Oncology Professional Resource Network

Genetic Marker Predicts Taxane-Induced Neuropathy - OncologySTAT

2012-01-16T10:04:00.000-07:00

Genetic Marker Predicts Taxane-Induced Neuropathy - OncologySTAT

This is from May 2011:

Optimism for a Genetic Predictor of Taxane Neurotoxicity

"The first potential biomarker useful in predicting taxane neurotoxicity may be near. A marker in the RWDD3 gene was identified in an ECOG study of 2204 patients with early-stage breast cancer after 12 weeks of weekly paclitaxel. Results are to be presented at ASCO. Divided into 3 genetic subgroups, neuropathy occurred in 27%, 40%, and 60% of patients at 15 months. A subset analysis is underway for African American patients, who had a twofold increase in neuropathy.
***
Older people and blacks, the same study found, are at elevated risk of developing neuropathy, which affects up to a third of people receiving chemotherapy with taxane drugs such as paclitaxel.
***
By looking at more than 1.2 million SNPs in each patient, Dr. Schneider and his colleagues were able to identify genetic subgroups most likely to develop neuropathy. "Those who carried two normal nucleotides in a specific regulatory gene had a 27% chance of experiencing neuropathy," the investigators wrote in their abstract. "But those who carried one normal nucleotide and one SNP had a 40% chance and those who carried two SNPs had a 60% chance."

Dr. Schneider and his colleagues also found that older patients and blacks were much more likely to have peripheral neuropathy. The likelihood of neuropathy increased 12.9% with every decade of age. Blacks saw a twofold increase in the likelihood of developing neuropathy.

Read full article @
http://oncologystat.com/news/Genetic_Marker_Predicts_Taxane-Induced_Neuropathy_US.html

New Genetic Markers May Tailor Leukemia Treatment - OncologySTAT

2012-01-16T09:46:00.001-07:00

New Genetic Markers May Tailor Leukemia Treatment - OncologySTAT

SAN DIEGO (EGMN) - "Novel genetic alterations have been identified in a new subtype of high-risk B-cell acute lymphoblastic leukemia that could be effectively targeted with existing therapies.
The subtype, termed Ph-like ALL, was first identified by the Children's Oncology Group in 2009 (N. Engl. J. Med. 2009;360:470-80), and accounts for up to 15% of pediatric acute lymphoblastic leukemia (ALL) cases.

"Until this study, the genetic basis of Ph-like ALL was unknown," said Kathryn G. Roberts, Ph.D., lead author of the cooperative research study.

Ph-like ALL is associated with alteration of lymphoid transcription factors, most commonly IKZF1, and has a gene expression profile similar to that of Philadelphia chromosome-positive (Ph+) ALL. Ph+ ALL accounts for just 5% of pediatric ALL cases, but because it is driven by the oncogenic tyrosine kinase, BCR-ABL1, it can be effectively treated with available tyrosine kinase inhibitors such as imatinib (Gleevec).

Ph-like ALL, however, is BCR-ABL negative, so patients with this poor-outcome subtype are currently treated with conventional chemotherapy. Higher doses and intensified regimens are limited by toxicity."

Read full article @:
http://www.oncologystat.com/news/New_Genetic_Markers_May_Tailor_Leukemia_Treatment_US.html

(Membership required - Free)

Tissue Drug Level May Hold Key to NSCLC Response - in Meeting Coverage, AACR-IASLC from MedPage Today

2012-01-10T14:42:00.001-07:00

Medical News: Tissue Drug Level May Hold Key to NSCLC Response - in Meeting Coverage, AACR-IASLC from MedPage Today

Action Points

- This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

- In this study, tumor levels of platinum-based chemotherapy proved to be the best predictor of response in patients with advanced non-small cell lung cancer.

- Patients whose tumors had low platinum concentrations also had a shorter time to recurrence and worse progression-free survival (PFS) and overall survival.

(Link to full text)

Rethink Breast Cancer presents: Your Man Reminder

2011-12-22T21:17:00.000-07:00

Breast cancer gene mutations may have link to heart problems | CTV News

2011-12-21T11:59:00.000-07:00

Breast cancer gene mutations may have link to heart problems CTV News

The Canadian Press
Date: Tuesday Dec. 20, 2011 11:35 AM ET

TORONTO — "Two new studies suggest women with gene mutations known to raise the risk of breast and ovarian cancer may also have a greater chance of developing heart disease.

And one of the studies suggests a chemotherapy drug commonly used to treat breast cancer may aggravate the problem in some of these women.

The studies are by researchers at Toronto's St. Michael's Hospital, and are published in the journals Nature Communications and the Journal of Biological Chemistry.

Lead researcher Dr. Subodh Verma says the proteins made by the genes BRCA1 and BRCA2 are critical for repairing damage to cellular DNA.

Women with mutations on the genes don't have enough of the protein, and that may be why they develop breast and ovarian cancer.

Verma's team says their work in mice and in tissue from human hearts suggests the proteins are also crucial for repairing damage to the heart, and women with the mutated genes may be at increased risk of heart disease as a result."

Read more: http://www.ctv.ca/CTVNews/Health/20111220/brca-genes-heart-disease-111220/#ixzz1hCHsbBLb

The mystery of pain as a disease: Elliot Krane on TED.com

2011-11-28T23:16:00.001-07:00

Cancer was leading cause of death in 2008: StatsCan - CTV News

2011-11-08T09:45:00.000-07:00

Cancer was leading cause of death in 2008: StatsCan - CTV News

CTVNews.ca Staff
Date: Tuesday Nov. 1, 2011 9:09 PM ET

"Statistics Canada says 2008 was the first year on record that cancer was
the leading cause of death in every Canadian province and territory.

The statistics agency said Tuesday that cancer caused 30 per cent of
all deaths in Canada that year, followed by heart disease (21 per cent) and
strokes (6 per cent)."

One Man at a Time — Resolving the PSA Controversy — NEJM

2011-10-27T12:15:00.001-06:00

One Man at a Time — Resolving the PSA Controversy — NEJM

Excerpt (follow link above for article):

"Our perspective is that this evidence of a possible small but finite benefit from the largest trial would best support a grade C recommendation for men 55 to 69 years of age. With a grade C recommendation, the task force would be recommending “against routinely providing the service” while indicating that “there may be considerations that support providing the service in an individual patient” and stipulating that “there would need to be at least moderate certainty that the net benefit is small.” The task force's suggestions for practice in the case of a grade C recommendation include the suggestion that they “offer/provide this service only if other considerations support offering or providing the service in an individual patient.”

A grade C recommendation would allow the patient to be involved in the decision to skip or choose a PSA screening test, after a discussion with a primary care provider about the magnitude of the known harms and the potential for some benefit. The patient could then provide his perspective on how he views the trade-off. Weighing the pros and cons to make a decision about PSA screening is an individual process, and different well-informed men will make different decisions."

Single Nucleotide Polymorphism Associations With Response and Toxic Effects in Patients With Advanced Renal-Cell Carcinoma Treated With First-Line Sunitinib: A Multicentre, Observational, Prospective Study - OncologySTAT

2011-10-27T10:05:00.001-06:00

Single Nucleotide Polymorphism Associations With Response and Toxic Effects in Patients With Advanced Renal-Cell Carcinoma Treated With First-Line Sunitinib: A Multicentre, Observational, Prospective Study - OncologySTAT

Excerpt: (for full story follow above link; may require login/registration which is free)

Abstract

Background: Sunitinib is a tyrosine kinase inhibitor with proven efficacy in renal-cell carcinoma, but some patients do not respond or need dose reductions due to toxicity. Because there are no validated molecular predictors of response or toxicity to sunitinib, we aimed to identify genetic markers predictive of outcome and toxic effects.

Findings: We enrolled 101 patients between Oct 10, 2007, and Dec 13, 2010. 95 of these patients were included in toxicity analyses and 89 in the efficacy analyses. Two VEGFR3 missense polymorphisms were associated with reduced PFS with sunitinib on multivariable analysis: rs307826 (hazard ratio [HR] per allele 3·57, 1·75—7·30; p unadjusted=0·00049, p adjusted=0·0079) and rs307821 (3·31, 1·64—6·68; p unadjusted=0·00085, p adjusted=0·014). The CYP3A5*1 (rs776746) high metabolising allele was associated in a multivariable analysis with an increased risk of dose reductions due to toxicity (HR per allele 3·75, 1·67—8·41; p unadjusted=0·0014, p adjusted=0·022). No other SNPs were associated with sunitinib response or toxicity.

Interpretation: Polymorphisms in VEGFR3 and CYP3A5*1 might be able to define a subset of patients with renal-cell carcinoma with decreased sunitinib response and tolerability. If confirmed, these results should promote interventional studies testing alternative therapeutic approaches for patients with such variants.

Study Finds No Cell Phone-Brain Cancer Link - in Oncology/Hematology, Brain Cancer from MedPage Today

2011-10-22T09:06:00.000-06:00

Medical News: Study Finds No Cell Phone-Brain Cancer Link - in Oncology/Hematology, Brain Cancer from MedPage Today: "Action Points:

*Explain that an updated Danish study found that there was no association between central nervous system tumors and subscription to a mobile phone service.

*Point out that there also were no associations between central nervous system tumors and mobile phone use when assessed by length of subscription or tumor type."

Medical News: ECTRIMS: Cancer Drug Wins in Early MS Trial - in Meeting Coverage, ECTRIMS from MedPage Today

2011-10-22T08:54:00.001-06:00

Medical News: ECTRIMS: Cancer Drug Wins in Early MS Trial - in Meeting Coverage, ECTRIMS from MedPage Today:

"Action Points:

*Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

*Explain that a low-dose regimen of the leukemia drug alemtuzumab (Lemtrada) decreased annualized relapse rates in patients with newly diagnosed multiple sclerosis compared with interferon-beta-1a (Rebif).

*Note that alemtuzumab was no better than interferon in the other primary outcome measure, the proportion of patients showing sustained six-month accumulation of disability."

'via Blog this'

Cochrane Review: Hormonal therapy in advanced or recurrent endometrial cancer

2011-10-19T10:41:00.000-06:00

Wiley Online Library: Book Abstract

Cochrane Review: (December 2010)
{Follow link above for full review}

Author's Conclusion:

"We found insufficient evidence that hormonal treatment in any form, dose or as part of combination therapy improves the survival of patients with advanced or recurrent endometrial cancer. However, a large number of patients would be needed to demonstrate an effect on survival and none of the included RCTs had a sufficient number of patients to demonstrate a significant difference. In the absence of a proven survival advantage and the heterogeneity of patient populations, the decision to use any type of hormonal therapy should be individualised and with the intent to palliate the disease. It is debatable whether outcomes such as quality of life, treatment response or palliative measures such as relieving symptoms should take preference over overall and PFS as the major objectives of future trials."

Vitamin Studies Spell Confusion for Patients - in Primary Care, Diet & Nutrition from MedPage Today

2011-10-15T09:39:00.000-06:00

Medical News: Vitamin Studies Spell Confusion for Patients - in Primary Care, Diet & Nutrition from MedPage Today: "If it's Monday, it must be bad news about multivitamin day -- or was that Wednesday? No, Wednesday was good news about vitamin D, not so good news about vitamin E -- if you're confused, join the club.

The alphabet soup of vitamin studies making headlines in the last few weeks has left more than one head spinning, and most clinicians scrambling for answers.

As the dust begins to settle, physicians interviewed by MedPage Today and ABC News agreed on a bit of simple wisdom -- a healthy diet is more important than a fistful of supplements."

'via Blog this'

Angiogenesis: A prognostic determinant in pancreatic cancer?

2011-10-07T13:14:00.000-06:00

Angiogenesis: A prognostic determinant in pancreatic cancer?

Sunitinib-induced hyperparathyroidism - Baldazzi - 2011 - Cancer - Wiley Online Library

2011-09-29T16:53:00.000-06:00

Sunitinib-induced hyperparathyroidism - Baldazzi - 2011 - Cancer - Wiley Online Library

ASCO Updates Guidelines on Antiemetics in Oncology - OncologySTAT

2011-09-29T16:00:00.000-06:00

ASCO Updates Guidelines on Antiemetics in Oncology - OncologySTAT

"A common chemotherapy regimen gets reclassified as high risk for emesis; a new approach is recommended to tackle treatments with high emetic potential; and a particular antiemetic drug is now preferred for patients at moderate risk - these are among the changes to clinical practice guidelines from the American Society of Clinical Oncology.The guidelines also include new recommendations for preventing nausea and vomiting associated with radiation treatment."

ECCO-ESMO: Synchronous Chemoradiation Cuts Breast Cancer Relapse - in Meeting Coverage, ECCO-ESMO from MedPage Today

2011-09-26T07:29:00.000-06:00

Medical News: ECCO-ESMO: Synchronous Chemoradiation Cuts Breast Cancer Relapse - in Meeting Coverage, ECCO-ESMO from MedPage Today: "STOCKHOLM -- Local recurrence in early breast cancer occurred 35% less often in women who received synchronous chemoradiation rather than sequential therapy, long-term follow-up data from a large clinical trial showed.

The five-year incidence of local recurrence was 2.8% with synchronous therapy, with radiation during or between cycles of chemotherapy, and 5.1% among women who received adjuvant chemotherapy followed by radiotherapy. Synchronous therapy also shortened the overall duration of treatment.

The findings were reported here at the European Multidisciplinary Cancer Congress, formerly known as the joint Congress of the European Cancer Organization and the European Society for Medical Oncology (ECCO-ESMO)."

'via Blog this'

Medical News: Brain Steroids Found Lacking in MS - in Clinical Context, Multiple Sclerosis from MedPage Today

2011-09-22T08:36:00.001-06:00

Medical News: Brain Steroids Found Lacking in MS - in Clinical Context, Multiple Sclerosis from MedPage Today

Excerpt:

"Individuals with multiple sclerosis (MS) may have impaired production of important neurosteroid molecules in their brains, so replacement therapy could be helpful, researchers said.

Autopsy findings from 16 MS patients showed high expression of micro-RNA molecules in white matter that suppress enzymes responsible for neurosteroid synthesis, particularly allopregnanolone, according to Christopher Power, MD, of the University of Alberta in Edmonton, and colleagues.

The researchers also confirmed that levels of allopregnanolone and other steroids were depressed in the MS patients' white matter, they reported online inBrain.

Similar findings emerged from analyses of mice with experimental autoimmune encephalitis (EAE), a standard model of MS.

Most strikingly, treating the animals with allopregnanolone partly normalized their behavioral deficits and reduced levels of neuroinflammation and injury to nerve fibers, Power and colleagues indicated.

"These studies are the first report of perturbed neurosteroidogenesis in multiple sclerosis and the related model, EAE, which also showed improved outcomes in terms of neurobehavioural deficits, neuropathology and neuromolecular changes with neurosteroid (allopregnanolone) replacement," they wrote.

"The neurosteroid allopregnanolone, or perhaps closely related compounds, might represent unique therapeutic options for people with multiple sclerosis."

Switching from oxycodone to methadone in advanced cancer patients

2011-09-12T12:38:00.000-06:00

Pain Management - Oncology Article Methadone

Switching from oxycodone to methadone in advanced cancer patients Supportive Care in Cancer, 09/12/2011 Clinical Article
Mercadante S et al.

– Switching from oxycodone to methadone is a reliable method to improve the opioid response in advanced cancer patients. A ratio of 3.3 appears to be reliable, even at high doses.

Results
- 19 out of 542 patients admitted to the unit in 1 year underwent a switching from oxycodone to methadone. Almost all substitutions were successful
- Prevalent indication for opioid switching uncontrolled pain and adverse effects (12 patients)
- No significant changes between the initial conversion ratio and final conversion ratio between the 2 opioids were found

The cancer that plagues Steve Jobs | Health & Fitness | Life | Toronto Sun

2011-09-12T09:26:00.000-06:00

The cancer that plagues Steve Jobs | Health & Fitness | Life | Toronto Sun:

"...estimated 12,000 to 15,000 Canadians who are affected by carcinoid neuroendocrine tumours (CNETs), or alternatively called neuroendocrine tumors (NETs) - the same cancer that has struck Jobs. But because the condition is underdiagnosed and misdiagnosed 90% of the time, there may be other Canadians who also have it.

Indeed, stories that circulated just after Jobs' resignation claimed that Jobs had pancreatic cancer, which he does not. The fact that CNETs are lumped in with other cancers is one reason why there needs to be more awareness of the condition, says Dr. Walter Kocha, a medical oncologist at the London Health Science Centre, in London, Ontario.

"This is a malignancy of a unique system of the body in that it doesn't comprise one of the major organ systems," Dr. Kocha explains. "It is comprised of single or groups of cells that have the unique ability to be used as a signalling system for the body for all sorts of functions such as the secretion of stomach acids, the movement of the bowels, and a whole number of other functions."

'via Blog this'

Projects In Knowledge: Practice-Based Strategies: Triple Negative Breast Cancer Case

2011-09-08T11:06:00.000-06:00

Link: Projects In Knowledge

Practice-Based Strategies: Triple Negative Breast Cancer Case (Tues., Sept. 13 - 8:00pm ET)

Join us for a mentor workshop by phone on strategies to manage metastatic
breast cancer in your patients with HER2-positive or triple-negative disease.
These case-based audio presentations, led by expert faculty, will be followed by
live Q & A. From the comfort of your home or office, you will have the
opportunity to interact with the faculty presenter and to learn from questions
posed by your colleagues nationwide. These 30-minute phone workshops are a
sequel to the data-driven webcast, "Targeting
the Treatment of Metastatic Breast Cancer."

Non-Small Cell Lung Cancer Drug Gets FDA Nod - in Oncology/Hematology, Lung Cancer from MedPage Today

2011-08-27T09:17:00.001-06:00

Medical News: Non-Small Cell Lung Cancer Drug Gets FDA Nod - in Oncology/Hematology, Lung Cancer from MedPage Today

"WASHINGTON -- The FDA has approved crizotinib (Xalkori), a novel targeted therapy for late-stage non-small cell lung cancer.

The Pfizer drug, an inhibitor of anaplastic lymphoma kinase, is a twice-daily pill intended for a select group of patients who express the abnormal anaplastic lymphoma kinase (ALK) gene, which causes cancer development and growth.

The FDA also approved a companion diagnostic called the Vysis ALK Break Apart FISH Probe Kid, made by Abbott Molecular, to help determine if a patient has the abnormal ALK gene.

"The approval of Xalkori with a specific test allows the selection of patients who are more likely to respond to the drug," Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research said in a press release. "Targeted therapies such as Xalkori are important options for treating patients with this disease and may ultimately result in fewer side effects."

Crizotinib's safety and effectiveness were established in two single-arm studies enrolling a total of 255 patients with late-stage ALK-positive non-small cell lung cancer. One of those studies, published in the New England Journal of Medicine last year, found that crizotinib shrank or eliminated 57% of ALK-positive non-small cell lung tumors.

The most common side effects reported in patients receiving crizotinib included vision disorders, nausea, diarrhea, vomiting, edema, and constipation."

Extended-Release Opioid Gets FDA OK - in Neurology, Pain Management from MedPage Today

2011-08-27T09:14:00.001-06:00

Medical News: Extended-Release Opioid Gets FDA OK - in Neurology, Pain Management from MedPage Today

"Tapentadol was also well-tolerated, the company said. Opioids can cause a number of side effects, including constipation, that may cause patients to discontinue their use.

A 2010 phase III study comparing the drug to oxycodone in patients with painful knee osteoarthritis found that tapentadol provided effective pain relief with fewer of the gastrointestinal side effects seen with oxycodone"

Northwestern researchers report breakthrough in ALS research - Chicago Sun-Times

2011-08-23T22:14:00.000-06:00

Northwestern researchers report breakthrough in ALS research - Chicago Sun-Times

"The apparent discovery of a common cause of all forms of amyotrophic lateral sclerosis — the fatal disease also known as Lou Gehrig’s disease — could give a boost to efforts to find a treatment for the fatal neurodegenerative disease, a new study by Northwestern University researchers contends.

Scientists have long struggled to identify the underlying disease process of ALS and weren’t even sure that a common disease process was associated with all forms of ALS.

In this new study, Northwestern researchers said they found that the basis of ALS is a malfunctioning protein recycling system in the neurons of the brain and spinal cord."

Vemurafenib approved for the treatment of patients with unresectable or metastatic melanoma

2011-08-17T12:42:00.000-06:00

From FDA:

On August 17, 2011, the U. S. Food and Drug Administration approved vemurafenib tablets (ZELBORAF, Hoffmann-La Roche Inc.) for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation as detected by an FDA-approved test.

The approval was based primarily on an international, randomized, open-label trial in patients with previously untreated metastatic or unresectable melanoma with the BRAFV600E mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems, Inc.). This companion diagnostic test was approved by the FDA concurrently with vemurafenib’s approval.

The trial enrolled 675 patients; 337 patients were assigned to vemurafenib, 960 mg orally twice daily, and 338 were assigned to dacarbazine, 1000 mg/m2 intravenously, every three weeks. Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. All patients had an ECOG performance status of 0 or 1, and 95% of patients had metastatic disease. The major efficacy outcome measures of the trial were overall survival (OS) and investigator-assessed progression-free survival (PFS). Other outcome measures included confirmed investigator-assessed best overall response rate.

The median follow-up at the time of the overall survival analysis was 6.2 and 4.5 months for the vemurafenib and dacarbazine arms, respectively. Overall survival was significantly improved in patients receiving vemurafenib compared to those receiving dacarbazine (HR=0.44; 95% CI: 0.33, 0.59; p< 0.0001, log-rank test). The median survival of patients receiving vemurafenib had not been reached (95% CI: 9.6 months, not reached) and was 7.9 months (95% CI: 7.3, 9.6) for those receiving dacarbazine.

Progression-free survival (PFS) was also significantly improved in patients receiving vemurafenib (HR=0.26; 95% CI: 0.20, 0.33; p<0.0001, log-rank test). The median PFS was 5.3 (95% CI: 4.9, 6.6) and 1.6 months (95% CI: 1.6, 1.7) in the vemurafenib and dacarbazine arms, respectively. Overall response rate (complete plus partial response rates) was 48.4% (95% CI: 41.6%, 55.2%) and 5.5% (95% CI: 2.8%, 9.3%) in the vemurafenib and dacarbazine arms, respectively.

Vemurafenib was also evaluated in a single-arm, multicenter trial that enrolled 132 patients with BRAFV600E mutation-positive metastatic melanoma who had received at least one prior systemic therapy. An independent review of treatment responses demonstrated a confirmed best overall response rate of 52% (95% CI: 43%, 61%), with a median response duration of 6.5 months (95% CI: 5.6, not reached).

The most common adverse reactions (≥30%) in patients treated with vemurafenib were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea. Cutaneous squamous cell carcinomas (cuSCC), including squamous cell carcinomas of the skin and keratoacanthomas, were detected in approximately 24% of patients treated with vemurafenib. CuSCCs were managed with excision in clinical trials, and patients were able to continue treatment without dose adjustment. Other adverse reactions, sometimes severe, reported in vemurafenib-treated patients included hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, uveitis, QT prolongation, and liver enzyme laboratory abnormalities.

The recommended dose of vemurafenib is 960 mg, orally twice daily administered approximately 12 hours apart, with or without a meal.

Confirmation of BRAFV600E mutation-positive melanoma using an FDA-approved test is required before treatment with vemurafenib. Vemurafenib is not recommended for use in patients with wild-type BRAF melanoma. The approval also contains a Medication Guide to inform health care professionals and patients of vemurafenib’s potential risks.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202429s000lbl.pdf

***

From Medscape:

Enthusiasms

This study is "practice changing," said Lynn Schuchter, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, who moderated the press conference.

Responses with the new oral therapy can be dramatic — patients can have improvement within 72 hours of treatment, she said.

With 2 agents — vemurafenib and ipilimumab (which is approved by the US Food and Drug Administration) — emerging as effective treatments for metastatic melanoma in the past year, it is a "time for celebration for our patients," said Dr. Schuchter — "a time for hope."

"The results of the BRIM-3 study represent a major shift in the way we think about and treat melanoma," writes Marc Ernstoff, MD, in an editorial that accompanies the published study. He is from the Dartmouth Medical School and Norris Cotton Cancer Center in Lebanon, New Hampshire.

Melanoma is a collection of heterogeneous tumors that are differentiated by means of molecular markers, says Dr. Ernstoff, and "each molecularly defined subgroup will probably have a different treatment algorithm."

For patients with metastatic melanoma and the BRAF V600E mutation, "the availability of vemurafenib is a major defining moment that will have an important effect on survival and quality of life," he summarizes.

"These are definitely absolutely remarkable results," said Petra Rietschel, MD, PhD, from the Montefiore Einstein Center for Cancer Care in the Bronx, New York. "As soon as it is on the market, I will most certainly be using it in my clinic for patients with V600E BRAF mutations," she told Medscape Medical News.

***

Via Wikipedia:

Two mechanisms of resistance to vemurafenib (covering 40% of cases) have been discovered:

The cancer cells begin to overexpress a cell surface protein PDGFRB creating an alternate survival pathway.
A second oncogene called NRAS mutates, reactivating the normal BRAF survival pathway.[6]

The V Foundation For Cancer Care: Jimmy V's 1993 ESPY Speech

2011-07-14T09:23:00.002-06:00

On March 4, 1993, Jim Valvano was awarded the inaugural Arthur Ashe Courage and Humanitarian Award at the first annual ESPY Awards. The preceding wass his acceptance speech.

Full transcript at The V Foundation's website:
http://www.jimmyv.org/remembering-jim/espy-awards-speech.html

About The V Foundation:

"Since 1993, The V Foundation has raised more than $100 million and awarded cancer research grants in 38 states and the District of Columbia. Researchers have developed their laboratories and taken their science from the labs to the clinics with the help of funds raised by The V Foundation.

The V Foundation started with the dream of Jim Valvano, the passionate and committed former NC State basketball coach and award-winning broadcaster, as he battled cancer. Wanting to see the battle through to victory, Valvano recruited friends and family to lead The V Foundation in his quest to eradicate the disease that ultimately claimed his life. With a dire need for early developmental, critical-stage grant support, the Foundation was formed to assist the brilliant young researchers that will eventually find cures for cancer.

A relatively young organization, The V Foundation has a strong presence in the scientific community that belies its youth."

Pain & Opiates 3D Animation

2011-07-08T20:44:00.000-06:00

The Mechanisms of Musculoskeletal Pain

2011-07-08T20:42:00.000-06:00

Pain Perception and the Human Brain

2011-07-08T20:41:00.000-06:00

Central Nervous System Mechanisms of Pain Modulation

2011-07-08T20:38:00.001-06:00

Phases of Nociceptive Pain

2011-07-08T20:38:00.000-06:00

FDA Okays Fentanyl Nasal Spray for Ca Pain - in Public Health & Policy, FDA General from MedPage Today

2011-07-07T11:52:00.002-06:00

Medical News: FDA Okays Nasal Spray for Ca Pain - in Public Health & Policy, FDA General from MedPage Today

By Cole Petrochko, Associate Staff Writer, MedPage TodayPublished:

July 02, 2011 WASHINGTO -- The FDA has approved a nasal spray formulation of the drug fentanyl (Lazanda) to manage breakthrough pain in cancer patients ages 18 and older who are already using opioid therapy. The drug comes in 100 mcg- and 400 mcg-spray doses.

Drug efficacy was established in a double-blind study that found fentanyl nasal spray outperformed placebo at the primary endpoint of sum of pain intensity difference at 30 minutes.

The nasal spray formulation is not equivalent to other fentanyl products for breakthrough pain on a microgram-per-microgram basis. Healthcare professionals prescribing Lazanda should not convert from other fentanyl products. A dosage conversion guide is not available at this time.

Everolimus Trial Stopped for Benefit in Breast Cancer - in Oncology/Hematology, Breast Cancer from MedPage Today

2011-07-07T11:09:00.002-06:00

Medical News: Everolimus Trial Stopped for Benefit in Breast Cancer - in Oncology/Hematology, Breast Cancer from MedPage Today

Excerpt:

"A phase III trial of everolimus (Afinitor) in locally advanced or metastatic breast cancer has been halted after an interim analysis indicated that the study's primary endpoint -- a significant difference in progression-free survival relative to a control therapy after six weeks -- was met, the drug's manufacturer said.

According to Novartis, the combination of everolimus and exemestane (Aromasin) was more effective than the latter drug and placebo in preventing tumor growth in women with estrogen receptor-positive, HER2-negative breast cancer that did not respond to other aromatase inhibitors.

The international trial, BOLERO-2, was testing everolimus at 10 mg/day orally plus 25 mg/day of oral exemestane. It included more than 700 patients randomized 2:1 to the combination versus the control regimen.

Novartis did not indicate the degree of improvement in progression-free survival with the combination. It promised that full results would be presented at "an upcoming medical conference" and that it would file marketing applications worldwide by the end of this year."

Medical News: FDA Warns of MI, PAD Risk With Varenicline - in Primary Care, Smoking & Tobacco from MedPage Today

2011-06-16T21:18:00.001-06:00

Medical News: FDA Warns of MI, PAD Risk With Chantix - in Primary Care, Smoking & Tobacco from MedPage Today

WASHINGTON -- The FDA warned today that smokers with a history of heart attack or stroke who use the smoking cessation drug varenicline (Chantix; Champix in Canada) may increase their risk of a second heart attack or new onset peripheral vascular disease.

The agency said an additional warning will be added to the drug's label and prescribing information describing a small, but measurable increase in the risk of cardiovascular events including nonfatal myocardial infarction, angina, and need for coronary revascularization.

Additionally, the label will warn that use of varenicline may increase the risk for a "new diagnosis of peripheral vascular disease or admission for a procedure for the treatment of peripheral vascular disease" among persons with a history of cardiovascular disease.

In its announcement, the FDA noted that smoking significantly increases the risk of cardiovascular events, so it advised physicians and patients to weigh the known benefits of varenicline treatment "against its potential risks when deciding to use the drug in smokers with cardiovascular disease."

Vandetanib Has Risk of Causing Torsades de Pointes

2011-06-16T11:13:00.001-06:00

Update from ArizonaCERT QT Drug Lists by Risk Groups:
http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm

"...on June 6, 2011, we added Vandetanib to the list of Drugs with a Risk of Causing Torsades de Pointes. Keep in mind that whenever a drug is added to any of our lists, it is also automatically included on our list of Drugs to be Avoided by CLQTS (congenital Long QT Syndrome) Patients.

Vandetanib, which will be marketed under the brand name Zactima®, is an anti-cancer drug of the tyrosine kinase inhibitor class. It was approved in April 2011 for use in adults with medullary thyroid cancer for whom surgery is not an option."

Ref: 1. “FDA approves new treatment for rare form of thyroid cancer” Retrieved 6/14/2011

Medical News: Cancer Risk Forces Actos Off French, German Markets - in Endocrinology, Diabetes from MedPage Today

2011-06-10T13:08:00.001-06:00

Medical News: Cancer Risk Forces Actos Off French, German Markets - in Endocrinology, Diabetes from MedPage Today

Excerpt:

Drug regulators in Germany and France have ordered doctors to stop prescribing the type 2 diabetes drug pioglitazone (Actos) following a French study suggesting a heightened risk of bladder cancer.

But the European Medicines Agency (EMA), the FDA, and their Japanese counterpart have withheld action pending additional review of the data.

The French study, conducted by the nation's health insurance agency, examined cancer rates in some 155,000 people taking pioglitazone in France from 2006 to 2009 and 1.3 million other diabetics who were not receiving the agent.

The researchers found an adjusted hazard ratio of 1.22 (95% CI 1.05 to 1.43) for bladder cancer among those on pioglitazone.

There also appeared to be a dose effect, with a higher risk (HR 1.75, 95% CI 1.22 to 2.50) among patients receiving a cumulative dosage of 28,000 mg or more during the study period.

The study was completed on Tuesday. France's regulatory agency officially suspended sales of pioglitazone on Thursday, and Germany followed suit early Friday.

Both agencies recommended that patients currently taking the drug continue to do so until they talk to their doctors about alternative medications.

Radiology Tutorials Website

2011-06-06T10:21:00.000-06:00

Radiology Masterclass is a growing resource in medical imaging education.

Interpreting x-rays takes time to learn. Many medical students (and other healthcare professionals may find beneficial) find they don't get enough formal teaching in radiology, and feel under-prepared when it comes to being a junior doctor. These tutorials will help you develop a structured approach, to avoid the many pitfalls.

Link:
http://radiologymasterclass.co.uk/tutorials/tutorials.html

Lymphedema: Basics, Management and New Research

2011-05-21T10:59:00.001-06:00

Gabapentin: Withdrawal Symptoms After Abrupt Discontinuation

2011-05-18T14:38:00.003-06:00

The anticonvulsant gabapentin, which was discovered over 40 years ago by the Japanese who were initially searching for an antispasmodic or muscle relaxant, is commonly used to treat neuropathic pain, possibly helping relieve symptoms of burning pain, shooting pain, hyperesthesia, and allodynia.

As per Medscape (June, 2010):

Patients who have abruptly discontinued gabapentin have reported symptoms of anxiety, diaphoresis, irritability, agitation, confusion, tachycardia, catatonia, and status epilepticus.^[16–22] The symptoms that have been associated with gabapentin withdrawal tend to mimic some of the same withdrawal symptoms associated with ethanol and benzodiazepine withdrawal, possibly because gabapentin augments GABA levels, as does ethanol and benzodiazepines.

In the setting of treating neuropathic pain, gabapentin can be tapering fairly quickly, but cautiously, monitoring for the above symptoms. I have seen it tapered and discontinued a number of ways with success:

50% of the total daily dose for 1 week, then stop.
Decreasing by 25% weekly (or even every 3 to 4 days) would be a more cautious approach.

What experiences can share from your practice?

***

On another note with respect to gabapentin, is that is becoming more widely know as a medication with a potential for abuse.

From BC Poison Control Centre:

It is becoming increasingly evident that gabapentin may be subject to abuse in particular populations. Case reports describe gabapentin misuse in patients with prior histories of substance abuse and dependency; either to deal with cravings or abstinence symptoms, or as a substitute for substances such as cocaine. Drug users seeking pleasurable effects (e.g., euphoria) abuse gabapentin at various doses, and are willing to share their experiences. Pharmacists should be alert to the potential abuse or misuse of prescription drugs, and may be surprised (and somewhat disconcerted) at the information readily available through sites such as Erowid.

Susan Lim: Transplant cells, not organs | Video on TED.com

2011-04-17T12:51:00.000-06:00

Susan Lim: Transplant cells, not organs | Video on TED.com

MD Anderson Proton Therapy Center

2011-04-17T12:01:00.001-06:00

Cancer: ppar gamma implication in cancer

2011-04-14T22:20:00.000-06:00

Cancer: Sorafenib (Nexavar) English

2011-04-14T22:17:00.001-06:00

Cancer: Fulvestrant (Faslodex ) Mechanism of Action.mov

2011-04-14T22:16:00.001-06:00

Cancer Growth Animation

2011-04-14T22:15:00.000-06:00

3D Medical Animation - What is Cancer?

2011-04-14T22:12:00.000-06:00

Cancer: Cisplatin

2011-04-14T22:10:00.001-06:00

Cancer: Antibody-Drug Conjugates (Anticorps conjugués à un médicament) T...

2011-04-14T22:04:00.001-06:00

Danny Hillis: Understanding cancer through proteomics | Video on TED.com

2011-02-24T19:21:00.000-07:00

Danny Hillis: Understanding cancer through proteomics | Video on TED.com

A pilot phase II trial of magnesium supplements to reduce menopausal hot flashes in breast cancer patients

2011-02-01T15:03:00.000-07:00

Via Supportive Care in Cancer:

Abstract

Background

We tested if magnesium would diminish bothersome hot flashes in breast cancer patients.

Methods

Breast cancer patients with at least 14 hot flashes a week received magnesium oxide 400 mg for 4 weeks, escalating to 800 mg if needed. Hot flash score (frequency × severity) at baseline was compared to the end of treatment.

Results

Of 29 who enrolled, 25 women completed treatment. The average age was 53.5 years; six African American, the rest Caucasian; eight were on tamoxifen, nine were on aromatase inhibitors, and 14 were on anti-depressants. Seventeen patients escalated the magnesium dose. Hot flash frequency/week was reduced from 52.2 (standard error (SE), 13.7) to 27.7 (SE, 5.7), a 41.4% reduction, p = 0.02, two-sided paired t test. Hot flash score was reduced from 109.8 (SE, 40.9) to 47.8 (SE, 13.8), a 50.4% reduction, p = 0.04. Of 25 patients, 14 (56%) had a >50% reduction in hot flash score, and 19 (76%) had a >25% reduction. Fatigue, sweating, and distress were all significantly reduced. Side effects were minor: two women stopped the drug including one each with headache and nausea, and two women had grade 1 diarrhea. Compliance was excellent, and many patients continued treatment after the trial.

Conclusions

Oral magnesium appears to have helped more than half of the patients and was well tolerated. Side effects and cost ($0.02/tablet) were minimal. A randomized placebo-controlled trial is planned.

***
From Livestrong.org:

Magnesium, a mineral found in tofu, grains, nuts, potatoes, leafy green vegetables, chocolate and cocoa powder, has been found to decrease during menopause, according to the University of Maryland Medical Center. Natural-Approaches-to-Menopause.com cites a study in which patients who increased their magnesium experienced decreased symptoms and eventual elimination of hot flashes, so supplementing magnesium levels may decrease the severity and frequency of your hot flashes.

***
From NaturalStandard.com (accessed Feb 1st/2011):

Brief Safety Summary:

Likely safe: When used orally, intravenously, or intramuscularly in people with normal renal function. Oral magnesium has been given in doses of 600-1,200mg daily for months without major adverse effects.

Interestingly:
"Hormonal effects: Oral magnesium has been reported to benefit mood changes associated with premenstrual syndrome (PMS) (6). Facchinetti et al. theorized that this effect may be due to raising intracellular magnesium levels."

Pharmacodynamics/Kinetics:

Magnesium is the second most abundant intracellular cation (positive ion) in the human body and is involved in more than 300 enzymatic reactions, including glucose use, the synthesis of fat, protein, and nucleic acids, the metabolism of adenosine triphosphate, muscle contraction, and some membrane transport systems (154). Magnesium is known to be essential for all ATPase activity, including its capability to facilitate movement of calcium across and within the cell membrane of cardiac and vascular tissues (155).

Absorption: Based on clinical review, 35-40% of ingested magnesium has been shown to be absorbed in the gastrointestinal tract (156). It has been found to reach steady-state after 2-3 hours and maximum concentrations at 4 hours (156). Magnesium is primarily absorbed in the small intestine (156).

Distribution: Normal serum magnesium levels are generally considered to be between 0.70 and 0.94mM/L; the average 70kg adult body contains approximately 24g of magnesium (60% is in the bone; 35% is in the muscles, particularly the heart and skeletal muscles; 1% is found in the extracellular fluid compartment). Approximately 35% of the body's magnesium is bound to albumin, with the rest primarily in ionized form (157).

Metabolism: Based on secondary sources, magnesium is not metabolized.

Excretion: Magnesium excretion is primarily via the kidneys and averages only 3-5% of the filtered load; excretion ranges from 10-5,000mg over a 24-hour period (156). Urinary magnesium and pH are known to modulate urinary calcium excretion; however, the underlying mechanism is unknown (158).

Dog Sniffing Out Cancer May Lead to Early Detection Test

2011-02-01T14:30:00.000-07:00

Via Medscape:

January 31, 2011 — The latest study demonstrating that dogs can sniff out cancer has confirmed the notion that a specific cancer smell does exist, and has added fuel to the idea of developing a test based on odor.

Previous studies have reported on dogs that can detect lung and breast cancer from breath samples, and there has been anecdotal evidence suggesting that dogs can detect melanoma, bladder, and ovarian cancers.

In this latest study, published online January 31 in Gut, a Labrador retriever was trained over several months to sniff out colorectal cancer in breath and watery stool samples.

The dog correctly identified cancer in 33 of 36 breath tests and in 37 of 38 stool tests. This equates to 95% accuracy overall for the breath test and 98% accuracy overall for the stool test, the researchers report.

The highest detection rates were among samples taken from patients with early-stage cancer, they add. Samples taken from smokers and from people with other gastrointestinal diseases, which might be expected to mask or interfere with cancer odors, did not appear to confuse the dog.

"This study shows that a specific cancer scent does indeed exist," the researchers conclude.

They are not suggesting using dogs in clinical practice, however. They point out that training the dog was expensive and time-consuming, and that ability and concentration vary between individual dogs and even the same dog on different days. The dog's concentration tends to decrease during the hot summer season; hence, they conducted their test between November and early June.

What they do propose is that this research could be used to develop cancer detection tests based on "odor materials."
This would involve identifying the cancer-specific volatile organic compounds (VOC) that are being detected by dogs using chemical analysis, and then developing an early cancer detection sensor that would substitute for the dog, they explain.

Timing of Commencing HRT Influences Breast Cancer Risk

2011-02-01T14:18:00.000-07:00

Via Medscape:

January 31, 2011 — Breast cancer risk associated with combination hormone replacement therapy (HRT) is greater if the therapy is started soon after menopause, according to the results of the observational Million Women Study conducted in the United Kingdom...

...Among current users of estrogen–progestin formulations, the relative risks for breast cancer were greater if use began less than 5 years after menopause (relative risk [RR], 2.04; 95% confidence interval [CI], 1.95 to 2.14) than if it began 5 years or more after menopause (RR, 1.53; 95% CI, 1.38 to 1.70)...

...Overall, for women who used combination HRT, compared with control subjects, there was a 39% increase in the relative risk of developing breast cancer in the Million Women Study and a 26% increase in the WHI trial, which the editorialists call "consistent" findings...

"The question of the effect of estrogen-only formulation use on breast cancer risk in postmenopausal women, even with longer-term hormone use, still stands unanswered," write the editorialists.

J Natl Cancer Inst. Published online January 28, 2011. Full text, Editorial

The other question that remains unanswered is what are the impact of other formulations of estrogen and progesteron supplementation for HRT.

For instance:
- Estrace & Prometrium
- "bioidentical" hormones (compounded)

Interestingly, here is an article that was published Feb '10 (epublished about 6 months ago) in the Gynecological Endocrinology Journal. This article looks at women who were administered natural estrogen plus progesterone with or without DHEA or testosterone. It is obviously not a long-term study looking at breast cancer incidence outcomes, but leaves one thinking "what if" and what would be the outcome should this be readily explored. Ethics may come into the equation, however, given the other mainstream evidence that has been published.

Link: http://bit.ly/bKbwGc

"Mental symptoms experienced upon presentation improved in 90% of the patients. Sixty percent of the patients, who had gained weight during menopause, lost an average of 14.8 lbs [SD 11.98 lbs]. Complications described with traditional HRT did not develop in this group of patients."

Eric Mead: The magic of the placebo | Video on TED.com

2011-01-27T21:12:00.000-07:00

Eric Mead: The magic of the placebo | Video on TED.com

San Antonio Breast Cancer Update 2010 - Video Highlights

2011-01-26T10:51:00.000-07:00

From OncologyEducation.ca (requires registration - Free)
http://www.oncologyeducation.ca/node/1639

4 Parts:

Part 1 - Hormone Receptor Positive
Part 2 - Adjuvant Bisphosphonates
Part 3 - Adjuvant Chemotherapy
Part 4 - Targeted Therapy
(Dr. Sunil Verma)

Thomas Goetz: It's time to redesign medical data | Video on TED.com

2011-01-25T20:58:00.000-07:00

Thomas Goetz: It's time to redesign medical data | Video on TED.com

Anders Ynnerman: Visualizing the medical data explosion | Video on TED.com

2011-01-20T19:36:00.000-07:00

Anders Ynnerman: Visualizing the medical data explosion | Video on TED.com

(TED = Ideas worth sharing)

Rank Ligand - Key mediator in bone destruction

2011-01-20T10:14:00.001-07:00

Rank Ligand

This link has been set up by Amgen Canada. It highlights Rank Ligand and its role as a key mediator in the vicious cycle of bone destruction.

The animations help explain in the link noted below.

Osteoblastic versus osteolytic bone metastases

Bone metastases are often characterized by their radiographic appearance as either osteolytic, osteoblastic, or mixed.

Most patients with breast cancer have predominantly mixed or osteolytic lesions. In contrast, patients with prostate cancer are often found to have predominantly osteoblastic lesions. However, regardless of appearance, there is significant osteolytic activity. In fact, osteolytic activity in these lesions often is comparable with, if not higher than, that typically seen in breast cancer and multiple myeloma. Such activity has been demonstrated by markedly elevated biochemical markers of bone resorption in the serum and urine of such patients. Only in multiple myeloma do purely lytic bone lesions develop.

Learn more at:

http://www.rankligand.ca/

Bleomycin-Induced Flagellate Hyperpigmentation

2011-01-18T09:45:00.001-07:00

The incidence may be as high as 20%.

Most tissues contain a cysteine proteinase capable of hydrolyzing and inactivating bleomycin.

The reduced concentration of bleomycin hydrolase in the skin and lung, as compared with other tissues, may explain the medication's adverse reaction profile.

The patient was counseled that the flagellate hyperpigmentation usually fades over a period of several months after the cessation of the medication.

During the past year, the hyperpigmentation in this patient has faded but not yet resolved.

(NEJM 363:e36December 9, 2010)

Nilotinib & QT Prolongation

2011-01-18T09:44:00.002-07:00

QT interval prolongation may occur, which may in turn result in torsades de pointes, leading to syncope, seizure, and/or death. Sudden deaths have been reported (0.1-1%); ventricular repolarization abnormalities may have contributed.

Prolongation is concentration-dependent. Significant prolongation may occur if taken inappropriately with food, and/or strong CYP3A4 inhibitors, and/or medicines with a known potential to prolong QT interval. The presence of hypokalemia and hypomagnesemia may further enhance this effect.

Drugs that prolong QT interval should be avoided due to the risk of potentially fatal arrhythmias.

Pain from Vinorelbine Infusion

2011-01-18T09:43:00.000-07:00

Pain in tumour-containing tissue (rare) as per BCCA.
It has been hypothesized that it is caused by a ‘‘two-step’’ pathogenetic mechanism.
First, surgery, radiotherapy, or the tumor itself causes a neural lesion.
Vinorelbine administration then induces production of pain modulators at the site of the lesion.
It could be classified and treated as an incident pain.
Patients in treatment with opioids could receive one-sixth of the daily dose 15 minutes before vinorelbine administration.
Opioid-naïve patients could be treated with low doses of morphine. Ketorolac alone does not allow effective control of pain and we do not recommend it to treat, or to prevent, vinorelbine associated pain.
Finally, PO administration (?compounded) does not seem to induce vinorelbine-related pain and a switch from IV to PO vinorelbine could be proposed as a method for opioid-resistant patients.

Fulvestrant Dose Approved by US FDA

2011-01-17T16:55:00.005-07:00

On September 10, 2010, the US Food and Drug Administration (FDA) approved the use of fulvestrant (Faslodex®, AstraZeneca) injection at a dose of 500 mg intramuscularly per month for hormone receptor–positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy. The previously approved dosing regimen was 250 mg monthly.

(J Clin Oncol. 2010;28(30):4594-4600).

Advancing the Art and Science of Prostate Cancer–Related Bone Disease Management (CME)

2011-01-17T16:52:00.002-07:00

http://www.boneoncologytx.com/home/index.cfm

Eribulin (Halaven) approved by US FDA

2011-01-17T16:51:00.000-07:00

Sea sponge - Halichondria okadai

- new treatment option for late-stage breast cancer

- Halaven is a synthetic form of a chemotherapeutically active compound derived from the sea sponge Halichondria okadai. This injectable therapy is a microtubule inhibitor, believed to work by inhibiting cancer cell growth. Before receiving Halaven, patients should have received prior anthracycline- and taxane-based chemotherapy for early or late-stage breast cancer.

US FDA News Release Nov. 15, 2010

Bevacizumab Status in Breast Cancer

2011-01-17T16:49:00.002-07:00

FDA begins process to remove breast cancer indication from Avastin label Drug not shown to be safe and effective in breast cancer patients

the results of four clinical studies of Avastin in women with breast cancer and determining that the data indicate that the drug does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh the significant risk to patients. These risks include severe high blood pressure; bleeding and hemorrhage; the development of perforations (or “holes”) in the body, including in the nose, stomach, and intestines; and heart attack or heart failure.

FDA: Bevacizumab (marketed as Avastin) Information http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm193900.htm

Potential tamoxifen & methadone interaction

2011-01-17T16:45:00.000-07:00

Drug Interactions

(as per Lexicomp Online accessed Jan 6/11)

Risk Rating D: Consider therapy modification

Summary: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the formation of highly potent active metabolites.

Severity: Major
Reliability Rating: Fair

Patient Management Moderate CYP2D6 inhibitors may reduce the clinical effectiveness of tamoxifen; consider alternative therapy with less of an effect on CYP2D6 activity when possible.

Cancer: HER3 pathway

2011-01-02T19:07:00.000-07:00

VEGF and EGFR pathways in detail: Target for new therapies against cancer

2011-01-02T19:03:00.000-07:00

EFALIZUMAB MOA animation

2011-01-02T18:57:00.000-07:00

Chemotherapy Part 1

2011-01-02T18:53:00.000-07:00

Understanding Radiation Therapy - part 1

2011-01-02T18:51:00.000-07:00

Nanotechnology for Targeted Cancer Therapy

2011-01-02T18:46:00.000-07:00

An Overview of LDN - Dr Tom Gilhooly Part 1

2011-01-02T18:44:00.000-07:00

LDN FAQs - Pharmacist Stephen Dickson (LDN = Low Dose Naltrexone)

2010-12-13T19:25:00.001-07:00

This is just one of a series of videos regarding LDN.

Pancreatic Cancer -- Beyond Standard Treatment

2010-12-13T19:14:00.000-07:00

Hockey — Not Cancer — On Henderson’s Mind: Anniversary Of THE Goal

2010-09-28T20:24:00.000-06:00

Here's a synopsis of my timely post today at The Hockey Writers.

Either I have forgotten or somehow the news eluded me when announced back in February, but Hockey Canada legend (a term which is probably used too loosely in the sports world, but not in this case) Paul Henderson was then diagnosed with CLL (Chronic Lymphocytic Leukemia).

Today (September 28^th) marks the 38^th anniversary of his historic and dramatic series clinching goal in the ’72 Summit Series, and it was great to hear Mike Richards in the Morning (Fan960.com) interview him today.

Henderson told CBC Sport back in February:

“In Canada, they wait for significant pain before starting chemotherapy,” he says. “It could be one year, two years, even three years.

Paul Henderson - Lucknow Mural {Flickr/Pampered Paws}

“I’m looking for alternative treatments, which are more prevalent in Europe.”
According to Henderson, the disease is in Stage Four. It is in his stomach. His chest. His blood. His lymph nodes. Eventually it will cause his body to decay. But not his spirit, he vows. Never his spirit.
“I have no fear, no angst,” he says. “There is no ‘Why me?’ After all, who has lived a greater life than me?
“I have a loving wife, kids, grandkids. I feel great. I work out five times a week. I can walk 36 holes of golf — at least I could in the fall.
“I always said I would live life to the fullest until the day I died. I just didn’t expect to die this soon,” he says with a laugh.

Read on by clicking on the following link and recapture some of the great moments in Canada sports history and catch up with Paul Henderson:
http://thehockeywriters.com/hockey-not-cancer-on-hendersons-mind-anniversary-of-the-goal/

Monoclonal Antibody Nomenclature

2010-09-10T15:58:00.000-06:00

So...you've just genetically engineered the latest and greatest MAB and want to give it the creative and unique name it deserves. Well...there are rules about naming such things which must be followed:

• ‘mab’ = monoclonal antibody

• Syllable directly before - humanized, chimeric, etc.

• Prefix = no meaning

• Second syllable = Where the Ab works

Letters - Target - Letters - Origin

Ci (r) - Cardiovascula -a- Rat

Tu (m) - Tumor -o- Mouse

Li (m) - Immune -xi- Chimeric human/mouse

Co (l) - Colon Tumor -zu- Humanized

Me (l) - Melanoma -u- Human

Go (v) - Ovarian Tumour -axo- Rat/murine hybrid

Pr (o) - Prostate

Links:

Medscape - Understanding the lingo: http://www.medscape.com/viewarticle/469843_2
WHO MAB's Genereal Policies: http://www.who.int/medicines/services/inn/Generalpoliciesformonoclonalantibodies2009.pdf
Wikipedia - Nomenclature of MABs http://en.wikipedia.org/wiki/Nomenclature_of_monoclonal_antibodies

Fixed combination of oxycodone with naloxone: a new way to prevent and treat opioid-induced constipation

2010-09-08T12:24:00.000-06:00

Courtesy of Peerview Institute:

Adv Ther. 2010 Sep;27(9):581-90. Epub 2010 Aug 11.

Mueller-Lissner S.

Park-Klinik Weissensee, Schönstrasse 80, 13086 Berlin, Germany. mueli@park-klinik.com

Abstract

Morphine and other opioids increase tone and reduce propulsive motility in several segments of the gut, enhance absorption of fluids, and inhibit secretion. This opioid-induced bowel dysfunction may present as infrequent stools, hard stools, difficult defecation, bloating, and sense of incomplete emptying of the bowels, but also dry mouth, gastroesophageal reflux, epigastric fullness, and abdominal cramping. It afflicts about one-third of patients on opioid treatment. Lifestyle measures, such as regular toilet visits, physical activity, and fiber-rich diet, are very unlikely to be successful. Laxatives, such as bisacodyl, sodium picosulfate, sennosides, macrogols, and prucalopride, may relieve opioid-induced constipation (OIC) in a proportion of patients only. A new approach to counteract OIC is the coadministration of an opioid antagonist devoid of the potential to penetrate the brain. In the EU, an oxycodone/naloxone combination has been approved for this purpose. Both components are included in an oral extended-release preparation. Following its release, naloxone acts locally on the gut and antagonizes the inhibitory effect of the opioid. After being absorbed in parallel with oxycodone, naloxone is rapidly and completely inactivated by a high first-pass effect in the liver. In a 2:1 dose ratio it may improve OIC without interfering with the analgesic effect.

PMID: 20714946 [PubMed - in process]

Vitamin D role in preventing aromatase inhibitor-induced arthralgia

2010-09-08T12:10:00.000-06:00

Courtesy of MDLinx.com:

Vitamin D threshold to prevent aromatase inhibitor-induced arthralgia: a prospective cohort study

Breast Cancer Research and Treatment, 08/04/2010
Exclusive author commentary
Prieto–Alhambra D et al.

Aromatase inhibitor (AI)–associated arthralgia limits adherence to therapy in breast cancer...After supplementation (daily 800 IU and additional 16,000 IU every 2 weeks), 50% of them still failed to reach adequate concentrations at 3 months. In the whole cohort, there was an increase in joint pain and the increase was significantly attenuated in those that reached concentrations of 25(OH)D of > or =40 ng/ml, with a lower risk of incident arthralgia. A target concentration of 40 ng/ml 25OHD may prevent development of AI arthralgia but higher loading doses are required to attain this level in women with deficiency at baseline.

Daniel Prieto-Alhambra (08/05/2010) comments:
Adherence to aromatase inhibitor(AI) therapy is required to improve survival in women with early breast cancer who can be treated with these drugs. AI-induced arthralgia is highly associated with discontinuation. We have shown for the first time that Vitamin D repletion (with target concentrations > or 40ng/ml) might prevent development of joint pain associated with AI therapy, and thus, may improve adherence. A randomized clinical trial is required now to ensure causality."

Smoking marijuana relieves some pain: Study

2010-09-07T11:08:00.000-06:00

From CBC:

People who suffer chronic neuropathic or nerve pain from damage or dysfunction of the nervous system have few treatment options with varying degrees of effectiveness and side-effects.

Neuropathic pain is caused by damage to nerves that don't repair, which can make the skin sensitive to a light touch.

Cannabis pills have been shown to help treat some types of pain but the effects and risks from smoked cannabis were unclear.

To find out more, Dr. Mark Ware, an assistant professor in family medicine and anesthesia at Montreal's McGill University, and his colleagues conducted a randomized controlled trial — the gold standard of medical research — of inhaled cannabis in 21 adults with chronic neuropathic pain.

Investigators used three different strengths of the active drug — THC levels of 2.5 per cent, six per cent and 9.4 per cent, as well as a zero per cent placebo.

"We found that 25 mg herbal cannabis with 9.4 per cent THC, administered as a single smoked inhalation three times daily for five days, significantly reduces average pain intensity compared with a zero per cent THC cannabis placebo in adult subjects with chronic post traumatic/post surgical neuropathic pain," the study's authors concluded in Monday's online issue of the Canadian Medical Association Journal.

Read more: http://www.cbc.ca/canada/british-columbia/story/2010/08/30/marijuana-medical-neuropathic-pain.html#ixzz0yrdJmxoi

"The authors should be congratulated for tackling such a worthwhile question as: does cannabis relieve neuropathic pain? particularly because the trial must have been a major nightmare to get through the various regulatory hurdles," Dr. Henry McQuay of Balliol College, Oxford University, U.K., said in a journal commentary accompanying the study.

McQuay concluded that the trial adds to the "trickle of evidence that cannabis may help some of the patients who are struggling at present."

Pain & Symptom Management Updates

2010-09-07T10:59:00.000-06:00

From the Pharmacist Letter, September 2010:

PAIN

New Canadian guidelines will clarify how to manage opioid therapy in patients with chronic non-cancer pain.

Opioid use is rising and so are abuse, diversion, and overdoses.

But on the other hand, chronic pain is still often undertreated and can lead to disability, depression, and other problems.

Recommend trying other options first, such as NSAIDs for inflammation, low-dose amitriptyline for neuropathic pain, etc.

Before going to chronic opioids, suggest assessing for substance abuse, getting informed consent, and setting up an opioid agreement.

Use pain severity and functional improvement to guide therapy.

Mild to moderate pain. Suggest codeine or tramadol first...then morphine, oxycodone, or hydromorphone if needed.

Recommend starting with a short-acting opioid...titrating the dose as needed...then switching to a long-acting formulation for maintenance to improve adherence and minimize breakthrough pain.

Suggest BuTrans (buprenorphine) for patients who can benefit from a once-a-week patch for moderate pain.

Severe pain. Recommend starting with morphine, oxycodone, or hydromorphone...and stepping up to fentanyl if needed.

Reserve methadone for the most resistant cases. Keep in mind that physicians need a special exemption to prescribe methadone.

Keep an eye on oral morphine equivalents...most patients can be managed on less than 200 mg/day. At higher doses, re-evaluate for tolerance, abuse, or a new cause for the pain. For help, see our chart, Equianalgesic Dosing of Opioids for Pain Management.

Suggest continuing NSAIDs or acetaminophen if they help.

Caution patients to limit acetaminophen doses. Consider recommending a maximum of just 2.6 g/day...instead of 4 g/day...to reduce the risk of developing liver toxicity.

Suggest stopping benzodiazepines before starting opioids...to decrease the risk of sedation and overdose.

Help patients have realistic expectations. Explain that a successful outcome is improving function and reducing pain intensity by about 30%. Also recommend exercise, physical therapy, and adequate rest.

Watch for possible interactions. Oxycodone levels may be increased by 3A4 inhibitors, such as clarithromycin. See our chart, Cytochrome P450 Drug Interactions, for other possible interactions.

View Detail-Document #260909

Tools for risk assessment, patient consent, pain contracts, and monitoring are available at:

PartnersAgainstPain.com
http://nationalpaincentre.mcmaster.ca/documents/opioid_guideline_part_b_v5_6.pdf. (See pages 65 to 67)
NIDA Resource Guide (read before using screening tool below): http://www.drugabuse.gov/nidamed/resguide/resourceguide.pdf
http://www.drugabuse.gov/nidamed/screening/nmassist.pdf
http://www.ohsu.edu/ahec/pain/form.html

Pain Updates: Butrans - Buprenorphine patch

2010-09-07T10:14:00.000-06:00

is a transdermal system (buprenorphine) indicated for moderate-to-severe chronic pain in patients requiring an around-the-clock opioid analgesic for an extended period of time.
exerts its analgesic effect via high affinity binding to μ opiate receptors in the CNS; displays partial mu agonist and weak kappa antagonist activity
intended to be used for the continual release of buprenorphine transdermally over a 7-day period per patch, for the management of persistent pain of moderate intensity. BuTrans can be used in either opioid naïve patients or patients previously treated with PRN (as needed) analgesics when the analgesic requirement has progressed to a need for continuous opioid analgesia.
Pallimed article: http://www.pallimed.org/2008/07/td-buprenorphine-for-everything-and.html
From: http://www.palliativedrugs.com/buprenorphine.html

Its release is controlled by the physical characteristics of the matrix and is proportional to the surface area of the patch. Absorption of the buprenorphine through the skin and into the systemic circulation is influenced by the stratum corneum and blood flow.
There are few practical differences in the use of the buprenorphine or fentanyl matrix patches.
Compared with fentanyl, TD buprenorphine adheres better. However, after patch removal, it is associated with more persistent erythema (± localized pruritus), and sometimes a more definite dermatitis.
Retrospective analysis suggests that, compared with TD fentanyl, patients receiving TD buprenorphine (as Transtec®) have a slower rate of dose increase and longer periods of dose stability.
Buprenorphine does slow intestinal transit, but possibly less so than morphine. Constipation may be less severe.
In contrast to other opioids, buprenorphine does not suppress the gonadal axis or testosterone levels.
Compared with morphine and other opioids, buprenorphine has little or no immunosuppressive effect.
With typical clinical doses, it is possible to use morphine (or other μ-opioid receptor agonist) for break-through (episodic) pain and to switch either way between buprenorphine and morphine (or other μ-opioid receptor agonist) without loss of analgesia.
Despite concerns that antagonism could occur, this is likely only with a very large dose; even with buprenorphine 32mg SL, only 84% of μ-opioid receptors are occupied.
A recent study in volunteers suggests that buprenorphine may have an antihyperalgesic effect as well as an analgesic effect.
Animal studies and case reports also suggest that buprenorphine may be of particular benefit in neuropathic pain. The implications for the clinical management of neuropathic pain, if any, need to be determined by controlled studies.

BMT Update: Bortezomib in a conditioning regimen for auto transplant in multiple myeloma

2010-09-07T10:06:00.000-06:00

Bortezomib is being used in a conditioning regimen for auto transplant in multiple myeloma. It is combined with high dose melphalan which is given as an inpatient (U57). This is based on the French study published in Blood. 7 Jan 2010. Volume 115:1. 32-37.

Bortezomib is given day -5, -2, which may be given as an out patient (TBCC), followed the remainder of the protocol given on U57 as an inpatient (melphalan day -1 and velcade day 1 and 4).

Statins Do Not Interfere with Rituximab Treatment for Lymphomas, Mayo Clinic Study Finds

2010-06-02T14:53:00.000-06:00

A medication review recently performed at our clinic identified a potential drug interaction with concurrent use of atorvastatin (Lipitor) and rituximab may result in decreased rituximab efficacy and impaired CD20 detection, according to Micromedex Online.

I had encountered the same interaction early last year and investigated further into this theoretically troublesome combination.

Micromedex Online (accessed June 2, 2010) states:

"Use caution when prescribing atorvastatin to patients who receive rituximab, as concomitant use of atorvastatin may cause interference with antilymphoma activity of rituximab. Atorvastatin may also interfere with the detection of CD20 binding to lymphocytes used to diagnose lymphomas (Winiarska et al, 2008)."

*However, upon further review of the reference Micromedex states in noting the theoretical major interaction between statins and rituximab, a further study has since been done by Grzegorz Nowakowski, M.D., Mayo Clinic hematologist, and others presented Dec 8/2008 at the 50th Annual Meeting of the American Society of Hematology in San Francisco. The results of this study "can provide reassurance to oncologists and their patients that statins will not reduce the effectiveness of rituximab and may in fact improve outcomes of some patients with lymphomas."

Conclusion: "This study shows we should not be concerned of the patient being on Lipitor (atorvastatin) while being treated with rituximab."

Please see the following link for more information:

http://www.mayoclinic.org/news2008-rst/5109.html

I will also be contacting the makers of Micromedex to inform them of this conflicting information.

Site Updates: DrugCoverage.ca Plus More Updates

2010-05-28T13:03:00.000-06:00

After a three week hiatus from the blogosphere due to my Euro-vacation, I am back with some updates to the site.

Note on the left hand side under "Useful Links" I have added a new section - "Drug Databases". Of the 7 current links listed, I would like to highlight a useful tool - DrugCoverage.ca .

"Reimbursement / Coverage Information for Medications Used in Cancer Treatment:

Click on the medication name (on the website) to view drug-specific information on reimbursement / coverage through private insurance, provincial / territorial drug benefit programs, federal plans and reimbursement assistance programs where available. This is a new section and the information for all the medications is not currently available. Alternately, for information on how cancer medicines in general are covered within each province or territory, click here."

Neoadjuvant Chemoradiotherapy with Capecitabine for Locally Advanced Rectal Cancer (LARC)

2010-05-28T10:39:00.000-06:00

{submitted by Frances Cusano}

Neoadjuvant Chemoradiotherapy with Capecitabine for Locally Advanced Rectal Cancer (LARC)

What is the standard of care for patients with LARC?

Preoperative (neoadjuvant) chemoradiotherapy is the standard of care for patients with locally advanced rectal cancer. The results of the German Intergroup trial demonstrated that patients treated with preoperative chemoradiotherapy had lower rates of local recurrence and toxicity with similar rates of overall survival when compared to patients who received post-operative chemoradiotherapy (1). In this trial, the chemotherapy was continuous infusion 5-fluorouracil during the first and fifth weeks of radiotherapy.

Randomized trials have studied different methods of dosing 5-fluorouracil during chemoradiotherapy for rectal cancer. A nonrandomized prospective study compared 22 patients who received continuous infusion of 5-fluorouracil to 12 patients who received bolus 5-fluorouracil with concurrent radiation in the neoadjuvant setting for LARC (2). The bolus 5-fluorouracil was administered on the first 3 – 5 days of radiation and repeated on days 28 – 33. The infusional 5-fluorouracil (225 mg/m² daily) was administered for the duration of radiation. Pathologic complete response was observed in 2 of 21 (10%) of patients treated with bolus 5-fluorouracil verses 8 of 12 (67%) of patients treated with continuous 5-fluorouracil infusion. There was no statistically significant difference in overall survival between the two groups. Based on these results, continuous 5-fluoruracil has been used in the neoadjuvant treatment of LARC.

What is the evidence for capecitabine replacing continuous 5-fluorouracil in the neoadjuvant chemoradiotherapy of LARC?

Currently, there are no published phase III trials comparing capecitabine-based therapies with continuous 5-fluorouracil based therapies as neoadjuvant therapy in LARC.

A phase I trial established that the maximal tolerated dose of capecitabine with radiation therapy for rectal cancer was 825 mg/m² orally twice daily (a daily dose of 1650 mg/m²) (3).

A Phase II trial published by Krishnan et al. (4) enrolled 54 patients with LARC. For radiotherapy, patients received 45 Gy over 25 fractions, with an additional 5 fractions of concomitant boost treatment during the last week. Patients received capecitabine 825 mg/m2 orally twice daily for the duration of radiotherapy, with the initial dose starting approximately 1 to 2 hours before radiotherapy. Of the 51 patients evaluated for pathologic response, 9 patients (18%) had a complete pathological response (pCR). Twenty-six of all 54 patients (51%) achieved T-downstaging and 15 of the 29 initially node positive patients (52%) achieved N-downstaging. Other phase II studies have shown similar results, with pCR between 9 and 24% (5).

The NSABP R-04 is a Phase III randomized trial currently in progress. This trial will compare the rate of local-regional relapse in patients receiving preoperative oral capecitabine + radiotherapy to patients receiving preoperative infusional 5-fluorouracil + radiotherapy.

What are the toxicities of capecitabine + radiotherapy vs infusional 5-fluorouracil + radiotherapy in the neoadjuvant setting in patients with LARC?

Phase II prospective studies of neoadjuvant capecitabine + radiotherapy in patients with LARC have shown that the treatment is generally well tolerated with no grade IV toxicity (5).

A retrospective Phase II study by Das et al. (6) compared preoperative chemoradiotherapy with capecitabine versus infusional 5-fluorouracil for rectal cancer. 89 patients with nonmetastatic rectal adenocarcinoma were treated with preoperative RT (45 Gy in 25 fractions in 5 weeks) and capecitabine (1650 mg/m2/day during radiotherapy). These patients were matched to 89 control patients who received preoperative radiotherapy (the same dose as in the capecitabine group) and continuous infusion 5-fluorouracil (median dose 300 mg/m2/day administered Monday to Friday each week of radiotherapy). No statistically significant differences were found between patients treated with capecitabine and those treated with continuous infusion for the rates of local control, distant control and overall survival. Patients treated with capecitabine had a greater rate of hand-foot syndrome (22% vs 3%, p< 0.01), but these were all Grade 1 or 2. Patients treated with protracted infusional 5-fluorouracil had a greater rate of mucositis (19% vs 6%, p = 0.03). Two patients in the capecitabine group experienced Grade 4 diarrhea, and 1 patient in the infusional 5-fluorouracil group experienced Grade 4 mucositis.

Conclusion

The results of NSABP-R04 will be used to evaluate whether capecitabine should be used as an alternative to infusional 5-fluorouracil in neoadjuvant chemoradiotherapy for LARC. While the evidence to date does not indicate that capecitabine is superior to infusional 5-fluorouracil or that it reduces the toxicity of neoadjuvant chemoradiotherapy, use of capecitabine does eliminate the need for indwelling catheters, which carry a risk of infections and thrombosis.

References

1. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-1740.

2. Mohiuddin M, Regine WF, John WJ et al. Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response. Int J Radiat Oncol Biol Phys 2000;46:883.

3. Dunst J, Reese T, Sutter T et al. Phase I Trial Evaluating the Concurrent Combination of Radiotherapy and Capecitabine in Rectal Cancer. J Clin Oncol 2002;20:3983-3991.

4. Krishnan S, Janjan N, Skibber J et al. Phase II study of capecitabine and concomitant boost radiotherapy in patients with locally advanced rectal cancer. Int J Radiation Oncology Biol Phys 2006;66(3):762-771.

5. Saif M, Hashmi S, Zelterman D et al. Capecitabine vs continuous infusion 5-FU in neoadjuvant treatment of rectal cancer. A retrospective review. Int J Colorectal Dis 2008;32:139-145.

6. Das P, Lin EH, Bhatia S et al. Preoperative chemoradiotherapy with capecitabine versus protracted infusion 5-fluorouracil for rectal cancer : A matched pair analysis. Int J Radiation Oncology Biol Phys 2006;66(5):1378-1383.

Adverse Effects of Androgen Deprivation Therapy in Men with Prostate Cancer

2010-04-15T16:52:00.000-06:00

Submitted by Frances Cusano April 15, 2009:

(Review of “Adverse Effects of Androgen Deprivation Therapy: Defining the Problem and Promoting Health Among Men with Prostate Cancer. Saylor PJ and Smith MR. JNCCN 2010;8)

Androgen deprivation therapy (ADT), which includes bilateral orchiectomies or treatment with a gonadotropin releasing hormone (GnRH agonist), improves overall survival when combined with external beam radiation in patients with locally advanced or high-risk non-metastatic prostate cancer. ADT also improves survival in men with nodal metastases after prostatectomy and pelvic lymphadenectomy. In men with metastatic prostate cancer, ADT decreases pain and modestly improves overall survival.

Because men often live for years with prostate cancer, treatment-related morbidity needs to be monitored. GnRH agonists have been shown to produce detrimental changes in body composition, lipid profile, insulin sensitivity and bone mineral density. As evidence based guidelines for the management of ADT adverse effects do not yet exist, the authors proposed practical management recommendations adopted from available guidelines by the National Osteoporosis Foundation, the American Diabetes Association, the National Cholesterol Education Program Adult Treatment Panel III and the American Heart Association.

Obesity

The first year of ADT causes lean body mass to decrease by about 3%, fat mass to increase by 10% and weight to increase by 2%. ADT-associated redistribution of weight has been shown to favour the accumulation of subcutaneous abdominal fat. Abdominal circumference has been associated with mortality in a large prospective cohort study. There are no evidence based prevention or treatment strategies at this time for ADT-associated changes in body composition. A study that randomized 155 men receiving ADT to a control group or a treatment arm that performed resistance exercise 3 times a week failed to demonstrate a difference in body composition between the two groups.

Lipid Alteration

GnRH agonists cause triglycerides to increase by approximately 26% and total cholesterol to rise by approximately 10%. High density lipoprotein (HDL) increases by about 8 to 11%. For prostate cancer patients who have received ADT, the authors recommend measuring fasting lipoproteins at baseline, within 1 year of ADT initiation, and as clinically indicated after that. Primary prevention guidelines include tobacco cessation and lifestyle changes (reducing dietary saturated fat and cholesterol, increasing physical activity and controlling weight). Statins are recommended as first-line treatment if lifestyle changes do not achieve target low density lipoprotein (LDL).

Insulin Resistance and Diabetes

GnRH agonists have been shown to decrease insulin sensitivity within 12 weeks after ADT initiation in non-diabetic men. Two large database analyses have demonstrated that GnRH agonist treatment is associated with an increased incidence of diabetes. The authors recommend screening with hemoglobin A1c or fasting plasma glucose at baseline and again within 1 year for patients treated with long-term ADT. Diabetes is considered when the hemoglobin A1c is greater than 6.5 % or the fasting plasma glucose is greater than 6.9 mmol/L. Patients with hemoglobin A1c between 6.0 % and 6.5 % or impaired fasting glucose (5.6 – 6.9 mmol/L) are at high risk of developing diabetes and should be counseled to pursue 5 to 10 % weight loss and 150 minutes or more per week of moderate physical activitiy.

Coronary Heart Disease

Data on the increase in risk for cardiovascular events due to ADT therapy is conflicting. Because studies in the general population have shown that patients with fewer known risk factors for cardiovascular disease have a lower incidence of heart disease and stroke, the authors recommend primary prevention. Recommendations include tobacco cessation, treatment of hypertension as per accepted guidelines, lifestyle interventions (reduced intake of saturated fat and cholesterol, increased physical activity and weight control), and low dose aspirin in men with 10-year coronary heart disease risk > 10%.

Osteoporosis and Fracture Risk

ADT has been associated with decreased bone mineral density (BMD) and elevated fracture risk. The authors recommend BMD testing at baseline, after 1 year of ADT, then every 2 years as clinically indicated. The online Fracture Risk Assessment Tool (FRAX) (http://www.shef.ac.uk/FRAX) uses patient factors such as age and use of tobacco and medication to assess the risk of fracture. Guidelines include supplemental calcium and vitamin D for all patients. Drug therapy is recommended for men who have a low T-score (-1.0 to -2.5) and a 10-year risk for hip fracture of at least 3%, or at least 20% for any osteoporosis-related fracture. Bisphosphonates increase BMD, but their impact on preventing treatment-related fractures has not been properly evaluated. Two recent phase III trials have shown that denosumab and toremifene are each effective in fracture prevention in men receiving ADT.

Development of guidelines for the management of adverse effects from ADT therapy give the clinical pharmacist a useful reference in managing prostate cancer patients receiving ADT.

Tamoxifen: To Crush Or Not To Crush?

2010-04-13T10:34:00.001-06:00

1. From: http://www.gghbpharmacy.scot.nhs.uk/Hospitals/Southern/NIL_BY_MOUTH.pdf

*States tamoxifen should not be crushed, but tablets can be dispersed in water.

2. From: http://www.rosemontpharma.com/education/healthcare-professional/tablets-not-to-crush & http://www.guardian.co.uk/uk/2006/oct/26/health.healthandwellbeing

Hormonal cytoxic or steroidal medicines (i.e. tamoxifen, methotrexate)

Risk assessment form requires completion if drug is to be crushed prior to administration. If the tablet is crushed, the drug may go into the air and the dose inadvertently received by the administrating nurse or carer.

3. From BCCA: http://www.bccancer.bc.ca/RS/CommunitiesOncologyNetwork/Educators/faqs.htm#One

1. How can we administer an oral cancer medication to a cancer patient who has just had an NG tube inserted? For safety reasons, we were told not to crush tablets or open capsules.

Oral cancer medications that are considered hazardous or cytotoxic should not be manipulated outside of a containment cabinet (ie. Biological Safety Cabinet) due to the risk of generating Hazardous Drug (HD) powder residue causing possible HD contamination and exposure. You may try dissolving or suspending the tablet/capsule particles in an enclosed system (i.e. syringe plus water) and administering the liquid through the NG tube.

If line occlusion occurs and impedes cancer drug administration you could consider holding the drug for a few days. For example; tamoxifen has an elimination half-life of ~ 5-7 days and the half-life of its active metabolite is ~ 9-14 days, so it is possible to hold tamoxifen therapy for ~2 weeks.

If the oral cancer medication cannot be withheld, it may be possible to compound it into a liquid dosage form. All activities likely to result in particle or aerosol generation, such as crushing tablets/capsules or compounding/pouring of oral solutions should be performed in a Biological Safety Cabinet (BSC) or Isolator. Oral solutions for hospital inpatients should be prepared in the pharmacy and dispensed to the ward in unit dose syringes. The nurses should not measure doses from a bottle.

Reference:

BCCA Division of Pharmacy. BCCA Pharmacy Practice Standards for Hazardous Drugs. 2008.

------

Any other thoughts out there on how to handle the situation where tamoxifen tablets cannot be swallowed?

Oxaliplatin-Induced Peripheral Sensory Neuropathy In Diabetes Patients

2010-04-08T17:01:00.000-06:00

Via OncologySTAT:

In conclusion, this pooled analysis indicated that patients with diabetes who are being treated with an oxaliplatin-containing regimen for CRC are not at increased risk of developing PSN. Because of limitations related to the design of the 3 studies, the role of the duration and type of diabetes in the development of PSN during oxaliplatin treatment remains uncertain. Various strategies to prevent oxaliplatin-associated neurotoxicity have been identified but require further study. Larger, prospective trials are needed to confirm the exact nature of any association between diabetes and oxaliplatin-induced neuropathy.

TAKE-HOME MESSAGE:

Patients with diabetes who were treated with FOLFOX4 for colorectal cancer were not at increased risk of developing peripheral sensory neuropathy.

Is Ginger effective in preventing Chemotherapy Induced Nausea and Vomiting (CINV)?

2010-04-01T10:05:00.000-06:00

Is Ginger effective in preventing Chemotherapy Induced Nausea and Vomiting (CINV)?

THE EVIDENCE:

Ginger root (Zingiber officinale) has been used as a medicinal herb for at least 2,000 years. In Chinese, Indian, Middle Eastern and western herbal medicine, ginger is used mainly to treat digestive disorders such as nausea, vomiting and diarrhea.

A presentation by Ryan et al (1) at the 2009 ASCO Annual Meeting described positive results with the use of ginger in the prevention of acute nausea. A multi-site, randomized, placebo-controlled double-blind trial accrued 644 patients who had experienced nausea following any chemotherapy cycle and were scheduled to receive at least 3 additional cycles. Patients were randomized into 4 arms (placebo, ginger 0.5 g per day, ginger 1 g per day and ginger 1.5 g per day). Patients took three 250 mg capsules of ginger/placebo twice daily for 6 days starting 3 days before chemotherapy, for the next 2 cycles. All patients received 5-HT3 receptor antagonists on Day 1. Nausea was reported by the patients using a 7 point rating scale. All doses of ginger significantly reduced nausea (P = 0.003), with the largest reduction in nausea occurring with 0.5 g and 1 g daily doses of ginger. There was no difference between groups in the incidence of vomiting.

Two other references report efficacy of ginger in treating acute nausea induced by chemotherapy (2) (3). Pace (2) studied 41 leukemic patients receiving chemotherapy who were randomized to receive oral ginger or placebo in addition to prochlorperazine. The results showed a significant reduction in nausea in patients receiving ginger compared to those receiving placebo. Unfortunately, these results were only published in abstract form, the dose of ginger was not indicated, and no P values were reported. Sontakke et al (3) conducted a randomized, prospective, cross-over double-blind study of 50 patients receiving cyclophosphamide-containing chemotherapy regimens who had experienced at least two episodes of vomiting in the previous chemotherapy cycle. Patients were randomized to receive ginger (1 g orally pre-chemotherapy and 1 g orally 6 hours post-chemotherapy) or metoclopramide (20 mg IV pre-chemotherapy and 10 mg orally 6 hours post-chemotherapy) or ondansetron (4 mg IV pre-chemotherapy and 4 mg orally 6 hours post-chemotherapy). Patients were monitored for 24 hours, and nausea was graded as none, mild to moderate, or severe. The effect of ginger was found to be comparable to that of metoclopramide (complete control of nausea was achieved in 62% of patients who received ginger and 58% of patients who received metoclopramide). Ondansetron was found to be better than both agents, with complete control of nausea in 86% of patients (P < 0.01). This study also assessed acute vomiting. The difference between the anti-emetic effect of metoclopramide and ginger was not statistically significant but ondansetron was significantly better than metoclopramide and ginger (P < 0.01).

Two published studies failed to demonstrate a benefit in the use of ginger in acute nausea and/or vomiting and in delayed nausea and/or vomiting (4) (5). Manusirivithaya et al (4) conducted a randomized, double-blind crossover study in 48 gynecologic cancer patients receiving cisplatin-based chemotherapy. All patients received metoclopramide IV, dexamethasone IV and lorazepam po pre- and post- chemotherapy. Patients randomly received 1 g ginger orally daily for 5 days starting on the first day of chemotherapy, or placebo for day 1 and metoclopramide 40 mg orally daily on days 2 to 5. Assessment of nausea and vomiting was performed by the investigators for the first 24 hours and by the patients for days 2 – 5. The number of vomiting episodes was recorded, and a 10 cm visual analog scale was used to indicate the intensity of nausea. Adding 1 g of ginger to the standard antiemetic regimen in patients receiving 75 mg/m2 of cisplatin had no benefit in controlling acute cisplatin-induced nausea or vomiting. In the delayed phase, 1 g/day of ginger had a control of nausea and vomiting which was not statistically different than that achieved with 40 mg metoclopramide/day. Zick et al (5) performed a randomized, double-blind, placebo-controlled trial in 162 patients with cancer who had experienced CINV during at least one previous chemotherapy cycle. Study participants received 1 g ginger daily, 2 g ginger daily or placebo for 3 days. All patients received a 5-HT3 receptor antagonist and/or aprepitant. Prevalence and severity of nausea and vomiting was recorded in a patient diary (intensity was recorded using a 6 point Likert scale). There was no significant difference between either of the ginger doses compared to placebo in the prevalence of acute or delayed nausea or vomiting. Participants who received the high dose of ginger (2 g) had significantly more severe delayed nausea compared to both placebo and low-dose ginger. Significantly more severe delayed nausea occurred with both doses of ginger in patients prescribed aprepitant.

CONCLUSION:

Ginger is generally well-tolerated and not associated with significant toxicity. Ginger may interfere with blood clotting, and should not be taken by patients with bleeding disorders or patients taking anticoagulants. The trial by Zick et al (5) indicated that when ginger was co-administered with aprepitant, the severity of delayed nausea was increased. The authors suggested that ginger could decrease the absorption of aprepitant by increasing gastrointestinal motility.

It is difficult to compare results between trials due to the variation in the ginger doses and dosing schedules used, variation in the nausea rating scales used, and variation in the emetogenicity of the chemotherapy regimens. In the prevention of CINV, the standard of care for patients receiving moderately emetogenic and highly emetogenic chemotherapy protocols includes a 5-HT3 antagonist. The two trials which studied acute CINV and included a 5-HT3 antagonist in their regimens were those by Ryan et al (1) and Zick et al (5). These trials gave conflicting results with regards to efficacy of ginger in treating acute nausea. The conclusion which may be drawn (using the methods and positive results of Ryan et al) is that ginger may be effective in preventing ACUTE NAUSEA at a dose of 0.5 g or 1 g orally daily (divided into twice daily dosing) taken for 6 days, beginning 3 days before chemotherapy (1). Both trials failed to demonstrate prevention of acute vomiting by ginger. No trial demonstrated prevention of delayed nausea and/or vomiting by ginger.

References:

1. Ryan JL, Heckler C, Dakhil SR et al. Ginger for chemotherapy-related nausea in cancer patients: A URCC CCOP randomized, double-blind, placebo-controlled clinical trial of 644 cancer patients. Journal of Clinical Oncology, 2009 ASCO Annual Meeting Proceedings (Post Meeting Edition) 27(15S):9511.

2. Pace J. Oral ingestion of encapsulated ginger and reported self-care action for the relief of chemotherapy-associated N & E. Dissertations Abstracts International 1987;47:3297-B.

3. Sontakke S, Thawani V, Naik MS. Ginger as an antiemetic in nausea and vomiting induced by chemotherapy: A randomized, cross-over, double blind study. Indian Journal of Pharmacology 2003;35:32-36.

4. Manusirivithaya S, Sripramote M, Tangjitgamol T et al. Antiemetic effect of ginger in gynecologic oncology patients receiving cisplatin. Int J Gynecol Cancer 2004;14:1063-1069.

5. Zick SM, Ruffin MT, Lee J et al. Phase II trial of encapsulated ginger as a treatment for chemotherapy-induced nausea and vomiting. Support Care Cancer 2009;17:563-572.

6. http://www.umm.edu/altmed/articles/ginger-000246.htm

Submitted by: Frances Cusano (March 26, 2010)

ProMED-mail - the Program for Monitoring Emerging Infectious Diseases

2010-03-18T16:22:00.000-06:00

I just wanted to highlight an excellent infectious disease web site that was passed along to me:

ProMED-mail is an Internet-based reporting system dedicated to rapid global dissemination of information on outbreaks of infectious diseases and acute exposures to toxins that affect human health, including those in animals and in plants grown for food or animal feed. Electronic communications enable ProMED-mail to provide up-to-date and reliable news about threats to human, animal, and food plant health around the world, seven days a week.

By providing early warning of outbreaks of emerging and re-emerging diseases, public health precautions at all levels can be taken in a timely manner to prevent epidemic transmission and to save lives.

ProMED-mail is open to all sources and free of political constraints. Sources of information include media reports, official reports, online summaries, local observers, and others.

http://www.promedmail.org/

For more information, see:
http://www.promedmail.org/pls/apex/f?p=2400:1950:4003647872063958::NO

Fentanyl Citrate Sublingual Dosing And Stability

2010-02-10T11:47:00.001-07:00

Fentanyl S/L:

- Use: incident pain

- Onset of action: 5-15 minutes

- Peak effect: within 20 minutes

- Duration of action: maximum 45minutes

- Supplied: 100mcg/2ml ampoules (Sublimaze®) – glass ampoules.

* Needs special authorization for Alberta Blue Cross

- Note: decreased saliva production can delay absorption of sublingual fentanyl

- If administered sublingually, the drugs have to remain there for at least 5 minutes.
- Oral bioavailability of fentanyl is negligible and therefore this medication cannot be taken orally.
- Patients are generally unable to keep more than 1.5ml to 2ml under the tongue before it dribbles into the mouth, rendering it inactive.

Counseling:

- Determine the maximum amount of liquid that can be held under the tongue using the cold water technique (pt should be able to feel cold water trickling down throat).

o Max 1.5 ml – 2ml (CHR long term care formulary)

o Max 0.5 ml – 1ml (cold water test)

- Fentanyl must remain under the tongue for at least 5 minutes to be absorbed.

o Oral bioavailability of fentanyl is negligible and therefore this medication cannot be taken orally.

- Any remaining/extra fentanyl in the amp should be drawn up to a syringe and kept in the fridge.

CHR Incident Pain Protocol*

Step 1: Fentanyl 12.5mcg (0.25ml)

Step 2: Fentanyl 25 mcg (0.5ml)

Step 3: Fentanyl 50 mcg (1ml)

Step 4: Fentanyl 100 mcg (2ml)

- Opioid naïve pt: start at Step 1.

- If the pt is opioid tolerant, then start at Step 2.

- If pt unable to tolerate the volume in a single dose then the volume may be given in 2 doses at an interval of 5-10minutes apart. (ie: 2ml – take 1ml twice 5 minutes apart).

- After 10-15 minutes, if the initial dose appears to be insufficient, then the same dose may be repeated up to 2 further doses, at 10-15 minute intervals.

- Consider moving to the next step of the protocol if the maximum number of doses (3) is required to achieve comfort. One may move to the next step of the protocol after one hour of the last dose of fentanyl.

- The Incident Pain Protocol may be used up to q1h.

Side Effects:

Drowsiness, sedation, nausea and vomiting. Respiratory depression is dose dependent, it could potentially occur with an initial fentanyl dose greater than 200mcg IV.

Stabilty:

Undiluted fentanyl citrate 50 mcg/mL was tested for stability in polypropylene syringes. The fentanyl citrate injection was filled into polypropylene syringes that were then capped off. The samples were stored for 28 days under refrigeration at 5 °C and at room temperature of 22 °C exposed to light. No change in color or clarity occurred. No loss of fentanyl citrate at either set of storage conditions occurred when evaluated using stability-indicating HPLC analysis.

*Hecq JD, Boitquin LP, Venbeckbergen DF et al. Effect of freezing, long-term storage, and microwave thawing on the stability of ketorolac tromethamine. Ann Pharmacother. 2005; 39:1654-8. [PubMed 16159993]

[Accessed Feb 10/10: Handbook on Injectable Drugs - 15th Ed. (2009)]

Pharmacy On-Call (Calgary Pharmacy) will premix syringes which are stable for 1 week.

*Calgary Health Region Long Term Care Formulary: fentanyl citrate injection.

Drug Interaction: Cyclophosphamide and Allopurinol

2010-02-05T12:15:00.000-07:00

*Interaction detected between allopurinol and cyclophosphamide, MAJOR increased toxicity (increase myelosuppression, nausea and vomiting) as per Micromedex Online
(Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically).

Onset: Delayed

Severity: Major

Documentation: Good

Summary: There may be an increase in cyclophosphamide levels and prolongation in half-life of cyclophosphamide (Anon, 1974; Stolbach et al, 1982).

Literature:

The Boston Collaborative Drug Surveillance Program examined the incidence of bone marrow depression in a series of 160 patients, 95 of whom were controls, during combined allopurinol use with either cyclophosphamide or other cytotoxic drugs (Anon, 1974). Their results indicated that the frequency of bone marrow depression in those patients who received allopurinol and cyclophosphamide was 57.7% as compared to 18.8% in those who did not receive allopurinol. In addition they noted that mortality may be somewhat higher in allopurinol recipient patients.

One study has reported that concomitant allopurinol and cyclophosphamide therapy results in significant elevations of cyclophosphamide cytotoxic metabolites, which may contribute to the increased bone marrow depression observed during concomitant therapy (Witten et al, 1980).

*At our centre and in this individual case, patient was on allopurinol 100 mg daily continuously for management of gout. The patient was to start FEC. After discussing with treating physician, there was insufficient time to temporarily discontinue allopurinol without delaying treatment. Therefore, it was decided to monitor CBCs carefully - that is, weekly (at least for the first cycle). It will then be decided if allopurinol will be held at all next cycle.

One possible recommendation would be to hold allopurinol for 5 days before and 2 days after chemotherapy treatment. This is based on half-life of active metabolite of allopurinol, oxypurinol, being 18-30 hours and cyclophosphamide's 3-12 hours.

Targeted Therapy Online Learning

2010-02-05T11:51:00.002-07:00

1. OnTarget: Common Side Effects Of Targeted Therapy

"To Build Confidence and Skill in the Prevention and Management of Common Side Effects of Targeted Oncology Therapy"

- Oct. 2009
- The Canadian Council on Continuing Education in Pharmacy has awarded this program 10 CEUs.
- Exp: Aug. 19 2012

"Who created this Resource Guide

A committee of practicing oncology pharmacists, experienced in hospital and community pharmacy practice, in conjunction with an expert review panel and in collaboration with the Groupe d’étude en oncologie du Québec, developed this Resource Guide."

2.Caring for Oncology Patients: Tips and Tools for Managing Targeted Therapy
http://www.projectsinknowledge.com/cp/index.cfm?thspage=curriculum&jn=1834
- An Ongoing Online CME/CE Curriculum

- This is a series of CEU modules from Projects In Knowldge.
- Currently, they have 12 different modules in the curriculum.

Note: CE Information: Pharmacists

Projects In Knowledge® is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education.
- They can be used as accredited CEUs for Alberta pharmacists.

"MIB","MAB" & "NIB" News

2010-02-03T11:08:00.001-07:00

*As per Medscape:

February 2, 2009 — Trastuzumab (Herceptin, Roche) has been approved for use in the treatment of HER2-positive gastric cancer by the European Commission. This is the first approval in the world for this label extension for trastuzumab, which is already marketed for use in the treatment of HER2-positive breast cancer.

*As per OncoSTAT:

A new drug has been found to slow the progression of advanced kidney cancer. The drug, pazopanib, was tested in a phase III study among 435 patients...Pazopanib targets multiple pathways involved in cancer cell growth and is an angiogenesis inhibitor. The drug is administered orally. Using supportive evidence from this study, the Food and Drug Administration approved pazopanib in October 2009 for the treatment of advanced renal cell carcinoma. The research results were published in the January 25 online issue of the Journal of Clinical Oncology.

*Also from OncoSTAT:

CORONADO, Calif. (EGMN) - Smokers with metastatic non-small cell lung cancer were able to tolerate much higher doses of the targeted therapy erlotinib than were their nonsmoking counterparts in a small, ongoing phase II clinical trial.

Opioids In The News Part 1

2009-12-10T16:30:00.001-07:00

Opioids In The News Part 1: Does Morphine Stimulate Cancer Growth?

Morphine was first isolated in 1803 by the German pharmacist Friedrich Wilhelm Adam Serturner, who named it 'morphium' after Morpheus, the Greek god of dreams.

Let's take a look at some recent, amazing associations made by the media regarding opioids!

As GeriPal stated:

Over the last week Reuters, ABC news, MSNBC,
BBC News, and more than 75 other outlets reported on how two "two new studies
add to growing evidence that morphine and other opiate-based painkillers may
promote the growth and spread of cancer cells."

Pallimed, on the same topic stated:

The headlines all blared hyperbolic and false
oversimplifications of the impact of the research. Now I am no opioid apologist,
but I do have to recognize that I spend a great deal of my education to
patients, families, staff, and other doctors de-stigmatizing opioids so they may
be used effectively for good pain control while balancing their manageable
risks. So while I nearly always am defending appropriate opioid prescribing, I
also want to recognize if there is potential harm in its use.

GeriPal goes on to state:

All these articles (most stemming from an
initial Reuters report) discussed the recent presentation by a group from the University of Chicago on the mu-opioid antagonist
methylnaltrexone (otherwise known as Relistor or “that new opioid induced
constipation medication”). This work, as presented at a meeting in Boston, revealed that use
methylnaltrexone prevented tumor-cell proliferation and migration in cultured
lung cancer cells.

The most important take home point is that none
of these studies actually looked at opioid use (although many of the news
articles vaguely cite these studies as evidence for morphine’s deleterious
effects on cancer). Even if you want to argue that these were high quality
studies and there is a clear benefit of regional anesthesia, opioids should not
be singled out as the cause.

Their take home message = “There is no clinical evidence that morphine, or any other opioids, cause real harm through stimulating cancer growth.” The evidence will definitely have to be more substantial before we sound the alarms for the general public!

Medication Pearls For Practice: Methadone In Cancer Pain Overview

2009-10-23T16:28:00.003-06:00

METHADONE

History2:

Methadone was developed in Germany (it is synthesized from 1,1-diphenylbutane-2-sulfonic acid and dimethylamino-2-chloropropane) in the late 1930s in anticipation of possible shortages of raw opium during the upcoming war and possible blockades by the enemy.
The drug was given the trade name Dolophine from the Latin dolor meaning pain (Cf. Dipidolor for piritramide, Dolantin for pethidine, and the "-dol" or "-phine" ending in so many trade and chemical names for analgesics of all types in German, English, French, and other languages) and was not named either in honour of or personally by Adolf Hitler, despite what Tom Cruise and the Church Of Scientology will have you believe.

Class1: Opioid analgesic.

Indications1:

Moderate–severe pain (an alternative in cases of intolerance to other strong opioids, morphine poorly-responsive pain)
pain relief in severe renal failure
cough
Also treatment of opioid addiction.

Potential uses1,3:

Neuropathic pain (refractory)
painful mouth ulcers: It has been used effectively as a mouthwash
Restless Leg Syndrome: methadone (5 to 20 mg) have been administered in divided doses, 1 to 2 hours prior to bedtime.3

Pharmacology/Pharmacodynamics1:

Methadone is a synthetic strong opioid with mixed properties. Thus, it is a μ-opioid receptor agonist, possibly a -opioid receptor agonist, an NMDA-receptor-channel blocker, and a presynaptic blocker of serotonin re-uptake.1
Methadone binds to Mu (μ), Kappa (κ), and Delta (δ) opioid receptors, producing analgesia as well as typical opioid side effects.6 (See Notes section at end of document for opioid receptor information.
There is no predictable relationship between methadone plasmalevel and pain relief.
Methadone is a racemic mixture; L-methadone is responsible for most of the analgesic effect, whereas D-methadone is antitussive.
Methadone is a non-acidic and lipophilic drug which is absorbed well from all routes of administration.

Partly because of its lipid-solubility methadone has a high volume of distribution with only about 1% of the drug in the blood.
Methadone accumulates in tissues when given repeatedly, creating an extensive reservoir.

Pharmacokinetics1:

While methadone can be administered by a number of routes: oral, rectal, intravenous, intramuscular, subcutaneous, epidural, and intrathecal – it is most commonly given orally in either tablets or solution.
Oral methadone is readily absorbed and very long-acting.
By comparison, its bioavailability is nearly 3 times that of morphine and its half-life is about 10 times greater than morphine.6

Bio-availability 80% (range 40–100%) PO.
Onset of action <30min PO, 15min IM.
Time to peak plasma concentration 4h PO; 1h IM.
Plasma halflife 8–75h; longer in older patients; acidifying the urine results in a shorter halflife (20h) and raising the pH with sodium bicarbonate a longer halflife (>40h).

*methadone has an extended terminal half-life, up to 190 hours. This half-life does not match the observed duration of analgesia (6-12 hours) after steady state is reached. This long half-life can lead to increased risk for sedation and respiratory depression, especially in the elderly or with rapid dose adjustments.5

Duration of action 4–5h PO and 3–5h IM single dose; 8–12h repeated doses.

Cautions:

In 2006, after a review of deaths and life-threatening adverse events (e.g. respiratory depression, cardiac arrhythmia) associated with unintentional overdose, drug interactions, and prolongation of the QT interval, the FDA in the USA issued a safety warning about the use of methadone. This highlighted the need for:

physicians to be fully aware of the pharmacology of methadone
close monitoring of the patient when starting methadone, particularly when switching from a high dose of another opioid
slow dose titration, and close monitoring of the patient when changing the dose of methadone
warning the patient not to exceed the prescribed dose.

Palliativedrugs.comconsiders that cumulation to a variable extent is bound to occur, particularly in elderly patients, and recommends p.r.n. dose titration to minimize the associated risk

Dosage:

Dose titration is different from morphine because of the wide interindividual variation in the pharmacokinetics of methadone. Several guidelines exist for switching from morphine to methadone.
Because of its long half life, plasma levels of methadone may take up to 10 days to stabilize. There must be a cautious balance between inadequate analgesia due to insufficient dosing and systemic toxicity due to excessive dose during the titration phase.6
For detailed dosing guidelines: http://pain-topics.org/pdf/OralMethadoneDosing.pdf
http://www.palliativedrugs.com/methadone.html#guidelines
From Lexicomp4:

Acute pain (moderate-to-severe):

Opioid-naive: Oral: Initial: 2.5-10 mg every 8-12 hours; more frequent administration may be required during initiation to maintain adequate analgesia. Dosage interval may range from 4-12 hours, since duration of analgesia is relatively short during the first days of therapy, but increases substantially with continued administration.

Chronic pain (opioid-tolerant): Conversion from oral morphine to oral methadone:

Daily oral morphine dose <100 mg: Estimated daily oral methadone dose*: 20% to 30% of total daily morphine dose
Daily oral morphine dose 100-300 mg: Estimated daily oral methadone dose: 10% to 20% of total daily morphine dose
Daily oral morphine dose 300-600 mg: Estimated daily oral methadone dose: 8% to 12% of total daily morphine dose
Daily oral morphine dose 600-1000 mg: Estimated daily oral methadone dose: 5% to 10% of total daily morphine dose.
Daily oral morphine dose >1000 mg: Estimated daily oral methadone dose: <5% of total daily morphine dose.
*in divided doses (commonly q12h, q8h or q6h)

Subsequent switching from methadone to other opioids can be difficult. In one series 12/13 patients experienced increased pain±dysphoria.1

Conversion:

Dose Adjustments1,6:

Renal and hepatic impairment do not affect methadone clearance.
When considering the use of methadone, the difficulty of subsequently switching from methadone to another opioid should also be borne in mind.
Methadone is an alternative strong opioid for patients with chronic renal failure who would be at risk of excessive drowsiness±delirium with morphine because of cumulation of morphine-6-glucuronide.2
Methadone is poorly removed by haemodialysis.30 However, for moribund patients, alfentanil is probably a better choice.
Unlike morphine or meperidine, the metabolism of methadone produces no active or toxic metabolites.
Only a minor fraction of methadone is cleared by the kidneys. Except in end-stage renal failure, it is usually unnecessary to adjust the dose of methadone because of renal disease.
For patients with severe chronic liver disease, the elimination half-life of methadone increases. However, mean plasma concentrations and dose-adjusted mean plasma concentration do not significantly differ from patients with mild or moderate liver disease (Säwe, 1986), and no dose adjustments are typically required for this degree of hepatic failure (Eap, 2002).

Monitor:

sedation
confusion
respiratory depression

Other Side Effects:

lightheadedness, weakness
dry mouth, urinary retention, constipation
sleep apnea (see http://onco-prn.blogspot.com/2009/10/medication-pearls-for-practice.html )

Interactions1:

Methadone is principally metabolized by CYP3A4
CYP2D6, CYP2C9, CYP2C19 and CYP1A2 may play minor roles
MAOIs may prolong and enhance the respiratory depressant effects of methadone.
Carbamazepine, phenobarbital, phenytoin and rifampicin increase the metabolism of methadone
amitriptyline, cimetidine, ciprofloxacin, fluconazole and SSRIs decrease its metabolism
Methadone increases plasma zidovudine concentration.
Efavirenz, lopinavir-ritonavir, nelfinavir, nevirapine and ritonavir (all antiretroviral agents) may reduce plasma methadone concentrations.
Other medications, especially the benzodiazepines, may act synergistically with methadone, increasing the apparent effect of methadone and likelihood for life threatening adverse events.
Certain medications may potentially influence the concentration of methadone indirectly. For example, topiramate is a carbonic anhydrase inhibitor and increases urinary pH alkalinization; Topamax PI 2007). Alkalinization of urine has been shown to increase the half-life of methadone to an average of 42 hours (Baselt 2004). Therefore, when used concomitantly with topiramate, methadone may reach higher plasma levels.
Check: http://pain-topics.org/pdf/OralMethadoneDosing.pdf
Always check reliable drug interaction sources such as Lexicomp and Micromedex

Patient Handout:

Great patient information (print page 4-5 of the document)

http://pain-topics.org/pdf/MethadoneHandout.pdf

Advantages:

Inexpensive
can use in patients with morphine allergy
ok with renal patients
generally less constipating
more effective for neuropathic pain in comparison with other opioids
suited for the management of difficult pain syndromes, particularly where activation of the NMDA recptors has resulted in CNS sensitization - hyperanalgesia and allodynia {Note: Without the d-isomer [racemic d- & l-isomer used in North America ] less impressive results may be observed.}

Interesting…

9th on list of most abused drugs in U.S. see: http://www.drugabuseclinic.org/methadone-abuse.html

Sources/References:

http://www.palliativedrugs.com/methadone.html
http://en.wikipedia.org/wiki/Methadone
Micromedex Online
Lexicomp Online
http://www.eperc.mcw.edu/FastFactPDF/Concept%20075.pdf
http://pain-topics.org/pdf/OralMethadoneDosing.pdf
Pallium Palliative Handbook 2008 www.pallium.ca

inical Effects

*NOTES:

Receptor > Clinical Effects:

Mu (μ): Analgesia, Euphoria, Respiratory depression, Physical dependence, Miosis, Decreased gastric motility
Kappa (κ ): Analgesia, Sedation, Respiratory depression
Delta (δ): Analgesia, Dysphoria, Hallucinations

*Adapted from: Warfield and Fausett, 2002

*(one pt - I.R. – took 90 mg qid + 60 mg q2h for over 700 mg/day – max we’ve seen)

Medications In The Pipeline: Intranasal Fentanyl Spray Versus Oral Transmucosal Fentanyl Citrate

2009-10-08T11:39:00.000-06:00

A comparison of intranasal fentanyl spray with oral transmucosal fentanyl citrate for the treatment of breakthrough cancer pain: an open-label, randomised, crossover trial

Current Medical Research and Opinion, 10/08/09

“Mercadante S et al. – In this open–label, randomised, crossover trial, significantly more patients attained faster ‘meaningful’ pain relief with intranasal fentanyl spray (INFS) than oral transmucosal fentanyl citrate (OTFC), and more patients preferred INFS to OTFC.”

Results:

Among the intention-to-treat population (n ¼ 139):
• median time to onset of ‘meaningful’ pain relief was 11 minutes with INFS versus 16 minutes with OTFC; 65.7% of patients attained faster time to ‘meaningful’ pain-relief onset with INFS ( p50.001). PID was statistically significantly greater for INFS than OTFC from 5 minutes post-dosing.
• Significantly more INFS-treated breakthrough pain episodes achieved clinically important pain relief (_33% and _50% PI reduction) up to 30 minutes post-dosing.
• The proportions of episodes treated with INFS and OTFC achieving a PI reduction of _33% at 5 minutes were 25.3% versus 6.8% ( p50.001), and at 10 minutes were 51.0% versus 23.6% ( p50.001), respectively
• The proportions of episodes treated with INFS and OTFC achieving a _50% PI reduction at 5 minutes were 12.8% versus 2.1% ( p50.001), and at 10 minutes were 36.9% versus 9.7% ( p50.001), respectively.
• Both treatments were well tolerated. In the safety population (n ¼ 139), 56.8% (n ¼ 79) of patients experienced _1 AE during the trial. The only AE that occurred in _5% of patients in either treatment group was nausea. Among those patients who experienced serious AEs (13.7%, n ¼ 19), none were considered to be related to either study medication.
• There was a weak correlation between effective INFS doses and background opioid doses.

Treatment administration:
• Up to four episodes of BTP per day were treated with study medication, intranasal fentanyl spray (INFS), as described below.
• Intranasal fentanyl spray has recently received marketing authorization from the Committee for Medicinal Products for Human Use and will be launched under the trade name Instanyl (Nycomed, Denmark).
• Doses of 50, 100 and 200 mg fentanyl (using INFS solutions of 0.5 mg/ml, 1.0 mg/ml and 2.0 mg/ml, respectively) were taken as a single dose in one nostril. A second INFS dose was permitted 10 minutes after the first, if required, taken in the other nostril. Rescue analgesics were permitted 10 minutes after the second INFS administration if pain relief was still insufficient.
• The comparator medication, oral transmucosal fentanyl citrate (OTFC) (Actiq, Cephalon, USA), was used at six doses: 200, 400, 600, 800, 1200 or 1600 mg in the form of single compressed lozenges with integral oromucosal applicators. One lozenge equalled one dose. OTFC was administered according to manufacturer’s recommendations (15 minutes in the oral cavity between cheek and gum). A second OTFC dose was permitted 30 minutes after the first, if required. Rescue analgesics were allowed, as needed, 45 minutes (if a second OTFC dose was not taken) or 60 minutes (if a second OTFC dose was taken) after start of administration.

Medication Pearls For Practice: Methadone And Sleep Apnea

2009-10-08T11:12:00.000-06:00

"Medication Pearls For Practice" is a new column to be a regular feature here at Onco-PRN. With my role in the Pain and Paliative Care Clinic, expect a lot of pain and symtom control related medication topics. Of course, oncology medications will also be featured.

In this post, key points taken from the Pharmacist's Letter are in bold and italicized.

From: Canadian Pharmacist's Letter 2008; 15(10):241007

Medications that Can Exacerbate Sleep Apnea

“A number of medications, especially CNS depressants such as opioids, benzodiazepines, and muscle relaxants can potentially exacerbate sleep apnea.

*Recently, central sleep apnea has been reported with chronic opioid use and up to 30% of stable methadone maintenance treatment patients have central sleep apnea. In one study (n=50), patients on methadone maintenance therapy were found to have significantly less rapid eye movement (REM) sleep. Central sleep apnea occurred more often in non-REM sleep in methadone maintenance therapy patients. In contrast, respiratory disturbances occur more often during REM sleep with obstructive apnea. These patients had normal resting cardiac function.

*In another study (n=140), the association of methadone, non-methadone opioids, and benzodiazepines with sleep apnea was examined. In the study, patients taking methadone and benzodiazepines concomitantly were found to have a significantly higher rate of central sleep apnea. In the 33% of patients taking methadone, the median daily dosage of morphine equivalents was 187.5 mg/day. The median daily dosage of sustained-release opioids other than methadone in morphine equivalents was 187.5 mg/day. In 36% of patients taking benzodiazepines, the median daily dosage in diazepam equivalents was 15 mg/day. Results of the study showed that 75% of the patients had apnea/hypopnea episodes during sleep. Thirty-nine percent had obstructive sleep apnea, 4% had sleep apnea of an indeterminate type, 24% had central sleep apnea, and 8% had both central and obstructive sleep apnea. Increased dosage of methadone was associated with a higher incidence of central sleep apnea. In contrast, equivalent doses of non-methadone opioids were not found to be associated with increased risk for sleep apnea. The combination of methadone and benzodiazepine also caused significantly more sleep apnea. There are data suggesting that benzodiazepines could possibly inhibit methadone metabolism, prolonging its effect; therefore, this combination should be used cautiously.

In both of these studies presentation of central sleep apnea was atypical compared to those with chronic heart failure (no Cheyne-Stokes respiration, no crescendo-decrescendo pattern of tidal volume).

The cause of central sleep apnea associated with chronic opioid use is likely multifactorial, involving the change of sleep architecture (REM, non-REM, sleep stages, etc) and respiratory depression effect.

Patients with sleep apnea are more likely to experience exacerbation of symptoms when treated with opioids. It is especially important to use caution when titrating opioid analgesic doses in this patient population. The use of patient controlled analgesia (PCA) should be monitored closely in this patient population.”

Feel free to comment below and if you would like to contribute to this featured column topic, "Medication Pearls For Practice", email me at: chrisral@albertahealthservices.ca

Continuing Education And Certificate Programs

2009-10-01T16:00:00.000-06:00

There are some great CEU programs out there. I wanted to highlight just a sampling of these.

Projects In Knowledge have some great individual CEUs, as well as various certificate programs. You can do individual courses or complete them all to obtain the certificate. All are free, but you need to register.

1. The Advanced Certificate Program: Lung Cancer Management
Curriculum I courses present a basic overview of management strategies for optimal personalized care of lung cancer patients. Curriculum II presents more-advanced courses that build on scientific advances and the topics covered in Curriculum I.

2. The Advanced Certificate Program: Breast Cancer Management
Curriculum I courses present a basic overview of management strategies for optimal personalized care of breast cancer patients. Curriculum II presents more advanced courses that build on new scientific developments and the topics covered in Curriculum I.

3. The Certificate Program in Advanced/Metastatic Colorectal Cancer features the very latest information about:
- Colorectal Cancer Diagnosis
- Colorectal Cancer Treatment
- Colorectal Cancer Disease Management

4. The Advanced Certificate Program in Hepatocellular Carcinoma

5. Caring for Oncology Patients: Tips and Tools for Managing Targeted Therapy
"The curriculum offered in this CME/CE program promises to be a timely and continuously updated source of practical information that can be immediately used in treating, monitoring, and managing side effects in cancer patients receiving targeted therapy."

Other CEUs to be had include:
- PainEDU CE Course:
"Interactive case-based learning modules address a range of topics in pain assessment and pain management. Articles and treatment recommendations explore a balanced approach to care with the patients who are prescribed opioids. Update your clinical skills, test your knowledge, and enhance your approach to care!"

- CaPHO's "HOPE" series of CE features topics such as: CINV, Epigenetics, and Molecular Biology of Cancer and Promise of Targeted Therapy.

- Advancing the Safe and Appropriate Use of Oral Chemotherapy Agents: An Interdisciplinary Educational Series for Healthcare Professionals

- http://www.oncologyeducation.ca/ - have to register

Feel free to post other CEUs you find in the comments.

Onco P.R.N. Has Been Linked!

2009-09-15T15:17:00.000-06:00

A great list of various Palliative Medicine blogs...Onco P.R.N. included!
http://www.pallimed.org/2009/09/updated-list-of-hospice-palliative.html