XELOX+BEVA

Note: a dose of capecitabine 750 mg/m² PO BID was used in a small phase 2 study in small bowel cancer (Overman MJ et al.)

REPEAT EVERY 21 DAYS

Until disease progression or unacceptable toxicity

Also refer to CCO Antiemetic Recommendations.

Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.

Oxaliplatin premedication (prophylaxis for infusion reactions):

• There is insufficient evidence that routine prophylaxis with pre-medications reduces IR rates.
• Consider corticosteroids and H1-receptor antagonists ± H2-receptor antagonists in high-risk patients (i.e. ≥ cycle 6, younger age, female gender, prior platinum exposure, platinum-free interval ≥ 3 years).

Bevacizumab premedication (prophylaxis for infusion reactions):

• Routine primary prophylaxis is not recommended; the use of secondary prophylaxis pre-medications should be based on clinical judgement.

Other Supportive Care:

• Topical emollients (e.g. hand creams, udder balm) therapy may ameliorate the manifestations of hand-foot syndrome in patients receiving capecitabine.
• Standard antidiarrheal agents (e.g. loperamide) should be initiated, as medically appropriate, as early as possible.
• Patients should be counselled about cold avoidance prior to receiving oxaliplatin, since cold temperatures can precipitate or exacerbate acute neurological symptoms.

Doses should be modified according to the protocol by which the patient is being treated.

Patients should be tested for DPD deficiency before starting treatment with capecitabine. Refer to the DPD Deficiency Guidance for Clinicians for more information. 

In patients with unrecognized DPD deficiency, acute, life-threatening toxicity may occur; if acute grade 2-4 toxicity develops, treatment should be stopped immediately and permanent discontinuation considered based on clinical assessment of the toxicities.

Bevacizumab should not be initiated in patients with recurrent hemoptysis, uncontrolled hypertension or wounds that require healing.

Prior to treatment, a dental evaluation should be performed and major dental procedures completed.

Do not retreat until neutrophils ≥ 1.5 x 10⁹ /L, platelet counts ≥ 100 x 10⁹ /L and major organ toxicity has resolved to ≤ grade 1. 

Oxaliplatin

Neurotoxicity was graded based on the following scales in some metastatic colorectal cancer trials. 

^Do not re-treat until the ANC ≥ 1.5 x 10⁹/L and the platelets ≥ 100 x 10⁹/L, GI and neurotoxicities have resolved and other non-hematologic toxicities ≤ grade 1
¹ Transient = >7days - <1 cycle;  persistent = ≥ 1 cycle
² For skin toxicity, reduce capecitabine dose only
³ If oxygen saturation is normal, an anxiolytic agent may be given.

Mandatory for gastrointestinal, dermatological toxicity and hyperbilirubinemia.  Practitioner may elect not to reduce dose for other toxicities unlikely to become serious or life-threatening. 

Missed or omitted doses of capecitabine should not be replaced. Doses should not be re-escalated if reduced for toxicity.

Dose reductions are not recommended. Bevacizumab should be held or discontinued based on toxicity.

Management of Infusion-related reactions:

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
 

Oxaliplatin:

* Up to 50% of patients can experience recurrent reactions during re-challenge despite using pre-medications (e.g. corticosteroid and H1/H2-receptor antagonist).

Bevacizumab:

*use capecitabine dose modification table above for hepatotoxicity during treatment

For oxaliplatin, patients ≥ 65 years had a higher incidence of GI toxicity, myelosuppression, syncope and fatigue. No dose adjustments were needed but caution should be exercised. 

For capecitabine, older patients are more susceptible to the effects of fluoropyrimidine-based therapies with increased grade 3 / 4 adverse effects, especially when used in combination. Starting dosage adjustment is not recommended, but dose modifications should be performed for toxicity (see tables above).

Use bevacizumab with caution; patients > 65 years old have an increased risk of arterial thrombotic events as well as myelosuppression, fatigue, proteinuria, hypertension, dizziness, dysphonia, anorexia and GI effects (except gastrointestinal perforation).

Dosage based on gender

Females were observed to have higher number of severe adverse effects with oxaliplatin than males.

Refer to oxaliplatin, capecitabine, bevacizumab drug monograph(s) for additional details of adverse effects

Refer to oxaliplatin, capecitabine, bevacizumab drug monograph(s) for additional details

• Concomitant use with sorivudine or analogues is contraindicated, given the increased risk of capecitabine toxicity (may be fatal). Wait at least 4 weeks after sorivudine (or chemically related analogues) treatment before starting capecitabine.

• Avoid concomitant administration with phenytoin; capecitabine may increase levels. Monitor phenytoin levels if must be given together.

• Do not use with diuretics in patients who are receiving bevacizumab and platinum-based chemotherapy (oxaliplatin).

• Monitor PT/INR when this treatment is administered with warfarin or other anticoagulants; adjust anticoagulant dose accordingly.

• Caution with the use of proton pump inhibitors and monitor for reduced effectiveness of capecitabine; consider switching to a magnesium and aluminum hydroxide-containing antacid.

• Caution and monitor with the coadministration of leucovorin as this may increase capecitabine toxicity.

• Monitor for toxicity when using oxaliplatin with other nephrotoxic drugs, QT-prolonging drugs or drugs associated with rhabdomyolysis.

Refer to oxaliplatin, capecitabine, bevacizumab drug monograph(s) for additional details

Administration:

Bevacizumab

Different bevacizumab products are not interchangeable.

• Do not administer as an IV push or bolus.

• Bevacizumab infusions should not be administered or mixed with dextrose or glucose solutions due to potential for drug degradation.

• Mix in 100 mL bag NS. (Final concentration should be 1.4 -16.5 mg/mL). 

• Compatible with PVC or polyolefin bags.

• Do not shake.  Should not be mixed or diluted with other drugs.

• Infuse over 90 minutes as loading dose, if tolerated next infusion can be given over 60 minutes; can thereafter be given over 30 minutes as maintenance dose

• Bevacizumab rapid infusion (over 10 minutes) has safely been administered with no significant increase in infusion reactions (for 5mg/kg and 7.5mg/kg doses).

• Refrigerate unopened vials and protect from light; do not freeze.

Oxaliplatin

• Oxaliplatin is administered by intravenous infusion.

• May be mixed in 250-500 mL bag (D5W only). Do not mix with NS, chloride containing or alkaline solutions.

• Administer by slow infusion. Concentration must be between 0.2 to 0.7 mg/mL

• Infuse IV over 2 hours. Increasing infusion time to 6 hours may decrease acute toxicity such as pharyngolaryngeal dysesthesia.

• Do not mix oxaliplatin with other drugs in the same infusion bag or infusion line.

• If another drug is given before oxaliplatin, flush infusion line with D5W before giving oxaliplatin. Flush the line with D5W after oxaliplatin before giving a subsequent drug.

• The compatibility of oxaliplatin solution for infusion has been tested with representative, PVC-based, administration sets.

• Do not use with injection equipment containing aluminum, as this can degrade platinum compounds.

• Unopened vials should be stored at 15-30°C; protect from light.

Capecitabine

• Oral self-administration; drug available by outpatient prescription.

• Doses are given orally approximately 12 hours apart, within 30 minutes after the end of a meal.

• Swallow tablets whole; do not crush or cut tablets.

• If a capecitabine dose is missed, skip this and give the next dose at the usual time. Missed or omitted doses should not be replaced.

• Store tablets at 15ºC to 30ºC in the original package.

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
 

Contraindications:

• Patients who have a known hypersensitivity to capecitabine, 5-fluorouracil, oxaliplatin or other platinum agents (e.g. cisplatin), bevacizumab, or any ingredient in the formulation or component of the container.

• Patients with known hypersensitivity to Chinese hamster ovary cell product or to other recombinant human or humanized antibodies

• Patients who are pregnant or breastfeeding

• Patients with severe renal impairment (CrCl <30 mL/min)

• Patients with untreated CNS metastases

• Patients with known near or complete absence of DPD (dihydropyrimidine dehydrogenase) deficiency. Refer to the DPD Deficiency Guidance for Clinicians for more information.

• Concomitant use with sorivudine or related analogues (i.e. brivudine), given potential fatal drug interaction

Warnings/Precautions:

• Patients be counselled about cold avoidance prior to receiving oxaliplatin, since cold temperatures can precipitate or exacerbate acute neurological symptoms.

• Oxaliplatin may cause dizziness or visual disturbances in some patients (including transient vision loss); patients should exercise caution when driving or operating machinery.

• Use capecitabine with extreme caution in patients with partial DPD deficiency. Refer to the DPD Deficiency Guidance for Clinicians for more information.

• Use capecitabine with caution in patients with risk factors for dehydration, pre-existing renal dysfunction or on nephrotoxic agents.

• Use capecitabine with caution in patients taking anticoagulants such as warfarin (see Interactions section)

• Use caution in patients with a history of cardiovascular disease, cardiac failure or arterial thromboembolism.

• Bevacizumab should not be initiated for at least 28 days following major surgery or until wound healing has occurred; hold for 28 days prior to major elective surgery

• The safety and efficacy of concurrent radiotherapy and bevacizumab has not been established

• Use bevacizumab with caution in:

  • Elderly patients

  • Patients with recurrent hemoptysis (>2.5ml), serious hemorrhage, or with squamous NSCLC

  • Patients with coagulopathies (congenital, acquired or therapeutic)

  • Patients with colorectal cancer and colorectal stents; increased risk of GI perforation has been reported

  • Patients given concurrent bisphosphonates or other anti-angiogenic agents, given increased risk of ONJ

• Capecitabine contains lactose and should not be used in patients with hereditary galactose/glucose/lactase disorders.

Pregnancy/Lactation:

• This regimen is contraindicated for use in pregnancy. Adequate contraception should be used by patients and their partners while on treatment and after the last treatment dose. Recommended methods and duration of contraception may differ depending on the treatment. Refer to the drug monograph(s) for more information.

• Breastfeeding is contraindicated during this treatment and after the last treatment dose. Refer to the drug monograph(s) for recommendations after the last treatment dose (if available).

• Fertility effects: Yes

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.

Recommended Clinical Monitoring

Suggested Clinical Monitoring

Outpatient prescription for home administration (capecitabine)

Bevacizumab, capecitabine and oxaliplatin drug monographs, Cancer Care Ontario.

BCCA protocol summary for palliative combination chemotherapy for metastatic colorectal cancer using oxaliplatin and capecitabine, Oct 2008.

Cassidy J, Clarke S, Dı´az-Rubio E, et al.  XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer 2011; 105: 58–64.

Cassidy J, Clarke S, Diaz-Rubio E et al. Randomized Phase III Study of Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid Plus Oxaliplatin As First-Line Therapy for Metastatic Colorectal Cancer. J Clin Oncol 2008; 26: 2006-2012.
 
Cassidy J, Tabernero J, Twelves C et al. XELOX (Capecitabine Plus Oxaliplatin): Active First-Line Therapy for Patients With Metastatic Colorectal Cancer. J Clin Oncol 2004; 22: 2084-2091.

Hochster HS, Hart LL, Ramanathan RK, et al.  Safety and Efficacy of Oxaliplatin and Fluoropyrimidine Regimens With or Without Bevacizumab As First-Line Treatment of Metastatic Colorectal Cancer: Results of the TREE Study.  J Clin Oncol 2009; 26: 3523-9.

Mahfoud T, Tanz R, Mesmoudi M, et al. Bevacizumab 5 or 7.5 mg/kg in Metastatic Colorectal Cancer Can Be Infused Safely Over 10 Minutes. J Gastrointest Cancer. 2011 Jan 4. [Epub ahead of print] Reidy DL, Chung KY, Timoney JP, et al. Bevacizumab 5 mg/kg can be infused safely over 10 minutes. J Clin Oncol. 2007;25(19):2691-5.

National Comprehensive Cancer Network. Colon Cancer (Version 2.2017). https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed June 30, 2017.

Overman MJ, Varadhachary GR, Kopetz S et al. Phase II Study of Capecitabine and Oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of vater.  JCO 2009; 27(16):2598-2603.

Reidy DL, Chung KY, Timoney JP, et al. Bevacizumab 5 mg/kg can be infused safely over 10 minutes. Journal of Clinical Oncology 2007; 25: 2691-5.
 
Rothenberg ML, Cox JV, Butt C, et al. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Annals of Oncology 2008; 19: 1720–6.

Saltz LB, Clarke S, Dı´az-Rubio, et al.  Bevacizumab in combination With oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008; 26:2013-9.

Van Cutsem E, Rivera F, Berry S, et al.  Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study.  Ann Oncol 2009; 20: 1842–7.

Zaanan A, Costes L, Gaauthier M et al.  Chemotherapy of advanced small-bowel adenocarcinoma: a multicentre AGEO study. Ann Oncol 2010; 21: 1786-93.

• Strategies of Sequential Therapies in Unresectable, Metastatic Colorectal Cancer Treated with Palliative Intent
• Continuous versus Intermittent Chemotherapy Strategies in Inoperable, Advanced Colorectal Cancer
• The Role of Primary Tumour Location in the Selection of Biologics for the Treatment of Unresectable Metastatic Colorectal Cancer