Thames Valley

Thames Valley Regimens Rare Tumours

Thames Valley Notes from the editor

These regimens are available on the Network website www.tvscn.nhs.uk.

Any correspondence about the regimens should be addressed to: Sally Coutts, Cancer Pharmacist, Thames Valley email: [email protected] Tel: 01865 857158 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

© Thames Valley 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

Thames Valley Thames Valley 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. Date published: October 2015 Date 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 & Neuroendocrine 11 Streptozocin/ / 5FU (FCiSt) Neuroendocrine 13 inpatient Sunitinib Neuroendocrine 16 & Capecitabine Neuroendocrine 18 Capecitabine Neuroendocrine, Carcinoid tumour 20 Cisplatin & Neuroendocrine, Thymoma 22 / Cisplatin/ / Thymoma 24 cylophosphamide (ADOC) , Vincristine and Thymoma, Thyroid cancer, 26 (CVD) Cabozantinib 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, and Metastatic penile cancer 37 (PMB) Pre and post-hydration regimen 39 Common Toxicity Criteria 40 Chemotherapy RegimenRegimens – Rare Cancers 3 of 44

Thames Valley List of amendments in this version

Regimen type: Rare Tumours Date due for review: October 2017 Previous Version number: 2.3 This version number: 2.4

Table 1 Amendments

Page Action Amendment Made/ Type asked by

Table 2 New regimens to be approved and checked included in this version

Name of regimen Indication Reason / Proposer

Cabozantinib Thyroid CDF

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Thames Valley 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 "double- up" 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 Version Date 2.4 Review: October 2017

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Thames Valley 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, or , and in some cases 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 : http://www.lysodren- europe.com/index.aspx

REFERENCES 1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC 20402. 2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA 1985; 253(11)1590-1592. 3. 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 02115. 4. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1:426-428. 5. 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) 258-263. 6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic Drugs in Hospitals. Am J Hosp Pharm 1990; 47:1033-1049. 7. Controlling Occupational Exposure to . (OSHA Work-Practice Guidelines). Am J Health-Syst Pharm 1996;53:1669-1685. 8. Fassnacht M et al Combination chemotherapy in advanced . NEJM 366;23 nejm.2190 org june 7, 2012

Mitotane Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Version Date 2.4 Review: October 2017 Chemotherapy RegimenRegimens – Rare Cancers 6 of 44

Thames Valley Everolimus Indication: Pancreatic neuroendocrine tumour 2nd 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 109/L ≥100 < 100 Neutrophils x 109/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 Version 2.4 Date: Review: October 2014

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Thames Valley 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 Version 2.4 Date: Review: October 2014

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Thames Valley STREPTOZOCIN + Modified DeGramont

Indication: Neuroendocrine

DRUG REGIMEN Day 1 STREPTOZOCIN 1000mg/m2 IV infusion in 250ml sodium chloride 0.9% over 1 hour CALCIUM LEVOFOLINATE 175mg in 250ml glucose 5% over 2 hours 400mg/m2 IV Bolus FLUOROURACIL 2800mg/m2 continuous infusion over 46 hours

Day 8 STREPTOZOCIN 1000mg/m2 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 Version 2.4 Review: October 2017

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Thames Valley INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration

Give Discuss Hb x g/dL ≥10 < 10 Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5

GFR assessed using 51Cr-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. 1993 An update of medical treatment of malignant endocrine pancreatic tumours. Acta Oncol. 32: 203-208 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.

Strep MDeG Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Version Date 2.4 Review: October 2017

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Thames Valley STREPTOZOCIN + CAPECITABINE

Indication: Neuroendocrine

DRUG REGIMEN Day 1 STREPTOZOCIN 1000mg/m2 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) 30 - 50 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 Version 2.4 Review: October 2017

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Thames Valley 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 0-1 100% - 2nd appearance Interrupt until resolved to grade 0-1 75% - 3rd appearance Interrupt until resolved to grade 0-1 50% - 4th appearance Discontinue treatment permanently Not applicable * Grade 3 - 1st appearance Interrupt until resolved to grade 0-1 75% - 2nd appearance Interrupt until resolved to grade 0-1 50% - 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 0-1 - 2nd 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 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5

GFR assessed using 51Cr-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 Version Date 2.4 Review: October 2017

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Thames Valley 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. 1993 An update of medical treatment of malignant endocrine pancreatic tumours. Acta Oncol. 32: 203-208 3) 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 Version Date 2.4 Review: October 2017

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Thames Valley STREPTOZCIN + CISPLATIN + 5FU (FCiST) inpatient

Indication: Neuroendocrine

DRUG REGIMEN Day 1 CALCIUM FOLINATE 45mg in 250ml sodium chloride 0.9% over 2 hours 2 FLUOROURACIL 500mg/m IV bolus STREPTOZOCIN 1000 mg/m2 in 1000ml sodium chloride 0.9% infusion over 2 hours

Pre hydration CISPLATIN 70 mg/m2 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 >2m2 calcium folinate should be 20mg/m2

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 Version Date 2.4 Review: October 2017 Chemotherapy RegimenRegimens – Rare Cancers 14 of 44

Thames Valley INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration

Give Discuss Hb x g/dL ≥10 < 10 Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.0 < 1.0 WBC x 109/L ≥3.0 <3.0 GFR assessed using 51Cr-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 20 ¬ 40 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 Version Date 2.4 Review: October 2017

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Thames Valley 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 109/L ≥100 < 100 Neutrophils x 109/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 Version Date 2.4 Review: October 2017

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Thames Valley 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 2008 2. Raymond E et al,Sunitinib malate for the treatment of pancreatic neuroendocrine tumours, N Engl J Med 2011; 364:501-513 February 10, 2011DOI:10.1056/NEJMoa1003825

Sunitinib Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Version 2.4 Review: October 2017

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Thames Valley TEMOZOLOMIDE + CAPECITABINE

Indication: Neuroendocrine

DRUG REGIMEN Days 1 to 14 CAPECITABINE 1000mg twice daily for 14 days

Days 10 to 14 TEMOZOLOMIDE 200 mg/m2 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 30 -50 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 0-1 100% - 2nd appearance Interrupt until resolved to grade 0-1 75% - 3rd appearance Interrupt until resolved to grade 0-1 50% - 4th appearance Discontinue treatment permanently Not applicable * Grade 3 - 1st appearance Interrupt until resolved to grade 0-1 75% - 2nd appearance Interrupt until resolved to grade 0-1 50% - 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 0-1 - 2nd appearance Discontinue permanently Not applicable

Tem + Cape Clinical Group Chair Authorisation: Page 1 of 3 Published: October 2015 Version Review: October 2017 2.4 Date Chemotherapy RegimenRegimens – Rare Cancers 18 of 44

Thames Valley Temozolomide: Dose range 150-200mg/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 109/L ≥100 < 100 Neutrophils x 109/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 Version Date 2.4 Review: October 2017

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Thames Valley

REFERENCES 1. Temozolomide Summary of Product Characteristics eMC 2. JCO abstract vol.24 No.3 2006. 3. 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 Version Date 2.4 Review: October 2017

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Thames Valley

CAPECITABINE

Indication: Neuroendocrine and carcinoid. This is an unlicensed indication

DRUG REGIMEN CAPECITABINE *1000mg/m2 twice daily (2000mg/m2/day) for 14 days followed by a 7 day rest

*Dose may be increased to 1250mg/m2 twice daily (2500mg/m2/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 30 -50 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 0-1 100% - 2nd appearance Interrupt until resolved to grade 0-1 75% - 3rd appearance Interrupt until resolved to grade 0-1 50% - 4th appearance Discontinue treatment permanently Not applicable * Grade 3 - 1st appearance Interrupt until resolved to grade 0-1 75% - 2nd appearance Interrupt until resolved to grade 0-1 50% - 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 0-1 - 2nd appearance Discontinue permanently Not applicable Capecitabine Clinical Group Chair Authorisation: Page 1 of 2 Published: October 2015 Version Dr C Blesing 2.4 Date Chemotherapy RegimenReview:Regimen Octobers – Rare 2017 Cancers 21 of 44

Thames Valley INVESTIGATIONS Routine Blood test

1) Blood results required before chemotherapy administration Give Discuss Hb x g/dL ≥10 < 10 Plt x 109/L ≥100 < 100 Neutrophils x 109/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 2004. 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 Version Date 2.4 Review: October 2017

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Thames Valley CISPLATIN and ETOPOSIDE

Indication: Neuroendocrine Thymoma

DRUG REGIMEN

Day 1 Pre-hydration 2 ETOPOSIDE 100mg/m infusion in 1000ml sodium chloride 0.9% over 60 minutes CISPLATIN 75mg/m2 infusion in 1000ml sodium chloride 0.9% over 2 hours (daypatient) or 4 hours (inpatient)

Post hydration 2 Day 2 ETOPOSIDE 100mg/m infusion in 1000ml sodium chloride 0.9% over 60 minutes Day 3 ETOPOSIDE 100mg/m2 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 60-180u/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 109/L ≥100 < 100 Neutrophils x 109/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.

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Thames Valley 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 20 ¬ 40 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): 458-511, 2004 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.

Cis + Etop Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Version Date 2.4 Review: October 2017 Chemotherapy RegimenRegimens – Rare Cancers 24 of 44

Thames Valley DOXORUBICIN + CISPLATIN + VINCRISTINE + CYCLOPHOSPHAMIDE (ADOC)

Indication: Thymoma

DRUG REGIMEN Day 1 DOXORUBICIN 40mg/m2 IV bolus

Pre-hydration CISPLATIN 50mg/m2 infusion in 1000ml sodium chloride 0.9% over 2 hours (daypatient) or 4 hours (inpatient) Post hydration Day 4 VINCRISTINE 0.6mg/m2 (maximum dose 1.2mg) IV in 50ml sodium chloride 0.9% over 10 minutes CYCLOPHOPHAMIDE 700 mg/m2 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/m2 (in normal cardiac function) = 400mg/m2 (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 Version 2.4 Review: October 2017

Chemotherapy RegimenRegimens – Rare Cancers 25 of 44

Thames Valley INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dL ≥10 < 10 Plt x 109/L ≥100 < 100 Neutrophils x 109/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 20 ¬ 40 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): 1419-23 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.

ADOC Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Version 2.4 Review: October 2017

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Thames Valley CYCLOPHOSPHAMIDE, VINCRISTINE and DACARBAZINE (CVD)

Indication: Thyroid Ca and thymoma

DRUG REGIMEN Day 1 CYCLOPHOSPHAMIDE 750mg/m2 IV bolus VINCRISTINE 1.4mg/m2 (max dose 2mg) in 50ml sodium chloride 0.9% over 10minutes DACARBAZINE 600mg/m2 in 500ml sodium chloride 0.9% infusion over 1hour Day 2 DACARBAZINE 600mg/m2 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 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5

 Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion  LFTs

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Thames Valley 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), 432-436 1994 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 Version Date 2.4 Review: October 2017

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Thames Valley 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 Clinical Group Chair Authorisation: Page 1 of 2 Published: October 2015 Version 2.4 thyroid Date Review: October 2017 Chemotherapy RegimenRegimens – Rare Cancers 29 of 44

Thames Valley INVESTIGATIONS Routine Blood test 1) Blood results required before drug administration Give Discuss Hb x g/dL 10 < 10 Plt x 109/L 100 < 100 Neutrophils x 109/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 2012 2. EU SPC

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Thames Valley DOXORUBICIN (Thyroid)

Indication: Metastatic thyroid cancer (resistant to 131I treatment)

DRUG REGIMEN Day 1 DOXORUBICIN 75mg/m2 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 = 450-550 mg/m2 (in normal cardiac function) = 400 mg/m2 (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 109/L ≥100 < 100 Neutrophils x 109/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 Clinical Group Chair Authorisation: Page 1 of 1 Published: October 2015 Version thyroid 2.4 Review: October 2017 Chemotherapy RegimenRegimens – Rare Cancers 31 of 44

Thames Valley 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 109/L 100 < 100 Neutrophils x 109/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

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Thames Valley 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

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Thames Valley 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 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 ECG (possible ECHO) required if patient has preexisting cardiac disease

Vandetanib Clinical Group Chair Authorisation: Page 1 of 2 Published: October 2015 Version thyroid Date 2.4 Review: October 2017 Chemotherapy RegimenRegimens – Rare Cancers 34 of 44

Thames Valley 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 Minimal emetic risk

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS QT prolongation and torsades de pointes Posterior reversible encephalopathy syndrome Skin reactions

REFERENCES SPC Vandetanib February 2012

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Thames Valley FLUOROURACIL + CYCLOPHOSPHAMIDE + DACARBAZINE

Indication: Parathyroid cancer

DRUG REGIMEN Day 1 to 4 FLUOROURACIL 500mg/m2/24hr continuous IV Infusion over 96hours

CYCLOPHOSPHAMIDE 500mg/m2 IV bolus DACARBAZINE 200mg/m2 in 1000ml sodium chloride 0.9% infusion over 1 hour

Cycle Frequency: Every 21 days for 6 cycles subject to tolerance and response

DOSE MODIFICATIONS Previous neutropenic sepsis, discuss with Consultant or Registrar

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

Cyclophosphamide: GFR >20ml/min give 100% dose GFR 10-20ml/min give 75% dose GFR <10ml/min give 50% dose

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 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5 Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion

2) Non-urgent blood tests Tests relating to disease response/progression

5fu + cyclo Clinical Group Chair Authorisation: Page 1 of 2 Published: October 2015 Version + dac 2.4 Review: October 2017 Chemotherapy RegimenRegimens – Rare Cancers 36 of 44

Thames Valley CONCURRENT MEDICATION Hickman line pack with cycle ONE only

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. 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 Cyclophosphamide may irritate bladder, drink copious volumes of water. 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 caoecitabine.

REFERENCES 1) Arch Intern Med. 1984 Feb; 144(2): 399-400. 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.

5fu + cyclo + Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Version dac Date 2.4 Review: October 2017 Chemotherapy RegimenRegimens – Rare Cancers 37 of 44

Thames Valley DOXORUBICIN + CISPLATIN + ETOPOSIDE (EDP)

Indication: Adrenal cancer

DRUG REGIMEN 2 Day 1 DOXORUBICIN 40mg/m IV bolus Day 2 ETOPOSIDE 100mg/m2 infusion in 1000ml sodium chloride 0.9% over 60 minutes

Days 3 & 4 Pre-hydration 2 ETOPOSIDE 100mg/m infusion in 1000ml sodium chloride 0.9% over 60 minutes CISPLATIN 40mg/m2 infusion in 1000ml sodium chloride 0.9% over 2 hours (daypatient) or 4 hours (inpatient) Post hydration

Cycle Frequency: Every 28 days for 6 cycles subject to tolerance and response

NB based on FIRM-ACT regimen. In the trial this arm is given with mitotane aiming at a blood level of 14-20mg/L.

DOSE MODIFICATIONS Cisplatin: GFR > 60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR < 45ml/min consider carboplatin 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 60-180u/L give 50% dose Bilirubin >51micromol/L or ALT/AST >180u/L omit dose

Doxorubicin: Clinical decision 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/m2 (in normal cardiac function) = 400mg/m2 (in combination with cardiac radiation treatment or in patients with cardiac risk factors)

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Chemotherapy RegimenRegimens – Rare Cancers 38 of 44

Thames Valley INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dL ≥10 < 10 Plt x 109/L ≥100 < 100 Neutrophils x 109/L ≥1.5 < 1.5

Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion

ECG (possible ECHO) required if patient has preexisting cardiac disease (Doxorubicin)

2) Non urgent ests 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 20 ¬ 40 mg Furosemide PO/IV OR 200ml Mannitol 10% IV

ANTIEMETIC POLICY Moderate emotogenic risk days 1, 2 Highly emetogenic. days 3, 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

REFERENCES 1) FIRM-ACT regimenregimen, April 24 2004 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. 4) Bradbury. P., Talbot. D. 2007 Systemic treatment of thymoma in “the thymus Gland”. Ed. Anastasiadis + Ratnatunga Springer-Verlag 91-975) Fassnacht M et al Combination chemotherapy in advanced adrenocortical carcinoma. NEJM 366;23 nejm.2190 org june 7, 2012

EDP Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Version Date 2.4 Review: October 2017 Chemotherapy RegimenRegimens – Rare Cancers 39 of 44

Thames Valley CISPLATIN, METHOTREXATE and BLEOMYCIN (PMB)

Indication: Metastatic or adjuvant penile cancer

DRUG REGIMEN Day 1 Pre-hydration regimen CISPLATIN 75mg/m2 in 1000ml sodium chloride 0.9% infusion over 2 hours (daypatient) or 4 hours (inpatient) METHOTREXATE 25mg/m2 IV bolus BLEOMYCIN 10,000 units IV bolus Post-hydration regimen

Day 8 METHOTREXATE 25mg/m2 IV bolus BLEOMYCIN 10,000 units IV bolus

Cycle Frequency: Every 21 days

DOSE MODIFICATIONS Cisplatin: GFR > 60ml/min give 100% dose GFR 45-60ml/min give 75% dose GFR < 45ml/min omit dose[1]

If patient complains of tinnitus, tingling of fingers and/or toes discuss with SpR or Consultant before administration

Bleomycin: GFR > 50 ml/min give 100% GFR 10-50 ml/min give 75% dose GFR < 10 ml/min give 50% dose Confirm with SpR or Consultant If patient is breathless discuss with Consultant

Methotrexate: GFR 45 - 60 mL/min give 65% dose GFR 30 - 45 mL/min give 50% dose GFR < 30 mL/min omit dose Bilirubin 51 - 85 micromol/L or ALT/AST > 180 give 75% dose Bilirubin >85 micromol/L omit

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Thames Valley INVESTIGATIONS Routine Blood test 1) Blood results required before chemotherapy administration Give Discuss Hb x g/dL ≥10 <10 Plt x 109/L ≥100 <100 Neutrophils x 109/L ≥1.5 <1.5 a. Creatinine clearance (GFR) calculated or EDTA at the Consultants discretion (Cisplatin) b. Pulmonary function tests are indicated if patient complains of dyspnoea or there are changes on x-ray.

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 20 ¬ 40 mg Furosemide PO/IV OR 200ml Mannitol 10% IV

Folinic acid 15mg PO at 24 and 36 hours post methotrexate OR Folinic acid 15mg PO/IV every 6 hours for 6 doses starting 24 hours after Methotrexate if: * Pleural effusions/ascots * Previous mucositis * Serum creatinine >120 micromols/L

ANTI-EMETIC POLICY Highly emetogenic day 1 Low emetogenic day 8

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS Pulmonary function tests (including transfer factor) prior to each cycle. If breathlessness or infiltrates appear not attributable to tumour or co-existence of lung disease bleomycin must be stopped immediately. Treat patients with and a broad spectrum antibiotic. Nephrotoxicity – ensure adequate pre and post hydration is prescribed. Ototoxicity – assess patient for tinnitus or hearing abnormalities. Methotrexate induced mucositis - folinic acid (calcium folinate) rescue (see concurrent medication)

REFERENCES 1) Haas et al. J Urol 1999; 161: 1823-5 2) Daniels, S. and S. Gabriel, Dosage adjustment for cytotoxics in renal impairment and hepatic impairment. 2009, The North London Cancer Network.

PMB Clinical Group Chair Authorisation: Page 2 of 2 Published: October 2015 Version 2.4

Review: October 2017

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Thames Valley Pre-hydration and post-hydration regimens Ensure adequate diuresis is obtained prior to administration and maintained during and after administration.

1. Inpatient Pre 1L sodium chloride 0.9% + 20mmol KCl + 8mmol MgSO4 infusion over 4 hours Give cisplatin in 1000ml volume over 4 hours Post 1L sodium chloride 0.9% + 20mmol KCl + 8mmol MgSO4 infusion over 4 hours 1L sodium chloride 0.9% + 20mmol KCl + 8mmol MgSO4 infusion over 4 hours

NB 1L sodium chloride 0.9% + 20mmol KCl + 8mmol MgSO4 infusion over 6 hours if oral intake is inadequate

2. Day case Pre 1L sodium chloride 0.9% + 20 mmol KCl + 8mmol MgSO4 infusion over 2 hours 200ml mannitol 10% infusion over 30 minutes Give cisplatin in 1000ml volume over 2 hours Post 1L sodium chloride 0.9% + 20 mmol KCl + 8mmol MgSO4 infusion over 2 hours

NB Furosemide 40mg may be added if required

Hydration Clinical Group Chair Authorisation: Page 1 of 1 Published: October 2015 Version Date 2.4 Review: October 2017

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Thames Valley Common Toxicity Criteria Toxicity 0 1 2 3 4 Allergic None Transient rash, Urticaria, drug Symptomatic Anaphylaxis drug fever <38C fever 38C bronchospasm (100.4F) (100.4F) and/or requiring asymptomatic parenteral bronchospasm medication(s) with or without urticaria; allergy related oedema / angioedema Alopecia Normal Mild hair loss Pronounced hair - - loss Anorexia None Loss of appetite Oral intake Requiring IV fluids Requiring feeding significantly tube or parenteral decreased nutrition Blood counts Within 1.5x109/l - 1.0-1.4x109/l 0.5-0.9x109/l <0.5x109/l Neutrophils normal normal limits Blood counts Within 10.0g/dl – normal 8.0 9.9g/dl 6.5-7.9g/dl <6.5g/dl Haemoglobin normal limits Blood counts Within 75x109/l - normal 50-74x109/l 10-49x109/l <10x109/l Platelets normal limits Blood counts Within 3.0x109/l - 2.0-2.9x109/l 1.0-1.9x109/l <1.0x109/l White blood normal normal count limits Diarrhoea None Mild increase in Moderate increase Severe increase Physiologic (patients with loose, watery in loose, watery in loose, watery consequences colostomy) colostomy output colostomy output colostomy output requiring intensive compared with compared with pre- compared with care, or pre-treatment treatment, but not pre-treatment, haemodynamic interfering with interfering with collapse normal activity normal activity Diarrhoea None Increase of <4 Increase of 4-6 Increase of 7-9 Increase of > 10 (patients stools/day over stools/day, or stools/day, or stools/day or without pre-treatment nocturnal stools incontinence; or bloody diarrhoea colostomy) need for or parenteral parenteral support support needed for dehydration Hand-foot None Skin changes or Skin changes with Skin changes with - skin reaction dermatitis pain, not interfering pain, interfering without pain with function with function Hepatic – UNL >ULN – 2.5x >2.5 – 5.0xULN 5.0 – 20.0xULN >20.0XULN alk phos ULN Hepatic – UNL >ULN – 1.5x >1.5 – 3.0xULN 3.0 – 10.0xULN >10.0XULN bilirubin ULN Lethargy None Increased fatigue Moderate Severe (decrease Bedridden or over baseline, (decrease in in performance disabling but not altering performance status status by 2 normal activities by level 1) or levels), or loss of causing difficulty ability to perform performing some some activities Chemotherapy RegimenRegimens – Rare Cancers 43 of 44

Thames Valley activities Nausea None Able to eat Oral intake No significant - significantly intake, requiring decreased IV fluids Neuropathy - Normal Subjective Mild objective Objective Paralysis motor weakness but no weakness weakness objective findings interfering with interfering with function, but not activities of daily interfering with living activities of daily living Neuropathy - Normal Loss of deep Objective sensory Sensory loss of Permanent sensory tendon reflexes loss or paresthesia paresthesia sensory loss that or paresthesia (including tingling), interfering with interferes with (including interfering with activities of daily function tingling) but not function, but not living interfering with interfering with function activities of daily living Pain None Mild pain not Moderate pain: Severe pain: pain Disabling interfering with pain or analgesics or analgesics function interfering with severely function but not interfering with interfering with activities of daily activities of daily living living Stomatitis / None Painless ulcers, Painful erythema, Painful erythema Severe ulceration mucositis erythema or mild oedema or ulcers oedema, or ulcers or requires soreness but can eat or requiring IV parenteral or swallow hydration enteral nutritional support or prophylactic intubation Vomiting None 1 episode in 24 2-5 episodes in 24 6 episodes in 24 Requiring hours hours hours, or need for parenteral IV fluids nutrition, or physiological consequences requiring intensive care; haemodynamic collapse

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