Month: August 2012

Systemic Therapy for Bone Metastases

August 24, 2012 Adverse Drug Reactions, Drug Informatics, Hematology, Pharmacology, Therapeutics No comments , , ,

zoledronic acid

Accelerated bone loss in patients with cancer is a frequent problem that may result from [1]invasion of the cancer to bone, [2]paraneoplastic tumor proteins, and/or [3]hormonal therapies utilized for cancer treatment.

  • Invasion of the cancer to bone;
  • Paraneoplastic tumor proteins;
  • Hormonal therapies utilized for cancer treatmen.

Invasion of cancer to bone is common complication in patients. The proportion of cancer invading to bone is 20% to 25% in kidney cancers, 65% to 75% in breast and prostate cancers, and almost all patients (70% to 95%) with multiple myeloma.

Mechanism of Bone Metastases

  1. Metabolically active tumor cells invade and populate bone and secrete growth factors that affect bone resorption and formation by stimulation of osteoclasts, cells that destroy bone by attacking the mineralized bone matrix.
  2. On the other hand osteoclasts also secrete growth factors that induce tumor cells in the bone to grow, spread, and stimulate the activity of osteoblasts, cells responsible for the formation of bone. However, osteoblastic activity creates new bone formation away from the sites of osteolytic bone resorption. So weakened areas are not strengthened by osteoblastic activity.
  3. Also, osteoblasts release receptor activator of nuclear factor κB ligand (RANKL), a key mediator of osteoclast formation, function, and survival, which is one of the mechanisms of metastatic bone disease.

Patients with osteolytic bone disease from multiple myeloma and bone metastases from solid tumors may develop a vicious cycle of bone destruction involving both ostelytic and osteoblastic effects. Consequently, a variety of skeletal-related events (SREs) may occur, including pathological fractures, hypercalcemia, spinal cord compression, and the need for surgical intervention and radiation therapy.

  • Pathological fractures;
  • Hypercalcemia;
  • Spinal cord compression;
  • The need for surgical intervention and radiation therapy.

Untreated patients with bone metastases are at risk for multiple SREs within a single year, ranging from 1.5 events for prostate cancer to 4.0 for breast cancer.

Treatment Agents

Now two types of agents are used to treat bone metastases – bisphosphonates and denosumab.

Bisphosphonates

Bisphosphonates are unique drugs with an affinity for bone mineral matrix with the ability to inhibit bone resorption. Bisphosphonates decrease bone resorption and increase mineralization by entering osteoclasts and inhibiting farnesyl diphosphate synthase, a key enzyme in the biosynthetic mevalonate pathway.

Bisphosphonates may also affect bone resorption through the inhibition of osteoclast precursor maturation, induction of apoptosis in mature osteoclasts, inhibition of tumor cell adhesion to bone, and inhibition of inflammatory cytokine production.

Nitrogencontaining bisphosphonates (N-BPs) have the greatest antiresorptive activity. Based on in vitro studies, zoledronic acid is the most potent aminobisphosphonate and is the only intravenous bisphosphonate found to be effective in all types of metastatic bone lesions.

Bisphosphonates also have a potential antitumor effect. Data from multiple studies suggest that bisphosphonates may directly or indirectly impair multiple processes required for cancer growth and metastases. Bisphosphonates have demonstrated an ability to induce apoptosis in a variety of cancer cell lines. These agents may also inhibit metastases by decreasing tumor cell adhesion, migration, and invasion. Inhibition of angiogenesis is another property associated with bisphosphonates. Furthermore, these pharmacologic agents may modulate the immune system with subsequent antitumor activity. Recent research also found that zoledronic acid may exert its antitumor activity by inhibiting mesenchymal stem cell migration and blocking mesenchymal stem cell secretion of factors involved in breast cancer progression.

However data from the FDA and the United Kingdom showed the issue of potential risk of esophageal cancer with oral bisphosphonate use was raised. The FDA recently announced plans to continue review of the conflicting studies.

Safety and efficacy data of intravenous bisphosphonates in the metastatic setting are predominantly limited to 24 months of treatment. The most frequently reported side effects from intravenous bisphosphonates are fever and myalgias, which may occur in up to 55% of patients, typically within 12 hours of the initial infusion. Antiinflammatory agents may easily provide relief. Diarrhea and gastric irritation may develop with the oral bisphosphonates ibandronate and clodronate, which are not approved in the management of bone metastases in the United States. Electrolyte abnormalities, including hypophosphatemia, hypocalcemia, hypomagnesemia, and hypermagnesemia, are rarely reported with intravenous bisphosphonates. Other condition such as  vitamin D deficiency, hypoparathyroidism, hypomagnesemia, or use of medication such as interferon, aminoglycosides, or loop diuretics may provoke these abnormalities. (more…)

How Is Drug-Resistant TB Treated?

August 19, 2012 Infectious Diseases, Therapeutics No comments , ,

Parenchymal Postprimary Tuberculosis.

Global challenges regarding the treatment of multidrug drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) include factors related to their diagnosis and treatment. The World Health Organization (WHO) states in their 2011 report on Global Tuberculosis Control that about 50,000 cases of MDR-TB were reported to the organization in 2010, which is equivalent to only 16% of the estimated 290,000 actual cases of MDR-TB worldwide.[1] A WHO global surveillance report indicated that from 2002-2007, about 50% of reported MDR-TB cases were from China and India; the third most prevalent country was the Russian Federation, with about 7% of cases.[2] The actual prevalence of MDR-TB is probably underestimated owing to lack of uniform drug susceptibility testing.

The efficacy of second-line agents, medication access, medication-related adverse effects, and concern about medication adherence during prolonged therapy are all important factors to consider. There have been no randomized controlled trials comparing second-line agents for MDR-TB, and data on the treatment of XDR-TB are extremely limited. This article discusses agents available for MDR-TB treatment in patients who are not co-infected with HIV and the recommendations included in the WHO guidelines.

The typical first-line treatment for non-drug-resistant TB consists of isoniazid, rifampin, ethambutol, and pyrazinamide.[3] The WHO defines MDR-TB as resistance to 2 of the 4 first-line anti-TB medications (isoniazid and rifampin). XDR-TB is defined as resistance to both of these agents, plus any fluoroquinolone and at least 1 of 3 injectable medications (amikacin, kanamycin, or capreomycin).[4] Patients with non-drug-resistant TB have an approximate 90% cure rate when treated with a total of 4 drugs over 6 months. Patients treated for MDR-TB have a 60%-75% cure rate with a 5-drug regimen given for a minimum of 20 months.[2]

Preferred agents not approved by the US Food and Drug Administration that are used to treat MDR-TB include fluoroquinolones (eg, moxifloxacin and levofloxacin) and aminoglycosides (amikacin, capreomycin, and kanamycin).[3] Additional agents used (although not recommended as initial MDR-TB treatment) are linezolid, amoxicillin/clavulanate, clarithromycin, and imipenem. The WHO guidelines recommend the following 5-agent treatment regimen for MDR-TB: pyrazinamide; a fluoroquinolone; a parenteral agent (typically amikacin or kanamycin); ethionamide (or prothionamide); and either cycloserine or para-aminosalicylic acid, with preference for cycloserine.[3]

For patients who have not previously received MDR-TB treatment, the intensive phase of therapy should last a minimum of 8 months (including the parenteral aminoglycoside), with a total treatment duration of at least 20 months.[3] Because data are limited data, there is no recommended treatment regimen for XDR-TB. Regimen design is similar to that for MDR-TB, and it is important to perform drug susceptibility testing to guide therapy. The WHO recommends monitoring MDR-TB treatment through monthly sputum-smear microscopy and culture to identify early treatment failure.[3]

As the basis of their MDR-TB treatment recommendations, the WHO guidelines focus on a pooled meta-analysis of data from 3 unpublished systematic reviews (The Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB. Unpublished data).[3] On the basis of this meta-analysis, aminoglycosides are the preferred parenteral agents, with no superior efficacy demonstrated among amikacin, capreomycin, and kanamycin. The cure rate was higher with ethionamide than with cycloserine, and with cycloserine than para-aminosalicylic acid. However, in patients previously treated for MDR-TB, ethionamide was associated with little efficacy. Among the additional agents (linezolid, macrolides, and imipenem), there was no difference in cure rates; however, patients treated with these agents had worse outcomes that were attributed to confounding factors (The Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB. Unpublished data).[3]

Dosing regimens for MDR-TB agents vary in the literature, and use of the lowest efficacious dose is important, because patients are at an increased risk for medication-related adverse effects owing to the prolonged treatment courses. Trials of oral levofloxacin have been dosed at 300 mg/day or 500 mg/day, while oral moxifloxacin has been studied at 400 mg/day.[5] Potential adverse effects associated with fluoroquinolones include but are not limited to central nervous system effects (eg, tremor, confusion, dizziness, and seizures), QTc prolongation, gastrointestinal disturbances, and tendon rupture.[5,6]

Amikacin and kanamycin are typically dosed at 15 mg/kg/day or 25 mg/kg 3 times per week intravenously, and both dosing regimens seem to be similar in limiting potential adverse effects with weekly serum level monitoring.[7] Potential adverse effects of aminoglycosides include but are not limited to nephrotoxicity and ototoxicity.[6] Varying doses of oral linezolid have been studied, including once-daily doses of 300 mg and 600 mg.[8,9] Bone marrow suppression, peripheral neuropathy, and neurotoxicity are all potential adverse effects of linezolid[8,9]; lower doses or once-daily administration has been considered in an attempt to minimize their occurrence or severity. Appropriate monitoring and patient counseling on potential medication-related adverse effects is essential for all MDR-TB agents.

The following is a potential empiric treatment regimen for a non-HIV-infected adult with normal renal function who is being treated for MDR-TB[6]:

  • Moxifloxacin 400 mg/day orally;
  • Amikacin 25 mg/kg intravenously 3 times per week;
  • Oral daily pyrazinamide, dosed on the basis of lean body weight: 1000 mg for patients weighing 40-55 kg, 1500 mg for those weighing 56-75 kg, or 2000 mg (maximum dose) for those weighing 76-90 kg;
  • Ethionamide 15-20 mg/kg/day orally; initial dose of 250 mg/day, with titration every 1-2 days as tolerated to an average dose of 750 mg/day (maximum of 1 g/day in 3-4 divided doses); and
  • Cycloserine 250 mg orally every 12 hours for 14 days, followed by 500-1000 mg/day, divided twice daily.

Potentially promising new agents for drug-resistant TB are being developed and have begun clinical testing. A new class is the bicyclic nitroimidazoles, which are prodrugs shown to be effective against both actively replicating and nonreplicating bacteria.[10] The difficulty in the eradication of nonreplicating bacteria is the reason why current treatment involves prolonged duration in order to achieve cure and avoid relapse.[10]

The active metabolite for the agent PA-824, des-nitroimidazole, has bactericidal activity against nonreplicating bacteria through the release of reactive nitrogen species, particularly nitric oxide.[10] A phase 2 trial of 8 weeks of combination therapy with PA-824, moxifloxacin, and pyrazinamide has been designed but not yet initiated.[11]

Patients receiving therapy for drug-resistant TB are at high risk for treatment failure owing to the use of second-line agents, which can be expensive, have significant adverse effect profiles, require a longer duration of treatment, are based on less rigorous data, and are less effective than first-line regimens for non-MDR-TB. With the aid of the WHO guidelines and drug susceptibilities, therapy should be patient-specific, with appropriate monitoring and patient education to achieve optimal response to therapy and minimize medication-related adverse effects.

Novel Approaches to the Treatment of Acute Myeloid Leukemia

August 14, 2012 Chemotherapy, Cytogenetics, Hematology, Therapeutics No comments , , , , , ,

Morphology of AML.

Yesterday and today I read an literature by Gail J. Roboz in the Education Program Book by American Society of Hematology (ASH), which is named “Hematology” and published annually by the ASH in one volume per year. The name is “Novel Approaches to the Treatment of Acute Myeloid Leukemia”. In this article the author discussed several aspects of Acute Myeloid Leukemia (AML) including: the general, the chemotherapy regimen, the stem cell transplantation, and the prognostic of AML. Now let’s get into this article.

In the introduction section. Approximately 12,000 adults are diagnosed with acute myeloid leukemia (AML) in the United States annually, with a median age of 67 years. Despite advances in therapeutics and supportive care, the majority of patients with AML die from their disease. But among the subtypes acute promyelocytic leukemia (APL) is an important exception to the general statement of AML. In this subtype >75% of patients are cured with a combination of anthracycline-based chemotherapy, all-trans retinoic acid, and arsenic trioxide. For some APL patients, it is possible to eliminate cytotoxic chemotherapy altogether and to achieve cure with arsenic and all-trans retinoic acid alone. In this article we don’t discuss this subtype of AML in detail.

For all other subtypes of AML, the mainstay of initial treatment was developed nearly 40 years ago as a combination of cytosine arabinoside (ara-C) with an anthracycline, and this regimen remains the worldwide standard of care. Without stem cell transplantation, the age of patients is an in dependent major determinant indicator of the prognostic. For patients <60 years of age approximately 70%-80% of those will achieve complete remission, but most ultimately relapse and overall survival is only 40%-45% at 5 years. Among patients >60 years of age, 40%-50% of those with a good performance status can achieve complete remission, but cure rates are <10% and median survival is <1 year. Later in another section we will discuss the older AML patients in detail.

Advances in genomics technologies have identified AML as a genetically highly heterogeneous disease. As the technologies is well developed today, we are able to assign AML patients to many subgroups based on their molecular genetic defects. First we can assign AML patients to two subgroups which are cytogenetically normal and cytogenetically abnormal.

Cytogenetically normal patients comprise the largest subgroup of AML. This subgroup can now be further divided into a myriad of molecular subgroups too. Some subtypes of molecular genetic defects are know to have significant prognostic implications. For example, mutations in FLT3-ITD have been associated with an aggressive disease phenotype and poor outcomes. In contrast, patients with biallelic mutations in CEBPA and NPM1 without concomitant mutations in FLT3-ITD have significantly more favorable outcomes.

Also there is subgroup with abnormal cytogenetics. For example, mutations in KIT may negate the “favorable” classification previously associated with t(8;21).

Treatment of Acute Myeloid Leukemia

The treatment paradigm for AML generally includes remission induction, followed by consolidation with either 1-4 cycles of chemotherapy or stem cell transplantation.

The drugs for remission and consolidation have been variations on a theme of ara-C combined with an anthracycline or anthracenedione. In 1973 Yates et al first reported the result of a pilot trial of infusional cytarabine combined with daunorubicin in AML. The treatment was called “7&3 DNR 45” to indicate the dose of daunorubicin, 45 mg/m2. And there are many former studies to show the effects of the anthracyclines. There are five recommands for the treatment of AML.

  • Cumulative anthracycline dose for induction should be at least 180 mg/mof daunorubicin or 36 mg/m2 of idarubicin and consider daunorubicin 270 mg/m(It’s called intensive therapy, we will discuss about it later) for patients up to 65 years of age with a good performance status and adequate cardiac function.
  • Consider carefully if offering intensive consolidation to patients >60 years of age because this has not been shown to prolong survival and is associated with significant toxicity.
  • Refer potential transplantation candidates immediately at time of diagnosis to allow adequate time for donor identification and transplantation planning.
  • Age is not a major determinant of outcome after reduced intensity allogeneic transplantation; do not exclude patients on the basis of chronological age alone and refer older patients with good performance status early.
  • Almost every patient with AML should be considered for a clinical trial, including those who are already in remission. (more…)

Recent Advances in Multiple Myeloma Therapy

August 10, 2012 Chemotherapy, Hematology, Therapeutics No comments , , ,

Lenalidomide Maintenance in Elderly Patients?

Alway lenalidomide maintenance therayp is not approved, but researchers now have the final results of the melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance study.

According to their study, this will probably translate into routine practice in the next year because it is probable that this therapy will be approved by the European Medicines Agency.

This regimen will be approved only in patients aged 65-75 years, on the basis of the results of that particular study.

Adding Bortezomib: The VISTA Trial

In a large randomized trial, melphalan/prednisone (MP) regimen was compared with the regimen bortezomib plus melphalan/prednisone (VPM). With a median follow-up of 5 years (4.5 years from the last patient enrolled), there was a significant overall survival benefit of more than 1 year (13.3 months) in favor of the experimental arm (VMP group). This benefit was observed across group analyses.

In addition, this study has shown something that is very important about the paradigm of using a more conventional approach (MP up front) and reserving the other drugs until the time of relapse. This study has clearly shown that it is better to use an optimized treatment up front.

The third message of the study was that for the first time, in the analysis of risk for second primary malignancies with the use of bortezomib (in this case, in combination with MP), it showed that the incidence is the same as in the control arm.

The study was not sufficiently powered to analyze the role of cytogenetics because the number of patients with high-risk cytogenetics was very small (22 patients in 1 group and 24 in the other). Initially, we saw an advantage for the experimental arm vs the MP group, but now with longer follow-up, the incidence of second primary malignancies was exactly the same. One could argue that at the time of relapse, fewer patients were receiving bortezomib, but this is not the right answer. The right answer is that no difference in risk for second primary malignancies was seen in this study.

In the VISTA study, we used biweekly dose of bortezomib. Now we have the once-a-week regimen of bortezomib. We had an update of the weekly administration of bortezomib.[3] This clearly indicated (especially in older patients) that not only is weekly bortezomib associated with better tolerance, but at the end of the day, the cumulative dose of bortezomib is higher. The complete response (CR) rate is the same, and there might even be a trend toward a better CR rate, especially with a maintenance phase in these trials. So, clearly, weekly administration of bortezomib is the way to go in older patients, and discussions are occurring about treating even older and frailer patients with weekly doses of bortezomib.

 Early vs Late Autologous Stem Cell Transplant

In younger patients who are eligible for high-dose therapy and autologous stem cell transplantation. A prospective comparison of melphalan/prednisone/lenalidomide vs melphalan (200 mg/mgMEL200 ) in tandem with autologous stem cell transplantation following an induction phase with lenalidomide-dexamethasone (len-dex) was also reported.

Today, early transplant should be considered the standard because the study that compared the conventional approach (a novel agent vs an autologous transplant approach including a novel agent) clearly showed that the use of the autologous transplant significantly improves progression-free survival (PFS). We do not yet have data in terms of overall survival, but there is a clear advantage in terms of PFS. For the younger patient, a strategy including a novel agent as induction, consolidation with high-dose melphalan in tandem with stem cell support, and maintenance should be introduced as quickly as possible. (more…)

Gout and the Antihypertensives

August 4, 2012 Adverse Drug Reactions, Cardiology, Therapeutics 1 comment , , , , , ,

The inflammatory arthritic condition of gout.

Gout, the inflammatory arthritic condition triggered by crystallization of uric acid within the joints, has risen in the United States. A research studied by Dr. Choi (Hyon K. Choi, MD, DrPH) and his colleagues shown that 74% of US gout patients also have hypertension. Dr. Choi’s group also has shown that hypertension is an important independent risk factor for gout. In patients with hypertension, the incidence of gout has been calculated as 3 times higher than in normotensive patients.

Simplistic speaking, much of this added risk is attributed to the use of diuretics, which are associated with increased serum uric acid levels. But hypertension itself is associated with increased risk of gout. Not only diuretics, but also other nondiuretic classes of antihypertensive drugs have been shown to affect serum uric acid levels.

Generally, with the use of diuretics, beta-blockers, ACEI, and non-losartan angiotensin II receptor blockers (ARBs), the risk of gout incresed.

However as antihypertensive drugs, calcium channel blockers (CCBs) and losartan (a kind of ARBs), are associated with reduced risk of gout.

In an editorial published alongside the study report, Luis M. Ruilope, MD, (Hospital 12 de Octubre and University Autonoma, Madrid, Spain) noted that a reduction in serum uric acid “as well as reducing incident gout, could also improve the cardiovascular and renal prognosis of patients with hypertension.” Thus, to control the serum uric level is important for hypertensive patients.

A number of variables affect serum uric acid levels and the risk of gout, including many life style factors such as adiposity, represented by BMI; dietary factors, particularly alcohol consumption, fructose-rich beverages such as sugary sodas, and a purine-rich diet, particularly animal sources of purine such as red meat or seafood. And in right here, finally, drugs can cause increased risk of gout.

The mechanism of increased risk of gout with hypertension is that as blood pressure elevates, serum uric acid concentration increases, which appears to be a dose-response relationship. Also urate excretion is lower in hypertensive patients than in normotensive individuals. Reduced renal blood flow with increased renal and systemic vascular resistance may also contribute to elevated serum uric acid levels. eventually leading to an increased risk of gout.

The mechanism of increased risk of gout with antihypertensive drugs are variable. Diuretics, the loop and thiazide-type diuretics, can increase serum uric acid levels and the risk of gout. The mechanism of the nondiuretic antihypertensive drugs include ACE inhibitors, non-losartan ARBs are unknown. But clinical trials has shown beta-blockers can increase serum uric acid levels slightly. the mechanism of beta-blockers is unknown neither.

Here I find some data. With beta-blockers, the risk of gout was 48% higher in people with hypertension. ACEIs also have the identical effect. But there is an exception – the diuretics.

Fortunately, specific antihypertensive drugs contribute to the reduce risk for gout. The unique ARB, losartan, lowered uric acid levels in one clinical trial. Bench studies have shown that losartan causes increased uric acid secretion (uricosuria) by inhibiting urate/anion transport in brush-border cells of the renal proximal tubules through inhibition of urate transporter 1 (URAT 1). That is losartan inhibits uric acid reabsorption, causing uricosuria, eventually driving down blood uric acid levels and the reduced risk of gout.

Also CCBs including dihydropyridines and nondihydropyridines have the ability to decrease the risk of gout. The mechanism is unkown. For people with hypertension, taking CCBs lowered their risk of gout by 13% compared with people with hypertension who were not taking a CCB.

To rudece the risk of gout in hypertensive patients, we couldn’t avoid these antihypertensive drugs such as ACEIs, ARBs, or diuretics. Because these patients benefits from these drugs. Thus when the antihypertensive regimen contains drugs increasing risk of gout, we may add another antihypertensive drug that decreases the risk of gout. With the use of the protective drugs, like CCB or losartan, the risk should become even lower.