Wednesday, August 05, 2015

Is England closing the international gap in cancer survival?

open access

Background:

We provide an up-to-date international comparison of cancer survival, assessing whether England is ‘closing the gap’ compared with other high-income countries.

Methods:

Net survival was estimated using national, population-based, cancer registrations for 1.9 million patients diagnosed with a cancer of the stomach, colon, rectum, lung, breast (women) or ovary in England during 1995–2012. Trends during 1995–2009 were compared with estimates for Australia, Canada, Denmark, Norway and Sweden. Clinicians were interviewed to help interpret trends.

Results:

Survival from all cancers remained lower in England than in Australia, Canada, Norway and Sweden by 2005–2009. For some cancers, survival improved more in England than in other countries between 1995–1999 and 2005–2009; for example, 1-year survival from stomach, rectal, lung, breast and ovarian cancers improved more than in Australia and Canada. There has been acceleration in lung cancer survival improvement in England recently, with average annual improvement in 1-year survival rising to 2% during 2010–2012. Survival improved more in Denmark than in England for rectal and lung cancers between 1995–1999 and 2005–2009.

Conclusions:

Survival has increased in England since the mid-1990s in the context of strategic reform in cancer control, however, survival remains lower than in comparable developed countries and continued investment is needed to close the international survival gap.

The gap in cancer survival between England and comparable countries has galvanised policymakers and clinicians since EUROCARE first launched its European survival comparisons (Berrino et al, 1995). Evidence that survival is generally lower in England has led to target setting and increased investment, aiming to raise survival in England to the standards achieved elsewhere.

Since the Calman–Hine Report recommended strategic improvements to cancer services in England, there has been a series of policy initiatives to improve survival (Expert Advisory Group on Cancer, 1995). The NHS Cancer Plan for England (Department of Health, 2000) was the second national cancer plan in the world (following Norway's). It emphasised centralisation, specialisation and use of multi-disciplinary teams (MDTs). A further suite of measures to improve prevention, earlier diagnosis and patient management was launched through the Cancer Reform Strategy (Department of Health, 2007) to address continuing concerns about the survival deficit in comparison to other high-income countries.

In 2009, the Department of Health in England formed the International Cancer Benchmarking Partnership (ICBP), a consortium of epidemiologists, clinicians and policymakers tasked with understanding survival differences between the United Kingdom and five other high-income countries with universal healthcare system coverage: Australia, Canada, Denmark, Norway and Sweden.....

Trends in 1- and 5-year net survival in Australia (A), Canada (C), Denmark (D), England (E), Norway (N) and Sweden (S) by period of diagnosis. Estimates of net survival are presented for the calendar periods of diagnosis 1995–1999, 2000–2004 and 2005–2009. Simple linear regression lines are presented for each combination of country and cancer using data from these three periods, to indicate the average change in survival. An estimate of net survival for England only is also presented for the calendar period of diagnosis 2010–2012.

.... For example, during 2000–2009, the percentage of women with ovarian cancer receiving surgery who were treated in a specialist trust rose from 43 to 76%, and the number treated by a specialist surgeon (caseload of >18 patients per year) rose from 20 to 55% (Butler et al, 2015).....

.....Despite steady improvement in survival from stomach, colon, rectal, lung, breast and ovarian cancers in England over the past two decades, survival remained lower than in Australia, Canada, Norway and Sweden for patients diagnosed in 2005–2009, and typically also for patients diagnosed in 2010–2012 in England compared with those diagnosed in 2005–2009 elsewhere. The improvement in survival between 1995–1999 and 2005–2009 was sometimes larger than in the leading countries, particularly in comparison with Australia, Canada and Sweden, leading to some narrowing of the international cancer survival gap......

..... Evidence that survival in England improved faster than in other countries during 1995–2009 was strongest in relation to Australia, Canada and Sweden. This could be explained by a partial ‘ceiling effect’ in those countries, given that they generally had the highest survival at the beginning of the study period. Alternatively, more regionalised health systems in those three countries might have limited the efficacy of national cancer control strategy and the power of national guidelines......

Tuesday, August 04, 2015

Anti–PD-1–Related Pneumonitis during Cancer Immunotherapy — NEJM

Correspondence

The clinical oncology community has rapidly expanding access to a variety of immunotherapeutic agents for the treatment of several types of cancers. Thus, knowledge of the spectrum of manifestations of autoimmune pneumonitis may assist other clinicians in managing this rare but potentially serious toxic effect.

2015 John Maddox Prize call for nominations · Sense about Science

2015

The prize is open to nominations for any kind of public activity, including all forms of writing, speaking and public engagement, in any of the following areas:

    Addressing misleading information about scientific or medical issues.
    Bringing sound evidence to bear in a public or policy debate.
    Helping people to make sense of a complex scientific issue.

The prize is open to nominations for any kind of public activity, including all forms of writing, speaking and public engagement, in any of the following areas:

Addressing misleading information about scientific or medical issues.
Bringing sound evidence to bear in a public or policy debate.
Helping people to make sense of a complex scientific issue.

- See more at: http://www.senseaboutscience.org/pages/maddox-prize-2015.html#sthash.vSq8H191.dpuf

The prize is open to nominations for any kind of public activity, including all forms of writing, speaking and public engagement, in any of the following areas:

Addressing misleading information about scientific or medical issues.
Bringing sound evidence to bear in a public or policy debate.
Helping people to make sense of a complex scientific issue.

- See more at: http://www.senseaboutscience.org/pages/maddox-prize-2015.html#sthash.vSq8H191.dpuf

Candidates for the John Maddox Prize must be nominated. The nominator should normally be an individual who is familiar with the work of the candidate but self-nomination will be considered in exceptional circumstances. This is a global prize: people from and in any country can be nominated.

the Oncologist - Giving Bad News (Editorial) - SPIKES

open access

refers to:
Editor's Note: See the related article, “Confronting Therapeutic Failure: A Conversation Guide,” on page 946 of this issue.

Combo Rx May Boost Ovarian Cancer Outcomes, But Too Few Get It

media

MONDAY Aug. 3, 2015, 2015 -- Chemotherapy delivered directly into the abdomen significantly improves survival among women with advanced ovarian cancer, a new study finds.
However, fewer than half of U.S. patients who could benefit from this treatment -- called intraperitoneal chemotherapy -- are receiving it, according to Dana-Farber/Brigham and Women's Cancer Center researchers.
The investigators studied whether a combination of intraperitoneal (IP) and intravenous (IV) chemotherapy was as effective in clinical practice as in a clinical trial involving women who'd had surgery for stage III ovarian cancer......

JCO (open access) Use and Effectiveness of Intraperitoneal Chemotherapy for Treatment of Ovarian Cancer

INTRODUCTION

Several randomized clinical trials have demonstrated that intraperitoneal and intravenous (IP/IV) chemotherapy improves survival in women with optimally resected, stage III ovarian cancer, compared with IV chemotherapy alone.^1–3 In 2006, the National Cancer Institute (NCI) issued a rare Clinical Announcement encouraging IP/IV chemotherapy use after the Gynecologic Oncology Group (GOG) conducted a randomized trial, GOG-172, that demonstrated a 16-month improvement in median overall survival.

To date, however, few studies have examined the impact of this announcement on the use of IP/IV chemotherapy in clinical practice or investigated whether the survival benefit in GOG-172 is representative of outcomes outside of clinical trials.

Specialty Society Clinical Practice Guidelines: Time for Evolution or Revolution?

JAMA Network

..... Therefore, to create CPGs that the public trusts, that clinicians and patients can readily implement, and for which compliance can be easily measured, the CPG development process should continue to be led by specialty societies but with a new model that integrates other stakeholders, including patients. Specialty societies will need to use a consortium process in which authors are not just from the specialty society ranks and the focus is on concise, rigorously evidence-based, highly practical, implementation- and measurement-focused CPGs with COI transparency. This approach could be disseminated broadly and adopted so that specialty society CPGs can be effectively used in critical efforts to improve the quality and safety of care and reduce cost.

Psychosocial Factors Associated With Withdrawal From the United Kingdom Collaborative Trial of Ovarian Cancer Screening After 1 Episode of Repeat Screening

open access (pdf)

Abstract: Objective: The United Kingdom Collaborative Trial of Ovarian Cancer Screening
(UKCTOCS) aims to establish the efficacy of 2 different ovarian cancer screening schedules. The psychosocial substudy examines the psychological factors associated with the screening program.

Methods: Women aged 50 to 75 years from 16 UK gynecologic centers randomized to annual multimodal screening or ultrasound screening (US) groups were followed up for 7 years. Psychosocial data from women who withdrew from the study after a repeat screen were examined.

Results: Sixteen percent (3499/21,733) of women requiring a repeat screening test in addition to annual screen withdrew from the study: 12.9% (1560/12,073) from the multimodal group and 20.1% (1939/9660) from the US group. An estimated relative risk of withdrawal is 1.46 (95% confidence interval, 1.36Y1.56; P e 0.001) for the US arm. High anxiety trait and increased psychological morbidity significantly influenced withdrawal, even when age, screening center, and group were taken into account (P G 0.001). The risk of withdrawal decreased significantly the longer a woman stayed in UKCTOCS, irrespective of the number of screens and intensity in the preceding year.

Conclusions: Withdrawal rate was greater in women undergoing US screening and in those who had repeats earlier inUKCTOCS. Having a high predisposition to anxiety, high current state anxiety, and above threshold general psychological morbidity all increased the withdrawal rate.

Interpretation
There are no other OCS studies of comparable design
and size with which to compare these UKCTOCS withdrawal
results. What we have shown is that women with a high
predisposition toward anxiety are more likely to drop out of
screening, as do those who experience high anxiety after their
most recent scan. Furthermore, the more invasive the initial
screening procedure is, that is TVS, rather than a multimodal
approach, the more likely withdrawal will be after a repeat
scan or false-positive result.

CONCLUSIONS
The United Kingdom Collaborative Trial of Ovarian
Cancer Screening included a comprehensive psychosocial
arm that has permitted an in-depth appraisal of not only the
psychosocial harms and benefits of OCS but also some of the
factors that might enhance or inhibit attendance and re attendance.
Next year, the National Screening Committee is
scheduled to review its policy on OCS in women after the
UKCTOCS study against criteria that include psychosocial
factors. These results should assist policy makers when
considering the optimal screening methods and any accompanying
educational resources, especially aimed at ameliorating
anxiety.

Monday, August 03, 2015

An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian (HGSC) cancer (CA125; carboplatin...)

open access - Nature Communications (technical)

Abstract: High-grade serous ovarian cancers (HGSCs) are deadly malignancies that relapse despite carboplatin chemotherapy. Here we show that 16 independent primary HGSC samples contain a CA125-negative population enriched for carboplatin-resistant cancer initiating cells.....
Discussion .... This study provides evidence that CA125-negative HGSC cells have stem properties and are inherently platinum resistant. The de novo platinum resistance of this tumour subpopulation can explain why these cancers consistently reappear after first-line platinum-based chemotherapy. On the basis of the promising preclinical results here, improving outcomes for this deadly malignancy could be achieved simply by supplementing existing therapies that work well against the majority of tumour cells with agents that sensitize the CA125-negative cells to carboplatin.

How to cite this article: Janzen, D. M. et al. An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer. Nat. Commun. 6:7956 doi: 10.1038/ncomms8956 (2015).

media (easier to comprehend)

A common type of ovarian cancer, high-grade serous ovarian cancer, often responds well to the chemotherapy drug carboplatin; however, it frequently recurs following the treatment. Now, UCLA researchers has discovered that malignant cells that do not produce the protein CA125, which is a biomarker used to test for ovarian cancer, have an increased ability to repair their DNA and resist cell death from the chemotherapy. This allows the cells to elude the drug and live long enough to regrow the original tumor. The results of the five-year study were published on August 3 in the peer-reviewed journal Nature Communications.......

Urinary melatonin and risk of ovarian cancer (eg. night shift work)

abstract

PURPOSE:

Melatonin has anti-carcinogenic properties, including modulation of estradiol production, cell cycle regulation, and promotion of apoptosis. Urinary melatonin has been inversely associated with breast cancer in some studies, but the association with ovarian cancer has not been investigated.

CONCLUSIONS:

These results are consistent with our previous study in which we reported no association between night shift work and ovarian cancer; however, given the small sample size in our study, additional evaluation in larger studies is warranted.

Cellular and molecular processes in ovarian cancer metastasis

abstract

Ovarian cancer is the most lethal gynecological malignancy. It is usually diagnosed at a late stage, with a 5-year survival rate of less than 30%. The majority of ovarian cancer cases are diagnosed after tumors have widely spread within the peritoneal cavity, limiting the effectiveness of debulking surgery and chemotherapy. Owing to a substantially lower survival rate at late stages of disease than at earlier stages, the major cause of ovarian cancer deaths is believed to be therapy-resistant metastasis³. Although metastasis plays a crucial role in promoting ovarian tumor progression and decreasing patient survival rates, the underlying mechanisms of ovarian cancer spread have yet to be thoroughly explored. For many years, researchers have believed that ovarian cancer metastasizes via a passive mechanism by which ovarian cancer cells are shed from the primary tumor and carried by the physiological movement of peritoneal fluid to the peritoneum and omentum. However, the recent discovery of hematogenous metastasis of ovarian cancer to the omentum via circulating tumor cells instigated rethinking of the mode of ovarian cancer metastasis and importance of the "seed and soil" hypothesis for ovarian cancer metastasis. In this review, we discuss the possible mechanisms by which ovarian cancer cells metastasize from the primary tumor to the omentum, the cross-talk signaling events between ovarian cancer cells and various stromal cells that play crucial roles in ovarian cancer metastasis, and the possible clinical implications of these findings in the management of this deadly, highly metastatic disease.

New and emerging factors in tumorigenesis: an overview

Blogger's Note: frequent references to ovarian cancer (serous, clear cell...)

open access

.... Alternatively, TP53 or PIK3CA mutations may drive cancers originating from different cell types. For example, the ovarian cancer found with high-frequency mutations in TP53 (Table 1) is the serous epithelial ovarian carcinoma subtype that makes up 90% of ovarian cancer. Another histologic subtype of ovarian cancer is called clear cell ovarian carcinoma that constitutes 1%–10% of ovarian cancers. The clear cell ovarian-subtype tumors have been shown to contain largely wild-type TP53 but high-frequency mutations in PIK3CA, up to 40%.28 Together, these may suggest that TP53 or PIK3CA mutations occur in different cell types, each driving a different subtype of cancer (serous ovarian cancer vs clear cell ovarian cancer).....

Radiologist, Meet Patient | Diagnostic Imaging

Blog

Do you have any information on the new FIGO stages of ovarian cancer| (question/answer)

Target Ovarian Cancer

An International Survey of Health Care Providers Involved in the Management of Cancer Patients Exposed to Cardiotoxic Therapy

Abstract

.... Cardiac oncology is a rapidly emerging but relatively new area of clinical medicine. It is encouraging to find a high level of concern for cardiac safety among health care providers treating cancer patients. Strikingly, there continues to be a lack of consensus on the definition of cardiotoxicity and a discrepancy in clinical practice between cardiologists and oncologists, the two specialties mostly involved in caring for cardiac oncology patients. These differences in opinion will need to be resolved through more effective research collaboration, formulation of evidence-based guidelines, and educational strategies to standardize the diagnosis, management, and monitoring of cardiac toxicity.....

Multimodality Imaging in Cardiooncology

open access

3. Cancer Treatment and Cardiotoxicity: Who Are the Actors?

The majority of studies on cardiotoxicity focus on patients treated with anthracyclines and trastuzumab. Anthracyclines (doxorubicin, daunorubicin, and epirubicin) use has been related to onset of HF within 1 year in about 2% of treated patients [1]. The HF incidence increases to 28% when the patients are exposed to the association of anthracyclines and trastuzumab [1]. Cardiotoxic effect has been described for classes of drugs other than the anthracyclines and trastuzumab such as inhibitors of tyrosine kinases (imatinib, dasatinib, nilotinib, sunitinib, sorafenib, and bevacizumab), antimetabolites (5-fluorouracil), alkylating agents (cisplatin, cyclophosphamide), and taxanes (docetaxel and paclitaxel) [10]. Radiotherapy has become an important instrument in the treatment of several malignances and is more often associated to standard chemotherapy treatment. Irradiation of the mediastinum with a cumulative dose >30 Gy and a daily fractioning >2 Gy appeared to be related to a high risk of developing cardiac dysfunction [11]......

Clinical Experience of Patients Referred to a Multidisciplinary Cardiac Oncology Clinic: An Observational Study

open access

Table 1: Patient demographics ( = 428). (Other tumour sites: gynaecologic, skin, sarcoma, neurologic, amyloidosis, thyroid, musculoskeletal.)

Cardiotoxicity is the second leading cause of long-term morbidity and mortality among cancer survivors. The purpose of this retrospective observational study is to report on the clinical and cardiac outcomes in patients with early stage and advanced cancer who were referred to our multidisciplinary cardiac oncology clinic (COC). A total of 428 patients were referred to the COC between October 2008 and January 2013. The median age of patients at time of cancer diagnosis was 60. Almost half of patients who received cancer therapy received first-line chemotherapy alone (169, 41.7%), of which 84 (49.7%) were exposed to anthracyclines. The most common reasons for referral to the cardiac oncology clinic were decreased LVEF (34.6%), prechemotherapy assessment (11.9%), and arrhythmia (8.4%). A total of 175 (40.9%) patients referred to the COC were treated with cardiac medications. The majority (331, 77.3%) of patients were alive as of January 2013, and 93 (21.7%) patients were deceased. Through regular review of cardiac oncology clinic referral patterns, management plans, and patient outcomes, we aim to continuously improve delivery of cardiac care to our patient population and optimize cardiac health.

1. Introduction

With the evolution of systemic and targeted therapies in cancer treatment, it has become increasingly evident that damage to the heart may occur as a result of cancer therapy. While cancer survivorship has significantly increased over the last decade [1], cardiotoxicity is the second leading cause of long-term morbidity and mortality among cancer survivors [2]. In addition, there are an increasing number of cancer patients with preexisting heart disease, for whom treatment with potentially cardiotoxic cancer therapy may pose a challenge [1]. Prevention and management strategies of cardiotoxicity will be important to optimize cancer care while maintaining cardiovascular health. Hence, the need for collaboration between oncologists and cardiologists from diagnosis to survivorship is imperative to ensure patients are receiving the best possible cancer care.......

FDA evaluating the risk of brain deposits with repeated use of gadolinium-based contrast agents for (MRI)

Drug Safety Podcasts

Sunday, August 02, 2015

Loss of heterozygosity: what is it good for?

open access

Ovarian tumour cohort
A tumour cohort (n = 86) comprising a variety of histological subtypes including serous (n = 45), endometrioid (n = 28), mucinous (n = 7) and clear cell (n = 6) were obtained through the Australia Ovarian Cancer Study, the Peter MacCallum Cancer Centre Tissue Bank, or from patients presenting to hospitals in the south of England [8].

Background

Loss of heterozygosity (LOH) is a common genetic event in cancer development, and is known to be involved in the somatic loss of wild-type alleles in many inherited cancer syndromes. The wider involvement of LOH in cancer is assumed to relate to unmasking a somatically mutated tumour suppressor gene through loss of the wild type allele.

Methods

We analysed 86 ovarian carcinomas for mutations in 980 genes selected on the basis of their location in common regions of LOH.

Results

We identified 36 significantly mutated genes, but these could only partly account for the quanta of LOH in the samples. Using our own and TCGA data we then evaluated five possible models to explain the selection for non-random accumulation of LOH in ovarian cancer genomes: 1. Classic two-hit hypothesis: high frequency biallelic genetic inactivation of tumour suppressor genes. 2. Epigenetic two-hit hypothesis: biallelic inactivation through methylation and LOH. 3. Multiple alternate-gene biallelic inactivation: low frequency gene disruption. 4. Haplo-insufficiency: Single copy gene disruption. 5. Modified two-hit hypothesis: reduction to homozygosity of low penetrance germline predisposition alleles. We determined that while high-frequency biallelic gene inactivation under model 1 is rare, regions of LOH (particularly copy-number neutral LOH) are enriched for deleterious mutations and increased promoter methylation, while copy-number loss LOH regions are likely to contain under-expressed genes suggestive of haploinsufficiency. Reduction to homozygosity of cancer predisposition SNPs may also play a minor role.

Conclusion

It is likely that selection for regions of LOH depends on its effect on multiple genes. Selection for copy number neutral LOH may better fit the classic two-hit model whereas selection for copy number loss may be attributed to its effect on multi-gene haploinsufficiency. LOH mapping alone is unlikely to be successful in identifying novel tumour suppressor genes; a combined approach may be more effective.

Shared genetics underlying epidemiological association between endometriosis and ovarian cancer

abstract

Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3,194 cases and 7,060 controls) and a large ovarian cancer dataset genotyped on the customised iCOGS arrays (10,065 cases and 21,663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI=0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI=0.07-0.89 and 0.40, 95% CI=0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI=0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.

Postoperative HRT for epithelial ovarian cancer patients: a systematic review/meta-analysis

abstract

BACKGROUND:

. Hormone replacement therapy (HRT) has been proven highly effective for menopausal symptoms caused by radical surgery. However, the impact of postoperative HRT on the clinical outcomes of patients previously treated for epithelial ovarian cancer (EOC) remains unclear.

OBJECTIVE:

. To determine whether postoperative HRT use has any positive or negative impacts on prognosis and recurrence among EOC survivors.

Saturday, August 01, 2015

A phase II study of ramucirumab (IMC-1121B) in the treatment of persistent or recurrent epithelial ovarian, FT or PP carcinoma

Abstract

2014 Sep;134(3):478-85. doi: 10.1016/j.ygyno.2014.06.029. Epub 2014 Jul 10.

A phase II study of ramucirumab (IMC-1121B) in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma.

OBJECTIVE:

Vascular endothelial growth factor (VEGF) receptor-mediated signaling contributes to ovarian cancer pathogenesis. Elevated VEGF expression is associated with poor clinical outcomes. We investigated ramucirumab, a fully human anti-VEGFR-2 antibody, in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Primary endpoints were progression-free survival at 6 months (PFS-6) and confirmed objective response rate (ORR).

METHODS:

Women who received ≥ 1 platinum-based chemotherapeutic regimen and had a platinum-free interval of <12 months with measurable disease were eligible. Patients received 8 mg/kg ramucirumab intravenously every 2 weeks.

RESULTS:

Sixty patients were treated; one patient remained on study as of September 2013. The median age was 62 years (range: 27-80), and median number of prior regimens was 3. Forty-five (75%) patients had platinum refractory/resistant disease. Thirty-nine patients (65.0%) had serous tumors. PFS-6 was 25.0% (n=15/60, 95% CI: 14.7-37.9%). Best overall response was: partial response 5.0% (n=3/60), stable disease 56.7% (n=34/60), and progressive disease 33.3% (n=20/60). The most common treatment-emergent adverse events possibly related to study drug were headache (65.0%; 10.0% Grade ≥ 3), fatigue (56.7%; 3.3% Grade ≥ 3), diarrhea (28.3%; 1.7% Grade ≥ 3), hypertension (25.0%; 3.3% Grade ≥ 3), and nausea (20.0%; no Grade ≥ 3). Two patients experienced intestinal perforations (3.3% Grade ≥ 3). Pharmacodynamic analyses revealed changes in several circulating VEGF proteins following initial ramucirumab infusion, including increased VEGF-A, PlGF and decreased sVEGFR-2.