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HSCT AmB Melphalan

Description
Chemotherapy Protocol HAEMATOLOGY – HSCT AUTOGRAFT AMBULATORY MELPHALAN (200mg/m2) Multiple Myeloma This regimen will only be available to prescribe at units
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/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Transplant/HSCT-AmB-Melphalan.pdf

Carboplatin-Pembrolizumab-Pemetrexed

Description
Chemotherapy Protocol LUNG CANCER – NON-SMALL CELL (NSCLC) CARBOPLATIN (AUC 5)-PEMBROLIZUMAB-PEMETREXED Regimen • NSCLC
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/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Lung-cancer-non-small-cellNSCLC/Carboplatin-Pembrolizumab-Pemetrexed.pdf

Carboplatin (AUC4)-Gemcitabine (day 1, 8) Retreat

Description
Chemotherapy Protocol GYNAECOLOGICAL CANCER CARBOPLATIN (AUC4)-GEMCITABINE (day 1, 8) Retreat Regimen • Ovary-Carbo
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/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Ovarian-cancer/CarboplatinAUC4-Gemcitabineday18Retreat.pdf

CarboplatinAUC4-Gemcitabine (day 1,8)

Description
Chemotherapy Protocol GYNAECOLOGICAL CANCER CARBOPLATIN (AUC4)-GEMCITABINE (day 1, 8) Regimen  Ovary-Carboplatin (
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/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Ovarian-cancer/CarboplatinAUC4-Gemcitabine-day18.pdf

Carboplatin (AUC4)-Gemcitabine (day 1) Retreat

Description
Chemotherapy Protocol GYNAECOLOGICAL CANCER CARBOPLATIN (AUC4)-GEMCITABINE (day 1) Retreat Regimen • Ovary-Carbopla
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/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Ovarian-cancer/CarboplatinAUC4-Gemcitabineday1Retreat.pdf

Sotorasib

Description
A Chemotherapy Protocol for Sotorasib, associated with Lung Cancer.
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/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Lung-cancer-non-small-cellNSCLC/Sotorasib.pdf

Cisplatin-Pembrolizumab-Pemetrexed

Description
Chemotherapy Protocol LUNG CANCER – NON-SMALL CELL (NSCLC) CISPLATIN-PEMBROLIZUMAB-PEMETREXED Regimen • NSCLC – Cisplatin-Pembrolizumab-Pemetrexed Indication • Pembrolizumab in combination with pemetrexed-based combination chemotherapy for treating untreated PD- L1-positive or negative locally advanced or metastatic non-squamous non-small-cell lung cancer where all the following criteria are met: - the patient has a histologically or cytologically-confirmed diagnosis of stage IIIB or IV non-squamous non-small cell lung cancer. - EGFR and ALK mutation negative disease - PD-L1 testing with an approved and validated test to determine the Tumour Proportion Score (TPS) has been attempted prior to treatment starting - the patient has not received previous systemic therapy for advanced / metastatic disease. Completion of treatment with chemotherapy and/or radiotherapy as part of neoadjuvant / adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of recurrent locally advanced or metastatic disease - the patient will be treated with a maximum of 4 cycles of pembrolizumab plus pemetrexed-based combination chemotherapy with either cisplatin or carboplatin - on completion of 4 cycles of pembrolizumab plus pemetrexed-based chemotherapy in combination with cisplatin or carboplatin and in the absence of disease progression, treatment with pembrolizumab in combination with ‘maintenance’ pemetrexed will continue for a total treatment duration of 2 years (or a maximum of 35 3-weekly cycles) or until disease progression or unacceptable toxicity or withdrawal of patient consent, whichever occurs first. - the patient has no symptomatically active brain metastases or leptomeningeal metastases. - the patient has not received prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody. - a formal medical review as to whether treatment with pembrolizumab in combination with pemetrexed plus cisplatin/carboplatin should continue or not will be scheduled to occur at least by the end of the first 6 weeks of treatment - treatment breaks of up to 12 weeks beyond the expected 3-weekly cycle length are allowed but solely to allow any immune toxicities to settle. - the patient has a performance status (PS) of 0 or 1 and is potentially fit for pemetrexed- and platinum-based chemotherapy in combination with pembrolizumab. Version 1 (March 2019) Page 1 of 15 NSCLC – Cisplatin-Pembrolizumab-Pemetrexed Toxicity Drug Cisplatin Pembrolizumab Pemetrexed Adverse Effect Neuropathy, nephrotoxicity, ototoxicity Pneumonitis, nephritis, colitis, thyroid disorders, hypophysitis, infusion related reactions, hepatitis Diarrhoea, skin reactions, neuropathy The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Disease • A baseline chest x-ray should be performed before starting treatment and up to date (ideally within 1 month) cross section imaging should also be performed Regimen • FBC, LFTs and U&Es before each cycle • EGFR and ALK mutation status prior to starting treatment (cycle one) • PD-L1 status prior to starting treatment (cycle one) • Thyroid function tests prior to staring treatment and then before each administration (cycle) or when clinically indicated. • A chest x-ray should be performed before each cycle • Consider formal audiology test if relevant Dose Modifications The dose modifications listed are for haematological, liver and renal function only. Dose adjustments may be necessary for other toxicities as well. In principle all dose reductions with chemotherapy due to adverse drug reactions should not be re-escalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Pembrolizumab belongs to the immunotherapy class of cancer treatments. Autoimmune toxicities are most frequently noted and can be life threatening. If autoimmune toxicities occur delaying treatment should be considered while investigations or treatments are organised. Some, but not all, toxicities mandate cessation of treatment. Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be interrupted or discontinued due to toxicity. Please seek guidance from relevant site specific specialist teams or oncologists / haematologists with experience of prescribing these agents. Clinicians should be aware that the current funding approval for pembrolizumab precludes further treatment after an interruption of 12 weeks or longer; this situation may change. Version 1 (March 2019) Page 2 of 15 NSCLC – Cisplatin-Pembrolizumab-Pemetrexed Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. The following is a general guide only. Doses should be adjusted according to the table below; Cisplatin Pemetrexed 0 75mg/m2 500mg/m2 Dose Level -1 56mg/m2 375mg/m2 -2 38mg/m2 250mg/m2 Haematology Prior to prescribing cycle one the following treatment criteria must be met; Criteria Neutrophil Platelets Eligible Level Greater than or equal to 1.5x109/L (unless due to bone marrow impairment) Greater than or equal to 100x109/L (unless due to bone marrow impairment Consider blood transfusion or erythropoietin if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL (80g/L). There is little need to adjust the dose of pembrolizumab for haematological toxicity. The following recommendations apply to carboplatin and pemetrexed only. Dose modifications must be based on the maximum toxicity experienced during a cycle. Toxicity needs to resolve to NCI-CTC grade 1 or below or baseline prior to resuming the next cycle of treatment. For individuals requiring a dose modification, each new cycle may be delayed if the scheduled off-drug periods are not adequate to allow for recovery. Reduction of one chemotherapy agent and not the other agent is appropriate if the toxicity is clearly related to one of the treatments. If the toxicity is related to the combination of both chemotherapy agents, both drugs should be reduced according to recommended dose modifications. Dose Modifications for Haematological Toxicity Platelets (109/L) Neutrophils (109/L) 50 or above and 0.5 and below 49 and below without and Any bleeding 49 and below with and any NCI CTC grade 2 bleeding any and 0.99 and below with fever Dose Level Cisplatin Pemetrexed -1 -1 -1 -1 -2 -2 -1 -1 Version 1 (March 2019) Page 3 of 15 NSCLC – Cisplatin-Pembrolizumab-Pemetrexed Hepatic Impairment Drug Cisplatin Pembrolizumab Pemetrexed Recommendation No dose reduction necessary No dose reduction is necessary in those with mild hepatic impairment (see below for hepatic adverse effects) Clinical decision Renal Impairment Drug Cisplatin Pembrolizumab Pemetrexed Dose (% of original dose) more than 60 100 45-59 75 less than 45 Consider carboplatin No dose adjustment is required for mild to moderate renal impairment (see below for renal adverse effects) If the creatinine clearance falls below 45ml/min consider dose reduction Cisplatin and Pemetrexed Nausea and Vomiting Diarrhoea Mucositis Neurotoxicity Transaminase Other NCI CTC Grade 3 and above 3 and above 3 and above 2 3 and above 3 4 3 and above Cisplatin Pemetrexed Dose Level 0 0 -1 0 -2 Discontinue -1 Discontinue -1 -1 -2 0 -1 -1 Discontinue -1 Pembrolizumab Hepatic Impairment For a hepatitis associated with an AST / ALT of 3-5xULN and / or a total bilirubin of 1.5-3xULN then withhold treatment and administer corticosteroids. Upon improvement to NCI-CTC grade 1 hepatic injury begin to taper the corticosteroid over a period of one month. The pembrolizumab may be re-started when the liver function remains at NCI-CTC grade 1 following corticosteroid taper. The pembrolizumab should be permanently discontinued when the hepatic injury does not improve to at least NCI-CTC grade 1 within 12 weeks of the last dose, the Version 1 (March 2019) Page 4 of 15 NSCLC – Cisplatin-Pembrolizumab-Pemetrexed corticosteroid dose cannot be reduced to 10mg or less of prednisolone or equivalent per day within 12 weeks or any NCI-CTC grade 3 or above reaction. Pembrolizumab should be permanently discontinued in the first instance when hepatitis develops that is associated with an AST / ALT equal to or greater than 5xULN, an increase in AST / ALT of 50% or greater relative to baseline and that lasts at least one week in patients with liver metastasis who begin treatment with moderate (grade 2) elevation of AST / ALT or where the bilirubin is greater than 3xULN. Renal Impairment Where a NCI-CTC grade 2 nephritis develops withhold treatment and administer corticosteroids. Upon improvement to NCI-CTC grade 1 or less, initiate corticosteroid taper over at least one month. Pembrolizumab may be resumed when the reaction remains at NCI-CTC grade 1 or below following tapering of the corticosteroid. The pembrolizumab should be permanently discontinued when the nephritis does not improve to at least NCI-CTC grade 1 within 12 weeks of the last dose, the corticosteroid dose cannot be reduced to 10mg or less of prednisolone or equivalent per day within 12 weeks or any NCI-CTC grade 3 or above reaction. Pembrolizumab should be permanently discontinued for any NCI-CTC grade 3 or above nephritis. Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. Pembrolizumab is associated with inflammatory adverse reactions resulting from increased or excessive immune activity, likely to be related to its pharmacology. Immune-related adverse reactions, which can be severe or life-threatening, may involve the gastrointestinal, liver, skin, nervous, endocrine, or other organ systems. Most occur during treatment, however, onset months after the last dose has been reported. Unless an alternate aetiology has been identified, diarrhoea, increased stool frequency, bloody stool, LFT elevations, rash and endocrinopathy must be considered inflammatory and pembrolizumab-related. Early diagnosis and appropriate management are essential to minimise life threatening complications. Pembrolizumab should be permanently discontinued for any NCI-CTC grade 3 or 4 pneumonitis, nephritis, infusion related reaction or a NCI-CTC grade 4 adverse reaction. Endocrine Pembrolizumab can cause inflammation of the endocrine system organs, specifically hypophysitis, hypopituitarism, adrenal insufficiency, and hypothyroidism. This may present with nonspecific symptoms resembling other causes such as brain metastasis or underlying disease. Version 1 (March 2019) Page 5 of 15 NSCLC – Cisplatin-Pembrolizumab-Pemetrexed Isolated hypothyroidism can be managed with replacement therapy, without treatment interruption or corticosteroids. If there are any signs of adrenal crisis such as severe dehydration, hypotension, or shock, immediate administration of intravenous corticosteroids with mineralocorticoid activity is recommended, the patient must be evaluated for presence of sepsis or infections. If there are signs of adrenal insufficiency but the patient is not in crisis, further investigations should be considered including laboratory and imaging assessment. Evaluation of laboratory results to assess endocrine function may be performed before corticosteroid therapy is initiated. If pituitary imaging or laboratory tests of endocrine function are abnormal, a short course of high-dose corticosteroid therapy is recommended to treat the gland inflammation. The scheduled dose of pembrolizumab should be omitted. It is currently unknown if the corticosteroid treatment reverses the gland dysfunction. Appropriate hormone replacement should also be initiated. Long-term hormone replacement therapy may be necessary. Once symptoms or laboratory abnormalities are controlled and overall patient improvement is evident, treatment with pembrolizumab may be resumed and initiation of corticosteroid taper should be based on clinical judgment. Hypophysitis can present as a diffuse, heterogenous enlargement of the pituitary on a brain MRI but can be completely normal. When hypophysitis with pituitary dysfunction is suspected, blood tests including thyroid stimulating hormone (TSH), free T4, adrenocorticotropic stimulating hormone, cortisol, leutinizing hormone, and follicle-stimulating hormone should be obtained in women, and the first four plus testosterone in men. Typically the anterior pituitary axis is involved, affecting thyroid, gonadal, and adrenal function, but isolated axis dysfunction can be seen. Hypophysitis will cause low free T4 as well as TSH. Hypophysitis with clinically significant adrenal insufficiency and hypotension, dehydration, and electrolyte abnormalities such as hyponatremia and hyperkalemia constitutes adrenal crisis. Hospitalization and intravenous steroids with mineralocorticoid activity, such as methylprednisolone, should be initiated while waiting for laboratory results. Infection and sepsis should be ruled out with appropriate cultures and imaging. Prednisolone 1 mg/kg by mouth should be administered if patients are clinically stable. Steroids can usually be tapered over 30 days to achieve physiologic replacement levels. Thyroid hormone and/or testosterone replacement therapy may not be permanent, as the need for those hormones may wane over months in some patients. Cortisone replacement may also not be permanent in a modest portion of patients. Eye Uveitis is associated with pembrolizumab. All attempts should be made to rule out other causes such as metastatic disease, infection or other ocular disease (e.g. glaucoma or cataracts). For NCI-CTC grade 1-2 events evaluation by an ophthalmologist is recommended. Treatment with topical corticosteroids eye drops and iridocyclitics can be tried. Discontinue pembrolizumab if symptoms persist despite treatment with topical immunosuppressive therapy. Discontinue pembrolizumab for NCI-CTC grade 3 or above ocular symptoms and consider treatment with systemic corticosteroids. When symptoms improve to NCI-CTC grade 1 taper the corticosteroids over at least four weeks. Version 1 (March 2019) Page 6 of 15 NSCLC – Cisplatin-Pembrolizumab-Pemetrexed Gastrointestinal Gastro-intestinal immune reactions include diarrhoea, increased frequency of bowel movements, abdominal pain or haematochezia, with or without fever. Diarrhoea or colitis occurring after initiation of pembrolizumab must be promptly evaluated to exclude infectious or other alternate causes. Immune-related colitis is often associated with evidence of mucosal inflammation, with or without ulcerations and lymphocytic and neutrophilic infiltration. NCI-CTC grade 1 diarrhoea or suspected mild colitis may continue on pembrolizumab. Symptomatic treatment and close monitoring are advised. For a NCI-CTC grade 2 – 3 colitis withhold the pembrolizumab and administer corticosteroids. Upon improvement to NCI-CTC grade 1 colitis begin to taper the corticosteroid over a period of one month. The pembrolizumab may be re-started when the colitis remains at NCI-CTC grade 1 following corticosteroid taper. The pembrolizumab should be permanently discontinued when the colitis does not improve to at least NCI-CTC grade 1 within 12 weeks of the last dose, the corticosteroid dose cannot be reduced to 10mg or less of prednisolone or equivalent per day within 12 weeks or any NCI-CTC grade 3 or above reaction. Lung Interstitial lung disease including pneumonitis and acute interstitial pneumonitis are associated with pembrolizumab. For NCI-CTC grade 1 events (asymptomatic with radiographic findings only) then the pembrolizumab may be continued with close monitoring. Radiologic findings should be followed on serial imaging studies and consideration given to pulmonary consultation and/or bronchoscopy, if clinically indicated. For NCI-CTC grade 2 events withhold the pembrolizumab and consider pulmonary consultation with bronchoscopy and biopsy/bronchoalveolar lavage (BAL) and pulmonary function tests. Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent. When symptoms improve to NCI-CTC grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Treatment with pembrolizumab may be resumed if the event improves to NCI-CTC grade 0 or 1 within 12 weeks and corticosteroids have been reduced to the equivalent of prednisolone 10 mg oral daily or less. Repeat chest imaging monthly as clinically indicated. Should a second episode of pneumonitis occur then discontinue pembrolizumab. For NCI-CTC grade 3 or 4 events discontinue pembrolizumab and consider pulmonary function tests and seek advice from a lung specialist. A bronchoscopy with biopsy and / Or BAL should be considered. Treatment involves corticosteroid therapy such as intravenous methylprednisolone 125mg. When symptoms improve to NCI-CTC grade 1 or less, a high dose oral steroid such as prednisone 1 to 2 mg/kg once per day can be considered. A reducing schedule should be considered over a period of at least four weeks. If intravenous corticosteroids followed by high dose oral corticosteroids do not reduce initial symptoms within 48 to 72 hours, consider treatment with infliximab at 5 mg/kg once every 2 weeks. Discontinue infliximab upon symptom relief and initiate a prolonged steroid taper over 45 to 60 days. If symptoms worsen during steroid reduction, initiate a re-tapering of steroids starting at a higher Version 1 (March 2019) Page 7 of 15 NSCLC – Cisplatin-Pembrolizumab-Pemetrexed dose followed by a more prolonged taper and consider administration of infliximab. The decision to start infliximab should be made by a consultant. Skin Serious skin reactions include dermatitis exfoliative, erythema multiforme, StevensJohnson Syndrome and toxic epidermal necrolysis. Pembrolizumab can also be associated with pruritus, rash, (generalized and maculo-papular) and vitiligo. All attempts should be made to rule out other causes such as metastatic disease, infection or allergic dermatitis. For NCI-CTC grade 1-2 skin reactions try symptomatic treatments such as topical corticosteroids or urea-containing creams in combination with oral antipruritics. Pembrolizumab can continue. For NCI-CTC grade 3 or above events withhold the pembrolizumab and consider a dermatology referral. Treatment with systemic corticosteroids such as prednisolone 1mg/kg each day may be necessary. When symptoms improve to NCI-CTC grade 1 or less then steroid taper should be started and continued over no less than 4 weeks. Regimen The total duration of treatment is two years or 35 cycles. That is 4 cycles of combination chemotherapy with immunotherapy followed by 31 cycles of immunotherapy plus maintenance pemetrexed. 21 day cycle for 4 cycles Drug Dose Days Administration Intravenous infusion in 1000ml Cisplatin 75mg/m2 sodium chloride 0.9% with 20mmol 1 potassium chloride at a maximum rate of 1mg cisplatin/min (minimum time 120 minutes) Intravenous infusion in 100ml Pembrolizumab 200mg 1 sodium chloride 0.9% over 30 minutes with a 0.2 micron filter Intravenous infusion in 100ml Pemetrexed 500mg/m2 1 glucose 5% or sodium chloride 0.9% over 10 minutes Followed by; Version 1 (March 2019) Page 8 of 15 NSCLC – Cisplatin-Pembrolizumab-Pemetrexed 21 day cycle for 31 cycles Drug Dose Days Administration Intravenous infusion in 100ml sodium Pembrolizumab 200mg 1 chloride 0.9% over 30 minutes with a 0.2 micron filter Pemetrexed 500mg/m2 1 Intravenous infusion in 100ml glucose 5% or sodium chloride 0.9% over 10 minutes Dose Information • Cisplatin will be dose banded in accordance with the national dose bands (1mg/ml) • Pemetrexed will be dose banded in accordance with the national dose bands (25NS) Administration Information • Cisplatin should be administered 30 minutes after the end of the pemetrexed infusion • Pembrolizumab will be administered before the cisplatin and pemetrexed. It should be administered using a using a low protein binding filter. • Pemtrexed may be administered in 100ml of either glucose 5% or sodium chloride 0.9% over 10 minutes. The choice of fluid will be dependant on the product stocked by pharmacy. The fluid and volume will not appear in the prescription but can be located in the instructions notepad. Extravasation • Cisplatin – exfoliant • Pembrolizumab - neutral • Pemetrexed - inflammitant Additional Therapy • Folic acid 5mg once daily starting 1 – 2 weeks prior to and continuing for three weeks after the last dose of pemetrexed. • Hydroxocobalamin intramuscular injection 1mg every three months starting 1 – 2 weeks prior to pemetrexed. • Antiemetics 15-30 minutes prior to chemotherapy (cycles 1, 2, 3, 4); Version 1 (March 2019) Page 9 of 15 NSCLC – Cisplatin-Pembrolizumab-Pemetrexed - aprepitant 125mg oral - ondansetron 8mg oral or intravenous As take home medication; - aprepitant 80mg once a day oral for 2 days - metoclopramide 10mg three times a day when required - ondansetron 8mg twice a day for 3 days Ensure the patient has taken the oral dexamethasone starting the day before pemetrexed. On the occasions where individuals attend for treatment and have forgotten to take the dexamethasone pre-medication administer dexamethasone 20mg intravenous 15-30 minutes before chemotherapy. As take home medication; - dexamethasone 4mg twice a day oral for 3 days starting the day before chemotherapy is due. 15-30 minutes prior to chemotherapy (cycles 5-35) - metoclopramide 10mg oral or intravenous Ensure the patient has taken the oral dexamethasone starting the day before pemetrexed. On the occasions where individuals attend for treatment and have forgotten to take the dexamethasone pre-medication administer dexamethasone 20mg intravenous 15-30 minutes before chemotherapy. As take home medication; - dexamethasone 4mg twice a day oral for 3 days starting the day before chemotherapy is due (not cycle 35) - metoclopramide 10mg three times a day when required • As required for the treatment of infusion related reactions (most common with pembrolizumab); - chlorphenamine 10mg intravenous - hydrocortisone 100mg intravenous - paracetamol 1000mg oral • Cisplatin pre and post hydration as follows; Pre Furosemide 40mg oral or intravenous 1000ml sodium chloride 0.9% with 20mmol potassium chloride and 16mmol magnesium sulphate over 60 minutes Version 1 (March 2019) Page 10 of 15 NSCLC – Cisplatin-Pembrolizumab-Pemetrexed Post 1000ml sodium chloride 0.9% with 20mmol potassium chloride and 16mmol magnesium sulphate over 60 minutes Patients should be advised to drink at least 3 litres of fluid in the 24 hours after administration of cisplatin. • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed • Prophylactic antibiotics can be considered if required Additional Information • Consideration should be given to draining pleural or peritoneal effusions prior to pemetrexed administration Coding • Procurement – X • Delivery – X References 1. Langer CJ, Gadgeel SM, Borghaei H et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced non-squamous non small cell lung cancer: a randomised phase 2 cohort of the open label KEYNOTE 021 study. Lancet Oncology 2016; 17 (11): 1497-1508. Version 1 (March 2019) Page 11 of 15 NSCLC – Cisplatin-Pembrolizumab-Pemetrexed REGIMEN SUMMARY Cisplatin-Pembrolizumab-Pemetrexed Cycle 1, 2, 3, 4 Day Minus One 1. Dexamethasone 4mg twice a day oral* Day One 2. Dexamethsone 4mg twice a day oral (from TTO)* 3. Aprepitant 125mg oral 4. Ondansetron 8mg oral or intravenous 5. Pembrolizumab 200mg intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Administration Instructions Pembrolizumab should be administered using a low protein binding filter 6. Pemetrexed 500mg/m2 intravenous infusion in 100ml glucose 5% or sodium chloride 0.9% over 10 minutes 7. Furosemide 40mg oral or intravenous 8. 1000ml sodium chloride 0.9% with 20mmol potassium chloride and 16mmol magnesium sulphate over 60 minutes 9. Cisplatin 75mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% with 20mmol potassium chloride at a maximum rate of 1mg cisplatin/minute (minimum time 120 minutes) Administration Instructions Start 30 minutes after the end of the pemetrexed infusion. 10. 1000ml sodium chloride 0.9% with 20mmol potassium chloride and 16mmol magnesium sulphate over 60 minutes 11.Chlorphenamine 10mg intravenous when required for the treatment of infusion related reactions 12.Hydrocortisone sodium succinate 100mg intravenous when required for the treatment of infusion related reactions 13. Paracetamol 1000mg oral when required for the relief of infusion related reactions Administration Instructions Please check if the patient has taken paracetamol. Maximum dose is 4g per 24 hours. There should be 4 hours between doses Version 1 (March 2019) Page 12 of 15 NSCLC – Cisplatin-Pembrolizumab-Pemetrexed Take Home Medicines 14. Dexamethasone 4mg twice a day oral for 3 days starting the day before the pemetrexed infusion* 15. Aprepitant 80mg once a day oral for 2 days starting on day two of the cycle 16. Metoclopramide 10mg three times a day when required oral 17. Ondansetron 8mg twice a day oral for 3 days starting on the evening of day one of the cycle Administration Instructions Start on the evening of day one of the cycle 18. Folic acid 5mg once a day oral Cycle 5-34 Day Minus One 1. Dexamethasone 4mg twice a day oral* Day One 2. Dexamethsone 4mg twice a day oral (from TTO)* 3. Metoclopramide 10mg oral or intravenous 4. Pembrolizumab 200mg intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Administration Instructions Pembrolizumab should be administered using a low protein binding filter 5. Pemetrexed 500mg/m2 intravenous infusion in 100ml glucose 5% or sodium chloride 0.9% over 10 minutes 7.Chlorphenamine 10mg intravenous when required for the treatment of infusion related reactions 8.Hydrocortisone sodium succinate 100mg intravenous when required for the treatment of infusion related reactions 9.Paracetamol 1000mg oral when required for the relief of infusion related reactions Administration Instructions Please check if the patient has taken paracetamol. Maximum dose is 4g per 24 hours. There should be 4 hours between doses Take Home Medicines 10. Dexamethasone 4mg twice a day oral for 3 days starting the day before the pemetrexed infusion* 11. Metoclopramide 10mg three times a day when required oral 12. Folic acid 5mg once a day oral Version 1 (March 2019) Page 13 of 15 NSCLC – Cisplatin-Pembrolizumab-Pemetrexed Cycle 35 Day Minus One 1. Dexamethasone 4mg twice a day oral* Day One 2. Dexamethsone 4mg twice a day oral (from TTO)* 3. Metoclopramide 10mg oral or intravenous 4. Pembrolizumab 200mg intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Administration Instructions Pembrolizumab should be administered using a low protein binding filter 5. Pemetrexed 500mg/m2 intravenous infusion in 100ml glucose 5% or sodium chloride 0.9% over 10 minutes 7.Chlorphenamine 10mg intravenous when required for the treatment of infusion related reactions 8.Hydrocortisone sodium succinate 100mg intravenous when required for the treatment of infusion related reactions 9.Paracetamol 1000mg oral when required for the relief of infusion related reactions Administration Instructions Please check if the patient has taken paracetamol. Maximum dose is 4g per 24 hours. There should be 4 hours between doses Take Home Medicines 11. Metoclopramide 10mg three times a day when required oral 12. Folic acid 5mg once a day oral Hydroxocobalamin will not be included as part of the Aria regime and must be prescribed separately on the cycle for which it is due. * In Aria Planner the dexamethasone 4mg twice daily will appear on days 1, 2, 3 of treatment. This is the supply for the next cycle. The patient should have been given the supply for cycle one in the pre-assessment or consent clinic. The administration instructions reflect this. Version 1 (March 2019) Page 14 of 15 NSCLC – Cisplatin-Pembrolizumab-Pemetrexed DOCUMENT CONTROL Version Date 1 February None 2019 Amendment Written By Dr Deborah Wright Pharmacist Approved By Dr Judith Cave Consultant Medical Oncologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury Hospitals NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. These protocols should be used in conjunction with other references such as the Summary of Product Characteristics and relevant published papers. Version 1 (March 2019) Page 15 of 15 NSCLC – Cisplatin-Pembrolizumab-Pemetrexed
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InP-Cisplatin-Ifosfamide-Paclitaxel (TIP) Ver1.2

Description
Chemotherapy Protocol GERM CELL CISPLATIN-IFOSFAMIDE-PACLITAXEL (TIP) Inpatient Regimen Regimen Germ Cell – InP-Cisplatin-Ifosfamide-Paclitaxel (TIP) Indication Relapsed Metastatic Germ Cell Tumours after failure of first line therapy Toxicity Drug Cisplatin Ifosfamide Paclitaxel Adverse Effect Neuropathy, nephrotoxicity, ototoxicity Haemorrhagic cystitis, encephalopathy, nephrotoxicity Hypersensitivity, hypotension, bradycardia, peripheral neuropathy, myalgia The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Drugs FBC, LFTs and U&Es (magnesium, phosphate and calcium) prior to each cycle Serum albumin prior to each cycle EDTA or calculated creatinine clearance Urine dip test for blood every four hours the day of and the day after ifosfamide administration Fluid balance monitoring every four hours the day of and the day after ifosfamide administration. Urine output should be maintained above 100ml/hour AFP, HCG on day 1 of the cycle Dose Modifications The dose modifications listed are for haematological, liver and renal function and drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. Version 1.2 (July 2015) Page 1 of 9 Germ Cell–InP-Cisplatin-Ifosfamide-Paclitaxel (TIP) In principle all dose reductions due to adverse drug reactions should not be re-escalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Haematological Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL. Prior to each cycle the following criteria should be met; Criteria Neutrophil Platelets Eligible Level equal to or more than 1x109/L equal to or more than 100x109/L After each cycle the following table applies to both ifosfamide and paclitaxel. Neutrophils (x109/L) 1 or above and 1 or above and 0.5 - 1 and 0.5 - 1 and Platelets (x109/L) 100 or above 75 - 100 75 - 100 50 - 75 Dose (% of original) (ifosfamide and paclitaxel) 100% 100% 75% 50% This is a potentially curative regimen. All dose reductions and delays should be discussed with the relevant consultant. In general if these levels are not met then treatment should be delayed for three days at a time. Treatment should re-start as soon as these haematological parameters are met. Dose delays rather than dose reductions are recommended. Cisplatin does not require a dose reduction based on haematological parameters. Hepatic Impairment Drug Cisplatin Bilirubin μmol/L N/A AST/ALT units/L N/A Dose No dose modification necessary Ifosfamide greater than ULN or greater than 2.5xULN or ALP greater than 2.5xULN Not recommended less than 25* and less than 10xULN 26-30* Paclitaxel 31-51* 52-85 more than 85 or greater than 10xULN *limits reflect local practice and may vary from published sources 175mg/m2 135mg/m2 75mg/m2 50mg/m2 omit Version 1.2 (July 2015) Page 2 of 9 Germ Cell–InP-Cisplatin-Ifosfamide-Paclitaxel (TIP) Renal Impairment Drug Cisplatin* Ifosfamide Creatinine Clearance (ml/min) Dose (% of original dose) more than 60 100% If the creatinine clearance is 59ml/min or below please discuss with the relevant consultant* more than 60 40-59 less than 40 100% 70% clinical decision Paclitaxel no dose modification necessary *In the original trial(2) cisplatin was given at full dose unless the creatinine clearance fell below 40 ml/min, in which case it was discontinued. If the creatinine clearance subsequently recovered to above this level, the cisplatin was initially recommenced at 75% of the original dose. Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. For all other non-haematological NCI-CTC grade 3 and above toxicities delay treatment until the adverse effect has resolved to NCI-CTC grade 1 or below. The dose of the causative agent(s) may then be reduced or discontinued at the discretion of the consultant. Ifosfamide In the case of a NCI-CTC grade 1 neurological toxicity, the dose of ifosfamide may be reduced for the next cycle. If a NCI-CTC grade 2 neurological toxicity appears or neurological toxicity worsens despite dose reduction, the ifosfamide should be stopped. Risk factors for CNS toxicity include a low albumin, renal impairment, prior administration of cisplatin, poor performance status, CNS tumour, bulky pelvic disease, concomitant psychotropic drugs and younger age. Methylene blue 50mg four times a day intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes can be used to prevent or treat ifosfamide induced encephalopathy. Version 1.2 (July 2015) Page 3 of 9 Germ Cell–InP-Cisplatin-Ifosfamide-Paclitaxel (TIP) Regimen 21 day cycle for 4 cycles Drug Paclitaxel Cisplatin Ifosfamide Mesna Mesna* Dose 175mg/m2 20mg/m2 1000mg/m2 500mg/m2 500mg/m2 Days 1 1,2,3,4,5 1,2,3,4,5 1,2,3,4,5 Administration Intravenous infusion in 500ml sodium chloride 0.9% over 180 minutes Intravenous infusion in 1000ml sodium chloride 0.9% with 20mmol potassium chloride over 120 minutes Intravenous infusion in 500ml sodium chloride 0.9% over 60 minutes Intravenous infusion in 1000ml sodium chloride 0.9% over 8 hours *The last bag of mesna on day 5 of the cycle may be replaced with oral administration at a dose of 400mg/m2 (rounded upwards to the nearest 400mg capsule) at 0, 2 and 6 hours after the end of the ifosfamide infusion. Dose Information Aria is set to dose cap all regimens at 2.4m2. This regimen must NOT be capped. Please override any doses that are capped. Cisplatin will be dose banded according to the CSCCN agreed bands Ifosfamide will be dose banded according to the CSCCN agreed bands Mesna will be dose banded according to the CSCCN agreed bands Paclitaxel will be dose banded according to the CSCCN agreed bands Administration Information Extravasation Cisplatin - exfoliant Ifosfamide - neutral Mesna - neutral Paclitaxel - vesicant Other Paclitaxel should be administered using a PVC free administration set with a 0.22 micron in-line filter Hypersensitivity reactions tend to occur with the first or second infusion of paclitaxel. Paclitaxel infusions should be interrupted for minor symptoms such as flushing or Version 1.2 (July 2015) Page 4 of 9 Germ Cell–InP-Cisplatin-Ifosfamide-Paclitaxel (TIP) localised rashes. If these resolve promptly (within 5 minutes) the infusion may be restarted at a lower rate with intensive monitoring. Immediately discontinue the infusion for severe reactions which include profound hypotension, bronchospasm and generalised erythema. In the event of a severe reaction the patient should not be rechallenged with the drug. Additional Therapy This is an inpatient regimen please ensure all supportive and take home medication not on Aria are prescribed on the inpatient chart or general electronic prescribing system. Paclitaxel premedication (this will be on Aria) 30 minutes prior to paclitaxel - chlorphenamine 10mg intravenous - dexamethasone 20mg intravenous - ranitidine 50mg intravenous Antiemetics Starting prior to chemotherapy - aprepitant 125mg once a day on day 1 and 80mg once a day on days 2, 3 - dexamethasone 4mg once a day on days 2, 3, 4, 5, 6, 7 oral - metoclopramide 10mg three times a day on days 1, 2 ,3 ,4, 5 then 10mg three times a day when required for nausea oral - ondansetron 8mg twice a day on days 1, 2, 3, 4, 5, 6, 7 oral Cisplatin pre hydration with 500ml sodium chloride 0.9% with 8mmol magnesium sulphate over 30 minutes. The post hydration is incorporated as part of the ifosfamide and mesna administration. Consider furosemide 40mg oral or intravenous for the treatment of fluid overload. Growth factor support according to local policy, for example; - filgrastim or bioequivalent 30 million units once a day for seven days starting on day seven of the cycle subcutaneous - lenograstim or bioequivalent 33.6 million units once a day for seven days starting on day seven of the cycle subcutaneous - pegfilgrastim or bioequivalent 6mg once a day for one day on day seven of the cycle Ciprofloxacin 500mg twice a day for 7 days starting on day 8 of the cycle oral Mouthwashes according to local or national policy on the treatment of mucositis Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. Version 1.2 (July 2015) Page 5 of 9 Germ Cell–InP-Cisplatin-Ifosfamide-Paclitaxel (TIP) Coding (OPCS) Procurement – X71.2 Delivery – Not Required (X72.1 for out-patients) References 1.Motzer RJ, Sheinfeld J, Mazumdar M. Paclitaxel, ifosfamide and cisplatin second line therapy for patients with relapsed testicular germ cell cancer. J Clin Oncol 2000; 18: 2413-2418. 2.Mead GM, Cullen MH, Huddart R et al. A phase II trial of TIP (paclitaxel, ifosfamide, cisplatin) given as second line (post BEP) chemotherapy for patients with metastatic germ cell cancer. Br J Cancer 2005; 93: 178-184. Version 1.2 (July 2015) Page 6 of 9 Germ Cell–InP-Cisplatin-Ifosfamide-Paclitaxel (TIP) REGIMEN SUMMARY InP-Cisplatin-Ifosfamide-Paclitaxel (TIP) Other than those listed below, supportive medication for this regimen will not appear in Aria as prescribed agents. The administration instructions for each warning describes the agents which must be prescribed on the in-patient chart or general electronic prescribing system Day 1 1. Warning – Check supportive medication prescribed Administration Instructions 1. aprepitant 125mg once a day on day 1 and 80mg once a day on days 2, 3 oral 2. dexamethasone 4mg once a day on days 2,3,4,5,6,7 oral 3. metoclopramide 10mg three times a day on days 1,2,3,4,5 then 10mg three times a day when required for the relief of nausea oral 4. ondansetron 8mg twice a day on days 1,2,3,4,5,6,7 oral 5. furosemide 40mg oral or intravenous when required for fluid overload 6. growth factor support according to local policy, for example; - filgrastim or bioequivalent 30 million units once a day for seven days starting on day seven of the cycle subcutaneous - lenograstim or bioequivalent 33.6 million units once a day for seven days starting on day seven of the cycle subcutaneous - pegfilgrastim or bioequivalent 6mg once a day for one day on day seven of the cycle 7. ciprofloxacin 500mg twice a day for 7 days starting on day 8 oral 2. Chlorphenamine 10mg intravenous 3. Dexamethasone 20mg intravenous 4. Ranitidine 50mg in 20ml water for injection intravenous over 2 minutes 5. Paclitaxel 175mg/m2 in 500ml sodium chloride 0.9% intravenous infusion over 180 minutes 6. Sodium chloride 0.9% 500ml with magnesium sulphate 8mmol intravenous infusion over 30 minutes 7. Cisplatin 20mg/m2 in 1000ml sodium chloride 0.9% with 20mmol potassium chloride intravenous infusion over 120 minutes 8. Ifosfamide 1000mg/m2 with mesna 500mg/m2 in 500ml sodium chloride 0.9% over 60 minutes 9. Mesna 500mg/m2 in 1000ml sodium chloride 0.9% over 8 hours Day 2, 3, 4, 5 10. Warning – Check supportive medication prescribed Administration Instructions 1. aprepitant 125mg once a day on day 1 and 80mg once a day on days 2, 3 oral 2. dexamethasone 4mg once a day on days 2,3,4,5,6,7 oral 3. metoclopramide 10mg three times a day on days 1,2,3,4,5 then 10mg three times a day when required for the relief of nausea oral 4. ondansetron 8mg twice a day on days 1,2,3,4,5,6,7 oral 5. furosemide 40mg oral or intravenous when required for fluid overload 6. growth factor support according to local policy, for example; - filgrastim or bioequivalent 30 million units once a day for seven days starting on day seven of the cycle subcutaneous - lenograstim or bioequivalent 33.6 million units once a day for seven days starting on day seven of the cycle subcutaneous - pegfilgrastim or bioequivalent 6mg once a day for one day on day seven of the cycle Version 1.2 (July 2015) Page 7 of 9 Germ Cell–InP-Cisplatin-Ifosfamide-Paclitaxel (TIP) 7. ciprofloxacin 500mg twice a day for 7 days starting on day 8 oral 11. Sodium chloride 0.9% 500ml with magnesium sulphate 8mmol intravenous infusion over 30 minutes 12. Cisplatin 20mg/m2 in 1000ml sodium chloride 0.9% with 20mmol potassium chloride intravenous infusion over 120 minutes 13. Ifosfamide 1000mg/m2 with mesna 500mg/m2 in 500ml sodium chloride 0.9% over 60 minutes 14. Mesna 500mg/m2 in 1000ml sodium chloride 0.9% over 8 hours Version 1.2 (July 2015) Page 8 of 9 Germ Cell–InP-Cisplatin-Ifosfamide-Paclitaxel (TIP) DOCUMENT CONTROL Version Date Amendment Written By Header changed Metoclopramide dose changed to 10mg Bolus removed from intravenous bolus throughout text Donna Kimber 1.2 July 2015 Mucositis recommendation Pharmacy changed Technician Hepatic impairment table updated, statement added Growth factor units updated Disclaimer added Mesna dose altered to reflect 1.1 June 2013 that used in clinical trial (reference two) Dr Deborah Wright Pharmacist 1 Jan 2013 None Rebecca Wills Pharmacist Dr Deborah Wright Pharmacist Approved By Rebecca Wills Pharmacist Dr Mathew Wheater Consultant Medical Oncologist Dr Joanna Gale Consultant Medical Oncologist Dr Mathew Wheater Consultant Medical Oncologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury Hospitals NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors which occur as a result of following these guidelines. Version 1.2 (July 2015) Page 9 of 9 Germ Cell–InP-Cisplatin-Ifosfamide-Paclitaxel (TIP)
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InP-Bleomycin-Cisplatin-Etoposide (5 day-Mod-BEP) Ver1.2

Description
Chemotherapy Protocol GERM CELL BLEOMYCIN-CISPLATIN-ETOPOSIDE (BEP 5 Day Modified) In-Patient Regimen Regimen Germ Cell – InP-Bleomycin-Cisplatin-Etoposide (5 day-Mod-BEP) Indication In patients 41 years and above with; - metastatic non-seminomatous germ cell tumours - metastatic seminoma where radiotherapy is not appropriate - renal impairment or a poor performance status Toxicity Drug Bleomycin Cisplatin Etoposide Adverse Effect Pulmonary toxicity, rigors, skin pigmentation, nail changes Neuropathy, nephrotoxicity, ototoxicity Hypotension on rapid infusion, alopecia, hyperbilirubineamia The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Drugs FBC, LFTs and U&Es on day one of the cycle AFP, HCG prior to day one of the cycle Chest x-ray Consider pulmonary function tests before starting therapy. These should be repeated if respiratory symptoms develop during treatment, particularly a drop in oxygen saturation on exercise. Bleomycin should be stopped until the results of such investigations are known. Dose Modifications The dose modifications listed are for haematological, liver and renal function and drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. Version 1.2 (July 2015) Page 1 of 8 Germ Cell–InP-Bleomycin-Cisplatin-Etoposide (5 day-Mod-BEP) In principle all dose reductions due to adverse drug reactions should not be re-escalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Patients are being treated with curative intent therefore dose modifications and delays should be kept to a minimum. Please discuss all dose reductions / delays with the relevant consultant before prescribing. The approach may be different depending on the clinical circumstances. Haematological Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL. Prior to each cycle the following criteria must be met Criteria Neutrophil Platelets Eligible Level equal to or more than 0.5x109/L equal to or more than 100x109/L This is a curative regimen. All dose reductions and delays should be discussed with the relevant consultant. In general if these levels are not met then treatment should be delayed for three days at a time. Treatment should re-start as soon as these haematological parameters are met. Dose delays rather than dose reductions are recommended. Hepatic Impairment Drug Bleomycin Bilirubin μmol/L AST/ALT units/L Dose (% of original dose) Clinical decision Cisplatin N/A N/A No dose modification necessary Etoposide 26-51 greater than 51 or 60-180 Consider dose reducing to 50% or greater than 180 Clinical decision Version 1.2 (July 2015) Page 2 of 8 Germ Cell–InP-Bleomycin-Cisplatin-Etoposide (5 day-Mod-BEP) Renal Impairment Drug Bleomycin Creatinine Clearance (ml/min) 50 or more less than 50 Dose (% of original dose) 100% discuss with consultant and omit Cisplatin 60 or greater 100% If the creatinine clearance is 59ml/min or below please refer to the responsible consultant for advice Etoposide greater than 50 15-50 less than 15 100% 75% 50% Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. For all other non-haematological NCI-CTC grade 3 and above toxicities delay treatment until the adverse effect has resolved to NCI-CTC grade 1 or below. The dose of the causative agent(s) may then be reduced or discontinued at the discretion of the consultant. Bleomycin The risk of bleomycin induced pneumonitis is greater in those individuals who are older than forty years of age, have a history of smoking, those with underlying lung disease, previous mediastinal radiotherapy or poor renal function. If pulmonary symptoms develop stop the bleomycin until they can be investigated fully and a diagnosis made. Regimen 21 day cycle for 4 cycles Drug Bleomycin Cisplatin Etoposide Dose 30,000 IU 20mg/m2 100mg/m2 Days 2 1,2,3,4,5 1,2,3,4,5 Administration Intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes Intravenous infusion in 1000ml sodium chloride 0.9% with 20mmol potassium chloride over 60 minutes Intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Version 1.2 (July 2015) Page 3 of 8 Germ Cell–InP-Bleomycin-Cisplatin-Etoposide (5 day-Mod-BEP) Dose Information Aria is set to dose cap all regimens at 2.4m2. This regimen must NOT be capped. Please override any doses that are capped. Patients over the age of 40 are at increased risk of pulmonary toxicity and therefore the maximum cumulative dose of bleomycin is limited to 120 000IU in this protocol. Cisplatin will be dose banded according to the CSCCN agreed bands Etoposide will be dose banded according to the CSCCN agreed bands Administration Information Extravasation Bleomycin – neutral Cisplatin – exfoliant Etoposide – irritant Additional Therapy This is an inpatient regimen please ensure all supportive and take home medication not on Aria are prescribed on the inpatient chart or general electronic prescribing system. Antiemetics 15 – 30 minutes prior to chemotherapy - aprepitant 125mg once a day on day 1 - aprepitant 80mg once a day on days 2, 3 - dexamethasone 4mg once a day on days 1, 2, 3, 4, 5, 6, 7 oral - metoclopramide 10mg three times a day when required oral - ondansetron 8mg twice a day on days 1, 2, 3, 4, 5, 6, 7 oral On days of bleomycin administration - hydrocortisone 100mg intravenous when required - chlorphenamine 10mg intravenous when required Cisplatin pre-hydration as follows - furosemide 40mg oral or intravenous as required - sodium chloride 0.9% 500ml with 8mmol magnesium sulphate over 30 minutes Cisplatin post hydration - sodium chloride 0.9% 500ml over 30 minutes Version 1.2 (July 2015) Page 4 of 8 Germ Cell–InP-Bleomycin-Cisplatin-Etoposide (5 day-Mod-BEP) Ciprofloxacin 500mg twice a day for 7 days starting on day 8 of the cycle Mouthwashes according to local or national policy on the treatment of mucositis Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. Coding (OPCS) Procurement – X70.3 Delivery – N/A References 1.de Wit R, Roberts JT, Wilkinson PM et al. Equivalence of 3 cycle BEP versus 4 cycles and of the 5 day schedule versus 3 days per cycle in good-prognosis germ cell cancer: a randomised study of the European Organisation for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 2001; 19: 1629-1640. 2.de Wit R, Stoter G, et al. Four cycles of BEP versus four cycles of VIP in patients with intermediate-prognosis metastatic testicular non seminoma: A randomised study of the EORTC Genitourinary Tract Cancer Cooperative Group. Br J Cancer 1998; 78(6): 828-832. 3.Nichols C, Catalano P, Crawford E et al. Randomised comparison of cisplatin and etoposide and either bleomycin or ifosfamide in the treatment of advanced disseminated germ cell tumours: An Eastern Cooperative Oncology Group, Southwest Oncology Group and Cancer and Leukemia Group B study. J Clin Oncol 1998; 16: 1287-1293. 5.Fossa SD, Kaye SB, Mead GM, Cullen MH, De Wit R, Borogi J, Van Groeningen C, De Mulder P, Stenning S and De Prijck L. Filgrastim (G-CSF) during combination chemotherapy of patients with poor prognosis metastatic germ cell malignancy (A phase III trial of the EORTC GU group/MRC testicular tumour working party) J Clin Oncol 1998: 16: 716-724 Version 1.2 (July 2015) Page 5 of 8 Germ Cell–InP-Bleomycin-Cisplatin-Etoposide (5 day-Mod-BEP) REGIMEN SUMMARY InP-Bleomycin-Cisplatin-Etoposide (5 day-Mod-BEP) Other than those listed below, supportive medication for this regimen will not appear in Aria as prescribed agents. The administration instructions for each warning describes the agents which must be prescribed on the in-patient chart or general electronic prescribing system Cycle 1, 2, 3, 4 Day 1 1. Warning – Check supportive medicines prescribed Administration Instructions - aprepitant 125mg once a day on day 1 - aprepitant 80mg once a day on days 2, 3 - dexamethasone 4mg once a day on days 1, 2, 3, 4, 5, 6, 7 oral - metoclopramide 10mg three times a day when required oral - ondansetron 8mg twice a day on days 1, 2, 3, 4, 5, 6, 7 oral - furosemide 40mg when required oral - chlorphenamine 10mg intravenous for bleomycin reactions - hydrocortisone 100mg intravenous for bleomycin reactions - ciprofloxacin 500mg twice a day for 7 days starting on day 8 oral 2. Sodium chloride 0.9% 500ml with magnesium sulphate 8mmol intravenous infusion over 30 minutes 3. Cisplatin 20mg/m2 in 1000ml sodium chloride 0.9% with 20mmol potassium chloride intravenous infusion over 60 minutes 4. Sodium chloride 0.9% 500ml over 30 minutes 5. Etoposide 100mg/m2 in 1000ml sodium chloride 0.9% intravenous infusion over 60 minutes Day 2 6. Warning – Check supportive medicines prescribed Administration Instructions - aprepitant 125mg once a day on day 1 - aprepitant 80mg once a day on days 2, 3 - dexamethasone 4mg once a day on days 1, 2, 3, 4, 5, 6, 7 oral - metoclopramide 10mg three times a day when required oral - ondansetron 8mg twice a day on days 1, 2, 3, 4, 5, 6, 7 oral - furosemide 40mg when required oral - chlorphenamine 10mg intravenous for bleomycin reactions - hydrocortisone 100mg intravenous for bleomycin reactions - ciprofloxacin 500mg twice a day for 7 days starting on day 8 oral 7. Sodium chloride 0.9% 500ml with magnesium sulphate 8mmol intravenous infusion over 30 minutes 8. Cisplatin 20mg/m2 in 1000ml sodium chloride 0.9% with 20mmol potassium chloride intravenous infusion over 60 minutes 9. Sodium chloride 0.9% 500ml over 30 minutes 10. Etoposide 100mg/m2 in 1000ml sodium chloride 0.9% intravenous infusion over 60 minutes Version 1.2 (July 2015) Page 6 of 8 Germ Cell–InP-Bleomycin-Cisplatin-Etoposide (5 day-Mod-BEP) 11. Bleomycin 30,000 IU in 100ml sodium chloride 0.9% intravenous infusion over 30 minutes Days 3, 4, 5 12. Warning – Check supportive medicines prescribed Administration Instructions - aprepitant 125mg once a day on day 1 - aprepitant 80mg once a day on days 2, 3 - dexamethasone 4mg once a day on days 1, 2, 3, 4, 5, 6, 7 oral - metoclopramide 10mg three times a day when required oral - ondansetron 8mg twice a day on days 1, 2, 3, 4, 5, 6, 7 oral - furosemide 40mg when required oral - chlorphenamine 10mg intravenous for bleomycin reactions - hydrocortisone 100mg intravenous for bleomycin reactions - ciprofloxacin 500mg twice a day for 7 days starting on day 8 oral 13. Sodium chloride 0.9% 500ml with magnesium sulphate 8mmol intravenous infusion over 30 minutes 14. Cisplatin 20mg/m2 in 1000ml sodium chloride 0.9% with 20mmol potassium chloride intravenous infusion over 60 minutes 15. Sodium chloride 0.9% 500ml over 30 minutes 16. Etoposide 100mg/m2 in 1000ml sodium chloride 0.9% intravenous infusion over 60 minutes Version 1.2 (July 2015) Page 7 of 8 Germ Cell–InP-Bleomycin-Cisplatin-Etoposide (5 day-Mod-BEP) DOCUMENT CONTROL Version Date Amendment Written By Header changed Renal and hepatic dose mods updated for etoposide Metoclopramide dose changed to 10mg Donna Kimber 1.2 July 2015 Bolus removed from intravenous Pharmacy bolus throughout text Technician Mucositis recommendation changed OPCS code updated Disclaimer added Name changed throughout. 1.1 June 2013 Bleomycin dose reductions in renal impairment changed Dr Deborah Wright Pharmacist 1 Jan 2013 None Rebecca Wills Pharmacist Dr Deborah Wright Pharmacist Approved By Rebecca Wills Pharmacist Dr Mathew Wheater Consultant Medical Oncologist Dr Joanna Gale Consultant Medical Oncologist Dr Mathew Wheater Consultant Medical Oncologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury Hospitals NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors which occur as a result of following these guidelines. Version 1.2 (July 2015) Page 8 of 8 Germ Cell–InP-Bleomycin-Cisplatin-Etoposide (5 day-Mod-BEP)
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Cabozantinib

Description
Chemotherapy Protocol RENAL CELL CANCER Regimen CABOZANTINIB • Renal Cell – Cabozantinib (60mg-tablets) Indication • Cabozantinib s indicated for the treatment of advanced renal cell carcinoma (RCC) in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy Toxicity Drug Cabozantinib Adverse Effect Hypertension, diarrhoea, osteonecrosis, QT interval prolongation, perforations, fistulas, intra-abdominal absesses, Posterior reversible encephalopathy syndrome, palmer-plantar erythrodysthesia, hypothyroidism, proteinuria The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Drugs • FBC, LFTs and U&Es prior to day one of treatment. This should include magnesium, potassium, calcium and phosphate. Abnormal levels should be corrected. • Thyroid function tests at baseline and 2, 4, 8 and 12 weeks and then every 12 weeks thereafter • ECG at baseline and 2, 4, 8 and 12 weeks and then every 12 weeks thereafter • Blood pressure prior to each cycle. Existing hypertension should be well controlled prior to starting treatment • Urine dipstick for protein prior to every cycle. Dose Modifications The dose modifications listed are for haematological, liver and renal function and drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. In principle all dose reductions due to adverse drug reactions should not be re-escalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Version 1 (December 2017) Page 1 of 7 Renal Cell-Cabozantinib (60mg-tablet) Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Haematological Dose modifications for haematological toxicity in the table below are for general guidance only. Always refer to the responsible consultant as any dose reductions or delays will be dependent on clinical circumstances and treatment intent. Low counts can be a consequence of bone marrow infiltration as well as drug toxicity. Consider blood transfusion if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL (80g/L). In general neutrophils should be greater than 1.5x109/L and platelets greater than 100x109/L prior to each cycle. Discuss lower than normal haematological findings and treatment doses with consultant. Hepatic Impairment Drug Cabozantinib Dose (% of original dose) Dose reductions should be considered when grade 2 elevated ALT, AST or bilirubin for longer than 1 week occurs. For grade 3 and above then treatment should be withheld until resolved to baseline levels and then restart treatment at lower dose Renal Impairment Drug Dose (% of original dose) Cabozantinib No information available Other Dose interruptions are required for management of NCI-CTC grade 3 or greater toxicities or intolerable grade 2 toxicities. Treatment may be resumed with a reduced dose according to the table below only after the toxicity has improved to NCI-CTC grade 1 toxicity. Toxicity is more commonly observed in patients aged 75 years or older. Cabozantinib Dose Level Dose 1st dose reduction 40mg 2nd dose reduction 20mg Version 1 (December 2017) Page 2 of 7 Renal Cell-Cabozantinib (60mg-tablet) QT interval change Cabozantinib should be used with caution in patients with a history of QT prolongation, patients who are taking anti-arrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. ECG QTc interval should not be greater than 480 msec. Serum calcitonin level should be greater than or equal to 500pg/ml. Posterior Reversible Encephalopathy Syndrome (PRES) PRES is a syndrome of subcortical vasogenic oedema diagnosed by a MRI of the brain. PRES has been observed in patients receiving carbozantinib. This syndrome should be considered in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Brain MRI should be performed in any patient presenting with seizures, confusion or altered mental status. Discontinue cabozantinib if PRES is diagnosed. Perforations, Fistulas and Intraabdominal Abscesses Serious and sometimes fatal perforations, fistulas and intraabdominal abscesses have been observed with cabozantinib. Treatment should be discontinued in patients who experience a GI perforation or a GI or non-GI fistula. Osteonecrosis of the Jaw Events of osteonecrosis of the jaw (ONJ) have been observed with cabozantinib. An oral examination should be performed prior to initiation of cabozantinib and periodically during cabozantinib therapy. Patients should be advised regarding oral hygiene practice. For invasive dental procedures, cabozantinib treatment should be held at least 28 days prior to scheduled surgery, if possible. Caution should be used in patients receiving agents associated with ONJ, such as bisphosphonates. Cabozantinib should be discontinued in patients who experience ONJ. Diarrhoea Administration of loperamide is recommended at the first sign of diarrhoea. If it is not controlled with loperamide alone, additional agents can be added but if combination therapy is not controlling the diarrhoea to tolerable levels then a dose reduction is recommended. Stop treatment in for NCI-CTC grade 3 diarrhoea. Re-start with a reduced dose once diarrhoea has subsided. Hypertension Blood pressure should be well controlled prior to initiating carbozantinib. Patients should be monitored for hypertension. If the blood pressure exceeds 150/100 mmHg then instigate treatment, either by increasing the dose of existing anti-hypertensives, adding additional agents or commencing therapy. In the case of persistent hypertension (blood pressure greater than 150/100mmHg), despite use of anti- hypertensive medicinal products, consider carbozantinib dose reduction. For patients who develop severe hypertension despite dose reduction and antihypertensives, cabozantinib should be discontinued. Version 1 (December 2017) Page 3 of 7 Renal Cell-Cabozantinib (60mg-tablet) Palmer- Plantar Erythrodesia Encourage regular use of moisturizers to hand and feet regularly. Advise minimizing activities that put pressure on feet or hands, as usually the pressure point areas are affected. Keeping skin cool is beneficial, avoiding extreme heat (such as strong sunlight or hot baths). Support use of non-deodorant, non-fragrance products. Consider products with anti-itch additions in pruritus, and exfoliating urea containing products in hyperkeratosis. Anti-dandruff shampoo may help in management of itchy scalp. Non-steroidal anti- inflammatory creams and analgesia may help but a 1-2 week dose interruption may be necessary for painful symptom. Proteinuria Monitor urinary protein prior to each cycle. Discontinue cabozantinib in patients who develop nephrotic syndrome. Regimen 28 day cycle until disease progression or intolerance (12 cycles will be set in ARIA) Drug Cabozantinib Dose 60mg Days 1-28 incl. Administration Oral Dose Information • The cabozantinib brand (Cabometyx) is licensed for the treatment of renal cell cancer. • Cabometyx (cabozantinib) tablets and Cometriq (cabozantinib) capsules are not bioequivalent and should not be used interchangeably. If a patient must switch from cabozantinib capsules to cabozantinib tablets, the patient should continue at a Cabometyx dose not to exceed 60 mg or the current Cometriq dose (whichever is lower). • Cabozantinib tablets are available as 20mg, 40mg and 60mg tablets Administration Information • Cabozantinib tablets should be swallowed whole and not crushed. Patients should be instructed to not eat anything for at least 2 hours before through 1 hour after taking the tablets. • If a patient misses a dose, the missed dose should not be taken if it is less than 12 hours before the next dose. Additional Therapy • Antiemetics Version 1 (December 2017) Page 4 of 7 Renal Cell-Cabozantinib (60mg-tablet) - metoclopramide 10mg three times a day when required oral Additional Information • The National Patient Safety Agency alert NPSA/2008/RRR001 must be followed when prescribing, dispensing or administering oral chemotherapy. • It must be made clear to all staff, including those in the community, that this is a course of oral chemotherapy that must be prescribed by specialist oncology professionals. • Patients should be assessed for suitability for oral chemotherapy prior to starting treatment. • Cabozantinib is associated with many drug interactions. Always check before prescribing. Coding • Procurement – X71.5 • Delivery – X73.1 References 1. National Institute for Health and Clinical Excellence. Technology Appraisal 463. Cabozantinib for previously treated advanced renal cell carcinoma. August 2017 DOH: London. Version 1 (December 2017) Page 5 of 7 Renal Cell-Cabozantinib (60mg-tablet) REGIMEN SUMMARY Cabozantinib (60mg-tablets) Day One Take Home Medicines 1. Cabozantinib 60mg once a day for 28 days oral Administration Instructions Oral chemotherapy. Cabometyx (cabozantinib) tablets and Cometriq (cabozantinib) capsules are not bioequivalent and should not be used interchangeably. If a patient must switch from cabozantinib capsules to cabozantinib tablets, the patient should continue at a Cabometyx dose not to exceed 60 mg or the current Cometriq dose (whichever is lower). Cabozantinib tablets should be swallowed whole and not crushed. Patients should be instructed to not eat anything for at least 2 hours before through 1 hour after taking the tablets. If a patient misses a dose, the missed dose should not be taken if it is less than 12 hours before the next dose. Available as 60mg, 40mg and 20mg tablets, please ensure dose modifications occur in multiples of these strengths. Version 1 (December 2017) Page 6 of 7 Renal Cell-Cabozantinib (60mg-tablet) DOCUMENT CONTROL Version Date Amendment Written By Approved By 1 December 2017 None Dr Deborah Wright Dr Mathew Wheater Pharmacist Consultant Oncologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury Hospitals NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. Version 1 (December 2017) Page 7 of 7 Renal Cell-Cabozantinib (60mg-tablet)
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