Heme/Onc

Recent Developments in the Treatment of Renal Cell Carcinoma

May 31, 2007

Commentary by Michael Seidman MD, Chief Oncology Fellow

New treatment options for both early and advanced Renal Cell Cancer have recently been published. Traditionally, treatment for early stage disease was partial or radical nephrectomy. In the metastatic setting, treatment options were limited to toxic cytokine therapy with IFN or IL-2.

Some recent literature has suggested that small, incidentally found renal tumors can safely be watched without the need for invasive surgery. Remzi et al [1] retrospectively reviewed 287 tumor bearing kidneys 4cm or less detected by imaging and surgically removed. High grade (poorer prognostic) tumors were seen in 4.2%, 5%, and 25.5% of tumors measuring 2 cm or less, 2.1-3.0 cm, and 3.1 to 4.0 cm respectively. Distant metastases were seen in 2.4% of tumors 3.0 cm or less compared to 10.8% of tumors 3.1-4.0 cm.

Schlomer et al [2] examined 349 renal masses form 331 patients. Malignant tumors were seen in 72.1% of tumors less than 2 cm compared to 93.7% of tumors greater than 7cm. The mean size of tumors in patients with symptoms at the time of diagnosis was 6.2cm compared to 3.7cm for tumors discovered incidentally. High grade histology was more common in larger tumors, occurring in 52 % of tumors >4cm compared to 7% and 29% in tumors measuring <2.0 cm and 2-4cm respectively.

These recent reports support the notion that most small renal tumors, especially those <3.0 cm are indolent in nature. In older patients, and those with multiple comorbidities, watchful waiting is an option. Newer technologies, specifically cryoablation and radiofrequency ablation, can provide good disease control with a less invasive procedure than nephrectomy. Matin et al [3] reported on 616 patients who underwent RFA and cryoablation. 10% of the patients had residual or recurrent disease after primary therapy. After salvage ablative therapy, failure was seen in only 4.2% of patients treated. 2 yr overall survival in patients with recurrent or residual disease was 82.5% with a 97.4% 2-year metastasis-free survival.

Read more »

New Guidelines on the Diagnosis and Treatment of Venous Thromboembolism-Part 2

April 19, 2007

Clotting CascadeCommentary By: Margaret Horlick, MD, PGY-3

New guidelines on the diagnosis and treatment of venous thromboembolism (VTE) were recently jointly issued by the American Academy of Family Physicians and the American College of Physicians. The guidelines are based on a systematic review of the evidence and are published, along with the systematic reviews, in the 2/2007 and 3/2007 issues of the Annals of Internal Medicine.

Part 1-Diagnosis

Part 2 Treatment

The treatment recommendations are summarized as follows:

  1. Low-molecular-weight heparin (LMWH), as opposed to unfractionated heparin, should be used whenever possible for the initial inpatient treatment of DVT; either is an appropriate choice for initial inpatient treatment of PE. The authors note the importance of achieving therapeutic anticoagulation quickly in patients with VTE. In previous trials of unfractionated heparin, this was not accomplished and instead, many patients had both subtherapeutic and supratherapeutic levels. This is contrasted with LMWH with which it is possible to reliably achieve therapeutic anticoagulation quickly. The current evidence, based on systematic reviews, shows that LMWH is at least as effective as unfractionated heparin in the treatment of PE but further trials need to be completed to establish it as the preferred treatment. There is, however, consistent evidence demonstrating both mortality benefit and a lower risk of major bleeding in trials of LMWH as the initial therapy of DVT.
  2. Outpatient treatment of DVT, and possibly PE, with LMWH is safe and cost-effective for carefully selected patients, and should be considered if the required support services are in place. The cited studies for this recommendation had strict inclusion and exclusion criteria; specifically, patients with previous VTEs, thrombophilic conditions or significant comorbid illnesses were excluded, as well as pregnant women and patients unlikely to adhere to outpatient therapy. Read more »

New Guidelines on the Diagnosis and Treatment of Venous Thromboembolism-Part 1

April 12, 2007

800px-parque_del_clot_03.JPGCommentary By: Margaret Horlick, MD, PGY-3

New guidelines on the diagnosis and treatment of venous thromboembolism (VTE) were recently jointly issued by the American Academy of Family Physicians and the American College of Physicians. The guidelines are based on a systematic review of the evidence and are published, along with the systematic reviews, in the 2/2007 and 3/2007 issues of the Annals of Internal Medicine.

According to the reviews, there are 600,000 cases of VTE in the US annually, and the importance of early diagnosis and treatment is underscored by the morbidity and mortality associated with VTE. The authors state that 26% of patients with undiagnosed and therefore untreated PE will have a subsequent fatal embolic event, while another 26% will have a nonfatal recurrent event that can eventually be fatal. DVTs carry their own risk of complication: those proximal to the knee are associated with an increased risk of PE and those located only in the calf veins are associated with the postthrombotic syndrome .

The following summarizes the recommendations on diagnosis:

  1. Validated clinical prediction rules should be used to estimate pretest probability of VTE. The Wells prediction rules for PE and DVT were most frequently evaluated in the literature and have been validated. It is worth noting that these perform better in younger patients without comorbidiites or a history of VTE than they do in other patients.
  2. In patients with a low pretest probability of DVT or PE, obtaining a high-sensitivity D-dimer is a reasonable option. If negative, the test indicates a low likelihood of VTE in these patients. Data quoted in the article state that patients with a low pretest probability of DVT and a negative D-dimer had a 0.5% 3-month incidence of DVT, while the 3 month incidence in patients with intermediate and high pretest probabilities and a negative D-dimer was 3.5% and 21.4%, respectively.
  3. Ultrasound is recommended for patients with intermediate to high pretest probability of DVT in the lower extremities. More specifically, ultrasound has a high sensitivity and specificity for diagnosing proximal DVTs (those located proximal to the knee) in symptomatic patients. Important limitations to this recommendation are that ultrasound is less sensitive both in patients who have DVTs limited to the calf, as well as asymptomatic patients. Contrast venography remains the definitive test to evaluate for DVT.
  4. Patients with intermediate or high pretest probability of PE require diagnostic imaging studies. The gold standard remains pulmonary arteriography; helical CT’s sensitivity is, at the best, 90% with a specificity of 95%. Current multidetector CT technology may have higher sensitivity but further studies will be required to establish this hypothesis.

Next Week: Part 2 Recommendations on Treatment

References:
Qaseem A et al. Current diagnosis of venous thromboembolism in primary care: A clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Intern Med 2007 Mar 20; 146:454-8.

Image: Parque del Clot, Barcelona, Spain Courtesy of Wikimedia Commons

Does Screening for Lung Cancer Improve Mortality?

April 10, 2007

Spiral CTCommentary By: Anna Dvorak, MDPGY-3

Lung cancer is the number one cause of cancer mortality in both men and women. Screening patients at risk for lung cancer might reduce mortality if it helps find cancers at an early stage while they are still resectable. Randomized studies done in the 1970s showed that screening for lung cancer with chest x-ray did not support this theory. Chest x-rays identified more small tumors, but resecting them did not improve mortality. The question of whether screening with chest CT can improve outcomes remains unanswered.

In October 2006, an observational study in the NEJM looked at screening of asymptomatic high-risk patients with CT. The International Early Lung Cancer Action Program (I-ELCAP) screened 31,000 patients and found 484 cancers. 85% of the cancers detected were stage I, and they estimated an 88% survival amongst these patients.  This is in contrast to the 70% ten-year survival currently seen in patients with stage I lung cancer. They concluded that CT screening could detect lung cancer that is curable. Read more »

Will my breast cancer patient need adjuvant chemotherapy? Gene Micro array technology may help answer this question��

March 20, 2007

Breast Cancer MammoCommentary By Sandra D’Angelo, PGY-3

Breast cancer is the most common cancer diagnosed in women, second only to lung cancer as a leading cause of death from cancer. Experts state that approximately 210, 000 women will be diagnosed in 2006 and about 40,000 will die from the disease.1 According to data compiled by the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, 61% of breast cancer cases are diagnosed while the cancer is still confined to the primary site (localized stage); 31% are diagnosed after the cancer has spread to regional lymph nodes or directly beyond the primary site; 6% are diagnosed after the cancer has already metastasized (distant stage) and, for the remaining 2%, the staging information was unknown. The corresponding 5-year relative survival rates were: 98.1% for localized; 83.1% for regional; 26.0% for distant; and 54.1% for unstaged.2 Therapy is directly dependent upon the stage of diagnosis. In addition, estrogen, progesterone and her2 neu status also play a major role in determining the appropriate therapy. The attached table briefly summarizes treatment based on stage.

Recently, the New York Times reported on the FDA approvalal of Mammaprint, an in vitro multivariate index assay that measures 70 gene markers in tumors. The information is then used to calculate an index to predict the likelihood of recurrence or metastasis. This test is not for everyone; in fact, it was only approved for woman who are under age 61, with stage I and II disease, tumor size <5cm and node negative disease.

Approximately 100,000 women are diagnosed with early stage disease each year. Often times, whether or not to use adjuvant chemotherapy in this setting is a diagnostic challenge. Frequetnly, there is significant morbidity associated with these toxic agents. Nonetheless, the benefit is clearly evident. The goal of this test is to help oncologists customize treatment based on a patient�Ѣs specific calculated risk. However, this test is far from a perfect test. The positive predictive value at five years was 23% and 29% at 10 years. The negative predictive value was 95% at 5 years and 90% at 10 years. In other words, 23% of women classified by this test as high risk had a recurrence somewhere in their body within 5 years, while only 5% classified as low risk had a recurrence in 5 years. Read more »

Ethics 101-How Do You Approach a Jehovah’s Witness Patient Who Needs a Transfusion?

February 5, 2007

A 76 year old man with a history of coronary artery disease, diabetes and hypertension was brought in by his wife with two days of lethargy, slurred speech and right arm weakness. On presentation, the patient was awake and intermittently involved in conversation.  He was afebrile, with a pulse of 90 and blood pressure of 166/98  His exam was remarkable for dysarthria, orientation only to person, pinpoint pupils, left sided tongue deviation, 3/5 motor strength in the right upper extremity, 4/5 motor strength in the proximal right lower extremity and right sided hyperreflexia.    A non-contrast head CT revealed an acute left thalamic hemorrhage with surrounding edema and midline shift.    The patient was evaluated by neurosurgery, but given the location of the bleed, no surgery was indicated.    Platelet transfusion was recommended, as the patient had medication induced platelet dysfunction.  The patient’s wife refused platelet transfusion as the patient was a long-standing Jehovah’s Witness.  She had a copy of his Advanced Directives in which she was appointed the health care proxy and it was clearly outlined that he would not accept any blood product transfusion.  An ethics consultation was requested.

Questions:

1. From an ethical and legal standpoint how should a physician handle these situations?
2. If the patient can indicate that he wishes to accept platelets at this time, should his Advanced Directives be disregarded?
3. Would the situation be different if the patient were a minor and the parent’s refused transfusion?

-Alana Choy-Shan PGY-3

Commentary By: Sathya Mahaswaren, MD Integrated Ethics Program Coordinator, VA New York Harbor Healthcare System

The care of Jehovah’s Witnesses raises ethical issues when a competent patient’s religious freedom and autonomy to refuse a treatment conflicts with the physician’s commitment to provide beneficial care while avoiding harm. Physicians should take care to avoid coercion and deception that can deny patient’s autonomy and can result in charges of battery. Read more »

Why Are Breast Cancer Rates Trending Down?

January 9, 2007

The recent finding of decreasing breast cancer rates made headlines throughout the media; including a NY Times article entitled, Reversing Trend, Big Drop is seen in Breast Cancer on December 15, 2006.

Striking epidemiological facts tells us that breast cancer is the most common cancer in women in the U.S., and only second to lung cancer as the most common cause of cancer deaths. It is estimated that approximately 212,920 American women will be diagnosed with breast cancer in the year 2006, and 40,970 women will die from this disease. (1)  The unfortunate truth is that during a woman’s life, she has a one in six chance of developing breast cancer.  Between 1940 and 1980 breast cancer rates rose 1.2% per year.  The more pronounced increase in early stage breast cancers during the 1980s was probably due to the use of screening mammography. Since 1987, there have been no significant changes.  Over recent years, we’ve seen that there has been a trend towards increased estrogen receptor/progesterone receptor (er/pr) positive disease and a decrease towards ER/PR negative disease. Read more »

Should we recommend mammography screening for women between the ages of 40-50?

December 22, 2006

In a recent article in the Lancet, this question was addressed by a group of investigators led by Sue Moss, Ph.D. from the University of Leeds.  Currently, the  National Cancer Institute, U.S. Preventative Health Services Task Force and the American Cancer Society all recommend screening at a younger age(those between 40-50).  The task force, however, does recommend educating your patients about the potential risks/benefits regarding mammography at a younger age.  Screening women older than 50 has been shown to reduce mortality from breast cancer by about 25%.  Benefit in younger women has been previously suggested in multiple trials.  In fact, a meta-analysis of the trials showed a 15% reduction in breast cancer mortality in these younger women.  However, previous trials have not been specifically designed to study the effect of screening in this particular age group.

In the AGE trial; 160,921 women aged 39-41 were randomly assigned in the ratio of 1:2 to an intervention group of annual mammography to age 48 years to a control group of usual medical care.  The control group would begin yearly screening at age 50-52 as recommend by the NHS in England.   Follow-up at 10 years found a reduction in breast-cancer mortality in the intervention group of 17%, which did not reach statistical significance.   These results are consistent with results from other trials of mammography in this age-group.  The absolute benefit is generally lower than for women older than 50.

Things to consider in this trial:

  • Single view mammography was used after the initial screen, because of concerns about the effect of radiation.  Two-view mammography improve detection rates, reduce recall rates and are the standard of care in the UK.
  • 20% of women in AGE trial did not actually undergo mammograms and 10% missed screening, therefore, the risk reduction was probably underestimated.
  • There was high attrition rate which may have contributed to decreased power of the trial.
  • Screening protocol used was the 1980s protocol which has less sensitivity than modern mammography.

Therefore, based on this paper, it is doubtful that many governing boards in the U.S. will stop recommending yearly screening starting at age 40.  Keep in mind that more modern screening protocols may eventually reveal a more dramatic mortality reduction.  It is important to always discuss the risk of false positives and unnecessary biopsies versus the benefit of early detection of breast cancer.

“Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years’ follow-up: a randomized controlled trial”  Lancet 2006; 368” 2053-2060

Click Here for Full Text

* Breast cancer mortality results of the randomised mammography trials in women younger than 50 years.

 


The First Joint Medical-Surgery Conference

December 21, 2006

The first monthly medical/surgery conference was a great success. Attended by resisdents and attendings from both departments the conference was a lively discussion regarding the controversies in caring for a 51 year old man who recently underwent a percutaneous coronary intervention with the placement of a Cypher stent after a non-st elevation myocardial infarction, who soon afterwards was found to have a gall bladder mass that needed to be resected. The complete slide presentation can be found here: Joint Medicine-Surgery Conference Slides
A short summary of teaching points follows.

Teaching Points
Cholangiocarcinoma

  • A gallbladder mass often presents with typical biliary symptoms such as biliary colic, acute cholecystitis, or obstructive jaundice. It is, therefore, often an incidental finding on ultrasound and asymmetrical thickness of one centimeter is used as a cutoff for intervention.
  • 74 to 92 % of patient with cholangiocarcinoma have gallstones.
  • chronic cholecystitis is a risk factor for the development of gallbladder cancer.
  • Resection is the only hope for cure.
  • Diagnosis is usually made by either ultrasound or CT scan with contrast and biopsies are rarely performed.
  • Carcinomas that are resected in early stages, T1, have a remarkably low 5-year mortality with around 85 to 100% of patients living 5 years after resection. Still, the overall 5-year mortality is dismal at around 5 to 10 % since most cancers are found at later stages. Open cholesystectomy is preferred over laparoscopic resection as a port site seeding has been a documented phenomenon.

The surgeons felt that given the highly vascular architecture of the liver and the fact that patients with hepatic dysfunction are already at higher risk of coagulopathy, hemostasis is extremely difficult and surgery would have to be delayed once the patient was off of anitplatelet therapy. Drug coated stents

  • Drug coated stents work by preventing early endothelialization and smooth muscle proliferation thereby decreasing the rate of restenosis.
  • By preventing early endothelialization, the metal structure of the drug coated stents is exposed. This metal structure is pro-thrombotic and can lead to in-stent thrombosis which is a life-threatening condition.
  • Clopidigrel is recommended for six weeks for bare metal stents, three months for Cypher stents, and six months for taxus stents.
  • Since there are no studies investigating whether anti-platelet therapy should be continued in patients requiring surgery, recommendations are that surgery should be delayed if possible. If not, possible, patients should be assessed for bleeding risk.
  • Patients undergoing a surgery with a low risk of bleeding should be continued on low dose plavix and aspirin, while patients with a higher risk can be bridged with either perioperative heparin or glycoprotein IIb/IIIa inhibitor

Mystery Quiz #1-The Answer…

December 20, 2006

Before you read the answer you will probably want to review the original post of the mystery quiz from last week.

The Answer:

The chest film shows a probable mass in the area of the left hilum and associated complete collapse of the left upper lobe.  The key findings are loss of volume of the left hemithorax indicated by elevation of the left hemidiaphragm and shift of the mediastinum to the left side.  Additionally, the arrows indicate the major fissure, ordinarily not visible, but now bordering the left upper lobe because it has shifted upward. The increased density seen at the left hilum (A)suggests the presence of a mass.  Click on the thumbnails below.

 

All of the above findings are more easily seen on the two CT  images below.  Note the cutoff of the left upper lobe bronchus by an intraluminal mass (arrow), and the airlessness of the collapsed left upper lobe (B).

This patient subsequently developed hoarseness related to involvement of the left recurrent laryngeal nerve which was invaded by tumor thus indicating non-resectability of this lesion.  The biopsy of the endobronchial lesion at the left upper lobe revealed non-small cell carcinoma.

Although a peanut or foreign body was not responsible for these findings, several respondents correctly identified the volume loss and implied collapse of the left upper lobe.

Epogen and Anemia-Less is More (Part 2)

December 14, 2006

Commentary By David Goldfarb, M.D. Professor of Medicine, NYU Medical Center, Chief Nephrology Section VA New York Harbor

 

2 weeks ago we reported on 2 lead articles in the New England journal that suggested that our targets for hemoglobin values when treating with erythropoietin were too high.

Last week, the New York Times reported that based on those NEJM articles (CHOIR and CREATE), the National Kidney Foundation, which publishes the Kidney Disease Outcomes Quality Initiative (KDOQI ), has constituted an advisory group to consider what the guidelines should say about the target hemoglobin. The optimal hemoglobin (whether for CKD and dialysis patients, or anyone with anemia) has still not been determined. The revision of the guidelines this year liberalized the target hemoglobin but in light of these recent data, it seems likely that will be scaled back. The increased mortality rate associated with higher hemoglobin values could be related to the hemoglobin itself, or to deleterious effects of erythropoeitin (e.g. hypertension) or iron (e.g. endothelial oxidative injury).

There are further savings to be realized.  This article which I co-authored suggests that CMS (Medicare) could reduce the expense of anemia management if the NKF’s (National Kidney Foundation) KDOQI guidelines (Kidney and Dialysis Outcomes Quality Initiative) were followed more closely. A large part of the sum could be saved if erythropoeitin was given subcutaneously instead of intravenously. Additionally, doses of epythropoeitin exceed those recommended by the KDOQI guidelines. The reasons for this are not clear and could be due to relative resistance to the effect of the drug, in which case it may not be possible to reduce the dose to the guideline-recommended values. But to the extent that last week’s NEJM suggested that target hemoglobins are too high, further savings are possible.

What Is Sezary Syndrome?

December 11, 2006

Morning Report-Tisch Hospital

Case Presentation: 83 year old with a past medical history of hypertension noted erytematous plaques with scale about 1 year ago.  The rash was associated with diffuse pruritis at that time.  The patient subsequently underwent several inconclusive biopsies.  She was eventially diagnosed with mycosis fungoides and treated with UV therapy.  Her rash progressed to a diffuse pruritic erythema covering the vast majority of her body, including palms and soles.  (erythroderma).  She was noted to have Sezary cells on peripheral smear and diagnosed with Sezary syndrome.  She was now admitted to TH with fevers likely secondary to cellulitis on her lower extremities, the site of significant skin breakdown.  The patient is improving on treatment with IV antibiotics and interferon alpha.  (image courtesy of The Internet Journal of Dermatology)

Teaching Points:

1. What is Mycosis fungoides:Extranodal Non-Hodgkins lymphoma of T-cell origin, with primary involvement of the skin

What is Sezary Syndrome:

  • Generalized erythroderma
  • Lymphadenopathy
  • Atypical T- cells (Sezary cells) in the peripheral blood

2. Tumor grades

  • T1 Limited patch/plaque (< 10 percent of total skin surface)
  • T2 Generalized patch/plaque (>10 percent of total skin surface)
  • T3 Tumors
  • T4 Generalized erythroderma

These four tumor grades correlate with median survivals approximately 30 years, 12 years, 5 years, 4 years, respectively.  Note that T1 and T2 are usually not dying of the disease while T3 and T4 are.

3. Therapy-correlates with prognosis. T1 and T2 will receive almost exclusively topical therapy with nitrogen mustard, UVA, UVB and Electron beam therapy.  T3 and T4 will likely require topical and systemic medications, immunomodulators and chemotherapy.

Short Powerpoint on Sezary Syndrome

Please note that the survival curves are for T1, T2, T3, and T4 tumor grade.  The photos how the diffuse patchy presentation, followed by erythroderma.

Becker, D. Clinical Correlations (NYU Internal Medicine Residency Blog) Dec. 11, 2006. Available from http:// Litvin, C. Clinical Correlations (NYU Internal Medicine Residency Blog) Dec. 12, 2006.  Available from https://www.clinicalcorrelations.org/?p=54