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

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

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Pancreatic Cancer -- Beyond Standard Treatment

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

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/

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Monoclonal Antibody Nomenclature

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

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

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]

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Vitamin D role in preventing aromatase inhibitor-induced arthralgia

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."

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Smoking marijuana relieves some pain: Study

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."

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Pain & Symptom Management Updates

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

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Pain Updates: Butrans - Buprenorphine patch

• 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.
  
  
  
  
  
   

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

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).

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

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.

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Site Updates: DrugCoverage.ca Plus More Updates

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."

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

{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.

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Adverse Effects of Androgen Deprivation Therapy in Men with Prostate Cancer

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.

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Tamoxifen: To Crush Or Not To Crush?

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.

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

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Oxaliplatin-Induced Peripheral Sensory Neuropathy In Diabetes Patients

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.

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

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)

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ProMED-mail - the Program for Monitoring Emerging Infectious Diseases

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

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Fentanyl Citrate Sublingual Dosing And Stability

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.

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Drug Interaction: Cyclophosphamide and Allopurinol

*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.

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Targeted Therapy Online Learning

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.

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

*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.

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