Simpler Induction Speeds Stem Cell Transplants for Multiple Myeloma
Reuters Health Information 2008. © 2008 Reuters Ltd.
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By Will Boggs, MD
NEW YORK (Reuters Health) Feb 21 – A simplified induction regimen of cyclophosphamide plus dexamethasone (Cy-Dex) for patients with newly diagnosed multiple myeloma eases the way to autologous stem cell transplantation (ASCT), researchers report.
In the January 15th issue of Cancer, the multicenter Nordic Myeloma Study Group reports on a trial in which patients received either 2 courses of Cy-Dex or the conventional regimen, consisting of 3 cycles of vincristine, doxorubicin, and dexamethasone (VAD), before high-dose melphalan and ASCT.
There was no significant difference between groups in the proportion of patients who underwent ASCT, mortality rate at 4 months after initiation of therapy, or response rate after ASCT. There was also no difference in median event-free survival (29 months in both groups) or overall survival at 3 years (75% in both groups).
There were, however, significantly more episodes of severe toxicity (grade 3 or higher) after VAD. Further, the authors explain, VAD requires central venous access and often, hospitalization.
The investigators point out that for the Cy-Dex patients, “the total period on therapy before remission/plateau phase was shortened.”
Senior author Dr. Ulf-Henrik Mellqvist, from Sahlgrenska University Hospital in Gothenburg, Sweden, told Reuters Health, “A simplified initial therapy will bring your patients quickly and with less toxicity to high dose therapy without loss of efficacy.”
“Since we in the Nordic Myeloma Study Group believe that the main issue is to bring patients quickly to high dose therapy, we are now focusing on consolidation therapy after high dose,” Dr. Mellqvist added. “Patients are randomized to receive no further therapy, standard, or consolidation with Velcade. Our next high dose study concerning initial therapy will hopefully start next spring and then we will probably test Velcade or an IMID as addition to Cy-Dex.”
“If we use combination therapy, it is important that all ingredients are proved to have an impact, and this is not the case with VAD,” Dr. Mellqvist said.
Cancer 2008;112:129-135.
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Fentanyl Buccal Tablets Safe, Well Tolerated in Cancer Patients
Stephanie Doyle
Medscape Medical News 2008. © 2008 Medscape
February 18, 2008 (Kissimmee, Florida) — The largest and longest study of its kind to date suggests that fentanyl buccal tablets (Fentora, Cephalon) generally are safe and well tolerated in the long-term treatment of breakthrough pain in opioid-tolerant cancer patients.
The findings were presented here at the American Academy of Pain Medicine 24th Annual Meeting, on the heels of an advisory from the US Food and Drug Administration (FDA) alerting health professionals and consumers to reports of life-threatening and sometimes fatal events in patients receiving fentanyl buccal tablets.
The events were associated with improper patient selection (for example, opioid-intolerant patients or patients who did not have cancer), improper dosing, and/or improper product substitution for nonequianalgesic fentanyl-containing products. The warning, issued in September 2007, strongly advised physicians and other healthcare professionals to follow product labeling when prescribing fentanyl tablets to minimize the risk for respiratory depression.
Fentanyl buccal tablets are designed to manage the breakthrough pain associated with chronic pain. The medication is 1 of only a few available to cancer patients for breakthrough pain that has a rapid onset of action, providing relief for pain that comes on suddenly, explained Sharon Weinstein, MD, director of pain management and palliative care at Huntsman Cancer Institute, in Salt Lake City, Utah, and lead investigator of the study.
Dr. Weinstein commented on the FDA advisory to Medscape Neurology & Neurosurgery: “Like all opioids, there are some guidelines that should be followed.” Of deaths related to fentanyl buccal tablets, see said, “Those are of course tragic and for the most part avoidable. When the proper medical oversight is used, this drug can be used safely.”
Breakthrough Pain
In the multicenter study presented here, which was funded by Cephalon, adults taking opioids around the clock for 1 to 4 episodes of breakthrough pain daily were maintained at the successful dose of fentanyl buccal tablets they attained in 1 of 2 previous clinical studies (120 rollover patients) or titrated to a successful new dose of between 100 µg and 800 µg (110 treatment-naive patients; 2 retitrated rollover patients).
Monthly assessments included the number of daily episodes of breakthrough pain, the daily dosage of fentanyl buccal tablets, and the number and type of adverse events.
As a result, 197 patients entered the dose-maintenance phase, including 79 patients who achieved a successful dose of fentanyl buccal tablets during titration.
During the maintenance phase, the median duration of exposure to fentanyl buccal tablets was 122 days (range, 1 – 698; 36 patients [18%] had exposure ≥12 months). The mean (± SE) dose per breakthrough-pain episode was 554.8 ± 18.6 µg. The final dose was the same as the initial successful dose for 136 patients (69%), including patients with dose changes during the study who shifted back to the initial dose.
Three patients discontinued therapy because of a lack of efficacy, and 71 discontinued because of adverse events typical of opioid use and consistent with those observed in short-term studies: during titration, nausea was reported in 27 patients, vomiting in 4, and dizziness in 29. During maintenance, nausea was reported in 62 patients, vomiting in 47, and dizziness in 20.
Serious adverse events included disease progression in 62 patients and pneumonia in 16; all serious adverse events were deemed by investigators to be unrelated to the study medication, except drug-withdrawal syndrome in 1 patient.
“Yes, it works, and yes, it’s safe,” said Todd Sitzman, MD, president of the American Academy of Pain Medicine, who was not involved in the study. “Some of the unfortunate consequences that were associated with this medicine earlier were in patients without tolerance to opioid analgesics.”
Funding was provided by Cephalon Inc. Dr. Weinstein has disclosed no relevant financial relationships.
American Academy of Pain Medicine (AAPM) 24th Annual Meeting: Abstract 119.
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Ask the Experts about Pharmacotherapy
What Is the Maximum Safe Dose of Opioids?
Jeffrey Fudin, BS, PharmD
Medscape Pharmacists. 2008; ©2008 Medscape
Posted 02/21/2008
Question
Is there a chart specifying the maximum safe dosage for oxycodone or other opioid narcotics?
Response from Jeffrey Fudin, BS, PharmD
Adjunct Associate Professor, Albany College of Pharmacy/Union University, Albany, New York; Clinical Pharmacy Specialist, Stratten VA Medical Center, Albany, New York
Charts and tables are readily available from multiple sources that attempt to correlate certain doses of oxycodone to other opioid narcotics. “Maximum safe dose” is patient-specific and dependent on current and previous opioid exposure, as well as on whether the patient is using such medications chronically.
When using single-agent opioid preparations (noncombination products), there is no maximum dose when appropriately titrated. The dose should be slowly escalated until adequate pain relief is seen or side effects preclude further escalation.[1,2] When using combination opioid products containing acetaminophen, aspirin, or ibuprofen (such as Percocet, Percodan, and Combunox), the dose limiting toxicity is generally attributable to acetaminophen, aspirin, or ibuprofen respectively. The maximum amount of acetaminophen should be no more than 4 g/day considering all combined
acetaminophen in 24 hours. Using more than 4 g/day of acetaminophen can cause acute hepatic failure.[3] Aspirin and ibuprofen have their own inherent toxicities, including but not limited to possible gastrointestinal bleeding, kidney dysfunction, hypertension, etc.
When switching between different opioid preparations, a narcotic analgesic conversion calculator or equi-analgesic table may be used as a guide. A conversion calculator is available at Globalrph.com.[4] Equi-analgesic tables are readily available from multiple sources, including NovaPain[5] and the American Pain Society.[6]
However, many equi-analgesic tables provide different information, depending on the source and the manner in which equivalency was calculated. There are drawbacks to these equivalency tables, in part because many do not consider a recommended 15% dose reduction for opioid cross-tolerance.[1,2,7] Some resources actually recommend that a dose reduction of up to 50% is appropriate when switching from one opioid to an alternative.[7] Another common problem with conversion tables is that many are based on single doses rather than steady-state concentrations, so certain data will not apply to chronic opioid users.
Most opioid conversion tables fail to elucidate the potential problems when converting a patient to methadone from another opioid, or from another opioid to methadone. Methadone conversion requires careful consideration because of its long half-life and unusual pharmacokinetic profile compared with most other opioids. In addition, converting methadone to morphine, for example, is not bidirectional.[8,9] Consider that the half-life of methadone is 15-30 hours. When switching from an established dose of methadone to another opioid, we must consider that measurable methadone serum levels will be around for days. Therefore, when placing a patient on a new opioid, even with the discontinuation of methadone, both drugs are now readily available to the mu receptors, increasing the overall risk for opioid toxicity.[10] When newly converting a patient on methadone from another opioid, the equivalent dose conversion changes in a triphasic pattern[10]: For example, the ratio of morphine (or a morphine equivalent) < 90 mg/day to methadone is 4:1; the ratio for morphine 90 mg/day – 300 mg/day is 8:1; and for morphine > 300 mg/day, the ratio is 12:1.[8,10]
Dosing opioids requires the clinician to account for a patient’s opioid history, physical tolerance, consideration of agents in mixed preparations, cross-tolerance, and conversion irregularities. It is always best to use caution when initiating and increasing opioid regimens.
The author wishes to acknowledge Michael S. Fox, student pharmacist, Albany College of Pharmacy, Albany, New York.
Submit a Question on Pharmacotherapy
References
1.National Guideline Clearinghouse. Pain Management Guideline. Available at http://www.guideline.gov/summary/summary.aspx?doc_id=9744&nbr=005217&string=opioid Accessed February 7, 2008.
2.Purdue Pharma LP. Package insert: OxyContin. Available at http://www.pharma.com/PI/Prescription/Oxycontin.pdf Accessed February 7, 2008.
3.Acetaminophen. Drug Products. [database on the Internet] Clinical Pharmacology. Tampa, Florida: Gold Standard. 2007.
4.GlobalRPH. Narcotic Analgesic Converter. Available at http://www.globalrph.com/narcoticonv.htm Accessed February 7, 2008.
5.NovaPain. Opioid Dosing Guidelines. Available at http://www.paindr.com/Perkins%20opioid%20dosing.pdf Accessed February 7, 2008.
6.American Pain Society. Resources for the Clinician. Available at http://www.ampainsoc.org/links/clinician.htm Accessed February 7, 2008.
7.Derby S, Chin J, Portenoy RK. Systemic opioid therapy for chronic cancer pain: practical guidelines for converting drugs and routes of administration. CNS Drugs. 1998;9:99-109.
8.Davis MP, Walsh D. Methadone for relief of cancer pain: a review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Support Care Cancer. 2001;9:73-83. Abstract
9.Wolff K, Sanderson M, Hay AWM, Raistrick D. Methadone concentrations in plasma and their relationship to drug dosage. Clin Chem. 1991;37:205-209. Abstract
10.Ripamonti C, Groff L, Brunelli C, Polastri D, Stavrakis A, De Conno F. Switching from morphine to oral methadone in treating cancer pain: what is the equianalgesic dose ratio? J Clin Oncol. 1998;16:3216-3221.
Jeffrey Fudin, BS, PharmD, Adjunct Associate Professor, Albany College of Pharmacy/Union University, Albany, New York; Clinical Pharmacy Specialist, Stratten VA Medical Center, Albany, New York
Disclosure: Jeffrey Fudin, BS, PharmD, has disclosed that he has served as an advisor or consultant to PriCara, a division of Ortho-McNeil, and Calloway Labs. Dr. Fudin has also disclosed that he has served on the speaker’s bureau for PriCara.
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J Soc Integr Oncol. 2008 Winter;6(1):37-40.
Living proof and the pseudoscience of alternative cancer treatments.
Vickers AJ, Cassileth BR.
Michael Gearin-Tosh was an English professor at Oxford University who was diagnosed with multiple myeloma in 1994. He rejected conventional chemotherapeutic approaches and turned to a variety of alternative cancer treatments, particularly those involving nutritional supplements and dietary change. In 2002, Dr. Gearin-Tosh published a book, Living Proof: A Medical Mutiny, recounting his experiences. The book gained significant public and media attention. One chapter was written by Carmen Wheatley, an advocate of alternative cancer treatments. In distinction to Dr. Gearin-Tosh’s personal story, Dr. Wheatley makes general claims about cancer treatment that are supposedly based on the research literature. This appears to provide scientific validation for a highly unconventional program of cancer care. However, the scientific case made for alternative cancer treatments in Living Proof does not bear serious examination. There are numerous inaccuracies, omissions, and misrepresentations. Many important claims are either entirely unsubstantiated or not supported by the literature cited. In conclusion, a highly publicized book gives the impression that alternative cancer treatments are supported by scientific research. It also suggests that little progress has been made in the conventional treatment of myeloma. This is highly misleading and may lead to cancer patients rejecting effective treatments.
PMID: 18302909 [PubMed - in process]
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: Minim Invasive Neurosurg. 2008 Feb;51(1):26-9.
Minimally invasive anterior approach for kyphoplasty of the first thoracic vertebra in a patient with multiple myeloma.
Gigante N, Pierangeli E.
1Neurological Sciences Department, Neurosurgery, “SS. Annunziata” Hospital, Taranto, Italy.
A vertebral body collapse of the first thoracic vertebra (T1) was diagnosed after radiological investigation in an adult male suffering for severe dorsal pain due to suspected multiple myeloma (MM). According to the principles of minimally invasive neurosurgery and the aesthetic needs of the patient, an open T1 kyphoplasty was performed by means of a right anterior approach through the inferior brow of the neck, generally utilized for the anterior approaches to the cervical spine. The histological examination confirmed the diagnosis of MM and the postoperative radiological investigation showed a good vertebral body (VB) restoration. No gross neurological deficit was noted and the patient was discharged within a few days after a good recovery. Kyphoplasty is a percutaneous technique utilized by means of a posterior approach for VB restoration from T4 to the fifth lumbar vertebra (L5) in patients with vertebral body compression fractures (VCFs) of osteoporotic, traumatic and neoplastic origin. Anatomic obstacles make the performance of posterior kyphoplasty from T1 to T4 very difficult. To the best of our knowledge no anterior approach for T1 kyphoplasty has been reported in the literature. Our experience gives us the opportunity to emphasize this approach and this technique for the minimally invasive treatment of the VCFs of this segment of the spine.
PMID: 18306128 [PubMed - in process]
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J Soc Integr Oncol. 2008 Winter;6(1):37-40.
Living proof and the pseudoscience of alternative cancer treatments.
Vickers AJ, Cassileth BR.
Michael Gearin-Tosh was an English professor at Oxford University who was diagnosed with multiple myeloma in 1994. He rejected conventional chemotherapeutic approaches and turned to a variety of alternative cancer treatments, particularly those involving nutritional supplements and dietary change. In 2002, Dr. Gearin-Tosh published a book, Living Proof: A Medical Mutiny, recounting his experiences. The book gained significant public and media attention. One chapter was written by Carmen Wheatley, an advocate of alternative cancer treatments. In distinction to Dr. Gearin-Tosh’s personal story, Dr. Wheatley makes general claims about cancer treatment that are supposedly based on the research literature. This appears to provide scientific validation for a highly unconventional program of cancer care. However, the scientific case made for alternative cancer treatments in Living Proof does not bear serious examination. There are numerous inaccuracies, omissions, and misrepresentations. Many important claims are either entirely unsubstantiated or not supported by the literature cited. In conclusion, a highly publicized book gives the impression that alternative cancer treatments are supported by scientific research. It also suggests that little progress has been made in the conventional treatment of myeloma. This is highly misleading and may lead to cancer patients rejecting effective treatments.
PMID: 18302909 [PubMed - in process]
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Autologous antitumor activity by NK cells expanded from myeloma patients using GMP-compliant components
Evren Alici1,2, Tolga Sutlu1, Bo Björkstrand1, Mari Gilljam1, Birgitta Stellan1, Hareth Nahi1, Hernan Concha Quezada1,2, Gösta Gahrton1, Hans-Gustaf Ljunggren2, and M. Sirac Dilber1
1 Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm; and 2 Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
Multiple myeloma (MM) is an incurable plasma cell malignancy with poor outcome. The most promising therapeutic options currently available are combinations of transplantation, targeted pharmacotherapy, and immunotherapy. Cell-based immunotherapy after hematopoietic stem-cell transplantation has been attempted, but with limited efficacy. Natural killer (NK) cells are interesting candidates for new means of immunotherapy; however, their potential clinical use in MM has not been extensively studied. Here, we explored the possibility of expanding NK cells from the peripheral blood of 7 newly diagnosed, untreated MM patients, using good manufacturing practice (GMP)–compliant components. After 20 days of culture, the number of NK cells from these patients had expanded on average 1600-fold. Moreover, expanded NK cells showed significant cytotoxicity against primary autologous MM cells, yet retained their tolerance against nonmalignant cells. Based on these findings, we propose that autologous NK cells expanded ex vivo deserve further attention as a possible new treatment modality for MM.
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Hematol Oncol. 2008 Mar 6 [Epub ahead of print]
Review of peripheral neuropathy in plasma cell disorders.
Silberman J, Lonial S.
Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
Peripheral neuropathy (PN) occurs frequently in patients with plasma cell disorders, a heterogeneous group of disorders resulting from the unregulated production of monoclonal proteins. This occurs both due to the dysproteinemia itself and as a consequence of the therapies used to treat the underlying plasma cell disorder. This comprehensive review of PN associated with plasma cell disorders will address both disease and therapy related PN, its pathogenesis and management with particular attention to multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), Waldenstrom’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) and amyloidosis. An understanding of this topic is critical for health care providers treating patients with plasma cell disorders due to the high frequency with which it occurs, the implications it has on selecting therapies for the underlying disorder and to best guide management of the neuropathy itself. Copyright (c) 2008 John Wiley & Sons, Ltd.
PMID: 18324611 [PubMed - as supplied by publisher]
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Semin Musculoskelet Radiol. 2007 Dec;11(4):312-21.
PET/CT in Malignant Bone Disease.
Even-Sapir E.
Department of Nuclear Medicine, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
The most commonly used positron emission tomography (PET) tracer in clinical practice, fluorine-18 fluorodeoxyglucose ( (18)F-FDG) is a glucose analogue that directly gains entry in excess into tumor cells. It is therefore sensitive for the detection of early bone marrow involvement prior to any identifiable bone changes. The introduction of (18)F-FDG-PET in the imaging algorithms of various malignant diseases often obviates the need to perform a separate assessment of malignant bone involvement with conventional bone scintigraphy. After therapy, disappearance of (18)F-FDG accumulation indicates success even when the bone remains morphologically abnormal. Novel hybrid systems composed of PET and computed tomography (CT) allow for acquisition of both modalities in the same clinical setting and the generation of fused functional-anatomical images. This technique has been found to improve the diagnostic accuracy of PET in detecting malignant bone involvement. This article discusses the role of PET/CT, primarily (18)F-FDG PET/CT, in the assessment of malignant bone involvement in patients with primary bone sarcomas, common solid malignancies, lymphoma, and multiple myeloma.
PMID: 18324596 [PubMed - in process]
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