Updates in Hematology and Medical Oncology Evidence published in 2011

Ehsan Chitsaz, MD, MHSc

Internal medicine resident, PGY-2

Dr. Adam Lerner, MD

Professor of Medicine and Director of Hematology Program

Jan 14, 2014

Background: Outpatient treatment of symptomatic DVT with LMWH is regarded as usual care.

Many practice guidelines recommending outpatient care for selected Hemodynamically stable PE as well.

However, still most treatment is inpatient-based

Previous studies of outpatient care for PE: restricted by small sample sizes, retrospective designs, and the absence of a randomized control group

Outpatient Treatment of Pulmonary Embolism (OTPE) trial :

To compare the effectiveness, safety, and efficiency of outpatient versus inpatient care for low-risk patients with acute, symptomatic pulmonary embolism

Aujesky D, Roy PM, Verschuren F, et al. Lancet. 2011;

Design:

open-label, randomized, non-inferiority clinical trial

Population:

19 emergency departments in Switzerland, France, Belgium, and the USA. 344 Consecutive adults aged >18 years with acute, symptomatic, and objectively verified pulmonary embolism -- at low risk of death based on the pulmonary embolism severity index (risk classes I or II).defined pulmonary embolism as the acute onset of dyspnoea or chest pain, together with

positive spiral CT or pulmonary angiography, a new high-probability ventilation-perfusion lung scan, or documentation of a new proximal DVT either by venous ultrasonography or contrast venography.


Exclusion:

- Arterial hypoxaemia (Sat < 90% on RA)

-SBP < 100

-chest pain necessitating parenteral opioids,

-active bleeding, high risk of bleeding defined as stroke during the preceding 10 days, gastrointestinal bleeding during the preceding 14 days or plt < 75000

-severe renal failure GFR<30

-extreme obesity (body mass >150 kg),

- history of heparin-induced thrombocytopenia or allergy to heparins

- therapeutic oral anticoagulation at the time of diagnosis of pulmonary embolism [INR] ≥2

-Any barriers to treatment adherence or follow-up (eg, current alcohol abuse, illicit drug use, psychosis, dementia, or homelessness),

-pregnancy, imprisonment,

-diagnosis of pulmonary embolism more than 23 h before the time of screening (to avoid enrolling already stabilised patients)


Intervention:

Outpatient arm: discharged < 24 hrs with teaching to inject enoxaparin 1 mg/kg bid by either patient, caregiver, or VNA.

Inpatient: same enoxaparin bid

Both arms were started on warfarin together with enoxaparin and enoxa was continued for 5 days or more once INR is > 2 for two consecutive days.

Contacted and asked all patients every day for the week after enrolment, and at 14, 30, 60, and 90 days about symptoms of recurrent venous thromboembolism, bleeding, and any use of health-care resources.

Outcome:

Primary outcome: recurrence of symptomatic VTE within 90 days

Safety Outcomes:

- major bleeding within 14 and 90 days of randomization

- all-cause mortality within 90 days.


Results:

344 were randomized; 171 outpatient vs 168 inpatient.

Modified ITT ( except lost to follow-up -- only 3 patients).

non-inferiority margin of 4%;

- 1 (0.6%) of 171 outpatients developed recurrent venous thromboembolism within 90 days compared with none of 168 inpatients (95% upper confidence limit [UCL], 2.7%; P 0.011).

-Only 1 (0.6%) patient in each treatment group died within 90 days (UCL, 2.1%; P 0.005)

-2 (1.2%) of 171 outpatients and no inpatients had major bleeding within 14 days (UCL, 3.6%; P 0.031).

-By 90 days, 3 (1.8%) outpatients but no inpatients developed major bleeding (UCL, 4.5%; P 0.086).

- Mean length of stay was 0.5 day (SD, 1.0) for outpatients and 3.9 days (SD, 3.1) for inpatients.


Caution:

1- The PE severity index risk score gives substantial weight to AMS, advanced age, cancer, or underlying lung disease. this study: predominantly young; did not have cancer or lung disease; generalizeability issue. the study was open label, but the authors attempted to mitigate this by enrolling patients consecutively and adjudicating outcomes by a committee blinded to the patients’ treatment status.Implications: In selected low-risk patients identified by thepulmonary embolism severity index, outpatient treatmentwith twice-daily subcutaneous enoxaparin was not inferiorto inpatient treatment in safety or efficacy, was well toleratedby patients, and reduced hospital length of stay.


Background: Without thromboprophylaxis DVT develops in 10 to 20% of medical patients in 40 to 60% of patients w major orthopedic Chemical thromboprophylaxis with LMWH : shown to be effective in acutely ill medical patients, but a mortality benefit has never been demonstrated.

Design: double-blind, placebo-controlled, randomized trialPopulation: China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia

> 40 years -- hospitalized within 48 hrs from randomization with acute decompensated heart failure, severe systemic infection with at least 1 risk factor for venous thromboembolism, or active cancer.

Kakkar AK, Cimminiello C, Goldhaber SZ, et al. N Engl J Med. 2011;365:2463-72.

Intervention:

Enoxaparin, 40 mg SQ or placebo (0.9% saline) daily during hospitalization, for 6 to 14 days (10±4 days).

Both groups received Knee-high elastic stockings that provided graduated pressure.

Outcome:

Primary outcome: All cause mortality within 30 days

Secondary outcome:

- Cardiopulmonary death in 14, and 90 days

- Sudden death or pulmonary embolism at days 14, 30, and 90 after randomization.

Safety Outcome: major hemorrhagic events during the treatment period.


Results: ITT

30 day all cause mortality 4.9 % vs 4.8 %


Caution:the observed mortality rate was 4.9% vs 4.8%, lower than expected 7% ( that was used for sample size calculation) maybe underpowered to detect the signal.

Graduated stockings was used in both groups that would dilute the effect of enoxaparin on VTE mortality.

Implications:

Enoxaparin plus elastic stockings with graduated compression versus elastic stockings with graduated compression alone was not associated with a reduced rate of death from any cause among hospitalized, acutely ill medical patients. This finding differs from results in similarly ill surgical hospitalized patients.


Background:

- Most allogeneic stem cell transplantations use granulocyte colony stimulating factor–induced, pheresis-derived, circulating peripheral blood stem cells (PBSCs) as the source of hematopoietic stem cells.

compared with bone marrow, PBSCs :

- engraft more rapidly at the expense of a higher incidence of acute and chronic

graft-versus-host disease (GVHD) and showed a trend toward a lower rate of relapse of leukemia. However, these trials have been of short duration and this remains controversial.

Friedrichs B, Tichelli A, Bacigalupo A, et al. Lancet Oncol. 2010;11:331-8.

Design:multicentre, prospective, randomised trial

Population: European Group for Blood and Marrow Transplantation-adults aged 18–55 years -de-novo AML or ALL in first or second remission, chronic myeloid leukaemia (CML) in first chronic or accelerated phase, or myelodysplastic syndrome (MDS).

Intervention: Compared outcomes of patients who received bone marrow transplantationswith those of patients who received PBSC transplantations.

Results: 329 patients were randomized.After 10 years of follow-up, overall survival and leukemia-free survival were the same between the 2 groups. More patients in the PBSC developed chronic GVHD, and as a result, more patients in the PBSC required immunosuppression 5 years after transplantation.Despite the higher incidence of chronic GVHD in the PBSC group, there were no differences between the 2 groups in performance status, return to work, or hematopoietic recovery.Friedrichs B, Tichelli A, Bacigalupo A, et al. Lancet Oncol. 2010;11:331-

8.


Caution: only patients with AML, ALL, CML. myeloma and lymphoma were not included. 14 cases of secondary cancer during the 10-year follow-up. no statistical difference between the 2 groups.Although performance status was found to be the same in the 2 groups, a more formal quality-of-life analysis was not done. Finally, subgroup analysis suggested a reduced relapse rate for patients with CML treated with PBSC transplantation, although the sample sizes were small. As such, small differences between transplanted bone marrow and PBSCs in certain patient groups cannot be excluded by this study.

Implications: This study supports PBSCs as a source for hematopoietic transplantation for patients with acute lymphoblastic, acute myeloid, or chronic myeloid leukemia.Peripheral blood stem cells:- easier to collect than bone marrow, which requires collection in the operating room.- PBSCs does not result in inferior outcomes compared with transplantations usingbone marrow. - Although the incidence of chronic GVHD may be increased with PBSCs, this finding did not seem toadversely affect patients’ ability to work and perform other activities of daily living.


Background:highly fatal disease

most often diagnosed at a late stage when no cure

average survival time is 1 to 2 years.

Screening to detect lung cancer attempted for decades, mostly with CXR but results disappointing

Aberle DR, Adams AM, Berg CD, et al. N Engl J Med. 2011;365:395-409.

Design:Radomized controlled trial.

Population: adults between 55 and 74 years history of cigarette smoking of at least 30 packyears, active or if former smokers, had quit within the previous 15 years.

Exclusion:previous diagnosis of lung cancer,chest CT within 18 months before enrollment,hemoptysis, or unexplained weight loss of more than 6.8 kg (15 lb) in the preceding year.

Intervention: Low dose CT vs one -view CXR :three screenings (T0, T1, and T2) at 1-year intervals, with the first screening (T0) performed soon after the time of randomization. Participants in whom lung cancer was diagnosed were not offered subsequent screening tests.Performed 2002-2004, followed up to 2009.


Outcomes:

Primary : Lung cancer mortality [during the follow up period ( median = 6.5 yrs ; max = 7.5 yrs)]

Secondary:

- death from any cause

- incidence of lung cancer

Results:

A total of 53,454 persons were enrolled; 26,722 were randomly assigned to screening with low-dose CT and 26,732 to screening with chest radiography.


Fifty-nine percent were men,

90% were white

approximately 50% were current smokers.

In the first screening ( T0) , 27% of patients who had CT and 9% of those who had chest

radiography had positive findings; however, in both groups, approximately 95% of the results were false positive.


Cancers diagnosed based on the screening strata:

After Positive

screening

After negative screening

Without screening

( missed or after trial was over)

Low Dose CT (N=1060)

649 44 367

CXR ( N =941)

279 137 525


Low-dose CT vs CXR : 356 and 443 deaths from lung cancer rates of death from lung cancer 247 and 309 deaths per 100,000person-years, respectively, a relative reduction in the rate of death from lung cancer with low doseCT screening of 20.0% (95% CI, 6.8 to 26.7; P = 0.004).



Caution:

-95% of pos results in the CT group were found to be false-positive by follow-up imaging

approximately 14% underwent invasive procedures.

Although the complication rate in the study was low, it was not 0, and it might be higher under less

well-controlled settings.

- It is possible that the study population was somewhat selected for good performance status and other

factors and thus is not representative of the general population of current and former smokers.

Implications: Routine low-dose CT as a screening tool to diagnose lung cancer in current and former smokers remains controversial. More than 95% of positive results proved to be false-positive, often resulting in unnecessary procedures. The decision to use low-dose CT screening is best made between patients and their physicians on the basis of the patients’ overall health and understanding of the risks and benefits of screening.

USPSTF 2013: age 55-80, with 30 py smoking, active or < 15 yrs quit


Background:

Screening can detect prostate cancer at earlier, asymptomatic stages, when treatments might be more effective.

Data Sources:

MEDLINE (2002 to July 2011) and the Cochrane Library Database (through second quarter of 2011).

Study Selection:

Randomized trials of prostate-specific antigen–based screening

Chou R, Croswell JM, Dana T, et al. Ann Intern Med. 2011;155:762-71.

Data Synthesis:

Of 5 screening trials, the 2 largest and highest-quality studies reported conflicting results.

One found that screening was associated with reduced prostate cancer– specific mortality compared with no screening in a subgroup of men aged 55 to 69 years after 9 years (relative risk, 0.80 [95% CI, 0.65 to 0.98]; absolute risk reduction, 0.07 percentage point).

The other found no statistically significant effect after 10 years (relative risk, 1.1 [CI, 0.80 to 1.5]). After 3 or 4 screening rounds, 12% to 13% of screened men had false positive results.

Serious infections or urine retention occurred after 0.5% to 1.0% of prostate biopsies.


Conclusion:

Prostate-specific antigen–based screening results in small or no reduction in

prostate cancer–specific mortality and is associated with harms related to

subsequent evaluation and treatments, some of which may be unnecessary.


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Updates in Hematology and Medical Oncology Evidence published in 2011

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