case-review are reported.
Two hundred and seventy-four patients were included (57.7% male, mean age 60.8 years). Practices were relatively compliant overall, with over 70% adherence for 10 criteria. Three criteria with perfect Delphi consensus had low adherence: receiving histological diagnosis before surgery, adequacy of histological diagnosis (adherence around 50% for both), and MDT discussion before surgery (adherence <30%). Treatment outside of specialized centers was associated with lower adherence for all three composite criteria, and specific tumor sites and/or features were associated with lower adherence for diagnostic imaging, methods, and MDT meetings. STS standardized incidence rates were 4.09 (European population) and 3.33 (World) /100 000 inhabitants.
Initial STS diagnosis and treatment across all stages (imaging, biopsy, and MDT meetings) need improving, particularly outside specialized centers. Educational interventions to increase surgeon's sarcoma awareness and knowledge and to raise patients' awareness of the importance of seeking expert care are necessary.
PMCID: PMC3868321  PMID: 24285018
Delphi technique; guideline adherence; incidence; quality indicators; health care; soft-tissue sarcoma
7.  Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: two sides of the same coin 
Alberti, P. | Rossi, E. | Cornblath, D. R. | Merkies, I. S. J. | Postma, T. J. | Frigeni, B. | Bruna, J. | Velasco, R. | Argyriou, A. A. | Kalofonos, H. P. | Psimaras, D. | Ricard, D. | Pace, A. | Galiè, E. | Briani, C. | Dalla Torre, C. | Faber, C. G. | Lalisang, R. I. | Boogerd, W. | Brandsma, D. | Koeppen, S. | Hense, J. | Storey, D. | Kerrigan, S. | Schenone, A. | Fabbri, S. | Valsecchi, M. G. | Cavaletti, G. | Cavaletti, G. | Cornblath, D.R. | Merkies, I.S.J. | Postma, T.J. | Valsecchi, M.G | Galimberti, S. | Rossi, E. | Cavaletti, G. | Frigeni, B. | Lanzani, F. | Mattavelli, L. | Piatti, ML. | Alberti, P. | Binda, D. | Bidoli, P.. | Cazzaniga, M. | Cortinovis, D. | Bruna, J. | Velasco, R. | Argyriou, AA. | Kalofonos, HP. | Psimaras, D. | Ricard, D. | Pace, A. | Galiè, E. | Briani, C. | Lucchetta, M. | Campagnolo, M. | Dalla Torre, C. | Merkies, ISJ. | Faber, CG. | Merkies, ISJ. | Vanhoutte, EK. | Bakkers, M. | Brouwer, B. | Lalisang, RI. | Boogerd, W. | Brandsma, D. | Koeppen, S. | Hense, J. | Grant, R. | Storey, D. | Kerrigan, S. | Schenone, A. | Reni, L. | Piras, B. | Fabbri, S. | Padua, L. | Granata, G. | Leandri, M. | Ghignotti, I. | Plasmati, R.. | Pastorelli, F. | Postma, TJ. | Heimans, JJ. | Eurelings, M. | Meijer, RJ. | Grisold, W. | Lindeck Pozza, E. | Mazzeo, A. | Toscano, A. | Tomasello, C. | Altavilla, G. | Penas Prado, M. | Dominguez Gonzalez, C. | Dorsey, SG. | Brell, JM.
Annals of Oncology  2013;25(1):257-264.
The perception of the severity and relevance of Chemotherapy Induced Peripheral Neurotoxicity (CIPN) is different for physicians and patients. This study provides the basis for a rationale use of different physician assessed scales and of European Organization for Research and Treatment of Cancer CIPN specific self-report questionnaire (EORTC QOL-CIPN20).
The different perception and assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) between healthcare providers and patients has not yet been fully addressed, although these two approaches might eventually lead to inconsistent, possibly conflicting interpretation, especially regarding sensory impairment.
Patients and methods
A cohort of 281 subjects with stable CIPN was evaluated with the National Cancer Institute—Common Toxicity Criteria (NCI-CTC v. 2.0) sensory scale, the clinical Total Neuropathy Score (TNSc©), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sumscore (mISS) and the European Organization for Research and Treatment of Cancer CIPN specific self-report questionnaire (EORTC QOL-CIPN20).
Patients' probability estimates showed that the EORTC QLQ-CIPN20 sensory score was overall more highly related to the NCI-CTC sensory score. However, the vibration perception item of the TNSc had a higher probability to be scored 0 for EORTC QLQ-CIPN20 scores lower than 35, as vibration score 2 for EORTC QLQ-CIPN20 scores between 35 and 50 and as grade 3 or 4 for EORTC QLQ-CIPN20 scores higher than 50. The linear models showed a significant trend between each mISS item and increasing EORTC QLQ-CIPN20 sensory scores.
None of the clinical items had a perfect relationship with patients' perception, and most of the discrepancies stood in the intermediate levels of CIPN severity. Our data indicate that to achieve a comprehensive knowledge of CIPN including a reliable assessment of both the severity and the quality of CIPN-related sensory impairment, clinical and PRO measures should be always combined.
PMCID: PMC3868322  PMID: 24256846
chemotherapy; neuropathy; assessment; patient-reported outcome measure; neurotoxicity
8.  Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network 
Annals of Oncology  2013;25(1):126-131.
Rare EGFR mutations were collected from 10117 non-small cell lung cancer samples analyzed by ERMETIC-IFCT French network. Among 1047 EGFR-mutated samples, 102 (10%) harboured rare mutations (41 in exon 18, 49 in exon 20, 12 with others). Association with smoking differed between exon 18 and 20, and control rate to EGFR-TKI was 47%, strongly varied between patients requiring individual assessment.
There is scarce data available about epidermal growth factor receptor (EGFR) mutations other than common exon 19 deletions and exon 21 (L858R) mutations.
Patients and methods
EGFR exon 18 and/or exon 20 mutations were collected from 10 117 non-small-cell lung cancer (NSCLC) samples analysed at 15 French National Cancer Institute (INCa)-platforms of the ERMETIC-IFCT network.
Between 2008 and 2011, 1047 (10%) samples were EGFR-mutated, 102 (10%) with rare mutations: 41 (4%) in exon 18, 49 (5%) in exon 20, and 12 (1%) with other EGFR mutations. Exon 20 mutations were related to never-smoker status, when compared with exon 18 mutations (P < 0.001). Median overall survival (OS) of metastatic disease was 21 months [95% confidence interval (CI) 12–24], worse in smokers than in non-smoker patients with exon 20 mutations (12 versus 21 months; hazard ratio [HR] for death 0.27, 95% CI 0.08–0.87, P = 0.03). Under EGFR-tyrosine kinase inhibitors (TKIs), median OS was 14 months (95% CI 6–21); disease control rate was better for complex mutations (6 of 7, 86%) than for single mutations (16 of 40, 40%) (P = 0.03).
Rare EGFR-mutated NSCLCs are heterogeneous, with resistance of distal exon 20 insertions and better sensitivity of exon 18 or complex mutations to EGFR-TKIs, probably requiring individual assessment.
PMCID: PMC3868323  PMID: 24285021
epidermal growth factor receptor mutations; exon 18 mutations; exon 20 mutations; non-small-cell lung cancer; tyrosine-kinase inhibitors
9.  Parameningeal rhabdomyosarcoma in pediatric age: results of a pooled analysis from North American and European cooperative groups 
Annals of Oncology  2014;25(1):231-236.
Parameningeal (PM) site is a well-known adverse prognostic factor in children with rhabdomyosarcoma (RMS). A pooled analysis of data from 1105 patients with PM RMS differentiates those with good prognosis (36% patients with 0-1 risk factor: 10-yr OS 80.9%) from high risk PM patients (28% with 3-4 factors: 10-yr OS 51.1%). Furthermore, this analysis reinforces the necessity for radiotherapy in PM RMS.
Parameningeal (PM) site is a well-known adverse prognostic factor in children with localized rhabdomyosarcoma (RMS). To identify risk factors associated with outcome at this site, we pooled data from 1105 patients treated in 10 studies conducted by European and North American cooperative groups between 1984 and 2004.
Patients and methods
Clinical factors including age, histology, size, invasiveness, nodal involvement, Intergroup Rhabdomyosarcoma Study (IRS) clinical group, site, risk factors for meningeal involvement (MI), study group, and application of radiotherapy (RT) were studied for their impact on event-free and overall survival (EFS and OS).
Ten-year EFS and OS were 62.6 and 66.1% for the whole group. Patients without initial RT showed worse survival (10-year OS 40.8% versus 68.5% for RT treated patients). Multivariate analysis focusing on 862 patients who received RT as part of their initial treatment revealed four unfavorable prognostic factors: age <3 or >10 years, signs of MI, unfavorable site, and tumor size. Utilizing these prognostic factors, patients could be classified into different risk groups with 10-year OS ranging between 51.1 and 80.9%.
While, in general, PM localization is regarded as an adverse prognostic factor, the current analysis differentiates those with good prognosis (36% patients with 0–1 risk factor: 10-year OS 80.9%) from high-risk PM patients (28% with 3–4 factors: 10-year OS 51.1%). Furthermore, this analysis reinforces the necessity for RT in PM RMS.
PMCID: PMC3868324  PMID: 24356633
meningeal involvement; parameningeal; radiotherapy; rhabdomyosarcoma
10.  The prognostic significance of left ventricular ejection fraction in patients with advanced cancer treated in phase I clinical trials 
Annals of Oncology  2014;25(1):276-282.
We investigated the clinical role of left ventricular ejection fraction (LVEF) in patients with cancer treated with phase I clinical trials.
The overall survival of patients with LVEF ≤ 35% was shorter compared to those with LVEF between 35% and 50%, which was similar to those with LVEF ≥ 50%.
Echocardiography would improve patient selection for enrollment in phase I clinical trials.
New targeted agents may cause acute cardiac events. The purpose of our study was to investigate the incidence and the prognostic significance of left ventricular ejection fraction (LVEF) in phase I trials.
Patients and methods
Between October 2008 and September 2011, the records of 1166 consecutive patients with advanced cancer treated in the Phase I Clinic who underwent echocardiography were retrospectively reviewed.
Most of the patients were White (78%), and the most common tumor types were colorectal cancer and melanoma. Of 1166 patients, 177 (15.2%) patients had an LVEF of <50%. No difference in overall survival (OS) between patients with LVEF ≥ 50% and patients with LVEF < 50% was seen (median OS 7.4 versus 7.0 months, P = 0.84). Patients with LVEF ≤ 35% had shorter survival compared with those with LVEF between 35% and 50% (median 4.2 versus 8.0 months; P = 0.005). In multivariate analysis of patients with LVEF < 50%, independent factors predicting longer survival were LVEF > 35%, ≤2 prior systemic therapies, ≤2 metastatic sites, and normal lactate dehydrogenase and albumin levels.
Echocardiography would improve patient selection for enrollment in phase I clinical trials. These data suggest that it is safe to treat patients with LVEF between 35% and 50%.
PMCID: PMC3895955  PMID: 24356639
biomarker; cardiac dysfunction; malignancy and phase I trial
11.  A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib 
Annals of Oncology  2014;25(1):236-240.
We conducted a phase II study evaluating the efficacy and toxicity of pazopanib, a broad spectrum TKI inhibiting KIT, VEGFRs (-1, -2, and -3), and PDGFR (-α and-β) in patients with advanced GIST following failure of at least imatinib and sunitinib. Pazopanib as a single agent has marginal activity in unselected heavily pretreated patients with advanced GIST.
Advanced GISTs are incurable, but often treatable for years with tyrosine kinase inhibitors (TKIs). The majority of GISTs harbor an oncogenic activating mutation in KIT or PDGFRA. Inhibition of this activating mutation with TKIs most often leads to durable disease control for many patients. However, almost all patients develop resistance to these TKIs, typically due to the development of secondary mutations, heralding the need for new therapeutic options. We conducted a phase II study evaluating the efficacy and toxicity of pazopanib, a broad spectrum TKI inhibiting KIT, VEGFRs (−1, −2, and −3), and PDGFR (-α and-β) in patients with advanced GIST following failure of at least imatinib and sunitinib.
Patients received pazopanib 800 mg orally once daily. All patients were assessed for efficacy with CT scans every 8 weeks (two cycles). Patients continued pazopanib until progression or unacceptable toxicity. The primary end point was the 24-week nonprogression [complete response+partial response+stable disease (SD)] rate (NPR) per RECIST 1.1. Secondary end points included PFS, OS, and toxicity.
Between August 2011 and September 2012, a total of 25 patients were treated at two institutions. Median number of prior therapy was 3 (range 2–7). A total of 90 cycles of pazopanib were administered, with a median of two cycles (range 1 to 17+) per patient. Best response of SD at any time was observed in 12 (48%) patients. The NPR was 17% [95% confidence interval (CI) 4.5–37]. All but one patient discontinued protocol either due to PD (n = 19) or intolerance (n = 4). One patient with succinate dehydrogenase (SDH)-deficient GIST exhibited continuing disease control after 17 cycles. The median PFS for the entire cohort was 1.9 months (95% CI 1.6–5.2), and the median OS was 10.7 months (95% CI 3.9–NR).
Pazopanib was reasonably well tolerated with no unexpected toxicities. Pazopanib as a single agent has marginal activity in unselected heavily pretreated patients with advanced GIST.
PMCID: PMC4271129  PMID: 24356634
GIST; KIT; pazopanib; tyrosine kinase inhibitors
12.  Phase I/II study of neoadjuvant bevacizumab, erlotinib and 5-fluorouracil with concurrent external beam radiation therapy in locally advanced rectal cancer 
Annals of Oncology  2014;25(1):121-126.
Anti-VEGF and anti-EGFR therapy in combination with chemoradiation have been studied separately in rectal cancer. In this study, we evaluate the combination of bevacizumab and erlotinib with chemoradiation. The purpose of this study is to determine the maximal tolerated dose of erlotinib when added to 5-fluorouracil (5-FU) chemoradiation and bevacizumab, and safety and efficacy of this combination in patients with locally advanced rectal cancer.
To determine the maximal tolerated dose of erlotinib when added to 5-fluorouracil (5-FU) chemoradiation and bevacizumab and safety and efficacy of this combination in patients with locally advanced rectal cancer.
Patients and methods
Patients with Magnetic resonance imaging (MRI) or ultrasound defined T3 or T4 adenocarcinoma of the rectum and without evidence of metastatic disease were enrolled. Patients received infusional 5-FU 225 mg/M2/day continuously, along with bevacizumab 5 mg/kg days 14, 1, 15 and 29. Standard radiotherapy was administered to 50.4 Gy in 28 fractions. Erlotinib started at a dose of 50 mg orally daily and advanced by 50 mg increments in the subsequent cohort. Open total mesorectal excision was carried out 6–9 weeks following the completion of chemoradiation.
Thirty-two patients received one of three dose levels of erlotinib. Erlotinib dose level of 100 mg was determined to be the maximally tolerated dose. Thirty-one patients underwent resection of the primary tumor, one refused resection. Twenty-seven patients completed study therapy, all of whom underwent resection. At least one grade 3–4 toxicity occurred in 46.9% of patients. Grade 3–4 diarrhea occurred in 18.8%. The pathologic complete response (pCR) for all patients completing study therapy was 33%. With a median follow-up of 2.9 years, there are no documented local recurrences. Disease-free survival at 3 years is 75.5% (confidence interval: 55.1–87.6%).
Erlotinib added to infusional 5-FU, bevacizumab and radiation in patients with locally advanced rectal cancer is relatively well tolerated and associated with an encouraging pCR.
PMCID: PMC4271130  PMID: 24356623
rectal cancer; radiation; bevacizumab; erlotinib
13.  Ovarian cancer: genomic analysis 
Annals of Oncology  2013;24(Suppl 10):x7-x15.
Despite improvements in the management of ovarian cancer patients over the last 30 years, there has been only a minimal improvement in overall survival. While targeted therapeutic approaches for the treatment of cancer have evolved, major challenges in ovarian cancer research persist, including the identification of predictive biomarkers with clinical relevance, so that empirical drug selection can be avoided. In this article, we review published genomic analysis studies including data generated in our laboratory and how they have been incorporated into modern clinical trials in a rational and effective way.
Multiple published genomic analysis studies were collected for review and discussion with emphasis on their potential clinical applicability.
Genomic analysis has been shown to be a powerful tool to identify dysregulated genes, aberrantly activated pathways and to uncover uniqueness of subclasses of ovarian tumors. The application of this technology has provided a solid molecular basis for different clinical behaviors associated with tumor histology and grade. Genomic signatures have been obtained to predict clinical end points for patients with cancer, including response rates, progression-free survival, and overall survival. In addition, genomic analysis has provided opportunities to identify biomarkers, which either result in a modification of existing clinical management or to stratification of patients to novel therapeutic approaches designed as clinical trials.
Genomic analyses have accelerated the identification of relevant biomarkers and extended our understanding of the molecular biology of ovarian cancer. This in turn, will hopefully lead to a paradigm shift from empirical, uniform treatment to a more rational, personalized treatment of ovarian cancers. However, validation of potential biomarkers on both the statistical and biological levels is needed to confirm they are of clinical relevance, in order to increase the likelihood that the desired outcome can be predicted and achieved.
PMCID: PMC3836569  PMID: 24265410
ovarian; cancer; genomics; clinical trials
14.  New developments in the treatment of ovarian cancer—future perspectives 
Annals of Oncology  2013;24(Suppl 10):x69-x76.
Over the past 40 years, the treatment of ovarian cancer has undoubtedly improved as a result of better multi-modality care and platinum-based chemotherapy. More recently, the introduction of anti-angiogenic therapy, PARP inhibitors and a weekly regimen for paclitaxel indicate that results are likely to improve further. However, major challenges remain and these will be reviewed in this article. We assess key issues in anti-angiogenic treatment including potential ways for addressing resistance; we review the current studies of PARP inhibitor treatment, which shows most promise in patients with germline BRCA mutations; we describe the potential for folate-receptor-directed therapy, given the high level of FR expression in ovarian cancer and we highlight the potential for molecular targeted therapy, focusing on specific subgroups of the disease with targets such as the PI3 K/AKT and RAS/RAF/MEK pathways and the ErbB family of oncogenes. We anticipate that progress will accelerate with a better understanding of the molecular pathogenesis of the various subtypes of ovarian cancer, leading to an increasingly personalized approach to treating women with this disease.
PMCID: PMC3836570  PMID: 24265409
15.  Clinical implications of using molecular diagnostics for ovarian cancers 
Annals of Oncology  2013;24(Suppl 10):x22-x26.
In the era of morphologic diagnostics, any epithelial tumor on or involving the ovaries was presumed to come from and be strictly of ovarian origin, apart from the rare but clearly metastatic tumors. Thus, many women who might have had small fallopian tube primary cancers that rapidly extended on to or into the ovary were deemed to have ovarian cancer. Now, as we begin to better understand that there are different types of cancers of nonuterine Muellerian origin, we expand upon the morphologic to add the molecular characteristics. Morphomolecular characteristics are being applied to drive clinical advances including development and optimization of predictive and prognostic biomarkers, redefinition of historical controls, and consideration of novel clinical trial designs. Ovarian cancer, not a common cancer to start with, is now subdivided into types, making ever smaller clinical cohorts. The first studies evaluating tubo-ovarian Muellerian cancers of morphomolecular types have begun. Deleterious mutations in BRCA1 or 2 have been validated as the first new predictive and prognostic biomarker of the high-grade serous ovarian cancer type and polyADPribose polymerase inhibitors, the first targeted agents for this morphomolecular entity. Similar progress is developing in other tubo-ovarian cancer types. This new knowledge is driving the building of a structure–function-type relationship that is generating novel clinically applicable hypotheses for testing.
PMCID: PMC3836571  PMID: 24265398
morphological; biomarker; high-grade serous ovarian cancer; molecular; therapeutics
16.  Expression of TP53 mutation-associated microRNAs predicts clinical outcome in head and neck squamous cell carcinoma patients 
Annals of Oncology  2013;24(12):3082-3088.
TP53 mutation is associated with decreased survival rate in head and neck squamous cell carcinoma (HNSCC) patients. We set out to identify microRNAs (miRNAs) whose expression associates with TP53 mutation and survival in HNSCC.
Patients and methods
We analyzed TP53 status by direct sequencing of exons 2 through 11 of a prospective series of 121 HNSCC samples and assessed its association with outcome in 109 followed-up patients. We carried out miRNA expression profiling on 121 HNSCC samples and 66 normal counterparts. miRNA associations with TP53 mutations and outcome were evaluated.
A TP53 mutation was present in 58% of the tumors and TP53 mutations were significantly associated with a shorter recurrence-free survival. This association was stronger in the clinical subgroup of patients subjected to adjuvant therapy after surgery.
The expression of 49 miRNAs was significantly associated with TP53 status. Among these 49, we identified a group of 12 miRNAs whose expression correlates with recurrence-free survival and a group of 4 miRNAs that correlates with cancer-specific survival. The two groups share three miRNAs. Importantly, miRNAs that correlate with survival are independent prognostic factors either when considered individually or as signatures.
miRNAs expression associates with TP53 status and with reduced survival after surgical treatment of squamous cell carcinoma of the head and neck.
PMCID: PMC3841017  PMID: 24107801
TP53 mutation; microRNA; HNSCC; clinical outcome
17.  Dual HER2 inhibition in combination with anti-VEGF treatment is active in heavily pretreated HER2-positive breast cancer† 
Annals of Oncology  2013;24(12):3004-3011.
Preclinical data indicate that dual HER2 inhibition overcomes trastuzumab resistance and that use of an HER2 inhibitor with an anti-angiogenic agent may augment responses.
Patients and methods
We conducted a dose-escalation, phase I study of a combination of trastuzumab, lapatinib and bevacizumab. The subset of patients with metastatic breast cancer was analyzed for safety and response.
Twenty-six patients with metastatic breast cancer (median = 7 prior systemic therapies) (all with prior trastuzumab; 23 with prior lapatinib; one with prior bevacizumab) received treatment on a range of dose levels. The most common treatment-related grade 2 or higher toxicities were diarrhea (n = 11, 42%) and skin rash (n = 2, 8%). The recommended phase 2 dose was determined to be the full Food and Drug Administration (FDA) approved doses for all the three agents (trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance dose, intravenously every 3 weeks; lapatinib 1250 mg daily, bevacizumab 15 mg/kg intravenously every 3 weeks). The overall rate of stable disease (SD) ≥6 months and partial or complete remission (PR/CR) was 50% (five patients with SD ≥6 months; seven PRs (including one unconfirmed); one CR). The rate of SD ≥6 months/PR/CR was not compromised in patients who had previously received study drugs, those with brain metastases, and patients treated at lower dose levels.
The combination of trastuzumab, lapatinib and bevacizumab was well-tolerated at maximally approved doses of each drug, and its activity in heavily pretreated patients with metastatic breast cancer suggests that it warrants further investigation. ID
PMCID: PMC3841018  PMID: 24158411
breast cancer; her2; bevacizumab; trastuzumab; lapatinib
18.  A multicenter phase II study incorporating high-dose rituximab and liposomal doxorubicin into the CODOX-M/IVAC regimen for untreated Burkitt's lymphoma 
Annals of Oncology  2013;24(12):3076-3081.
Despite improvement with intensive multi-agent chemotherapy, 2-year progression-free survival (PFS) rates for adults with high-risk Burkitt's lymphoma (BL) remains <55%.
Patients and methods
We conducted a phase II trial for newly diagnosed classic BL utilizing liposomal doxorubicin (Adriamycin) in lieu of doxorubicin and incorporating intravenous rituximab (at 500 mg/m2 twice/cycle) into the CODOX-M/IVAC regimen. Correlative analyses included paired serum and cerebrospinal fluid (CSF) rituximab levels and close examination of cardiac function.
Among 25 BL patients, the median age was 44 years (23–70) and 4 patients were HIV positive. There were 20 high-risk and 5 low-risk patients. At baseline, 40% of high-risk patients had bone marrow involvement, 35% had bulky disease and 15% had central nervous system involvement. The overall response rate was 100% (complete remission 92%). At 34-month median follow-up, the 2-year PFS and overall survival (OS) rates for all patients were 80% and 84%, respectively (low-risk: both 100%; high-risk: 76% and 81%, respectively). Furthermore, the 2-year PFS, OS, and disease-specific survival (DSS) rates for high-risk, HIV-negative patients were 84%, 89% and 100%, respectively. Adverse events (AEs) appeared to be consistent with prior CODOX-M/IVAC data, although there were several grade 3 cardiac events noted (all declined ejection fraction without clinical symptoms). The mean serum rituximab levels at 24 h after cycles 1 and 3 for patients without relapse were 258 and 306 μg/ml, respectively, versus 131 and 193 μg/ml, respectively, for patients with early progression (P = 0.002 and 0.002, respectively). The mean CSF rituximab levels for all patients were 0.11 and 0.24 μg/ml, respectively, at cycle 1 (24/72 h), which equated to serum:CSF ratios of 0.05% and 0.20%, respectively.
The integration of rituximab into CODOX-M/IVAC for adult BL was feasible and tolerable, while changes in cardiac function warrant continued examination. This regimen was associated with excellent survival rates for HIV-negative BL. Further investigation of the predictive value of serum rituximab is needed. NCT00392990.
PMCID: PMC3841019  PMID: 24146219
burkitt's lymphoma; cancer; liposomal doxorubicin; non-Hodgkin's lymphoma; prognosis; rituximab
19.  Coming into focus: the nonovarian origins of ovarian cancer 
Annals of Oncology  2013;24(Suppl 8):viii28-viii35.
The traditional view of epithelial ovarian cancer asserts that all tumor subtypes share a common origin in the ovarian surface epithelium (OSE)
A literature review was carried out to summarize the emerging understanding of extraovarian sources of epithelial ovarian carcinomas.
Historically, there were no diagnostic criteria for documenting the origin of ovarian epithelial carcinomas. Moreover, there are no normal epithelial tissues in the ovary with morphologic similarities to these tumors. In fact, no precursor lesions have ever been reproducibly identified in the ovary. However, there is a strong correlation between extrauterine Müllerian tissue and the development of ovarian carcinomas, tumors of low malignant potential, and cystadenomas. The most recent support for this hypothesis comes from the careful analysis of risk-reducing bilateral salpingo-oopherectomy specimens from BRCA1 or BRCA2 mutation carriers. These studies showed that a significant majority of high-grade serous ovarian carcinomas, the most common subtype, arise from the fallopian tube fimbriae rather than the OSE.
Mounting evidence indicates that the vast majority of epithelial ovarian carcinomas are not ovarian in origin. Extrauterine Müllerian epithelium from various sites in the reproductive tract likely accounts for the diverse morphology and behavior of these tumors.
PMCID: PMC3805308  PMID: 24131966
coelomic epithelium; extrauterine Müllerian epithelium; fallopian tube fimbriae; ovarian carcinoma; primary peritoneal carcinoma
20.  Ulcer, gastric surgery and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case–Control Consortium (PanC4) 
Annals of Oncology  2013;24(11):2903-2910.
Peptic ulcer and its treatments have been associated to pancreatic cancer risk, although the evidence is inconsistent.
We pooled 10 case–control studies within the Pancreatic Cancer Case–control Consortium (PanC4), including 4717 pancreatic cancer cases and 9374 controls, and estimated summary odds ratios (OR) using multivariable logistic regression models.
The OR for pancreatic cancer was 1.10 [95% confidence interval (CI) 0.98–1.23] for history of ulcer (OR = 1.08 for gastric and 0.97 for duodenal ulcer). The association was stronger for a diagnosis within 2 years before cancer diagnosis (OR = 2.43 for peptic, 1.75 for gastric, and 1.98 for duodenal ulcer). The OR was 1.53 (95% CI 1.15–2.03) for history of gastrectomy; however, the excess risk was limited to a gastrectomy within 2 years before cancer diagnosis (OR = 6.18, 95% CI 1.82–20.96), while no significant increased risk was observed for longer time since gastrectomy. No associations were observed for pharmacological treatments for ulcer, such as antacids, H2-receptor antagonists, or proton-pump inhibitors.
This uniquely large collaborative study does not support the hypothesis that peptic ulcer and its treatment materially affect pancreatic cancer risk. The increased risk for short-term history of ulcer and gastrectomy suggests that any such association is due to increased cancer surveillance.
PMCID: PMC3811904  PMID: 23970016
anti-ulcer drugs; case–control study; gastrectomy; pancreatic cancer; peptic ulcer; pooled analysis
21.  Advanced chondrosarcomas: role of chemotherapy and survival 
Annals of Oncology  2013;24(11):2916-2922.
There are limited data about the role of chemotherapy in patients with
advanced chondrosarcomas.
The medical charts of 180 patients with advanced chondrosarcomas having received chemotherapy in 15 participating institutions between 1988 and 2011 were reviewed.
Median age was 52 years. Sixty-three percent of patients had conventional chondrosarcoma and 88% had metastatic disease. Combination chemotherapy was delivered in 98 cases (54.5%). One hundred and thirty-one patients (73%) received an anthracycline-containing regimen. Using RECIST, the objective response rate was significantly different according to histological subtype, being 31% for mesenchymal chondrosarcoma, 20.5% for dedifferentiated chondrosarcoma, 11.5% for conventional chondrosarcoma and 0% for clear-cell chondrosarcoma (P = 0.04). Median progression-free survival (PFS) was 4.7 months [95% confidence interval (CI) 3–6.5]. Performance status (PS) ≥2, number of metastatic sites ≥1 and single-agent regimen were independently associated with poor PFS. Median overall survival (OS) was 18 months (95% CI 14.5–21.6). PS, number of metastatic sites and palliative surgery were independently associated with OS.
Conventional chemotherapy have very limited efficacy in patients with advanced chondrosarcoma, the highest benefit being observed in mesenchymal and dedifferentiated chondrosarcoma. These data should be used as a reference for response and outcome in the assessment of investigational drugs in advanced chondrosarcoma.
PMCID: PMC3811906  PMID: 24099780
chondrosarcoma; chemotherapy; prognosis; treatment
22.  GDC-0449 in patients with advanced chondrosarcomas: a French Sarcoma Group/US and French National Cancer Institute Single-Arm Phase II Collaborative Study 
Annals of Oncology  2013;24(11):2922-2926.
Pre-clinical data have suggested a therapeutic role of Hedgehog (Hh) pathway inhibitors in chondrosarcoma.
This phase II trial included patients with progressive advanced chondrosarcoma. They received GDC-0449 150 mg/day (days 1–28, 28-day cycle). The primary end point was the 6-month clinical benefit rate (CBR) defined as the proportion of patients with non-progressive disease at 6 months. A 6-month CBR of 40% was considered as a reasonable objective to claim drug efficacy.
Between February 2011 and February 2012, 45 patients were included. Twenty had received prior chemotherapy. Thirty-nine were assessable for efficacy. The 6-month CBR was 25.6% (95% confidence interval 13.0–42.1). All stable patients had grade 1 or 2 conventional chondrosarcoma with documented progression within the 6 months before inclusion. All but one with available data also had overexpression of the Hh ligand. Median progression-free and overall survivals were 3.5 and 12.4 months, respectively. The most frequent adverse events were grade 1 or 2 myalgia, dysgeusia and alopecia.
GDC-0449 did not meet the primary end point of this trial. Results suggest some activity in a subset of patients with progressive grade 1 or 2 conventional chondrosarcoma. Further studies assessing its role in combination with chemotherapy are warranted. Identifier
PMCID: PMC3811907  PMID: 24170610
chondrosarcoma; Hedgehog pathway; treatment; GDC-0449
23.  Metastasis-free survival is associated with overall survival in men with PSA-recurrent prostate cancer treated with deferred androgen deprivation therapy 
Annals of Oncology  2013;24(11):2881-2886.
Clinical trials in men with biochemically recurrent prostate cancer (BRPC) have been hampered by long survival times, making overall survival (OS) a difficult end point to reach. Intermediate end points are needed in order to conduct such trials within a more feasible time frame.
Patients and methods
This is a retrospective analysis of 450 men with BRPC following prostatectomy treated at a single institution between 1981 and 2010, of which 140 developed subsequent metastases. Androgen deprivation therapy (ADT) was deferred until after the development of metastases. Cox regression models were developed to investigate factors influencing OS.
Median metastasis-free survival (MFS) was 10.2 years [95% confidence interval (CI) 7.6–14.0 years]; median OS after metastasis was 6.6 years (95%CI 5.8–8.4 years). Multivariable Cox regressions identified four independently prognostic variables for OS: MFS (HR 0.77; 95% CI 0.63–0.94), number of metastases (≤3 versus ≥4; HR 0.50; 95% CI 0.29–0.85), pain (absent versus present; HR 0.43; 95% CI 0.25–0.72), and bisphosphonate use (yes versus no; HR 0.60; 95% CI 0.37–0.98).
MFS emerged as an independent predictor of OS in men with BRPC treated with deferred ADT after the development of metastases. MFS may be a reasonable intermediate end point in future clinical trials. This observation requires prospective validation.
PMCID: PMC3888237  PMID: 23946329
clinical trial end points; metastasis-free survival; prostate cancer
24.  Mammographic density, MRI background parenchymal enhancement and breast cancer risk 
Annals of Oncology  2013;24(Suppl 8):viii37-viii41.
Mammographic density (MD), representing connective and epithelial tissue (fibroglandular tissue, FGT) is a major risk factor for breast cancer. In an analysis of an autopsy series (Bartow SA, Pathak DR, Mettler FA. Radiographic microcalcification and parenchymal patterns as indicators of histologic “high-risk” benign breast disease. Cancer 1990; 66: 1721–1725, Bartow SA, Pathak DR, Mettler FA et al. Breast mammographic pattern: a concatenation of confounding and breast cancer risk factors. Am J Epidemiol 1995; 142: 813–819), MD was found to be strongly correlated with the collagen and epithelial content of the breast (Li T, Sun L, Miller N et al. The association of measured breast tissue characteristics with MD and other risk factors for breast cancer. Cancer Epidemiol Biomarkers Prev 2005; 14: 343–349), and another report showed that breast epithelium was highly concentrated in the areas of collagen concentration (Hawes D, Downey S, Pearce CL et al. Dense breast stromal tissue shows greatly increased concentration of breast epithelium but no increase in its proliferative activity. Breast Cancer Res 2006; 8: R24). Collagen comprises the overwhelming majority of the FGT, occupying an area on the slides obtained from the autopsy series some 15 times the area of glandular tissue. The relationship of MD with breast cancer risk appears likely to be due to a major extent to increasing epithelial cell numbers with increasing MD. FGT is also seen in breast magnetic resonance imaging (breast MRI) and, as expected, it has been shown that this measure of FGT (MRI-FGT) is highly correlated with MD. A contrast-enhanced breast MRI shows that normal FGT ‘enhances’ (background parenchymal enhancement, BPE) after contrast agent is administered(Morris EA. Diagnostic breast MR imaging: current status and future directions. Radiol Clin North Am 2007; 45: 863–880, vii., Kuhl C. The current status of breast MR imaging. Part I. Choice of technique, image interpretation, diagnostic accuracy, and transfer to clinical practice. Radiology 2007; 244: 356–378), and a recent study suggests that BPE is also a major breast cancer risk factor, possibly as important as, and independent of MD (King V, Brooks JD, Bernstein JL et al. BPE at breast MR imaging and breast cancer risk. Radiology 2011; 260: 50–60). BPE is much more sensitive to the effects of menopause and tamoxifen than is FGT (King V, Gu Y, Kaplan JB et al. Impact of menopausal status on BPE and fibroglandular tissue on breast MRI. Eur Radiol 2012; 22: 2641–2647, King V, Kaplan J, Pike MC et al. Impact of tamoxifen on amount of fibroglandular tissue, BPE, and cysts on breast MRI. Breast J 2012; 18: 527–534). Changes in MD and BPE may be most useful in predicting response to chemopreventive agents aimed at blocking breast cell proliferation. More study of the biological basis of the effects of MD and BPE is needed if we are to fully exploit these factors in developing chemopreventive approaches to breast cancer.
PMCID: PMC3894109  PMID: 24131968
breast cancer; breast background parenchymal enhancement; breast MRI; mammographic density
25.  A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer 
Annals of Oncology  2013;24(11):2844-2849.
The contribution of induction chemotherapy (IC) before preoperative chemoradiation for esophageal cancer (EC) is not known. We hypothesized that IC would increase the rate of pathologic complete response (pathCR).
Trimodality-eligibile patients were randomized to receive no IC (Arm A) or IC (oxaliplatin/FU; Arm B) before oxaliplatin/FU/radiation. Surgery was attempted ∼5–6 weeks after chemoradiation. The pathCR rate, post-surgery 30-day mortality, overall survival (OS), and toxic effects were assessed. Bayesian methods and Fisher's exact test were used.
One hundred twenty-six patients were randomized dynamically to balance the two arms for histology, baseline stage, gender, race, and age. Fifty-five patients in Arm A and 54 in Arm B underwent surgery. The median actuarial OS for all patients (54 deaths) was 45.62 months [95% confidence interval (CI), 27.63–NA], with median OS 45.62 months (95% CI 25.56–NA) in Arm A and 43.68 months (95% CI 27.63–NA) in Arm B (P = 0.69). The pathCR rate in Arm A was 13% (7 of 55) and 26% (14 of 54) in Arm B (two-sided Fisher's exact test, P = 0.094). Safety was similar in both arms.
These data suggest that IC produces non-significant increase in the pathCR rate and does not prolong OS. Further development of IC before chemoradiation may not be beneficial.
Clinical trial no.: NCT 00525915 (
PMCID: PMC3937600  PMID: 23975663
esophageal carcinoma; induction chemotherapy; chemoradiation; randomized trial; pathologic complete response; esophageal preservation

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