Thames Valley. Thames Valley Chemotherapy Regimens Rare Tumours

Transcription

1 Chemotherapy Regimens Rare Tumours

2 Notes from the editor These regimens are available on the Network website Any correspondence about the regimens should be addressed to: Sally Coutts, Cancer Pharmacist, Tel: to leave a message Acknowledgements These regimens have been compiled by the network pharmacy group in collaboration with the Chemotherapy Cross Cutting Group Andrew Weaver, Consultant Oncologist, OUH Denis Talbot, Consultant Medical Oncologist, OUH Paul Rogers, Consultant Oncologist, RBFT Cancer Network. All rights reserved. Not to be reproduced in whole or part without permission of the copyright owner. Chemotherapy RegimenRegimens Rare Cancers 2 of 44

3 Chemotherapy Regimens Rare Tumours Network chemotherapy regimens used in the management of Rare Tumours or are rarely used regimens All regimens in this document must include references and do not come under the remit of a particular PODG. published: October 2015 of review: October 2017 Chemotherapy regimens Name of regimen Indication Page List of amendments in this version 4 Mitotane Metastatic adrenal cancer 5 Everolimus Neuroendocrine 7 Streptozocin & Modified De Gramont Neuroendocrine 9 Streptozocin & Capecitabine Neuroendocrine 11 Streptozocin/ Cisplatin/ 5FU (FCiSt) Neuroendocrine 13 inpatient Sunitinib Neuroendocrine 16 Temozolomide & Capecitabine Neuroendocrine 18 Capecitabine Neuroendocrine, Carcinoid tumour 20 Cisplatin & Etoposide Neuroendocrine, Thymoma 22 Doxorubicin/ Cisplatin/ Vincristine/ cylophosphamide (ADOC) Cyclophosphamide, Vincristine and Dacarbazine (CVD) Cabozantinib Thymoma 24 Thymoma, Thyroid cancer, 26 Thyroid cancer Doxorubicin (Thyroid) Thyroid cancer 28 Sorafenib Thyroid cancer 29 Vandetanib Thyroid cancer 31 5-FU/ Cyclophosphamide/ Parathyroid carcinoma 33 Dacarbazine Doxorubicin/ Cisplatin/ Etoposide Adrenal gland 35 (EDP) Cisplatin, Methotrexate and Metastatic penile cancer 37 Bleomycin (PMB) Pre and post-hydration regimen 39 Common Toxicity Criteria 40 Chemotherapy RegimenRegimens Rare Cancers 3 of 44

4 List of amendments in this version Regimen type: Rare Tumours due for review: October 2017 Previous number: 2.3 This version number: Table 1 Amendments Page Action Type Amendment Made/ asked by Table 2 New regimens to be approved and checked included in this version Name of regimen Indication Reason / Proposer Cabozantinib Thyroid CDF Chemotherapy RegimenRegimens Rare Cancers 4 of 44

5 Mitotane (Lysodren) Indication: the treatment of inoperable metastatic adrenal cortical carcinoma of both functional and nonfunctional types, neuroendocrine tumors DRUG REGIMEN The recommended treatment schedule is to start the patient at 2 to 6 g of mitotane per day in divided doses, either three or four times a day. Doses are usually increased incrementally to 9 to 10 g per day. (mitotane is available as 500 mg scored tablets) Treatment should be continued as long as clinical benefits are observed. Maintenance of clinical status or slowing of growth of metastatic lesions can be considered clinical benefits if they can clearly be shown to have occurred. If no clinical benefits are observed after 3 months at the maximum tolerated dose, the case would generally be considered a clinical failure. However, 10% of the patients who showed a measurable response required more than 3 months at the MTD. A number of patients have been treated intermittently with treatment being restarted when severe symptoms have reappeared. Patients often do not respond after the third or fourth such course. Experience accumulated to date suggests that continuous treatment with the maximum possible dosage of mitotane is the best approach DOSE MODIFICATIONS If severe side effects appear, the dose should be reduced until the maximum tolerated dose is achieved. If the patient can tolerate higher doses and improved clinical response appears possible, the dose should be increased until adverse reactions interfere. Experience has shown that the maximum tolerated dose (MTD) will vary from 2 to 16 g per day, but has usually been 9 to 10 g per day. The highest doses used in the studies to date were 18 to 19 g per day. MISSED DOSES: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not "doubleup" the dose to catch up. INVESTIGATIONS Routine Blood test as required Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion LFTs Mitotane levels [patients at ORH are sent to Baggot & Drake ward in OCDEM with appropriate biochemistry form blood is spun down and sent to France for analysis. Usually takes at least 14 days to get result back]. Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy. Mitotane Clinical Group Chair Authorisation: Page 1 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 5 of 44

6 CONCURRENT MEDICATION Mitotane has been reported to accelerate the metabolism of warfarin by the mechanism of hepatic microsomal enzyme induction, leading to an increase in dosage requirements for warfarin. Therefore, closely monitor patients for a change in anticoagulant dosage requirements when administering mitotane to patients on coumarin-type anticoagulants. In addition, mitotane should be given with caution to patients receiving other drugs susceptible to the influence of hepatic enzyme induction. ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS A very high percentage of patients treated with LYSODREN have shown at least one type of side effect. The main types of adverse reactions consist of the following: Gastrointestinal disturbances, which consist of anorexia, nausea or vomiting, and in some cases diarrhea occur in about 80% of the patients. Central Nervous System side effects occur in 40% of the patients. These consist primarily of depression as manifested by lethargy and somnolence (25%), and dizziness or vertigo (15%). Skin toxicity has been observed in about 15% of the cases. These skin changes consist primarily of transient skin rashes which do not seem to be dose related. In some instances, this side effect subsided while the patients were maintained on the drug without a change of dose. Infrequently occurring side effects involve the eye (visual blurring, diplopia, lens opacity, toxic retinopathy); the genitourinary system (hematuria, hemorrhagic cystitis, and albuminuria); cardiovascular system (hypertension, orthostatic hypotention, and flushing); and some miscellaneous effects including generalized aching, hyperpyrexia. patient info sheets and drug characteristics on the Lysodren website : REFERENCES 1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA 1985; 253(11) National Study Commission on Cytotoxic Exposure Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1: Jones, RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA A Cancer Journal for Clinicians 1983; (Sept/Oct) American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic Drugs in Hospitals. Am J Hosp Pharm 1990; 47: Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines). Am J Health-Syst Pharm 1996;53: Fassnacht M et al Combination chemotherapy in advanced adrenocortical carcinoma. NEJM 366;23 nejm.2190 org june 7, 2012 Mitotane Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 6 of 44

7 Everolimus Indication: Pancreatic neuroendocrine tumour 2 nd line Ensure funding is available for patient prior to prescribing. DRUG REGIMEN Day 1 Everolimus 10mg orally daily Cycle Frequency: Daily for 4 weeks continuously until progression DOSE MODIFICATIONS Everolimus: Any dose modifications should be discussed with a Consultant. Renal impairment No dose adjustment is required in patients with renal impairment. Hepatic impairment For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mg daily. Everolimus has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) and is not recommended for use in this patient population. INVESTIGATIONS Routine Blood test 1) Blood results required before drug administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 Routine bloods: FBC, renal function, liver function. Random blood sugar, lipid profile; if elevated to repeat on fasting blood Baseline imaging: CT and/or MRI at baseline and every three months. 2) Non urgent tests Tests relating to disease response/progression CONCURRENT MEDICATION ANTIEMETIC POLICY Minimal emetic risk Everolimus Clinical Group Chair Authorisation: : Page 1 of 2 Published: October 2013 Review: October 2014 Chemotherapy RegimenRegimens Rare Cancers 7 of 44

8 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Increased glucose, lipids and triglycerides Decreased haemoglobin, lymphocytes, neutrophils and platelets Hypersensitivity reactions Pneumonitis, Infections Oral ulceration REFERENCES 1. SPC May 2010 Everolimus Clinical Group Chair Authorisation: : Page 1 of 2 Published: October 2013 Review: October 2014 Chemotherapy RegimenRegimens Rare Cancers 8 of 44

9 STREPTOZOCIN + Modified DeGramont Indication: Neuroendocrine DRUG REGIMEN Day 1 STREPTOZOCIN 1000mg/m 2 IV infusion in 250ml sodium chloride 0.9% over 1 hour CALCIUM LEVOFOLINATE 175mg in 250ml glucose 5% over 2 hours FLUOROURACIL 400mg/m 2 IV Bolus FLUOROURACIL 2800mg/m 2 continuous infusion over 46 hours Day 8 STREPTOZOCIN 1000mg/m 2 IV infusion in 250ml sodium chloride 0.9% over 1 hour Cycle Frequency: Repeat every 14 days up to 12 cycles subject to tolerance and response NB Calcium folinate, folinic acid, leucovorin, calcium leucovorin are all equivalent and NOT the same as Calcium levofolinate. Calcium levofolinate is the single isomer of folinic acid and the dose is generally half that of calcium folinate. If calcium levofolinate is not available calcium folinate (leucovorin) 350mg may be used instead. DOSE MODIFICATIONS Streptozocin: Discuss if serum creatinine > 150 micromol/l Streptozocin is only available on a named patient basis. (ORH - Baxter need to be informed prior to use so that stocks may be ordered for whole course) Fluorouracil: Consider dose reduction in severe renal impairment only Bilirubin > 85micromol/L or ALT/AST >180 omit Clinical decision: Moderate hepatic impairment; reduce initial dose by 1/3. Severe hepatic impairment, reduce initial dose by 1/2. Increase dose if no toxicity Strep MDeG Clinical Group Chair Authorisation: Page 1 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 9 of 44

10 INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 GFR assessed using 51 Cr-EDTA result or calculated creatinine clearance at the Consultant s discretion. LFTs 2) Non urgent tests Tests relating to disease response/progression Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy. CONCURRENT MEDICATION Hickman line pack with cycle ONE only Drugs to be AVOIDED CONCURRENTLY phenytoin ANTIEMETIC POLICY High emetogenic risk days 1 and 8 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (hand foot syndrome) causing red palms and soles treat with pyridoxine 50mg tds (can be increased to 150mg po tds) Mucositis use routine mouth care Diarrhoea treat with loperamide or codeine Streptozocin can cause burning along veins during rapid infusion Streptozocin can cause severe hypoglycaemia. Monitor BMs if signs of hypoglycaemia occur. Streptozocin has also been associated with renal tubule toxicity, hepatotoxicity and anaemia. REFERENCES 1) Eriksson. B., Oberg. K An update of medical treatment of malignant endocrine pancreatic tumours. Acta Oncol. 32: ) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment. 2009, The North London Cancer Network. 3) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in hepatic impairment. 2009, The North London Cancer Network. Strep MDeG Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 10 of 44

11 STREPTOZOCIN + CAPECITABINE Indication: Neuroendocrine DRUG REGIMEN Day 1 STREPTOZOCIN 1000mg/m 2 IV infusion in 250ml sodium chloride 0.9% over 1 hour CAPECITABINE 625mg/m2 po twice daily days 1 to 21 Cycle Frequency: Repeat every 21 days for 6 cycles DOSE MODIFICATIONS Streptozocin: Discuss if serum creatinine > 150 micromol/l Streptozocin is only available on a named patient basis. (ORH - Baxter need to be informed prior to use so that stocks may be ordered for whole course) Capecitabine: Check CrCl prior to every cycle CrCl (ml/min) > 50 give 100% dose CrCl (ml/min) give 75% dose CrCl (ml/min) < 30 contraindicated Hepatic impairment SPC recommends interruption of capecitabine therapy if treatment related elevations in bilirubin of > 3 x ULN or ALT/AST > 2.5 x ULN occur. Treatment may be resumed when bilirubin decreases to < 3 x ULN or hepatic aminotransferases decrease to < 2.5 x ULN. Please refer to summary of product characteristics (SPC) for detailed guidance on dose modifications due to toxicity (including plantar palmar, erythema and gastro intestinal toxicity). Toxicity can be managed by symptomatic treatment and/or modification of the dose (treatment interruption or dose reduction). Once the dose has been reduced it should not be increased at a later time. Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and handfoot syndrome. Strep Cape Clinical Group Chair Authorisation: Page 1 of 3 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 11 of 44

12 Toxicity Grades Dose changes within Dose adjustment for next a treatment cycle cycle/dose (% of startingdose) * Grade 1 Maintain dose level Maintain dose level * Grade 2-1st appearance Interrupt until resolved to grade % - 2nd appearance Interrupt until resolved to grade % - 3rd appearance Interrupt until resolved to grade % - 4th appearance Discontinue treatment permanently Not applicable * Grade 3-1st appearance Interrupt until resolved to grade % - 2nd appearance Interrupt until resolved to grade % - 3rd appearance Discontinue treatment permanently Not applicable * Grade 4-1st appearance Discontinue permanently OR 50% If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade nd appearance Discontinue permanently Not applicable INVESTIGATIONS Routine Blood test 2) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 GFR assessed using 51 Cr-EDTA result or calculated creatinine clearance at the Consultant s discretion. LFTs 2) Non urgent tests Tests relating to disease response/progression Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy. CONCURRENT MEDICATION Hickman line pack with cycle ONE only Drugs to be AVOIDED CONCURRENTLY phenytoin ANTIEMETIC POLICY High emetogenic risk day 1 Strep Cape Clinical Group Chair Authorisation: Page 2 of 3 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 12 of 44

13 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (hand foot syndrome) causing red palms and soles treat with pyridoxine 50mg tds (can be increased to 150mg po tds) Mucositis use routine mouth care Diarrhoea treat with loperamide or codeine Streptozocin can cause burning along veins during rapid infusion Streptozocin can cause severe hypoglycaemia. Monitor BMs if signs of hypoglycaemia occur. Streptozocin has also been associated with renal tubule toxicity, hepatotoxicity and anaemia. REFERENCES 1) NET01 regimenregimen 2) Eriksson. B., Oberg. K An update of medical treatment of malignant endocrine pancreatic tumours. Acta Oncol. 32: ) Royal Free Oncology RegimenRegimen based on ASCO abstract 100; 2004, D.Sarker and.williams et al 5FU, CISPLATIN and STROPTOZCIN (FCiST) an effective new regimen for advanced pancreatic neuroendocrine tumours 4) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment. 2009, The North London Cancer Network. 5) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in hepatic impairment. 2009, The North London Cancer Network. Strep Cape Clinical Group Chair Authorisation: Page 3 of 3 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 13 of 44

14 STREPTOZCIN + CISPLATIN + 5FU (FCiST) inpatient Indication: Neuroendocrine DRUG REGIMEN Day 1 CALCIUM FOLINATE 45mg in 250ml sodium chloride 0.9% over 2 hours FLUOROURACIL 500mg/m 2 IV bolus STREPTOZOCIN 1000 mg/m 2 in 1000ml sodium chloride 0.9% infusion over 2 hours Pre hydration CISPLATIN 70 mg/m 2 in 1000ml sodium chloride 0.9% infusion over 4 hours Post hydration Cycle Frequency: Repeat day 21 for 6 cycles subject to tolerance and response NB Calcium folinate, folinic acid, leucovorin, calcium leucovorin are all equivalent and NOT the same as Calcium levofolinate. Calcium levofolinate is the single isomer of folinic acid and the dose is generally half that of calcium folinate. NB Patients with a BSA >2m 2 calcium folinate should be 20mg/m 2 DOSE MODIFICATIONS Fluorouracil: Consider dose reduction in severe renal impairment only Bilirubin > 85micromol/L or ALT/AST >180 omit Clinical decision: Moderate hepatic impairment; reduce initial dose by 1/3. Severe hepatic impairment, reduce initial dose by 1/2. Increase dose if no toxicity Streptozocin: Discuss if serum creatinine > 150 micromol/l Streptozocin is only available on a named patient basis. [ORH- Baxter need to be informed prior to use so that stocks may be ordered for whole course] Cisplatin: GFR > 60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR < 45ml/min consider carboplatin Discuss with Consultant re omission / substitution If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration FCiST Clinical Group Chair Authorisation: Page 1 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 14 of 44

15 INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.0 < 1.0 WBC x 10 9 /L 3.0 <3.0 GFR assessed using 51 Cr-EDTA result or calculated creatinine clearance at the Consultant s discretion. 2) Non-urgent tests Tests relating to disease response/progression Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy. CONCURRENT MEDICATION Ensure adequate pre-and post-hydration prescribed as per TVCN regimens. If fluid balance is > 2L positive after 8 hours post hydration OR urine output is < 100ml/hour during IV administration post Cisplatin give mg Furosemide PO/IV OR 200ml Mannitol 10% IV Drugs to be AVOIDED CONCURRENTLY Phenytoin ANTI-EMETIC POLICY High emetogenic risk ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (hand foot syndrome) causing red palms and soles treat with pyridoxine 50mg tds (can be increased to 150mg po tds) Mucositis use routine mouthcare Diarrhoea treat with codeine or loperamide Nephrotoxicity ensure adequate pre and post hydration is prescribed Cisplatin- Patients may complain of metallic taste during administration Streptozocin can cause burning along veins during rapid infusion Streptozocin has also been associated with renal tubule toxicity, hepatoxicity and anaemia. Streptozocin can cause hypoglycaemia. Monitor BMs if signs of hypoglycaemia occur. REFERENCES 1) Royal Free Oncology RegimenRegimen based on ASCO abstract 100; 2004, D.Sarker and.williams et al 5FU, CISPLATIN and STROPTOZCIN (FCiST) an effective new regimen for advanced pancreatic neuroendocrine tumours 2) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment. 2009, The North London Cancer Network. 3) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in hepatic impairment. 2009, The North London Cancer Network. FCiST Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 15 of 44

16 Sunitinib Indication: Pancreatic neuroendocrine carcinoma, no previous VEGF targeted therapy Ensure Individual funding is available before being prescribed. DRUG REGIMEN Day 1 Sunitinib 37.5mg orally daily for 4 weeks Cycle Frequency: Daily for 28 days DOSE MODIFICATIONS Sunitinib: Any dose modifications should be discussed with a Consultant. Renal impairment No data available for use in impaired renal function Hepatic impairment No dose adjustment is required in mild or moderate hepatic impairment. No data available for severe hepatic impairment INVESTIGATIONS Routine Blood test 1) Blood results required before drug administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 Blood tests should initially be performed 4 weekly, but later in the treatment course can be done less often in stable patients. Creatinine Liver function tests (LFT) Thyroid function tests Ask GP to monitor blood pressure on a regular basis, weekly initially 2) Non urgent tests Tests relating to disease response/progression Sunitinib Clinical Group Chair Authorisation: Page 1 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 16 of 44

17 CONCURRENT MEDICATION ANTIEMETIC POLICY Minimal emetic risk ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Skin - skin discolouration and depigmentation of the hair and skin may occur. Palmar / plantar syndrome Neutropenia Mouth pain / irritation / sensitivity may occur Haemorrhage an increased risk of bleeding may occur. Hypertension treatment induced hypertension. Sunitinib treatment should temporarily be suspended until hypertension is controlled. Gastrointestinal serious gastrointestinal complications including gastrointestinal perforation have occurred rarely. Hypothyroidism REFERENCES 1. SPC September Raymond E et al,sunitinib malate for the treatment of pancreatic neuroendocrine tumours, N Engl J Med 2011; 364: February 10, 2011DOI: /NEJMoa Sunitinib Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 17 of 44

18 TEMOZOLOMIDE + CAPECITABINE Indication: Neuroendocrine DRUG REGIMEN Days 1 to 14 CAPECITABINE 1000mg twice daily for 14 days Days 10 to 14 TEMOZOLOMIDE 200 mg/m 2 once daily for 5 days Cycle Frequency: Every 28 days for 6 cycles subject to tolerance and response NB Capecitabine available as 150 mg and 500 mg tablets NB Temozolomide available as 5 mg, 20 mg, 100 mg or 250 mg capsules DOSE MODIFICATIONS Capecitabine: Check CrCl prior to every cycle CrCl (ml/min) > 50 give 100% dose give 75% dose < 30 contraindicated Hepatic impairment SPC recommends interruption of capecitabine therapy if treatment related elevations in bilirubin of > 3 x ULN or ALT/AST > 2.5 x ULN occur. Treatment may be resumed when bilirubin decreases to < 3 x ULN or hepatic aminotransferases decrease to < 2.5 x ULN. Please refer to summary of product characteristics for detailed guidance on dose modifications due to toxicity (including plantar palmar, erythema and gastrointestinal toxicity). Toxicity can be managed by symptomatic treatment and/or modification of the dose (treatment interruption or dose reduction). Once the dose has been reduced it should not be increased at a later time. Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and handfoot syndrome. Toxicity Grades Dose changes within Dose adjustment for next a treatment cycle cycle/dose (% of startingdose) * Grade 1 Maintain dose level Maintain dose level * Grade 2-1st appearance Interrupt until resolved to grade % - 2nd appearance Interrupt until resolved to grade % - 3rd appearance Interrupt until resolved to grade % - 4th appearance Discontinue treatment permanently Not applicable * Grade 3-1st appearance Interrupt until resolved to grade % - 2nd appearance Interrupt until resolved to grade % - 3rd appearance Discontinue treatment permanently Not applicable * Grade 4-1st appearance Discontinue permanently OR 50% If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade nd appearance Discontinue permanently Not applicable Tem + Cape Clinical Group Chair Authorisation: Page 1 of 3 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 18 of 44

19 Temozolomide: Dose range mg/m² days 10 to 14 of each 28 day cycle. if neutrophils <1.5 AND the platelets <100 on day 28 consider delaying treatment if neutrophils <1.0 OR the platelets <50 during any cycle the next cycle should be reduced to the next dose level; 150mg/m² then 100mg/m² INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion 2) Non-urgent tests Tests relating to disease response/progression Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy. CONCURRENT MEDICATION Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increased phenytoin plasma concentrations. Capecitabine enhances the anticoagulant effects of warfarin. Patients taking warfarin concomitantly with capecitabine must have regular monitoring of INR. ANTIEMETIC POLICY Low emetogenic risk days 1 to 9 Moderate emetogenic risk days 10 to 14 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (hand foot syndrome) causing red palms and soles treat with pyridoxine 50mg tds. Diarrhoea treat with loperamide or codeine Hepatic injury, including fatal hepatic failure, has been reported in patients treated with temozolomide. Baseline liver function tests should be performed prior to treatment initiation. If abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should be repeated midway during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For patients with significant liver function abnormalities, physicians should assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with temozolomide. Temozolomide should be taken on an empty stomach. Cardiotoxicity- special attention is advisable in treating patients with a history of heart disease, arrhythmias or angina pectoris or those who develop chest pain during treatment with capecitabine. Tem + Cape Clinical Group Chair Authorisation: Page 2 of 3 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 19 of 44

20 REFERENCES 1. Temozolomide Summary of Product Characteristics emc 2. JCO abstract vol.24 No Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment. 2009, The North London Cancer Network. 4. Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in hepatic impairment. 2009, The North London Cancer Network. Tem + Cape Clinical Group Chair Authorisation: Page 3 of 3 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 20 of 44

21 CAPECITABINE Indication: Neuroendocrine and carcinoid. This is an unlicensed indication DRUG REGIMEN CAPECITABINE *1000mg/m 2 twice daily (2000mg/m 2 /day) for 14 days followed by a 7 day rest *Dose may be increased to 1250mg/m2 twice daily (2500mg/m 2 /day) for 14 days followed by a 7 day rest. Cycle Frequency: Every 21 days for 6 cycles subject to tolerance and response DOSE MODIFICATIONS Capecitabine: Check CrCl prior to every cycle CrCl (ml/min) > 50 give 100% dose give 75% dose < 30 contraindicated Hepatic impairment SPC recommends interruption of capecitabine therapy if treatment related elevations in bilirubin of > 3 x ULN or ALT/AST > 2.5 x ULN occur. Treatment may be resumed when bilirubin decreases to < 3 x ULN or hepatic aminotransferases crease to < 2.5 x ULN. Please refer to summary of product characteristics for detailed guidance on dose modifications due to toxicity (including plantar palmar, erythema and gastrointestinal toxicity). Toxicity can be managed by symptomatic treatment and/or modification of the dose (treatment interruption or dose reduction). Once the dose has been reduced it should not be increased at a later time. Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and handfoot syndrome. Toxicity Grades Dose changes within Dose adjustment for next a treatment cycle cycle/dose (% of startingdose) * Grade 1 Maintain dose level Maintain dose level * Grade 2-1st appearance Interrupt until resolved to grade % - 2nd appearance Interrupt until resolved to grade % - 3rd appearance Interrupt until resolved to grade % - 4th appearance Discontinue treatment permanently Not applicable * Grade 3-1st appearance Interrupt until resolved to grade % - 2nd appearance Interrupt until resolved to grade % - 3rd appearance Discontinue treatment permanently Not applicable * Grade 4-1st appearance Discontinue permanently OR 50% If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade nd appearance Discontinue permanently Not applicable Capecitabine Clinical Group Chair Authorisation: Dr C Blesing Page 1 of 2 Published: October 2015 Chemotherapy RegimenRegimens Review: October Rare 2017 Cancers 21 of 44

22 INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion 2) Non urgent tests Tests relating to disease response/progression Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy. CONCURRENT MEDICATION Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increased phenytoin plasma concentrations. Capecitabine enhances the anticoagulant effects of warfarin. Patients taking warfarin concomitantly with capecitabine must have regular monitoring of INR. ANTIEMETIC POLICY Low emetogenic risk ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Palmar plantar (hand foot syndrome) causing red palms and soles treat with pyridoxine 50mg tds. Diarrhoea treat with loperamide or codeine Cardiotoxicity- special attention is advisable in treating patients with a history of heart disease, arrhythmias or angina pectoris or those who develop chest pain during treatment with capecitabine. REFERENCES 1) Cancer Research (Dec 2003vs 1) amended November An Open Label Phase II Study of Capecitabine in the Treatment of Neuroendocrine Tumours 2) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment. 2009, The North London Cancer Network. 3) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in hepatic impairment. 2009, The North London Cancer Network. Capecitabine Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 22 of 44

23 CISPLATIN and ETOPOSIDE Indication: Neuroendocrine Thymoma DRUG REGIMEN Day 1 Pre-hydration ETOPOSIDE 100mg/m 2 infusion in 1000ml sodium chloride 0.9% over 60 minutes CISPLATIN 75mg/m 2 infusion in 1000ml sodium chloride 0.9% over 2 hours (daypatient) or 4 hours (inpatient) Post hydration Day 2 ETOPOSIDE 100mg/m 2 infusion in 1000ml sodium chloride 0.9% over 60 minutes Day 3 ETOPOSIDE 100mg/m 2 infusion in 1000ml sodium chloride 0.9% over 60 minutes Cycle Frequency: Every 21 days for 6 cycles subject to tolerance and response Etoposide doses <200mg may be administered in 500ml sodium chloride 0.9% DOSE MODIFICATIONS Cisplatin: GFR > 60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR < 45ml/min omit dose If patient complains of tinnitus, tingling of fingers and/or toes, discuss. Etoposide: CrCl > 50ml/min give 100% dose CrCl 15-50ml/min give 75% dose CrCl <15ml/min give 50% dose Bilirubin 26-51micromol/L or ALT/AST u/L give 50% dose Bilirubin >51micromol/L or ALT/AST >180u/L Clinical decision INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion 2) Non urgent tests Tests relating to disease response/progression Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy. Cis + Etop Clinical Group Chair Authorisation: Page 1 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 23 of 44

24 CONCURRENT MEDICATION Ensure adequate pre-and post-hydration prescribed as per TVCN rregimens. Daypatient: If urine output is < 100ml/hour or if patient gains >2kg weight during IV administration post Cisplatin give 20-40mg Furosemide PO/IV or 200ml Mannitol 10% IV Inpatient: If fluid balance is > 2L positive after 8 hours post hydration OR urine output is < 100ml/hour during IV administration post Cisplatin give mg Furosemide PO/IV OR 200ml Mannitol 10% IV ANTIEMETIC POLICY Highly emetogenic day 1 Low emetogenic risk days 2, 3 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Nephrotoxicity ensure adequate pre and post hydration is prescribed. Ototoxicity assess patient for tinnitus or hearing abnormalities. Cisplatin- Patients may complain of metallic taste during administration REFERENCES 1) Kaltsas et al, Endocrine Reviews 25 (3): , ) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment. 2009, The North London Cancer Network. 3) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in hepatic impairment. 2009, The North London Cancer Network. Cis + Etop Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 24 of 44

25 DOXORUBICIN + CISPLATIN + VINCRISTINE + CYCLOPHOSPHAMIDE (ADOC) Indication: Thymoma DRUG REGIMEN Day 1 DOXORUBICIN 40mg/m 2 IV bolus Pre-hydration CISPLATIN 50mg/m 2 infusion in 1000ml sodium chloride 0.9% over 2 hours (daypatient) or 4 hours (inpatient) Post hydration Day 4 VINCRISTINE 0.6mg/m 2 (maximum dose 1.2mg) IV in 50ml sodium chloride 0.9% over 10 minutes CYCLOPHOPHAMIDE 700 mg/m 2 IV bolus Cycle Frequency: Every 21 days for 6 cycles subject to tolerance and response DOSE MODIFICATIONS Cisplatin: GFR > 60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR < 45ml/min omit dose If patient complains of tinnitus, tingling of fingers and/or toes, discuss. Doxorubicin: Dose reduce in severe renal impairment. Bilirubin 20-50micromol/L give 50% dose Bilirubin 51-85micromol/L give 25% dose Bilirubin >85micromol/L omit If ALT/AST is 2-3 x ULN give 75% dose If ALT/AST is >3 x ULN give 50% dose Maximum cumulative dose = 450mg/m 2 (in normal cardiac function) = 400mg/m 2 (in combination with cardiac radiation treatment or in patients with cardiac risk factors) Cyclophosphamide: GFR >20ml/min give 100% dose GFR 10-20ml/min give 75% dose GFR <10ml/min give 50% dose Vincristine: Bilirubin 25-50micromol/L or normal ALT/AST give 50% dose Bilirubin >51micromol/L and ALT/AST >180u/L omit In the presence of motor weakness or severe sensory symptoms, discuss reducing or withholding vincristine with a consultant. ADOC Clinical Group Chair Authorisation: Page 1 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 25 of 44

26 INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 Creatinine clearance (GFR) or EDTA at the Consultants discretion ECG (possible ECHO) required if patient has preexisting cardiac disease 2) Non urgent tests Tests relating to disease response/progression Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy. CONCURRENT MEDICATION Ensure adequate pre-and post-hydration prescribed as per TVCN regimens. Daypatient: If urine output is < 100ml/hour or if patient gains >2kg weight during IV administration post Cisplatin give 20-40mg Furosemide PO/IV or 200ml Mannitol 10% IV Inpatient: If fluid balance is > 2L positive after 8 hours post hydration OR urine output is < 100ml/hour during IV administration post Cisplatin give mg Furosemide PO/IV OR 200ml Mannitol 10% IV ANTIEMETIC POLICY Highly emetogenic. day 1 Moderate emotogenic risk day 4 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Nephrotoxicity ensure adequate pre and post hydration is prescribed. Ototoxicity assess patient for tinnitus or hearing abnormalities. Cardiotoxicity monitor cardiac function. Doxorubicin may be stopped in future cycles if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue Cyclophosphamide may irritate bladder, drink copious volumes of water. Vincristine may cause neurotoxicity. REFERENCES 1)Fornasiero et al. J Clin Oncol 1990 Aug; 8(8): ) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment. 2009, The North London Cancer Network. 3) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in hepatic impairment. 2009, The North London Cancer Network. ADOC Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 26 of 44

27 CYCLOPHOSPHAMIDE, VINCRISTINE and DACARBAZINE (CVD) Indication: Thyroid Ca and thymoma DRUG REGIMEN Day 1 CYCLOPHOSPHAMIDE 750mg/m 2 IV bolus VINCRISTINE 1.4mg/m 2 (max dose 2mg) in 50ml sodium chloride 0.9% over 10minutes DACARBAZINE 600mg/m 2 in 500ml sodium chloride 0.9% infusion over 1hour Day 2 DACARBAZINE 600mg/m 2 in 500ml sodium chloride 0.9% infusion over 1hour Cycle Frequency: Every 21 days for 6 cycles subject to tolerance and response DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar Cyclophosphamide: GFR >20ml/min give 100% dose GFR 10-20ml/min give 75% dose GFR <10ml/min give 50% dose Vincristine: Bilirubin 25-50micromol/L or normal ALT/AST give 50% dose Bilirubin >51micromol/L and ALT/AST >180u/L omit In the presence of motor weakness or severe sensory symptoms, discuss reducing or withholding vincristine with a consultant. Dacarbazine: CrCl 45-60ml/min give 80% dose CrCl 30-45ml/min give 75% dose CrCl <30ml/min give 70% dose Can be hepatotoxic consider dose reduction. INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion LFTs CVD Clinical Group Chair Authorisation: Page 1 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 27 of 44

28 2) Non-urgent tests Tests relating to disease response/progression Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy. CONCURRENT MEDICATION ANTIEMETIC POLICY Highly emetogenic ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Dacarbazine- Patients have experienced an influenza type syndrome of fever, myalgias and malaise usually occurring after large single doses and approximately seven days after treatment lasting 7-21 days. Increases in AST, ALT, alk phos, LDH. Levels usually return to normal within two weeks Dacarbazine- Anaphylaxis can occur very rarely following administration. Dacarbazine- Photosensitivity reactions may occur rarely. Cyclophosphamide may irritate bladder, drink copious volumes of water. Vincristine- may cause neuro-toxicity REFERENCES 1) Cancer 73 Issue(2), ) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment. 2009, The North London Cancer Network. 3) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in hepatic impairment. 2009, The North London Cancer Network. CVD Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 28 of 44

29 Cabozantinib (Thyroid) Indication: Medullary thyroid cancer, histologically confirmed, unresectable, locally advanced or metastatic medullary thyroid cancer, progressive, symptomatic disease. No previous tyrosine kinase therapy unless intolerant of vandetanib within 3 months of starting therapy and toxicity, which cannot be managed by dose delay or dose modification and in the absence of disease progression in vandetanib. Ensure funding has been obtained for each individual patient prior to prescribing. DRUG REGIMEN Day 1 Cabozantinib 140mg orally daily Cycle Frequency: Continuous Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs. DOSE MODIFICATIONS Cabozantinib: Withhold cabozantinib for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: - If previously receiving 140 mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) - If previously receiving 100 mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) - If previously receiving 60 mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue cabozantinib Permanently discontinue cabozantinib for any of the following: - development of visceral perforation or fistula formation - severe hemorrhage - serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction) - nephrotic syndrome - malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management - osteonecrosis of the jaw - reversible posterior leukoencephalopathy syndrome Renal impairment Cabozantinib should be used with caution in patients with renal impairment. Cabozantinib is not recommended for use in patients with severe renal impairment since there is limited data in patients with severe renal impairment, and safety and efficacy have not been established. Hepatic Impairment cabozantinib is not recommended for use in patients with moderate and severe hepatic impairment Cabozantnib thyroid Clinical Group Chair Authorisation: Page 1 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 29 of 44

30 INVESTIGATIONS Routine Blood test 1) Blood results required before drug administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 Blood tests should initially be performed 4 weekly, but later in the treatment course can be done less often in stable patients. Creatinine Liver function tests (LFT) Thyroid function tests Blood tests should initially be performed 4 weekly, but later in the treatment course can be done less often in stable patients. Ask GP to monitor blood pressure on a regular basis, weekly initially. 2) Non urgent blood tests Tests relating to disease response/progression ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Perforations and fistulas Haemorrhage Thrombotic events Wound complications Hypertension Osteonecrosis jaw REFERENCES 1. US prescribing information EU SPC Cabozantnib thyroid Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 30 of 44

31 DOXORUBICIN (Thyroid) Indication: Metastatic thyroid cancer (resistant to 131 I treatment) DRUG REGIMEN Day 1 DOXORUBICIN 75mg/m 2 IV bolus Cycle Frequency: Every 21 days for 6 cycles subject to tolerance and response DOSE MODIFICATIONS Doxorubicin: Dose reduce in severe renal impairment. Bilirubin 20-50micromol/L give 50% dose Bilirubin 51-85micromol/L give 25% dose Bilirubin >85micromol/L omit If ALT/AST is 2-3 x ULN give 75% dose If ALT/AST is >3 x ULN give 50% dose Maximum cumulative dose = mg/m 2 (in normal cardiac function) = 400 mg/m 2 (in patients with cardiac dysfunction or exposed to mediastinal irradiation) INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 ECG (possible ECHO) required if patient has preexisting cardiac disease 2) Non urgent tests Tests relating to disease response/progression Urine pregnancy test in women aged 12-55, unless sterilised or undergone a hysterectomy. CONCURRENT MEDICATION ANTIEMETIC POLICY Moderately emetogenic ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Cardiotoxicity monitor cardiac function. Doxorubicin may be stopped if signs of cardiotoxicity e.g. cardiac arrhythmias, pericardial effusion, tachycardia with fatigue. REFERENCES 1) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment. 2009, The North London Cancer Network. 2) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in hepatic impairment. 2009, The North London Cancer Network. Doxorubicin thyroid Clinical Group Chair Authorisation: Page 1 of 1 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 31 of 44

32 Sorafenib (Thyroid) Indication: Inoperable/metastatic papillary or follicular thyroid cancer Ensure funding has been obtained for each individual patient prior to prescribing. DRUG REGIMEN Day 1 Sorafenib 400mg orally twice daily Cycle Frequency: Continuous DOSE MODIFICATIONS Sorafenib: Renal impairment No dose adjustment is required in patients with mild, moderate or severe renal impairment. No data is available in patients requiring dialysis. Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised Hepatic impairment No dose adjustment is required in mild or moderate hepatic impairment. No data available for severe hepatic impairment INVESTIGATIONS Routine Blood test 1) Blood results required before drug administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 Blood tests should initially be performed 4 weekly, but later in the treatment course can be done less often in stable patients. Creatinine Liver function tests (LFT) 2) Non urgent blood tests Tests relating to disease response/progression CONCURRENT MEDICATION Take one hour before or two hours after meals Sorafenib thyroid Clinical Group Chair Authorisation: Page 1 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 32 of 44

33 ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Skin - Palmar / plantar syndrome Neutropenia Mouth pain / irritation / sensitivity may occur Haemorrhage an increased risk of bleeding may occur. Hypertension An increased incidence of arterial hypertension. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was amenable to management with standard antihypertensive therapy. Blood pressure should be monitored regularly and treated. Gastrointestinal gastrointestinal perforation have occurred rarely. REFERENCES SPC September 2010 Sorafenib thyroid Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 33 of 44

34 VANDETANIB (Thyroid) Indication: Treatment of locally advanced and unresectable or metastatic medullary thyroid cancer, who have had no previous biological therapy No previous tyrosine kinase therapy unless intolerant of cabozantinib within 3 months of starting therapy and toxicity which cannot be managed by dose delay or dose modification and in the absence of disease progression on cabozantinib Ensure funding has been obtained prior to prescribing DRUG REGIMEN Day 1 VANDETANIB 300mg once daily Cycle Frequency: Continuously until no longer benefiting from treatment DOSE MODIFICATIONS Vandetanib: Renal Vandetanib is not recommended for use in patients with moderate or severe renal impairment since there is limited data, and safety and efficacy have not been established Hepatic Vandetanib is not recommended for use in patients with hepatic impairment (serum bilirubin greater than 1.5 times upper limit of normal), since there is limited data in patients with hepatic impairment, and safety and efficacy have not been established. Pharmacokinetic data from volunteers, suggests that no change in starting dose is required in patients with mild, moderate or severe hepatic impairment QTc interval should be carefully assessed prior to initiation of treatment. In the event of common terminology criteria for adverse events (CTCAE) grade 3 or higher toxicity or prolongation of the ECG QTc interval, dosing with vandetanib should be at least temporarily stopped and resumed at a reduced dose when toxicity has resolved or improved to CTCAE grade 1. The 300 mg daily dose can be reduced to 200 mg (two 100 mg tablets), and then to 100 mg if necessary. The patient must be monitored appropriately. Due to the 19-day half-life, adverse reactions including a prolonged QTc interval may not resolve quickly. INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dl 10 < 10 Plt x 10 9 /L 100 < 100 Neutrophils x 10 9 /L 1.5 < 1.5 ECG (possible ECHO) required if patient has preexisting cardiac disease Vandetanib thyroid Clinical Group Chair Authorisation: Page 1 of 2 Published: October 2015 Chemotherapy RegimenRegimens Rare Cancers 34 of 44