Written by: Jonas Congelli, RPh Hematology Oncology Associates of CNY
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Description: To discuss prevention and management of Hand-Foot Syndrome.

Background: Palmar-plantar erythrodysesthesia, also known as hand-foot syndrome (HFS) is a widely recognized dose-limiting toxicity of certain chemotherapy agents. A comprehensive list can be found in the supplemental information section. Typically, HFS occurs within the first six weeks of starting targeted therapy and after two months for chemotherapy. Preventative measures should be taken to prevent HFS. Effective education and preventative measures, like the use of 10-20% urea cream, has been shown to reduce the severity and time to developing HFS.

PQI process: Upon receipt of a new prescription known to cause HFS:

  • Educate patients on signs and symptoms of HFS
  • Provide urea cream
  • Follow up with the patient within seven days of initial dispense and with every refill
    • Inform provider if symptoms develop and document in the EMR
    • Topical and systemic pain relievers may be needed for the treatment of HFS related pain

Patient Centered Activities:

  • Provide Oral Chemotherapy Education (OCE) Supplemental Sheet
  • Educate patient on signs and symptoms of HFS
    • Numbness
    • Tingling
    • Burning
    • Itching
    • Redness
    • Swelling
    • Tenderness
    • Rash
    • Cracked Skin
    • Flaking Skin
    • Blistered Skin
    • Sores
  • Counsel patient on non-medical interventional strategies including
    • Limit use of hot water and sources of heat to hands and feet
    • Use of lotion within three minutes of bathing
    • Avoid activities that cause excessive rubbing to hands and feet (ex. Jogging)
    • Use of cotton gloves or socks at bedtime or throughout the day
    • Increased water intake and limiting diuretics and dehydrating agents (ex. alcohol, caffeine)
    • Importance of good nail care
    • Importance of wearing shoes/avoiding going barefoot
  • Provide urea cream and counsel on importance of use
  • Ensure patient knows when and who to call regarding onset of HFS symptoms

References:

  1. Hofheinz RD, Gencer D, Schulz H, et. Al Mapisal Versus Urea Cream as Prophylaxis for Capecitabine-Associated Hand-Foot Syndrome: A Randomized Phase III Trial of the AIO Quality of Life Working Group DOI: 10.1200/JCO.2014.60.4587 Journal of Clinical Oncology 33, no. 22 (August 01, 2015) 2444-2449.

 

Supplemental Information:

Medications That Commonly Cause Hand-Foot Syndrome

  • Axitinib (Inlyta®)
  • Cabozantinib (Cabometyx®, Cometriq®)
  • Capecitabine (Xeloda®)
  • Cytarabine
  • Docetaxel (Taxotere®)
  • Doxorubicin
  • Fluorouracil (5FU®)
  • Floxuridine
  • Idarubicin (Idamycin®)
  • Paclitaxel (Taxol®)
  • Pazopanib (Votrient®)
  • Regorafenib (Stivarga®)
  • Sorafenib (Nexavar®)
  • Sunitinib (Sutent®)
Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional.  This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented.  NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.

 

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Written by: Jeff Engle, PharmD, MS
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Description: This PQI will discuss effective management of adverse effects of sorafenib in the treatment of hepatocellular carcinoma and discuss data supporting the sequencing of patients to second-line therapy with regorafenib for increased survival benefit.

Background: Hepatocellular carcinoma (HCC) is associated with a high mortality rate and historically the treatment options have been limited. Prior to 2018, sorafenib was the only Food and Drug Administration approved targeted therapy for the initial treatment of unresectable HCC in patients diagnosed with late stage or metastatic disease.7 Second-line treatment options, though growing in number, have limited and at times conflicting survival data; and all factors of options should be considered.14, 18 A retrospective study of the RESORCE trial ascertained median time from start of sorafenib to death in patients receiving sequential therapy to regorafenib.  Exploratory analysis revealed time from sorafenib initiation to death as 26 months for regorafenib patients vs. 19.2 months for placebo patients.16

PQI Process: Upon receipt of a prescription for sorafenib:

  • Obtain CBC with differential, metabolic panel including magnesium and phosphorus, liver function tests, lipase and amylase prior to starting therapy and then monthly until labs have stabilized
  • Consider obtaining thyroid stimulating hormone level at baseline, every 4 weeks for 4 months, and then every 2-3 months thereafter
  • Monitor blood pressure at baseline and weekly during the first 6 weeks of sorafenib, and then monitor blood pressure, utilizing clinic appointments and treatment any developing hypertension as needed
  • Treatment associated hypertension and dermatologic toxicity are managed with dose interruptions and reductions.8 Grade 1 dermatologic toxicity may not require dosage adjustments (see table 3 for dose reductions due to toxicity)
  • Consider proactively discussing 2nd line treatment options following progression or intolerance

If regorafenib is considered for 2nd line tyrosine kinase inhibitor transitioning

  • Ensure recovery from sorafenib mediated adverse effects and that patient did not permanently discontinue sorafenib due to toxicity or inability to tolerate doses
    • RESORCE trial required that patients be able to tolerate at least 400 mg a day of sorafenib for 20 days of the last 28 days prior to withdrawal to be eligible
  • Determine Child-Pugh Class status and make appropriate recommendation for therapy
  • If underlying hypertension exists or developed while on sorafenib, ensure appropriate blood pressure control prior to starting regorafenib
  • Refer to Regorafenib (Stivarga®) In the Treatment of Hepatocellular Carcinoma PQI for managing adverse effects

Patient Centered Activities:

Counseling for sorafenib

  • Provide patient Oral Chemotherapy Education (OCE) sheet
  • Counsel patient on the signs and symptoms of hand-foot syndrome and other dermatologic side effects
  • Counsel on appropriate management of chemotherapy induced diarrhea
  • Counsel on measuring blood pressure weekly at home (first 6 weeks) and instruct to report blood pressures > 140/90 mmHg
  • Dose adjustments for baseline hepatic and renal dysfunction have been recommended based on a phase I pharmacokinetic study and are included in Table 1 and 215

Counseling for regorafenib

 

Supplemental Information:

Table 1: Dose Adjustments for Baseline Hepatic Dysfunction15*

Degree of Hepatic ImpairmentCriteriaSorafenib Dose
MildBilirubin >1 to ≤1.5 times ULN and/or AST >ULN400 mg twice daily
ModerateBilirubin >1.5 to ≤3 times ULN; any AST200 mg twice daily
SevereAlbumin <2.5 g/dL with any bilirubin/AST200 mg once daily
Bilirubin >3 to 10 x ULN with any ASTNo tolerable dose identified

*Reference used differs slightly from sorafenib prescribing information reference

 

Table 2: Dose Adjustments for Baseline Renal Dysfunction15

Baseline Creatinine ClearanceSorafenib Dose
40-59 mL/min400 mg twice daily
20-39 mL/min200 mg twice daily
< 20 mL/minUnable to define dose
Hemodialysis200 mg once daily

 

Table 3: Dose Reduction Levels for Adverse Effects*

Dose ReductionSorafenib Dose
Starting400 mg twice daily
1200 mg twice daily
2200 mg once daily or 400 mg every other day
3Discontinue

 

Patient Assistance

Sorafenib patients can utilize the REACH support program while on therapy

  • Nurse counselors are available for answering questions and providing patient education including Patient Starter Kits
  • Service counselors are available to discuss patient access services including co-pay assistance

References:

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019 Jan;69(1):7-34.
  2. Cronin KA, Lake AJ, Scott S, et al. Annual report to the nation on the status of cancer, part I: National cancer statistics. Cancer. 2018 Jul 1;124(13):2785-2800.
  3. Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology. 2004; 127: S87–96.
  4. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264–73.e1.
  5. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018 Aug;68(2):723-750.
  6. National Comprehensive Cancer Network. Hepatobiliary cancers version 1.2019. https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed February 10, 2019.
  7. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390.
  8. Nexavar (sorafenib) [prescribing information]. Wayne, NJ: Bayer Healthcare Pharmaceuticals Inc; October 2010.
  9. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib (RESORCE): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56-66.
  10. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMat 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492-2502.
  11. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940-952.
  12. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54-63.
  13. Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Feb;20(2):282-296.
  14. Merck Provides Update on KEYNOTE-240, a Phase 3 Study of KEYTRUDA® (pembrolizumab) in Previously Treated Patients with Advanced Hepatocellular Carcinoma. Merck. Published February 19, 2019. https://bit.ly/2SQ6J45. Accessed March 18, 2019.
  15. Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol. 2009 Apr 10;27(11):1800-5.
  16. https://www.ncoda.org/chemotherapy-induced-diarrhea/
  17. https://www.ncoda.org/regorafenib-in-the-treatment-of-hepatocellular-carcinoma/
  18. Finn RS et. Al Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC. J Hepatol.2018 Aug;69(2):353-358. doi: 10.1016/j.jhep.2018.04.010.
Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional.  This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented.  NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.

 

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Written by: Tammy McClellan, PharmD
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Description: The purpose of this PQI is to expand on therapy management of ibrutinib when used in combination with obinutuzumab.

Background: This FDA has extended the indications for ibrutinib; already approved as a single agent OR in combination with bendamustine and rituximab. Ibrutinib is indicated for Mantle Cell Lymphoma (MCL) and Marginal Zone Lymphoma (MZL) at doses of 560 mg daily. Ibrutinib is also indicated for Waldenstrom’s Macroglobulinemia (WM), chronic Graft versus Host disease (cGVHD) and Chronic Lymphocytic Lymphoma/Small Lymphocytic Lymphoma (CLL/SLL) at doses of 420 mg daily.

Ibrutinib in combination with obinutuzumab has been approved for adult patients with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). This indication is a non-chemotherapy option for treatment naïve patients diagnosed with CLL/SLL, which may further help reduce the need for chemotherapy. As an oral and IV combination therapy, coordination of the medically integrated pharmacy team is critical. The Illuminate trial4 found ibrutinib and obinutuzumab to show to be efficacious as first-line, non-chemotherapy regimen in CLL/SLL patients regardless of age or disease status. The median follow-up was 31.3 months and the most common grade 3 or 4 adverse effect was neutropenia and thrombocytopenia. After a median follow-up of 31.3 months (IQR 29.4–33.2), median progression-free survival was significantly longer in the ibrutinib plus obinutuzumab group (median not reached [95% CI 33.6–non-estimable]) than in the chlorambucil plus obinutuzumab group (19.0 months [15.1–22.1]; hazard ratio 0.23; 95% CI 0.15–0.37; p<0.0001). Estimated 30-month progression-free survival was 79% (95% CI 70–85) in the ibrutinib plus obinutuzumab group and 31% (23–40) in the chlorambucil plus obinutuzumab group.

PQI Process: Upon receiving a new prescription for ibrutinib for specific use in combination with obinutuzumab:

  • Verify an established CLL/SLL diagnosis (independent of patient’s del(17p) status, comorbidities and age) in the treatment naive patient and relevant dosing
  • Assess risk for Tumor Lysis Syndrome (laboratory abnormalities of potassium, uric acid, phosphate, serum creatinine) which commonly occurs during the first cycle
  • Dosing:
    • Ibrutinib 420 mg by mouth once daily with:
      • Obinutuzumab 100 mg IV on Day 1
      • then Obinutuzumab 900 IV mg on Day 2
      • then Obinutuzumab 1000 mg IV on Day 8 and Day 15 every 28 days for 1 Cycle
    • Followed by Ibrutinib 420 mg by mouth once daily with:
      • Obinutuzumab 1000 mg IV on Day 1 every 28 Days for 5 Cycles
  • When administering ibrutinib in combination with obinutuzumab, consider administering ibrutinib prior to obinutuzumab when given on the same day
  • Consider if a dose modification for ibrutinib is warranted (hypertension, dermatologic toxicities, risk of bleeding, hepatic impairment, fluid retention, cardiac arrhythmias or abnormalities)

PQI Process continued:

  • Verify scheduling of premeditations for obinutuzumab:
    • Acetaminophen 650 mg – 1000 mg at least 30 minutes prior
    • Antihistamine (ex: diphenhydramine 50 mg) at least 30 minutes prior
    • IV glucocorticoid (ex: dexamethasone 20 mg) at least 60 minutes prior
  • Review standard laboratory findings (CBC, CMP, hepatitis, LDH, and quantitative immunoglobulins) monthly and as indicated
  • Verify recommended antiviral (herpes and varicella virus) and pneumocystis prophylaxis are initiated Consider antibacterial and antifungal prophylaxis for at risk patients
  • Confirm baseline EKG has been obtained

Patient Centered Activities:

  • Provide ibrutinib Oncology Chemotherapy Education (OCE) sheet
  • Counsel patient on disease state, treatment regimen, what to expect and verify patient understanding
  • Ibrutinib should be taken at the same time each day with a glass of water and prior to obinutuzumab
  • Swallow medication whole. Avoid grapefruit products and Seville oranges.
  • Advise patient to take a missed dose as soon as possible on the same day and to resume normal dosing schedule for the next day

Supplemental Information:

Ibrutinib is approved in first-line therapy for CLL/SLL patients but is also considered as an option for the following populations as well:

  • Patients with and without del(17p)/TP53 mutation who are:
    • 64 years old and younger without significant comorbidities
    • 65 years old and older with significant comorbidities

References:

  1. IMBRUVICA® (Package Insert). Pharmacyclics LLC in conjunction with Janssen Biotech INC, Sunnyvale, CA; 2019. Assessed at: https://www.imbruvica.com/docs/librariesprovider7/default-document-library/prescribing-information.pdf.
  2. Gazyva® (Package Insert). Genetech, South San Fransico, CA; 2019. Assessed at: https://www.gene.com/download/pdf/gazyva_prescribing.pdf
  3. Micromedex Online, Ann Arbor, MI: IBM Watson Health, Inc.; updated 6/18/19; accessed 6/18/19. https://www.micromedexsolutions.com/micromedex2/librarian/.
  4. Moreno C, Greil R, Demirkan F, et al: Ibrutunib plus Obintuzumab versus Chlorambucil plus Obintuzumab in first-line treatment of chronic lymphocytic leukemia (ILLUMINATE): A multicenter, randomized, open-label, phase 3 trial. Lancet Oncol 20:43-56,2019.
  5. https://www.ncoda.org/ibrutinib-management/ .
  6. U.S National Library of Medicine (clinicaltrials.gov). Ibrutunib in Treating patients with Relapsed Hairy Cell Leukemia. Assessed at: https://clinicaltrials.gov/ct2/show/NCT01841723. 6-28-19.
  7. Younes A, Sehn LH, Johnson P, et al. Randomized phase III trial of Ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma [published online March 22, 2019]. J Clin Oncol. Doi:10.1200/jco.18.02403.
  8. Cancer Therapy Advisor Online, New York, NY: Haymarket Media, Inc.; Revised 11/2016; accessed 8/19/19. https://www.cancertherapyadvisor.com/home/cancer-topics/hematologic-cancers/chronic-lymphocytic-leukemia-small-lymphocytic-lymphoma-cll-sll/?utm_source=newsletter&utm_medium=email&utm_campaign=cta-spotlight-.
  9. Cancer Therapy Advisor Online, New York, NY: Haymarket Media, Inc.; Published August 6, 2019; accessed 8/19/19. Use of MRD status following Obinutuzumab/Ibrutinib therapy to Guide in Subsequent Therapy Selection in CLL. https://www.cancertherapyadvisor.com/home/cancer-topics/chronic-lymphocytic-leukemia/chronic-leukemia-cll-obinutuzumab-ibrutinib-mrd-status-guide-treatment.
  10. Targeted Oncology. Ibrutinib Plus Obinutuzumab Approved by FDA as Frontline CLL/SLL Treatment. Assessed at: https://www.targetedonc.com/news/ibrutinib-plus-obinutuzumab-approved-by-fda-as-frontline-cllsll-treatment. 8-19-19.
Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional.  This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented.  NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.
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Written by: Natasha Heimbigner, PharmD, Summit Cancer Centers
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Description of PQI: The use of immunotherapy in cancer treatment has been expanding over the last several years. The most common adverse effect with these medications are dermatologic toxicities, gastrointestinal, hepatic, and endocrine toxicities. Management of immunotherapy related rash is an important intervention for the patient’s quality of life and buy in to continuation of therapy.

Background: Immunotherapy is being used more and more in cancer treatment; improving outcomes for many patients with melanoma, non-small cell lung cancer, breast cancer, and a growing number of tumor types.1 Although these agents have a range of adverse effects, the most commonly seen is dermatologic. These dermatologic adverse effects can manifest weeks to months after the first treatment, manifesting as a maculopapular or pruritic rash.2,3,4 Other potential toxicities skin reactions include but are not limited to: bullous eruptions and Stevens–Johnson syndrome so understanding the difference of these specific skin reactions as well is important.

PQI Process:

  • Identify high risk patients – All immunotherapy patients
    • Note – patients may be reluctant to bring up adverse effects that they are experiencing. Ask directly if they have a rash
  • Determine the grading of the rash (pharmacist or provider)

  • Grade 1 – Covers < 10% body surface area or without symptoms. Mild or localized itching
  • Grade 2 – Covers 10-30% body surface area with or without symptoms. Intense or widespread itching
  • Grade 3-4 – Covers > 30% body surface area, limiting actives of daily living, severe itching, affects sleep, life threatening or requiring possible hospitalization

PQI Process Continued:

  • Recommended appropriate treatment based on grade of rash (additionally discuss therapy to physician/document in EMR) NOTE: Dose reduction of immunotherapy is not a recommended option. View associated NCCN references and sources for further information4
    • Grade 1
      • Use fragrance free soaps for bathing and detergents for clothes
        • Consult with medically integrated team to determine best relief care for patient
      • Topical corticosteroids twice daily
        • Triamcinolone 0.1% lotion or fluocinonide 0.05% cream
    • Grade 2
      • Topical corticosteroids twice daily
        • Triamcinolone 0.1% lotion or fluocinonide 0.05% cream
      • Oral antihistamines or GABA agonists for puritus
        • Hydroxyzine 10 mg TID or Gabapentin 300 mg TID or Pregabalin 50 mg TID
    • Grade 3
      • Hold immunotherapy until rash is grade 1 or symptoms have resolved
      • Oral corticosteroids until rash is grade 1 or symptoms have resolved
        • Prednisone 0.5-1 mg/kg/day (or equivalent)
    • Grade 4
      • Permanently discontinue immunotherapy
      • Consider topical antibiotics in combination with oral retinoids, IV corticosteroids, IM/IV antihistamines, IV Antibiotics and/or hydration

Patient Centered Activities:

  • Provide education:
  • Infection Prevention
  • Monitor skin
    • Importance of calling provider if rash worsens

References:

  1. Linardou, Helena, and Helen Gogas. “Toxicity Management of Immunotherapy for Patients with Metastatic Melanoma.” Annals of Translational Medicine, AME Publishing Company, 4 July 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC4971373/.
  2. “Toxicities Associated with Checkpoint Inhibitor Immunotherapy.” UpToDate, www.uptodate.com/contents/toxicities-associated-with-checkpoint-inhibitor-immunotherapy#H645515. 23 March 2018.
  3. “ICLIO.” Institute for Clinical Immuno-Oncology, accc-iclio.org/.
  4. National Comprehensive Cancer Network. Management of Immunotherapy-Related Toxicities (Version 1.2018). https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed May 1, 2018.
Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.
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Written by: Jody Agena, PharmD, Virginia Cancer Specialists
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Description: Understand how to identify eligible patients and manage adverse effects of regorafenib treatment in hepatocellular carcinoma.

Background: Regorafenib is a kinase inhibitor indicated for the treatment of patients (Childs Pugh A) with Hepatocellular Carcinoma (HCC) who have been previously treated with sorafenib.  In the phase III – RESORCE Trial, regorafenib was assessed in patients with HCC who have progressed on sorafenib and concluded that there was an improved overall survival compared to placebo (10.6 months vs. 7.8 months). This study also portrayed the difficulties of maintaining therapy, as the discontinuation rate due to adverse events within the treatment arm was observed at 25% and 43% due to progression. The most common grade (all grade) adverse events occurring more frequently in the regorafenib group included:  Hand-foot skin reaction (51%), asthenia/ fatigue (42%), diarrhea (41%), and hypertension (31%). In addition to regorafenib, other 2nd line options include nivolumab.  Patients that are not eligible for nivolumab may include those with comorbidities including but not limited to: pneumonitis, thyroid disorders, renal dysfunction, colitis, previous transplants.

PQI Process: Consider reviewing all current HCC patient in EMR for appropriateness of regorafenib therapy
Upon receipt of a new prescription for Regorafenib:

  • If the typical starting dose of 160 mg by mouth once a day is written, consider initiating dose titration based on the mCRC ReDos trial in metastatic colorectal cancer (mCRC)
    • Initiate patient at 80mg for the first week of cycle 1
    • If no significant drug-related toxicities, escalate to 120 mg for the second week of cycle 1, otherwise hold therapy at current dose
    • If no significant drug-related toxicities, escalate to 160 mg for the third week of cycle 1, otherwise hold therapy at current dose
    • For following cycles, start therapy at current tolerated dose (no dose escalation)
  • Coordinate and establish a weekly follow up call with the patient or caregiver for the first 8 weeks
  • Monitor baseline LFTs
  • CBC with differential and platelets and serum electrolytes at baseline and monthly
  • Monitor blood pressure weekly for the first 6 weeks of therapy, then every cycle
  • Monitor for hand-foot skin reaction (HFSR) weekly for 2 cycles, then every cycle
  • Monitor for signs/symptoms of cardiac issues, bleeding, GI perforation or fistula, infection, and/or neurological symptoms
  • Monitor for impaired wound healing – Hold medication for 2 weeks prior to surgery to allow proper wound healing
  • Consider providing urea base moisturizer
  • Consider use of anti-diarrheals

Patient Centered Activities:

  • Provide Oral Chemotherapy Education (OCE) Sheet
    • Emphasize counseling on side effect table
    • Educate patients on side effects and report adverse effects to prescriber and recommend dose adjustments in 40 mg increments as tolerated
    • Dosing is once daily for 3 weeks on therapy then 1 week off therapy per cycle
    • Medication expires 7 weeks after opening bottle
      • Packaging now available in 21 count bottle
    • Take dosage with low fat meal (< 600 calories)
      • Examples of Low Fat food choices5
        • Dairy and dairy-like products
          • Low-fat (1%) or fat-free (skim) yogurt, cottage cheese, or milk
          • Fat-free American cheese or other types of fat-free cheeses
        • Fish, meat, poultry, and other protein
          • Egg whites or egg substitutes
          • Crab, white fish, shrimp, and light tuna (packed in water)
          • Chicken and turkey breast (without skin), or ground turkey breast
          • Beans, peas, and lentils, cooked (or canned) without added fats
        • Grains, cereals, and pastas
          • Hot (oatmeal or grits) and cold cereals (except granola types)
          • Whole grain brown rice or noodles (watch out for fat in added sauces)
          • Whole grain bagels, pita bread, or English muffins
          • Low-fat crackers and breads
          • Soft tortillas – corn or whole wheat
        • Fruits- including fresh, frozen, or canned (in their own juice)
        • Vegetables- including fresh, frozen, or canned (choose lower-sodium varieties)
        • Other foods
          • Broth type soups with a vegetable base
          • Sauces, pudding, or shakes made with skim milk

References:

  1. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Bruix, Jordi et al. The Lancet, Volume 389 , Issue 10064 , 56 – 66.
  2. Ou FS, Bekaii-Saab T. ReDOS* trial presented at the ASCO GI Cancers Symposium 2018. ReDOS poster from ASCO GI, Jan. 2018.
  3. NCCN Clinical Practice Guidelines in Oncology (NCCN guidelines®) for colon cancer v.2.2018. © Page COL-D 9 of 10. National Comprehensive Cancer Network 2018. All rights reserved. Accessed May 10, 2018.
  4. Bekaii-Saab T, Ou FS, Ciombor KK, et al. Regorafenib dose optimization study (ReDOS): A phase II randomized study of lower starting dose regorafenib compared to standard dose regorafenib in patients with refractory metastatic colorectal cancer (mCRC). Journal of Clinical Oncology 2016 34:15_suppl, TPS3630-TPS3630.
  5. STIVARGA® (Regorafenib) [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, April 2017.
  6. https://www.cancer.org/healthy/eat-healthy-get-active/take-control-your-w.
Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.
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