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Hepatic advanced sorafenib

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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

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

Caution with oral antineoplastic agents

Select link for information on the safe prescribing, dispensing and administration of orally administered antineoplastic agents. 

Read more about oral anticancer 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 antineoplastic 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 antineoplastic agents
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.
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.
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
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 antineoplastic 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 alr

Haematological toxicityr
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:
1st occurrence: Reduce sorafenib to 200 mg TWICE daily
2nd occurrence: Reduce sorafenib to 200 mg ONCE daily
3rd occurrence: 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:
1st occurrence: Reduce sorafenib to 200 mg TWICE daily
2nd occurrence: Reduce sorafenib to 200 mg ONCE daily
3rd occurrence: 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:
1st occurrence: No dose reduction
2nd occurrence: Reduce sorafenib to 200 mg TWICE daily
3rd occurrence: Reduce sorafenib to 200 mg ONCE daily
4th occurrence: Omit sorafenib
Grade 3

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

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

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 Antineoplastic agents may alter the anticoagulant effect of warfarin Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant (e.g. LMWH or unfractionated heparin)
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

Interaction with both CYP3A4 and P-gp inhibitors /inducers.

DOAC and antineoplastic 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 Antineoplastic agents 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 antineoplastic 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 antineoplastic 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 (reproductive risk only)

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.

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.

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, radiotherapy 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

Antineoplastic agents 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 antineoplastic agents. 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 antineoplastic agents
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 antineoplastic treatment.   

Read more about nail toxicities

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.

Efficacyr  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 Progressionr

© New England Journal of Medicine 2008

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.

Toxicityr 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
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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.

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. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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Review due:

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

16 Jun 2019