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Mayer RJ et al. N Engl J Med. 2015;372:1909–1919

 

Trifluridine/tipiracil 35 mg/m2/dose (dose based on trifluridine component, maximum dose = 80 mg); administer orally twice per day, with a glass of water within 1 hour of completion of the morning and evening meals, on days 1–5 and days 8–12; repeated every 28 days until disease progression (total dose of trifluridine per 28-day cycle = 700 mg/m2; total maximum dose of trifluridine per 28-day cycle = 1600 mg)

Notes:

  • Round each dose to the nearest 5 mg (maximum dose = 80 mg) and administer a combination of 15 mg and/or 20 mg tablets (trifluridine component) as necessary to provide the calculated dose

  • Patients who delay taking a trifluridine/tipiracil dose at a regularly scheduled time or who vomit after taking a dose of trifluridine/tipiracil should take the next dose at the next regularly scheduled time

 

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE

See Chapter 39 for antiemetic recommendations

 

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

 

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

  • Antibacterial—not indicated

  • Antifungal—not indicated

  • Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

 

Diarrhea management

Latent or delayed-onset diarrhea:

  Loperamide 4 mg orally initially after the first loose or liquid stool, then

  Loperamide 2 mg orally every 2 hours during waking hours, plus

  Loperamide 4 mg orally every 4 hours during hours of sleep

  • Continue for at least 12 hours after diarrhea resolves

  • Recurrent diarrhea after a 12-hour diarrhea-free interval is treated as a new episode

  • Rehydrate orally with fluids and electrolytes during a diarrheal episode

  • If a patient develops blood or mucus in stool, dehydration, or hemodynamic instability, or if diarrhea persists >48 hours despite loperamide, stop loperamide and hospitalize the patient for intravenous hydration

  Alternatively, a trial of diphenoxylate hydrochloride 2.5 mg with atropine sulfate 0.025 mg (eg, Lomotil)

  • Initial adult dose is 2 tablets 4 times daily until control has been achieved, after which the dose may be reduced to meet individual requirements. Control may often be maintained with as little as 2 tablets daily

  • Clinical improvement of acute diarrhea is usually observed within 48 hours. If improvement of chronic diarrhea after treatment with a maximum daily dose of 8 tablets is not observed within 10 days, control is unlikely with further administration

Persistent diarrhea:

  Octreotide 100–150 mcg subcutaneously 3 times daily. Maximum total daily dose is 1500 mcg

Antibiotic therapy during latent or delayed-onset diarrhea:

  A fluoroquinolone (eg, ciprofloxacin 500 mg orally every 12 hours) if absolute neutrophil count <500/mm3 with or without accompanying fever in association with diarrhea

  • Antibiotics should also be administered if patient is hospitalized with prolonged diarrhea and should be continued until diarrhea resolves

Patient Population Studied

A multicenter, randomized, double-blind, phase 3 trial involved 800 patients with biopsy-documented adenocarcinoma of the colon or rectum. Eligible patients were aged ≥18 years, with ECOG (Eastern Cooperative Oncology Group) performance status ≤1, had previously received ≥2 regimens of standard chemotherapies, and had either experienced tumor progression within 3 months after last administration of chemotherapy or had clinically significant adverse events from standard chemotherapies that precluded readministration of those therapies. Patients who had not previously received chemotherapy with a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab and (in those with KRAS wildtype tumors) either cetuximab or panitumumab were not eligible. Patients were randomly assigned (2:1) to receive trifluridine+tipiracil (TAS-102) or placebo

Efficacy (N = 800)

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Efficacy (N = 800)

Median overall survival

7.1 months vs. 5.3 months with placebo

HR 0.68, 95% CI 0.58–0.81, P <0.001

Median progression-free survival

2.0 months vs. 1.7 months with placebo

HR 0.48, 95% CI 0.41–0.57, P <0.001

Complete or partial response

1.6% vs 0.4% with placebo; P = 0.29

Disease control

44% vs 16% with placebo; P <0.001

Tumor response was assessed in 760 patients

Disease control was defined as complete or partial response or stable disease at least 6 weeks after randomization

Therapy Monitoring

  1. CBC with differential at a minimum prior to and on day 15 of each cycle. CBC as often as weekly early on in treatment to assess if dose is appropriate

  2. Serum bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle; CEA if being used to follow disease

  3. Every 2–3 months: CT scans to assess response

Treatment Modifications

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TRIFLURIDINE AND TIPIRACIL
Dose Levels

Starting dose

35 mg/m2/dose (maximum dose = 80 mg) twice daily on days 1–5 and days 8–12 of each 28-day cycle

Dose Level -1

30 mg/m2/dose (maximum dose = 70 mg) twice daily on days 1–5 and days 8–12 of each 28-day cycle

Dose Level -2

25 mg/m2/dose (maximum dose = 60 mg) twice daily on days 1–5 and days 8–12 of each 28-day cycle

Dose Level -3

20 mg/m2/dose (maximum dose = 50 mg) twice daily on days 1–5 and days 8–12 of each 28-day cycle

Alternately find trifluridine and tipiracil dosage calculator at: https://itunes.apple.com/us/app/lonsurf-dosage-calculator/id1231067439 or https://www.lonsurfhcp.com/dosing/dosage-calculator (accessed July 29, 2018)

Adverse Event

Treatment Modification

If at start of new cycle ANC <1500/mm3; febrile neutropenia; platelets < 75,000/mm3; G3/4 nonhematologic adverse reactions

Withhold the start of trifluridine/tipiracil until ANC ≥1500/mm3; febrile neutropenia is resolved; platelets ≥75,000/mm3; G3/4 nonhematologic adverse reactions have resolved to G0/1 and resume with previous dose

Uncomplicated G4 neutropenia (<1000/mm3) that has recovered to ≥1500/mm3 or G4 thrombocytopenia (<25,000/mm3) that has recovered to ≥75,000/mm3 but that did not delay start of cycle by >1 week

Resume trifluridine/tipiracil at previous dose

Febrile neutropenia

After recovery resume trifluridine/tipiracil reducing dose by 5 mg/m2/dose. Do not escalate trifluridine/tipiracil dose after it has been reduced

Uncomplicated G4 neutropenia (<1000/mm3) that has recovered to ≥1500/mm3 or G4 thrombocytopenia (<25,000/mm3) that has recovered to ≥75,000/mm3 but that delayed start of cycle by >1 week

Nonhematologic G3/4 adverse reactions (except for G3 nausea and/or vomiting controlled by antiemetic therapy or G3 diarrhea responsive to antidiarrheal medication)

If within a treatment cycle ANC <500/mm3; febrile neutropenia; platelets <50,000/mm3; G3/4 nonhematologic adverse reactions

Withhold trifluridine/tipiracil until ANC ≥500/mm3; febrile neutropenia is resolved; platelets ≥50,000/mm3; G3/4 nonhematologic adverse reactions have resolved to G0/1

Mild hepatic impairment (total bilirubin <1.5× ULN and normal transaminases)

No adjustment to the starting dose of trifluridine/tipiracil is recommended

Baseline moderate or severe hepatic impairment (total bilirubin >1.5× ULN and any AST elevation)

Do not initiate trifluridine/tipiracil

Moderate renal impairment (creatinine clearance = 30–59 mL/min)

May require dose modifications for increased toxicity

Severe fatigue

Reduce trifluridine/tipiracil dose by 5 mg/m2

G ≥2 nausea/vomiting

Institute antiemetic therapy; after resolution of symptoms resume trifluridine/tipiracil at the dose being used

Note: Trifluridine/tipiracil can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment

Adverse Events (N = 798)

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Adverse Events (N = 798)
 

Trifluridine+Tipiracil (TAS-102)

Placebo

Grade (%)

Grade 1/2

Grade ≥3

Grade 1/2

Grade ≥3

Any event

29

69

42

52

Nonhematologic Adverse Events

Nausea

47

2

23

1

Decreased appetite

35

4

25

5

Increase in alkaline phosphatase level

31

8

34

11

Increase in total bilirubin

27

9

15

12

Fatigue

31

4

18

6

Diarrhea

29

3

12

<1

Increase in AST level

25

4

29

6

Vomiting

26

2

14

<1

Increase in ALT level

22

2

23

4

Abdominal pain

19

2

15

4

Fever

17

1

14

<1

Asthenia

15

3

8

3

Increase in creatinine level

13

<1

11

<1

Stomatitis

8

<1

6

0

Hand-foot syndrome

2

0

2

0

Cardiac ischemia

<1

<1

0

<1

Hematologic Adverse Events

Leukopenia

56

21

5

0

Anemia

58

18

30

3

Neutropenia

29

38

<1

0

Febrile neutropenia

0

4

0

0

Thrombocytopenia

37

5

8

<1

According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03

Denotes those events of special interest for fluoropyrimidine treatment

Note: Toxicities are included in the table if all-grade events occurred in ≥10% of patients in the TAS-102 group and occurred more frequently in that group than in the controls, or were of special interest

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