92-Hepatic advanced soRAFENib

Check for clinical trials in this patient group. Link to Australian Clinical Trials website

Treatment schedule Treatment schedule

Overview
Detail

Drug	Dose	Route
soRAFENib	400 mg TWICE a day	PO

Continuous until disease progression or unacceptable toxicity

Notes:: Overall management should be in consultation with a gastroenterologist.

Drug status:

Sorafenib is PBS authority

Sorafenib is available as 200 mg tablets.

Cost:: ~ $5,150 per cycle "How this cost is calculated"
The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m²; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Continuous treatment
soRAFENib	400 mg (PO)	TWICE a day on an empty stomach one hour before food or two hours after food

Continuous until disease progression or unacceptable toxicity

Treatment schedule - Overview

Drug	Dose	Route
soRAFENib	400 mg TWICE a day	PO

Continuous until disease progression or unacceptable toxicity

Notes:: Overall management should be in consultation with a gastroenterologist.

Drug status:

Sorafenib is PBS authority

Sorafenib is available as 200 mg tablets.

Cost:: ~ $5,150 per cycle "How this cost is calculated"
The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m²; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

Treatment schedule - Detail

Continuous treatment
soRAFENib	400 mg (PO)	TWICE a day on an empty stomach one hour before food or two hours after food

Continuous until disease progression or unacceptable toxicity

Indications and patient population

Advanced BCLC Stage C hepatocellular carcinoma
- Child Pugh Grade A.

Clinical information

Caution with oral anti-cancer drugs	Select links for information on the safe prescribing, dispensing and administration of orally administered anti-cancer drugs. Read more about the COSA guidelines and oral anti-cancer therapy
Emetogenicity MINIMAL	No antiemetics should be routinely administered before treatment in patients without a history of nausea and vomiting. If patients experience nausea and/or vomiting, consider using the low antiemetic prophylaxis regimen. Read more about preventing anti-cancer therapy induced nausea and vomiting
Cardiac toxicity	Tyrosine kinase inhibitors have been associated with cardiac complications of varying degrees and severity. Patients, especially those with pre-existing cardiovascular disease, should have a baseline cardiac assessment of echocardiogram (ECHO), electrocardiogram (ECG) and biochemistry and be closely monitored. Cardiac assessment should be repeated as clinically indicated. Read more about cardiac toxicity associated with anti-cancer drugs
Prolongation of QT interval	This treatment may prolong the QT interval and increase the risk of cardiac arrhythmia. Use with caution in patients with a congenital long QT syndrome, patients treated with a high cumulative dose of anthracycline therapy, patients taking medications that may prolong the QT interval and those with electrolyte disturbances. Risk factors (e.g. electrolyte abnormalities) should be corrected, where possible, prior to commencement of treatment and the concurrent use of drugs that may prolong the QT interval should be avoided. Baseline and periodic monitoring of electrocardiogram (ECG) and electrolytes (potassium, magnesium, calcium) should be considered in patients at high risk of QT prolongation. Read more about drugs that may prolong QTc interval
Hypertension	Pre-existing hypertension should be adequately controlled prior to commencing treatment. Baseline blood pressure monitoring and repeat weekly for the first 6 weeks then regularly throughout treatment. In severe or uncontrolled hypertension, treatment should be withheld until hypertension is controlled. Dose modification or permanent discontinuation may be necessary.
Diarrhoea	Antidiarrhoeals (e.g. loperamide) are usually prescribed with this treatment. Read more about treatment induced diarrhoea
Wound healing	This treatment may impair wound healing and temporary interruption of treatment is recommended in patients undergoing major surgical procedures. Resume treatment based on clinical judgement of adequate wound healing.
Hand-foot syndrome	Hand-foot syndrome (palmar-plantar erythrodysaesthesia) and rash are common adverse effects with this treatment which generally appear during the first 6 weeks of therapy. Read more about hand food syndrome or palmar plantar erythrodysaesthesia (PPE)
Elevations in lipase and amylase	Transient elevations of lipase and amylase have been reported. In some cases, this has been associated with pancreatitis. Monitor patient as clinically indicated.
Blood tests	FBC, EUC, LFTs, calcium, magnesium and phosphate at baseline, repeat at week 2, then every 4 weeks. INR as clinically indicated.
Hepatitis B screening and prophylaxis	Routine screening for HBsAg and anti-HBc is NOT usually recommended for patients receiving this treatment. Read more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy
Vaccinations	Live vaccines, including BCG, MMR, zoster and varicella vaccines, are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease. Refer to the recommended schedule of vaccination for immunocompromised patients, as outlined in the Australian Immunisation Handbook. Read more about COVID-19 vaccines and cancer.
Effects of cancer treatment on fertility	Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive age prior to commencing treatment. Read more about the effect of cancer treatment on fertility

Dose modifications

Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences. Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Haematological dose modifications are adapted from the trial by Llovet et al^r

Haematological toxicity^r
ANC x 10⁹/L (at any stage of the cycle)
1.0 to less than 1.5	No dose modification necessary
0.5 to less than 1.0	Reduce sorafenib to 200 mg TWICE daily and continue with treatment
less than 0.5	Delay treatment until ANC 1.0 or greater and reduce sorafenib to 200 mg TWICE daily for subsequent doses
Febrile neutropenia	Delay treatment until ANC 1.0 or greater and reduce sorafenib to 200 mg TWICE daily for subsequent doses
Platelets x 10⁹/L (at any stage of the cycle)
50 to less than 100	No dose modification necessary
25 to less than 50	Reduce sorafenib to 200 mg TWICE daily and continue with treatment
less than 25	Delay treatment until platelets 50 or greater and reduce sorafenib to 200 mg TWICE daily for subsequent doses

Renal impairment
Creatinine clearance (mL/min)
30 to 50	Consider starting sorafenib at 200 mg TWICE daily and dose escalate as tolerated * (Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is recommended)
less than 30	No recommendations available; use with caution

Hepatic impairment
Hepatic dysfunction
Mild	No dose modification necessary
Moderate	Consider starting sorafenib at 200 mg TWICE daily and dose escalate as tolerated *
Severe	Omit sorafenib

Mucositis and stomatitis
Grade 3	Delay treatment until toxicity has resolved to Grade 2 or less and reduce the dose for subsequent cycles as follows: 1^st occurrence: Reduce sorafenib to 200 mg TWICE daily 2^ndoccurrence: Reduce sorafenib to 200 mg ONCE daily 3^rdoccurrence: Omit sorafenib
Grade 4	Omit sorafenib

Diarrhoea
Grade 3	Delay treatment until toxicity has resolved to Grade 2 or less and reduce the dose for subsequent cycles as follows: 1^st occurrence: Reduce sorafenib to 200 mg TWICE daily 2^ndoccurrence: Reduce sorafenib to 200 mg ONCE daily 3^rdoccurrence: Omit sorafenib
Grade 4	Omit sorafenib

Hand foot syndrome (link to Hand foot syndrome (Palmar-plantar erythrodysaesthesia))
Grade 2	Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose for subsequent cycles as follows: 1^st occurrence: No dose reduction 2^ndoccurrence: Reduce sorafenib to 200 mg TWICE daily 3^rdoccurrence: Reduce sorafenib to 200 mg ONCE daily 4^thoccurrence: Omit sorafenib
Grade 3	Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose for subsequent cycles as follows: 1^st occurrence: Reduce sorafenib to 200 mg TWICE daily 2^ndoccurrence: Reduce sorafenib to 200 mg ONCE daily 3^rdoccurrence: Omit sorafenib

*These recommendations have been adapted from the study by Miller et al.^r

Interactions

References & Disclaimer

Sorafenib
	Interaction	Clinical management
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.)	Reduced efficacy of sorafenib possible due to increased clearance	Avoid combination or monitor for decreased clinical response to sorafenib
Drugs that may prolong the QTc interval (e.g. azole antifungals, tricyclic antidepressants, antiarrhythmics etc.)	Additive effect with sorafenib; may lead to torsades de pointes and cardiac arrest	Avoid combination or minimise additional risk factors (e.g. correct electrolyte imbalances) and monitor ECG for signs of cardiac arrhythmia
Paracetamol	Risk of liver toxicity due to inhibition of metabolism of paracetamol by sorafenib	Avoid combination or monitor liver function closely
Neomycin	Reduced efficacy of sorafenib possible due to increased clearance (neomycin interferes with enterohepatic recycling of sorafenib)	Avoid combination or monitor for decreased clinical response to sorafenib

General
	Interaction	Clinical management
Warfarin	Anti-cancer drugs may alter the anticoagulant effect of warfarin.	Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran	Interaction with both CYP3A4 and P-gp inhibitors /inducers. DOAC and anti-cancer drug levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).	Apixaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. If treating VTE, avoid use with strong CYP3A4 and P‑gp inducers. Rivaroxaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. Dabigatran: avoid combination with strong P‑gp inducers and inhibitors. If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin	Anti-cancer drugs can damage the lining of the intestine; affecting the absorption of digoxin.	Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics	Both altered antiepileptic and anti-cancer drug levels may occur, possibly leading to loss of efficacy or toxicity.	Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate. Also monitor closely for efficacy of the anti-cancer therapy.
Antiplatelet agents and NSAIDs	Increased risk of bleeding due to treatment related thrombocytopenia.	Avoid or minimise combination. If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine)	Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.)	Avoid combination. If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia). For more information link to TGA Medicines Safety Update
Vaccines	Diminished response to vaccines and increased risk of infection with live vaccines.	Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy. For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Administration

This is a continuous oral treatment

Safe handling and waste management (reproductive risk only)

Safe administration

General patient assessment prior to each treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

Treatment - Time out

Sorafenib

administer orally TWICE a day
to be swallowed whole with a glass of water; do not break, crush or chew
to be taken on an empty stomach, one hour before or two hours after food
monitor blood pressure at baseline and regularly throughout treatment.

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Discharge information

Sorafenib tablets

Sorafenib tablets with written instructions on how to take them.

Antidiarrhoeals

Antidiarrhoeals as prescribed.

Patient information

Ensure patient receives patient information sheet.

Side effects

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Nausea and vomiting	Read more about prevention of treatment induced nausea and vomiting

Early (onset days to weeks)
Neutropenia	Abnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. Read more about neutropenia
Thrombocytopenia	A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding. Read more about thrombocytopenia
Oral mucositis	Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following chemotherapy, radiation therapy to the head, neck or oesophagus, and high dose chemotherapy followed by a blood and marrow transplant (BMT). Read more about oral mucositis
Anorexia	Loss of appetite accompanied by decreased food intake. Read more about anorexia
Diarrhoea	Read more about treatment induced diarrhoea
Fatigue	Read more about fatigue
Arthralgia and myalgia	Generalised joint pain or and/or stiffness and muscle aches, often worse upon waking or after long periods of inactivity. Can improve with movement. May be mild or severe, intermittent or constant and accompanied by inflammation. Read more about arthralgia and myalgia
Palmar-plantar erythrodysaesthesia (PPE) - hand-foot syndrome (HFS)	Bilateral erythema, tenderness, pain, swelling, tingling, numbness, pruritus, dry rash, or moist desquamation and ulceration of the palms and soles. It is also known as hand-foot syndrome (HFS). Symptoms appear to be dose dependent and palms are affected more than soles. Read more about hand-foot syndrome associated with chemotherapy
Skin rash	Anti-cancer drugs can cause a number of changes in the skin with maculo-papular rash the most common type of drug-induced skin reaction. Read more about skin rash
Hypertension	High blood pressure is commonly associated with many anti-cancer drugs. Pre-existing hypertension should be controlled prior to initiation of drugs capable of causing hypertension.
Haemorrhage
Cardiotoxicity	Cardiotoxicity may manifest as asymptomatic reduction in left ventricular ejection fraction (LVEF), arrhythmia, cardiomyopathy, hypertension, cardiac ischaemia and congestive heart failure (CHF). The risk of cardiotoxicity is increased by a number of factors, particularly a history of heart disease and electrolyte imbalances. Read more about cardiotoxicity associated with anti-cancer drugs
Hypocalcaemia	Abnormally low levels of calcium in the blood.
Hypokalaemia	Abnormally low levels of potassium in the blood.

Late (onset weeks to months)
Anaemia	Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. Read more about anaemia
Alopecia - partial	Hair thinning and/or patchy hair loss. Patients can also experience mild to moderate discomfort of the hair follicles, and rarely pain as the hair is falling out. Read more about alopecia
Nail changes	Hyperpigmentation, paronychia, onycholysis, splinter haemorrhage, pyogenic granuloma formation, subungal haematoma and subungal hyperkeratosis are some of the nail changes associated with anti-cancer drugs. Read more about nail toxicities

Evidence

The evidence for this protocol comes from a randomised, multicenter, phase III, double blind, placebo-controlled trial conducted by the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) Investigators Study Group reported by Llovet et al.^r

Between March 10 2005 and April 11 2006, a total of 602 patients were randomised to either the sorafenib group (299 patients) or the placebo group (303 patients).

The primary endpoints were overall survival and time to symptomatic progression and the secondary endpoints included time to radiologic progression, disease control rate and safety.

The efficacy and safety of sorafenib for hepatocellular in the Asia-Pacific population was studied in a multicentre, double-blind, placebo-controlled RCT involving 271 patients. Median overall survival was 6.5 vs 4.2 months (HR=0.68; 95% CI 0.50-0.93; p=0.014) and median time to treatment progression was 2.8 vs 1.4 months (HR=0.57; 95% CI 0.42-0.79;p=0.0005) in the sorafenib and placebo arms respectively. Sorafenib was generally well tolerated with hand-foot skin reaction (10.7%), diarrhoea (6%), and fatigue (3.4%) the most frequently reported adverse events.^r

Efficacy

The median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; p<0.001).

There was no significant difference in the median time to symptomatic progression between the sorafenib group and the placebo group (4.1 months vs 4.9 months respectively; p=0.77).

The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (p<0.001). 7 patients in the sorafenib group and 2 patients in the placebo group had a partial response; no patient had a complete response.

Efficacy^r	Sorafenib (n=299)	Placebo (n=303)	p-value
Overall Survival	10.7 months	7.9 months	<0.001
Time to symptomatic progression	4.1 months	4.9 months	0.77
Time to radiologic progression	5.5 months	2.8 months	<0.001

Kaplan-Meier Analysis of Overall Survival and Time to Symptomatic Progression^r

Toxicity

The overall incidence of treatment-related adverse events, predominantly grade 1 or 2, was 80% in the sorafenib group and 52% in the placebo group. Diarrhoea, weight loss, hand-foot skin reaction, alopecia, anorexia, voice changes, hypophosphataemia and thrombocytopenia occurred at a higher frequency in the sorafenib group than in the placebo group.

Rates of discontinuation of treatment were similar in the two groups (38% in the sorafenib and 37% in the placebo). Gastrointestinal events (6%), fatigue (5%), and liver dysfunction (5%) were the most frequent causes of discontinuation of sorafenib.

Toxicity^r	Sorafenib (%)	Placebo (%)	p-value
Diarrhoea	39	11	<0.001
Weight loss	9	1	<0.001
Hand-foot skin reaction	21	3	<0.001
Alopecia	14	2	<0.001
Anorexia	14	3	<0.001
Voice changes	6	1	<0.001
Hypertension	5	2	0.05
Bleeding	7	4	0.07

References References

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History

Version 3

Date	Summary of changes
23/03/2010	Approved and transferred to eviQ.
01/09/2010	Administration of tablets with reference to a fatty meal was considered confusing and updated to a general statement "taken on an empty stomach, at least 1 hour before or 2 hours after the meal".
03/04/2012	New format to allow for export of protocol information. Protocol version number changed to V.2. Additional Clinical Information, Key Prescribing table and Key Administration table combined into new section titled Clinical Considerations. Drug specific information placed behind the drug name link.
13/09/2013	Protocol reviewed at Medical Oncology Reference Committee meeting. Evidence updated to include study in the Asia-pacific population. Dose modifications updated as per recommendations in SHARP study. Side effects: Added hypocalcaemia and hypokalaemia. Next review in 2 years.
16/12/2015	Protocol reviewed electronically by Medical Oncology Reference committee. No changes and next review in 2 years.
09/11/2016	The following change made post Medical Oncology Reference Committee meeting held on 21 October 2016: Link to AGITG and ANZCTR added.
31/05/2017	Transferred to new eviQ website. Version number changed to V.3. Hepatitis B screening changed to NOT recommended.
16/02/2018	Protocol reviewed at Medical Oncology Reference Committee Meeting, no changes. Review in 2 years.
25/09/2020	Protocol reviewed electronically by the Medical Oncology Reference committee. Nil changes. Next review in 2 years.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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First approved:: 23 March 2010
Last reviewed:: 25 September 2020
Review due:: 31 December 2022

The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/92

19 Sep 2021