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 10041 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

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.

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: 485-93 Cassidy J et al. Ann Oncol 2002;13:566–75

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.

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.

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

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

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.

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.

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.

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

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

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.

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.

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.

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

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

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.

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.

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.

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.

Patient education is an integral part of capecitabine treatment