27 augustus 2014: Wie de bijwerkingen van chemo bij specifiek darmkanker tegen wilt gaan kan wellicht deze lijst eens bekijken:
4 juli 2005: Bron: The Oncologist
Vaak reageren kankerpatiënten met ernstige bijwerkingen voor chemokuren als oxaliplatin en andere zogeheten platina chemo's en zijn daarvoor hooggevoelig. In het Umass Medisch Centrum ontwikkelden de artsen een protocol van toediening van oxaliplatin dat bij een vrouw als case studie werd uitgeprobeerd. De vrouw bleek hypergevoelig voor oxaliplatin maar met het nieuwste protocol bleken de bijwerkingen veel en veel minder en kon de vrouw de kuur gewoon afmaken. Hier alleen vertaalt het protocol omdat elders wel te lezen is wat de voordelen en nadelen van oxaliplatin zijn bij uitgezaaide darmkanker. Het Engelstalige artikel plaatsen we wel volledig en ongewijzigd.
Een OXALIPLATIN protocol om hypergevoeligheid hiervoor tegen te gaan
Het protocol om de hypergevoeligheid voor oxaliplatin te verminderen en welke succesvol werd uitgeprobeerd in een casestudie beschrijft de volgende stappen: vier opeenvolgende mengsels (1:10,000, 1:1,000, 1:100, en 1:10) van de totale dosis oxaliplatin worden elk geprepareerd in 100 ml dextrose en 5% in water (D5W) (Table 1). Startend met de laagste dosis (zak 1), elk mengsel wordt over 60 minuten ingebracht via een infuus met zorgvuldige monitoring van belangrijke optredende verschijnselen. Een laatste zak (zak 5), bevat 90% van de totale dosis in 500 ml D5W, en wordt dan over twee uur intraveneus toegediend. (Table 1).
Hier het volledige originele artikel met op het eind de beschrijving van het protocol:
Hypersensitivity Reactions to Oxaliplatin and the Application of a Desensitization Protocol David Gammona, Pankaj Bhargavab, Michael J. McCormickc a Department of Pharmacy, b Division of Hematology/Oncology, and c Division of Pulmonary, Allergy and Critical Care Medicine, UMass Memorial Medical Center, Worcester, Massachusetts, USA Correspondence: David C. Gammon, BS.Ph., UMass Memorial Medical Center, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA. Telephone: 508-856-2915; Fax: 508-856-4141; e-mail: firstname.lastname@example.org
Oxaliplatin (Eloxatin®; Sanofi-Synthelabo Inc.; New York, NY) is a third-generation platinum agent indicated for the treatment of colorectal cancer. Severe hypersensitivity reactions to oxaliplatin rarely occur; however, they do represent a threat to the small number of patients that are occasionally affected. We developed a desensitization protocol and successfully applied it to a patient with severe, grade 3, hypersensitivity to oxaliplatin. For patients who have mild sensitivity to oxaliplatin, slowing the run rate down and giving an antihistamine and/or a steroid usually suffice. Desensitization will help to provide the small number of patients who experience severe hypersensitivity reactions with the ability to further receive an effective therapy for their colorectal cancer. The desensitization protocol is described in detail.
Oxaliplatin (Eloxatin®; Sanofi-Synthelabo Inc.; New York, NY) is a third-generation platinum agent indicated for the second-line treatment of colorectal cancer in combination with 5-fluorouracil (5-FU) and leucovorin (LV). Results from the pivotal phase III clinical study, reported in 2002, showed that patients who received oxaliplatin plus 5-FU/LV, compared with those treated with 5-FU/LV alone, had a higher response rate, longer time to progression (5.6 months versus 2.6 months, respectively; p < 0.0001), and higher rate of relief from tumor-related symptoms (28% versus 15%, respectively; p < 0.002) . These results led to U.S. Food and Drug Administration (FDA) approval of oxaliplatin for metastatic colorectal cancer. Oxaliplatin was generally well tolerated but resulted in higher rates of grade 3 and 4 neuropathies; toxicities did not result in a higher rate of treatment discontinuation [1, 2].
The oxaliplatin plus 5-FU/LV combination was recently shown to have clinical activity in the first-line treatment of advanced colorectal cancer. In an intergroup study that enrolled patients with stage IV colorectal cancer, patients who received oxaliplatin plus 5-FU/LV were compared with those receiving irinotecan (Campostar®; Pfizer Pharmaceuticals; New York, NY) plus 5-FU/LV; the former experienced a significantly longer median time to progression (7 months versus 6.9 months, respectively; p = 0.0014), greater response rate (45% versus 31%, respectively; p = 0.02), and longer overall survival (19.5 months versus 15 months, respectively; p = 0.002) . In addition, fewer grade 3/4 toxicities were experienced in patients treated with oxaliplatin plus 5-FU/LV than in patients in the other treatment arm, with the exception of late paresthesias and neutropenia, which occurred with a higher incidence in oxaliplatin plus 5-FU/LV-treated patients. Results of that trial led to the recent approval of oxaliplatin in combination with 5-FU/LV for the treatment of first-line colorectal cancer by the FDA.
Oxaliplatin plus 5-FU/LV is also the first chemotherapeutic combination to demonstrate superiority over 5-FU/LV in adjuvant colorectal cancer. In a large phase III study that included patients with completely resected stage II/III colorectal cancer, patients who received oxaliplatin plus 5-FU/LV experienced a significantly greater 3-year disease-free survival rate than patients who received 5-FU/LV alone (78% versus 73%, respectively; p < 0.01) . Furthermore, the risk of recurrence was 23% lower in patients treated with oxaliplatin plus 5-FU/LV. Overall, oxaliplatin plus 5-FU/LV was shown to be safe, although more patients in that treatment arm experienced neutropenia (<2% febrile neutropenia). More patients in the oxaliplatin plus 5-FU/LV treatment arm also experienced grade 3 paresthesias; however, the incidence was reduced to 1% at a 1-year follow-up.
Despite the large number of chemotherapeutic agents used to treat cancer, hypersensitivity reactions tend to occur only in association with the use of a limited number of agents in a small number of patients. These agents include the taxanes paclitaxel (Taxol®; Bristol-Myers Squibb; Princeton, NJ) and docetaxel (Taxotere®; Aventis Pharmaceuticals Inc.; Bridgewater, NJ); the platinum-containing compounds cisplatin (Platinol®; Bristol-Myers Squibb), carboplatin (Paraplatin®; Bristol-Myers Squibb), and oxaliplatin; the epipodophyllotoxins teniposide (Vumon®; Bristol-Myers Squibb) and etoposide (Etopophos®, VePesid®; Bristol-Myers Squibb); asparaginase (Elspar®; Merck & Company, Inc.; West Point, PA); procarbazine (Matulane®; Sigma Tau Pharmaceuticals, Inc.; Gaithersburg, MD); and, occasionally, doxorubicin (Adriamycin®; Bedford Laboratories; Bedford, OH; Rubex®; Bristol-Meyers Squibb) and 6-mercaptopurine. A hypersensitivity reaction can occur either during (acute reaction) or following (delayed reaction) administration of a chemotherapeutic agent. Symptoms may include, but are not limited to, flushing, alterations in heart rate and blood pressure, dyspnea/bronchospasm, back pain, chest discomfort, fever, pruritis, erythema, nausea, and rash [5, 6]. The precise mechanisms responsible for hypersensitivity reactions are currently unknown. Some reactions may be caused by the nonimmune-mediated release of histamine or cytokines, as many patients can subsequently tolerate reexposure after premedication with antihistamines and steroids . Multiple factors, including the route and rate of administration, previous exposure, form of the drug, whether it is given as a single agent or in combination, concomitant medications, concurrent autoimmune disease, and possibly disease state, can affect the hypersensitivity reaction rate to a given drug .
The platinum-containing agents cisplatin and carboplatin are most commonly used to treat gynecologic malignancies and adenocarcinoma of the lung. Platinum-containing agents are associated with hypersensitivity reactions, which have been reported to occur in 10% to 27% of patients treated with cisplatin or carboplatin . The incidence of hypersensitivity reactions increases with multiple courses of the drugs and generally occurs after four to six courses [6, 7]. Symptoms of hypersensitivity reactions to platinum-containing agents, which usually occur within minutes of administration in patients with prior exposure, include facial edema, bronchospasm, hypotension, tachycardia, pruritis, and erythema . In contrast to what occurs with taxanes, premedication with steroids and antihistamines may not prevent hypersensitivity reactions to platinum-containing agents . Hypersensitivity reactions to platinum-containing compounds are thought to be mediated by IgE and/or the direct release of vasoactive substances . The results of intradermal skin tests with carboplatin have been shown to be fairly reliable predictors of hypersensitivity reactions to the drug .
Only a small number of patients experienced hypersensitive reactions to oxaliplatin in clinical trials, and less than 1% experienced grade 3/4 reactions [7, 9, 10]. These hypersensitivity reactions were experienced after a median of seven (range 2–25) courses of oxaliplatin [7, 11, 12]. Most reactions were acute, occurring either during or shortly after infusion. Symptoms of hypersensitivity reactions to oxaliplatin in patients with colorectal cancer are similar in nature and severity to those reported with other platinum-containing agents and include facial flushing, erythema, pruritis, fever, tachycardia, dyspnea, tongue swelling, rash/hives, headache, chills, weakness, vomiting, burning sensations, dizziness, and edema [7, 10–12]. Symptoms are generally mild; severe hypersensitivity reactions to oxaliplatin are rare [7, 11, 12]. A recent trial evaluating oxaliplatin for the second-line treatment of colorectal cancer reported a grade 3 hypersensitivity reaction necessitating treatment discontinuation in only one patient . The type of hypersensitivity reaction was not further specified. The most recent trial investigating oxaliplatin for the first-line treatment of colorectal cancer did not report any hypersensitivity reactions . When hypersensitivity reactions to oxaliplatin do occur, symptoms generally subside upon discontinuation of treatment and administration of steroids and antihistamines.
Mild hypersensitivity reactions to oxaliplatin and other platinum compounds can be ameliorated in some patients through the use of steroids and antihistamines before administration of subsequent cycles . However, premedication cannot prevent all hypersensitivity reactions, and mild reactions may escalate to severe reactions even when steroids and antihistamines are administered prior to oxaliplatin infusion. There are case reports in the literature describing patients who experienced hypersensitivity reactions during initial therapy with oxaliplatin and experienced similar and sometimes more severe symptoms during subsequent cycles despite receiving prophylactic steroids and antihistamines [7, 13]. In all cases of severe hypersensitivity to oxaliplatin, treatment had to be discontinued. In such cases, initiation of a desensitization protocol may allow the patient to continue treatment with oxaliplatin.
Desensitization protocols have been successfully used to manage hypersensitivity reactions to paclitaxel and platinum-containing compounds [5, 8]. Based on a carboplatin desensitization protocol developed by Windom et al. , Goldberg et al.  reported the success of a desensitization regimen in two patients that involved administration of increasing concentrations of carboplatin over a prolonged period of time. The dose of carboplatin was slowly titrated up so that the patients subsequently received infusions of 1/1,000, 1/100, and 1/10 of the total carboplatin dose; each infusion lasted from 90 minutes to 15 hours. The final infusion contained 90% of the total drug dose and was administered for 11–50 hours. In both patients, carboplatin intradermal skin tests, which were positive prior to the desensitization regimen, were negative at the same concentration of carboplatin following the regimen, indicating that desensitization had indeed occurred.
While some investigators have concluded that patients who develop severe hypersensitivity reactions to oxaliplatin are unlikely to tolerate further therapy , others have reported the successful implementation of oxaliplatin desensitization protocols based on the Goldberg et al. protocol [8, 11, 12, 15]. The specific details of the protocol used by Meyer et al. are not available. The patient reported by Qureshi et al. was premedicated with dexamethasone (Decadron®; Merck and Company, Inc.), famotidine (Pepcid®; Merck and Company, Inc.), and diphenhydramine (Benadryl®; Pfizer Pharmaceuticals) and was then given consecutive 90-minute infusions of 1/1,000, 1/100, and 1/10 of the total oxaliplatin dose. The final dose (90% of the total oxaliplatin dose) was infused over 6 hours. Subsequent cycles were administered over 6 hours with similar premedications and were well tolerated.
AN OXALIPLATIN DESENSITIZATION PROTOCOL
The desensitization protocol that was successfully used in the case study described below involves the following steps. Four serial dilutions (1:10,000, 1:1,000, 1:100, and 1:10) of the total oxaliplatin dose are each prepared in 100 ml dextrose 5% in water (D5W) (Table 1). Starting with the lowest dose (bag 1), each dilution is infused over 60 minutes with careful monitoring of vital signs. A final infusion bag (bag 5), containing 90% of the total dose in 500 ml D5W, is then infused over 2 hours (Table 1).
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