1. Education of patients taking capecitabine
These slides focus on the importance of patient education for managing toxicity related to capecitabine.
Extra details particularly relevant to the MINDACT protocol have been added when applicable.
EORTC BIG 3-04 Intergroup Study
MINDACT (Microarray In Node-negative Disease may Avoid ChemoTherapy):
A prospective, randomized study comparing the 70-gene signature with the common clinical-pathological criteria in selecting patients for adjuvant chemotherapy in node-negative breast cancer

2. Oral capecitabine = chemotherapy at home
Treatment with capecitabine is home-based
The patient takes an active role in treatment administration
The patient must take an active role in the management of toxicity
The patient must receive proper education to manage home-based chemotherapy
Unlike intravenous chemotherapy, capecitabine is administered as tablets at home and therefore the patient has an active role in treatment administration.
To a higher degree compared with intravenous chemotherapy, the patient must take an active role in the management of toxicity.
Considering the active role of the patient for both treatment administration and management of toxicity, it is of crucial importance that the patient receives proper education to manage home-based chemotherapy.

3. Treatment interruptions prevent worsening toxicity
Studies show that
if capecitabine is interrupted at onset of toxicity, it usually resolves quickly (2-3 days)
capecitabine can be re-started at same dose
if capecitabine is not interrupted in time, toxicity worsens and may lead to permanent treatment discontinuation
Interruption of capecitabine at onset of moderate (grade 2) toxicity is the most common way to manage toxicity.
Brief drug interruptions and/or dose adjustments lead to the reinstitution of treatment in most patients.
If capecitabine is not interrupted at onset of moderate toxicity, the toxicity may worsen and may lead to permanent treatment discontinuation.
Blum JL et al. J Clin Oncol 1999; 17:
Cassidy J et al. Ann Oncol 2002;13:566–75

4. Patients need to understand importance of early capecitabine interruption
may not easily accept the idea of interrupting capecitabine
are often prepared to experience toxicities and do not want to interrupt treatment for fear it may decrease efficacy
Not accepting short interruptions is counter-productive as it may lead to increased toxicity and treatment discontinuation or low dose intensity
Patients with cancer are usually prepared to accept treatment toxicity and fear that interruption of treatment may decrease efficacy. Therefore they may not easily accept to interrupt capecitabine at onset of moderate toxicity.
It is one of the main tasks of the educator to make the patient understand that capecitabine must be interrupted at onset of moderate toxicity. Not respecting this rule may lead to increased toxicity and either treatment discontinuation or low dose intensity because dose reductions will be needed in case of severe and/or life threatening toxicity.

5. Patients must be reassured that protocol compliant dose modifications will not compromise efficacy
It is very important to inform and reassure the patients that the dose modifications according to the protocol (interruptions and dose reductions due to toxicity) will not compromise efficacy.

6. Capecitabine dose modification reduces the recurrence of adverse events
No. of patients
100 80 60 40 20
Grade 2
Grade 3
Grade 4
Analyses performed in previous trials show that dose modifications due to toxicity reduce the recurrence of toxicity. Presented here is the analysis of the impact of dose modification on recurrence of hand foot syndrome, diarrhea and stomatitis. This analysis was performed in patients treated with capecitabine monotherapy in two clinical trials in metastatic colorectal cancer and it is a part of the integrated safety analysis of these two trials published in Annals of Oncology 2002 (Cassidy J et al.)
Before After Before After Before After
Hand-foot syndrome Diarrhea Stomatitis
Cassidy J et al. Ann Oncol 2002;13:566–75

7. Capecitabine dose modification does not compromise efficacy
HR=0.97
p=0.78
5-FU/LV
HR=1.12
p=NS
Decreased risk
of disease
progression
Increased risk
of disease
progression
No difference in
risk of disease
progression
Analyses performed in previous trials show that dose modifications of capecitabine due to toxicity do not compromise efficacy. Presented here is the analysis of the impact of dose modification on treatment efficacy in terms of time to disease progression. This analysis was also performed in patients treated with capecitabine monotherapy in two clinical trials in metastatic colorectal cancer being a part of the integrated safety analysis of these two trials published in Annals of Oncology 2002 (Cassidy J et al.)
HR = hazard ratio for disease progression in patients with versus without dose reduction
Cassidy J et al. Ann Oncol 2002;13:566–75

8. Detailed instructions should be given to patients
If patients experience any of the following
moderate diarrhea (increase of 4 to 6 stools a day) and/or diarrhea at night
2-5 vomiting episodes in 24 hours
pain, redness and/or swelling of the mouth
pain, swelling and redness of the hands or feet
The intensity of diarrhea, nausea/vomiting, stomatitis and is described in CTCAE v.3 and patients must learn what exactly is moderate (grade 2) intensity for these key toxicities.
For diarrhea, moderate intensity means increase of 4-6 stools/day compared to the stool habits before treatment start and/or diarrhea at night. This is a relative scale.
For nausea/vomiting, moderate intensity means 2-5 vomiting episodes in 24 hours.
The patient must also recognize
- moderate stomatitis: pain, redness and/or swelling of the mouth
- moderate hand foot syndrome: pain, swelling and redness of the hands and feet.

9. If  grade 2 non-hematologic toxicity, patient should stop capecitabine and call you
They should
STOP taking capecitabine
TELEPHONE their investigator / study nurse immediately
Begin treatment if available
Drink plenty of water ( 2L/day)
The patients must get clear instruction what to do at onset of moderate toxicity. To stop capecitabine is the right action but not the only one. The patients must also get in touch with their investigator / study nurse and the quickest way is to use the telephone.
For some but not all toxicities treatment is available. If treatment is available the patients should have the medication at home and start using it at onset of moderate toxicity.
As a general recommendation: remind the patient to drink plenty of water.

10. The investigator / study nurse can advise on treatment at home
Phone contact permits investigator / study nurse to advise patient on further management
The investigator / study nurse can advise on
treatment at home
set appointment for further phone follow-up
re-starting capecitabine
need to come to the clinic for further assessment
possibly hospitalization
The contact with the investigator / study nurse is very important as, depending of the nature and intensity of the toxicity, treatment may be given at home or the patients must come to the clinic for further assessment which may lead to hospitalization.
It is important to set appointments for further phone follow-up. Thus further instructions can be communicated depending on the clinical development. If toxicity resolves patients may be advised to re-start capecitabine.

11. Proactive patient contact may further improve patient management
Sites contacting patients on a regular basis proactively between clinic visits might discover potential adverse events earlier, resulting in
earlier treatment, decreased duration of treatment and/or less aggressive treatment of adverse event
reduction in number of adverse events reaching grade 3 / 4 severity
decreased possibility that capecitabine dose will have to be held or reduced in order to manage the event
increased patient comfort and confidence in taking a home-based chemotherapy

12. Interrupt capecitabine for grade  2 non-hematologic toxicities
Grade 2, 3, or 4 non-hematologic toxicity
Diarrhea
Nausea / vomiting *
Stomatitis / mucositis
Hand-foot syndrome
INTERRUPT
CAPECITABINE
IMMEDIATELY
The key toxicities are non-hematologic: diarrhea, nausea/vomiting, stomatitis and hand foot syndrome. The patient must learn to recognize the onset of moderate intensity of these toxicities and stop capecitabine if toxicity occurs during treatment.
The MINDACT protocol does not necessarily require interruption of capecitabine for nausea / vomiting. Sites should follow local guidelines.
* Occuring under adequate antiemetic treatment Note per MINDACT protocol: sites should follow local guidelines – antiemetics and/or corticoids

13. GI toxicity requires prompt management
The most common problem is GI toxicity: diarrhea, nausea, vomiting
In case of diarrhea grade ≥ 2 patients should be instructed to STOP taking capecitabine and START taking loperamide
If diarrhea is not properly managed it may worsen, leading to life-threatening dehydration and even death
The most common toxicity with capecitabine is gastro-intestinal, especially diarrhea. In case of moderate or more intensive (grade 2 or more) diarrhea, patients must stop capecitabine and start taking loperamide.
Diarrhea is potentially dangerous. If not properly managed it may worsen leading to life-threatening dehydration and even death.

14. Supportive management of diarrhea in MINDACT: loperamide and fluids
Loperamide (patient should have at home)
4 mg first onset, then 2 mg every 2 hours until 12 hours after last loose stool (total treatment duration should not exceed 48 hrs)
Do not re-start capecitabine until diarrhea has resolved to < grade 1 with the last loperamide dose given at least 24 hours beforehand
prophylaxis not recommended
laxatives should not be used
Note: under Capecitabine monotherapy 2mg Loperamide every 6 hrs is usually enough to successfully treat diarrhea
The patients must have loperamide (Imodium) at home and get clear instructions how to use it: 4 mg (2 tablets) at onset then 2 mg (1 tablet) every 2 hrs (combination therapy) or every 6th hour (monotherapy) until 12 hours after last loose stool. Prophylactic treatment with loperamide in absence of diarrhea is not recommended as it can lead to constipation and in worst case to intestinal obstruction.
The high dose loperamide regimen recommende in the Mindact protocol should not be used longer than 48 hours.

15. Supportive management of diarrhea cont.: loperamide and fluids
Tell patient to drink at least 2 L water per day
Hospitalization with fluid and electrolyte support when clinically indicated or diarrhea persists after 48 hrs of recommended Loperamide treatment
Remind the patients to drink at least 2 L water per day.
Patients should not only stop capecitabine and start loperamide but make contact with the investigator / study nurse. If clinically indicated, the patients may need hospitalization for fluid and electrolyte support.
The MINDACT protocol requires that patients be hospitalized for parenteral support if diarrhea persists for more than 48 hours.

16. Management of other non-hematological adverse events  grade 2
In case of grade ≥ 2
Patients should STOP taking capecitabine and start
Nausea/vomiting *
Anti-emetics, suitable food & drink
Mucositis/Stomatitis
Mouth washes, suitable food & drink
Hand-foot-syndrome
Skin emollients, avoid putting pressure on palms and soles
Treatment is available not only for diarrhea but also for nausea/vomiting, stomatitis and hand foot syndrome.
In case of nausea of moderate or worse intensity (grade 2 or more), patients should start treatment with antiemetics at home. Give also advice about suitable food and drink.
The MINDACT protocol does not necessarily require interruption of capecitabine for nausea / vomiting. Sites should follow local guidelines.
In case of stomatitis of moderate or worse intensity (grade 2 or more), patients should start treatment with mouth washes. Give also advice about suitable food and drink.
For moderate or worse intensity (grade 2 or more) hand foot syndrome, patients should use skin emollients (e.g., E-45 or Neutrogena skin cream). Give also advice to avoid very hot water, abrasives and putting pressure on palms and soles.
* Note per MINDACT protocol: sites should follow local guidelines – antiemetics and/or corticoids

17. Dose-reduction tables
If dosereductions are necessary please use the following dose reduction tables

18. Total dose per administration (mg)
Pill combinations to be taken based on a 25% dosereduction for capecitabine (620 mg/m2 bid)
75% dose level
Body Surface Area (m2)
Total dose per administration (mg)
Morning pills
Evening pills
150 mg
500 mg
< 1.48
800 2 1
1.49 – 1.69
1000
1.70 – 1.90
1150
1.91 – 2.30
1300
> 2.31
1500 3
Use this dosing table in patients who require a 25% decrease in their capecitabine dose.

19. Total dose per administration (mg)
Pill combinations to be taken based on a 50% dosereduction for capecitabine (412.5 mg/m2 bid)
50% dose level
Body Surface Area (m2)
Total dose per administration (mg)
Morning pills
Evening pills
150 mg
500 mg
< 1.48
500 1
1.49 – 1.69
650
1.70 – 2.30
800 2
> 2.31
1000
Use this dosing table in patients who require a 50% decrease in their capecitabine dose.

20. Patient education must be clear and face-to-face
The educator should take enough time to inform patients
A longer initial information session is a good investment
Avoid fragmentation of information (several persons giving pieces of information without coordinating their efforts)
Repeat information during treatment
Establish clear communication lines
Patient education is very important for safe administration of capecitabine. The educator should allocate enough time for patient information / education. The amount of time may vary between patients. A longer initial information session is necessary and is a good investment for treatment safety.
Avoid fragmentation of information. If several persons give information, coordinate their efforts.
Information must be repeated during treatment.
The patient should know whom to ask: establish clear communication lines.

21. Use the available tools
Patients should have written information leaflets at home as a reminder of the information received at the site
Educators should use the provided check lists for patient education
Use the available education material: patients should have written information leaflets at home. This is a reminder of the information received at the study site.
Use the recently provided checklist for patient education.
For the educators, the study protocol and CTCAE v.3 should be easily accessible.

22. Patient education is an integral part of capecitabine treatment