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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