Correspondence/Author's Response: Paraneoplastic Thrombocytosis in Ovarian Cancer — NEJM

Paraneoplastic Thrombocytosis in Ovarian Cancer — NEJM

Correspondence

Paraneoplastic Thrombocytosis in Ovarian Cancer

N Engl J Med 2012; 366:1840 May 10, 2012

To the Editor:

The mean platelet volume (MPV), analogous to the calculation of the mean corpuscular volume, is calculated as the plateletcrit divided by the total number of platelets. Although the MPV is readily available on a routine blood count, many laboratories do not report the MPV to clinicians because of the lack of standardization and the dependency of the results on the age of the sample and the method of measurement. Stone et al. (Feb. 16 issue)1 found that thrombocytosis was associated with shortened survival and advanced disease in patients with ovarian cancer. A recent population-based study has shown the MPV to be a predictor of venous thromboembolism.2 Other studies have shown the MPV to be a predictor of cardiovascular risk, with an elevated MPV associated with increased mortality after acute myocardial infarction and an increased rate of restenosis after coronary angioplasty.3 Similarly, an elevated MPV is associated with a worse outcome for acute ischemic cerebrovascular events, independent of other clinical factors.4 We would like to know whether the investigators obtained data on the MPV in their study cohort, and if so, whether they found any correlation between the MPV and survival, independent of thrombocytosis.

Harris V. Naina, M.D.
Samar Harris, M.D.
UT Southwestern, Dallas, TX
harris.naina@utsouthwestern.edu

No potential conflict of interest relevant to this letter was reported.
4 References

Author/Editor Response

Platelet size, as measured by the MPV and platelet distribution width, correlates with platelet reactivity.1 Retrospective data suggest that the MPV has potential prognostic and diagnostic value in hematologic and cardiovascular disorders.2 However, it is not known whether the MPV is a useful prognostic marker in patients with cancer. Although the focus of our investigation was on the mechanisms and effect of thrombocytosis on clinical outcomes in ovarian cancer, in response to the inquiry from Naina and Harris, we examined the association among the MPV, thrombocytosis, and survival in 150 patients with newly diagnosed advanced epithelial ovarian cancer. In this data set, the median MPV was 8 fl (range, 6 to 11). MPV levels were inversely correlated with platelet count (r=–0.45, P<0.001). Survival rates were not associated with the MPV (where a high MPV was defined as an MPV greater than either the median or the cutoff value used by our institution [>10.4 fl]). The value of alternative cutoff levels for MPV for prognostic evaluation is unknown.

Rebecca L. Stone, M.D.
Vahid Afshar-Kharghan, M.D.
Anil K. Sood, M.D.
University of Texas M.D. Anderson Cancer Center, Houston, TX

Correspondence/Aurthor's Response: Thromboprophylaxis in Patients Receiving Chemotherapy — NEJM

Thromboprophylaxis in Patients Receiving Chemotherapy — NEJM

Correspondence

Thromboprophylaxis in Patients Receiving Chemotherapy

N Engl J Med 2012; 366:1839-1840May 10, 2012

Article

To the Editor:

In their article on the results of the SAVE-ONCO study (ClinicalTrials.gov number, NCT00694382), which showed that semuloparin reduced the risks of deep-vein thrombosis in the lower or upper limbs and pulmonary embolism among patients receiving chemotherapy for cancer, Agnelli and colleagues (Feb. 16 issue)1 do not mention the development of central-venous-catheter thrombosis. Indeed, deep-vein thrombosis related to a central venous catheter is a frequent complication, reported in 4% of patients with symptomatic events and 20 to 30% of patients with asymptomatic events detected by means of venography or ultrasonography; this complication is associated with the risk of pulmonary embolism and loss of central venous access.2 A recent Cochrane review did not show any efficacy of heparins or vitamin K antagonists for the prevention of central-venous-catheter thrombosis.3 Accordingly, national guidelines mention no prophylactic treatment; specifically, they recommend no prophylactic doses of low-molecular-weight heparin or low-dose warfarin.2 Only the placement of the distal tip of the central venous catheter at the junction between the superior vena cava and the right atrium, and insertion on the right side are indicated.2,4 Therefore, was central-venous-catheter thrombosis observed in the study, and was semuloparin an effective prophylactic treatment?

Claude Bachmeyer, M.D.
Jean-Charles Pellen, M.D.
Tenon Hospital, Paris, France
claude.bachmeyer@tnn.aphp.fr

No potential conflict of interest relevant to this letter was reported.
4 References

Author/Editor Response

Bachmeyer and Pellen wonder whether central venous catheter–related thrombosis was observed in the study and whether semuloparin was an effective prophylactic treatment for this complication. In our study, a central venous catheter was present in 19.7% of patients in the semuloparin group and 18.8% of patients in the placebo group. Symptomatic deep-vein thrombosis of the upper limbs, including central-venous-catheter thrombosis, was part of the composite primary efficacy outcome. During the efficacy analysis period, symptomatic deep-vein thrombosis of the upper limbs occurred in 9 of 1604 patients in the placebo group (0.6%) and 3 of 1608 patients in the semuloparin group (0.2%) (hazard ratio, 0.33; 95% confidence interval, 0.07 to 1.18). All these patients had a central venous catheter. The risk reduction in deep-vein thrombosis of the upper limbs (including central-venous-catheter thrombosis) associated with semuloparin was consistent with the risk reduction in the other components of the composite primary efficacy outcome of the study, but the number of observed events is small.

Giancarlo Agnelli, M.D.
University of Perugia, Perugia, Italy
agnellig@unipg.it
Alexander G.G. Turpie, M.D.
McMaster University, Hamilton, ON, Canada

U of Michigan: Outpatient surgery patients also at risk for dangerous blood clots | University of Michigan Health System

 
Outpatient surgery patients also at risk for dangerous blood clots | University of Michigan Health System

"...With the information, the researchers created and validated a risk-stratification tool that can be used to predict a patient’s risk for VTE. The tool identified a 20-fold variation in VTE risk from 0.04 percent to 1.12 percent among the outpatient surgery population.
“These data are in stark contrast to provider and patient expectations that outpatient surgery is a low-risk event,” Pannucci says. “It also underscores the importance of evaluating a patient’s individual risk factors as opposed to procedure-type alone.”.....

abstract: Postoperative venous thromboembolism predicts survival in cancer patients

Postoperative venous thromboembolism predicts survi... [Ann Surg. 2012]

OBJECTIVES:

To determine whether a postoperative venous thromboembolism (VTE) is associated with a worse prognosis and/or a more advanced cancer stage and to evaluate the association between a postoperative VTE and cancer-specific survival when known prognostic factors, such as age, stage, cancer type, and type of surgery, are controlled.

CONCLUSIONS:

Postoperative VTE in oncology patients with limited disease and a complete surgical resection is associated with an inferior cancer survival. A postoperative VTE remains a poor prognostic factor, even when controlling for age, stage, cancer type, and surgical procedure further supporting an independent link between hypercoagulability and cancer survival.

abstract: Variation in thromboembolic complications among patients undergoing commonly performed cancer operations

Variation in thromboembolic complications among patients undergoing commonly performed cancer operations

Compared with breast cancer, the incidence of VTE ranged from a 1.31-fold increase in VTE associated with gastrectomy to a 2.68-fold increase associated with hysterectomy.

press release: Survey Reveals a Majority of Cancer Patients, Survivors Are Unaware of Higher Risk for Developing Deep-Vein Thrombosis and Pulmonary Embolism

Survey Reveals a Majority of Cancer Patients, Survivors Are Unaware of Higher Risk for Developing Deep-Vein Thrombosis and Pulmonary Embolism

NEW YORK, March 7, 2012 /PRNewswire/ — Focusing attention on patient groups at high risk for deep-vein thrombosis (DVT), the Coalition to Prevent DVT has found that a majority of people with cancer were not aware of an increased risk for DVT and its potentially fatal complication, pulmonary embolism (PE). Additionally, few had discussed their risk with their healthcare provider, according to a survey released by the Coalition as part of the ninth annual DVT Awareness Month.
Up to 2 million Americans are affected by DVT annually, and complications from DVT/PE kill up to 300,000 people in the U.S. each year – more than AIDS and breast cancer combined.^1,2 Up to 20 percent of all cases of DVT and PE occur in cancer patients,³ and DVT/PE are the second leading cause of death among cancer patients.⁴
“Almost anyone fighting cancer is at heightened risk for developing a DVT,” said Coalition steering committee member Craig Kessler, M.D., professor of medicine and pathology, Georgetown University Medical Center.........

open access: British Journal of Cancer - Effects of erythropoietin receptors and erythropoiesis-stimulating agents on disease progression in cancer (safety, adverse events, disease progression, conflicting research.....)

Blogger's Note: note ties to industry
          
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"Erythropoiesis-stimulating agents (ESAs) increase red blood cell (RBC) production in bone marrow by activating the erythropoietin receptor (EpoR) on erythrocytic-progenitor cells. Erythropoiesis-stimulating agents are approved in the United States and Europe for treating anaemia in cancer patients receiving chemotherapy based on randomised, placebo-controlled trials showing that ESAs reduce RBC transfusions.

Erythropoiesis-stimulating agent-safety issues include thromboembolic events and concerns regarding whether ESAs increase disease progression and/or mortality in cancer patients. Several trials have reported an association between ESA use and increased disease progression and/or mortality, whereas other trials in the same tumour types have not provided similar findings.

This review thoroughly examines available evidence regarding whether ESAs affect disease progression. Both clinical-trial data on ESAs and disease progression, and preclinical data on how ESAs could affect tumour growth are summarised. Preclinical topics include (i) whether tumour cells express EpoR and could be directly stimulated to grow by ESA exposure and (ii) whether endothelial cells express EpoR and could be stimulated by ESA exposure to undergo angiogenesis and indirectly promote tumour growth.

Although assessment and definition of disease progression vary across studies, the current clinical data suggest that ESAs may have little effect on disease progression in chemotherapy patients, and preclinical data indicate a direct or indirect effect of ESAs on tumour growth is not strongly supported."

"This review summarised results from clinical and preclinical studies that evaluated whether ESAs affect disease progression. Although there are important limitations on the quality and assessment of disease progression in these studies, the current meta-analyses suggest no overall effect of ESAs on disease progression. Several individual studies have shown a potential trend associating ESA use with increased disease progression. This suggests that ESAs may affect disease progression in particular cancer patient populations (e.g., head and neck cancer patients receiving radiotherapy only) and that additional research is needed to define these populations and how ESAs mediate this effect. Although indirect effects on tumours induced by increased RBC production are theoretically possible, preclinical data to date suggest that tumour cells either do not express EpoR or express low levels of EpoR molecules that are non-functional and/or are not present at the cell surface. Overall, the balance of current evidence does not support an effect of ESAs on either activating EpoR on tumour cells or indirectly stimulating disease progression via angiogenesis. Future clinical trials, meta-analyses, and preclinical research should provide additional data to guide evidence-based use of ESAs in cancer patients."

abstract - EvidenceUpdates: Cochrane Review: Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy (including professional commentaries)

Abstract

BACKGROUND:  Venous thromboembolism (VTE) often complicates the clinical course of cancer disease. The risk is further increased by chemotherapy but the safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. OBJECTIVES:  To assess the efficacy and safety of primary thromboprophylaxis in ambulatory cancer patients receiving chemotherapy.  AUTHORS' CONCLUSIONS:   Primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. However, the lack of power hampers definite conclusions on the effects on major safety outcomes, which mandates additional studies to determine the risk to benefit ratio of LMWH in this setting.

Comments from Clinical Raters
Oncology - Breast

Largest Trial of VTE (blood clots) Prophylaxis in Cancer Patients on Chemo

Blogger's Note: several articles posted on the same subject, some easier to read (plain english)

Largest Trial of VTE Prophylaxis in Cancer Patients on Chemo:
The new trial adds to previous data showing a benefit, but it is up to individual patients to decide whether or not to use this option, says editorialist.
Medscape Medical News

February 15, 2012 — The largest study to date of thromboprophylaxis in cancer patients on chemotherapy shows that the use of a heparin product significantly reduces the risk for thromboembolic events with no apparent increase in bleeding.
The positive results add to several previous studies showing a benefit from thromboprophylaxis in cancer patients, and reopen an ongoing debate about whether such use should be routine.
The latest study, known as SAVE-ONCO, was conducted in 3212 cancer patients who were beginning chemotherapy and used the hemisynthetic ultra-low-molecular-weight heparin (LMWH) semuloparin (Visamerin, Sanofi; marketed in Europe, but not available in the United States). The study, by Giancarlo Agnelli, MD, from the University of Perugia, Italy, and colleagues, is published in the February 16 issue of the New England Journal of Medicine......

Low Molecular Weight Heparin Use in Cancer Treatment

Low Molecular Weight Heparin Use in Cancer Treatment

The blood thinning effect of heparin is well established, but should it be used in cancer treatment?

Newswise — Hamilton, ON (Feb. 13, 2012) -
"For decades, the blood thinner heparin has been used to prevent and treat blood clots. Could it be just as effective in treating cancer?
In an editorial published today in the New England Journal of Medicine, researchers from McMaster University and the University at Buffalo suggest conclusive answers to key questions on the benefits of low molecular weight heparin (LMWH) for cancer patients remain elusive - despite promising results from large studies...."

abstract: the Oncologist - Outpatient Use of Low Molecular Weight Heparin Monotherapy for First-Line Treatment of Venous Thromboembolism in Advanced Cancer

 Abstract

Background. Evidence-based treatment guidelines recommend low molecular weight heparin (LMWH) monotherapy for cancer-associated venous thromboembolism (VTE). This analysis assessed the first-line treatment strategies for VTE in patients with advanced solid tumors.


Conclusions. Adoption of LMWH monotherapy as initial treatment for cancer-associated VTE was low but increased steadily over the study period. Future studies should explore reasons underlying the underutilization of this preferred evidence-based treatment as well as the comparative effectiveness of LMWH versus warfarin-based anticoagulation in real-world cancer patients with VTE.

Table 1. Baseline cohort patient characteristics, risk factors and comorbidities,....

open access: Risk of venous and arterial thromboembolic events associated with anti-EGFR agents: a meta-analysis of randomized clinical trials

summary: Risk of Venous and Arterial Thromboembolic Events Associated With Anti-EGFR Agents: A Meta-Analysis of Randomized Clinical Trials - OncologySTAT

 

SUMMARY

OncologySTAT Editorial Team

"Venous and arterial thromboembolism events (VTEs and ATEs) are common in patients with cancer and are a frequent cause of mortality in these patients. Antiangiogenic agents that target vascular endothelial growth factor receptor (VEGFR), such as sunitinib, sorafenib, and bevacizumab, are associated with increased risk of VTEs and ATEs. Other drugs target the epidermal growth factor receptor (EGFR), such as the monoclonal antibodies cetuximab and panitumumab, and the oral tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. This meta-analysis evaluated the risk of VTEs and ATEs associated with the anti-EGFR agents cetuximab, panitumumab, erlotinib, and gefitinib.
Medline and EMBASE were searched for randomized controlled phase II or III trials in which cetuximab, panitumumab, erlotinib, or gefitinib was used as treatment for patients with cancer....."

abstract: Acute Abdominal Venous Thromboses-The Hyperdense CT Sign (blood clots)

CONCLUSION:

Acute abdominal VT (acute abdominal venous thrombosis) can be detected on unenhanced CT in more than two thirds of the cases by identifying hyperdense venous segments.

abstract: Prevention and treatment of venous thromboembolism (blood clots) in patients with cancer

Abstract/full free access: Risk factors for perioperative venous thromboembolism (blood clots) : A retrospective study in Japanese women with gynecologic diseases

Ovarian metastasis following gallbladder carcinoma

Abstract

BACKGROUND: Mucinous ovarian cancer raises problems of differential diagnoses because it is often difficult to distinguish the primary from the metastatic form. Most metastatic ovarian tumors originate from the gastrointestinal tract, mainly colorectal, gastric, pancreatic; the gallbladder is a very rare source of ovarian metastases.
CASE: We report a case of ovarian metastases from a gallbladder cancer, incidentally diagnosed more than 2.5 years earlier during a laparoscopic intervention for biliary lithiasis.
CONCLUSION: The interest of this case lies in the long progression-free survival, the venous thromboembolism syndrome that preceded by a few months the diagnosis of the ovarian mass and the discrepancy between the radiologic and the laparoscopic stage assessment.

Postoperative Pulmonary Embolism Including Asymptomatic Case... : International Journal of Gynecological Cancer

Conclusions: A substantial number of postoperative PEs were occult, and identification of high-risk patients and routine SpO₂ level monitoring would reduce the diagnostic delay of PE after gynecologic surgery. Increasing age, longer operation time, and obesity were risks. The use of a perioperative intermittent pneumatic compression device in multimodal conditions might thus prevent PE. (pulmonary embolism/blood clot)

EvidenceUpdates-Cochrane Collaboration review/commentaries: Self-monitoring and self-management of oral anticoagulation (Warfarin)

Note - warfarinCONCLUSIONS:
Compared to standard monitoring, patients who self-monitor or self-manage can improve the quality of their oral anticoagulation therapy. The number of thromboembolic events and mortality were decreased without increases in harms. However, self-monitoring or self-management were not feasible for up to half of the patients requiring anticoagulant therapy. Reasons included patient refusal, exclusion by their general practitioner, and inability to complete training.

Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor Bevacizumab in cancer patients: A meta-analysis of randomized controlled trials

abstract