Abstract Background Oral tyrosinase inhibitor (TKI) therapy is a major advance in the treatment of renal cell carcinoma (RCC). Several such agents are available, the most used of which is sunitinib, which can extend progression-free survival to 11 months. However, as the duration of treatment increases, drug side effects also increase, which can reduce patients’ quality of life. As a result, clinicians and patients are looking forward to the development of a set of standards for monitoring, treating and managing side effects. Although there are many physicians who are summarizing their experiences in dealing with these problems and making recommendations, these are after all only single-center experiences and some medical centers have a small number of cases. Methods and Results Our study is based on two aspects: (1) an extensive review and analysis of the available literature; and (2) a consensus opinion of 12 German experts (each with experience in treating at least 30 patients with TKI). Conclusions Taking into account the available clinical evidence and the expert consensus, this article gives general recommendations for the management of adverse reactions due to sunitinib. Keywords: Sunitinib, adverse reactions, management Overview Introduction Sunitinib is the main targeted drug used for the treatment of metastatic RCC, and most patients are treated with this drug. A recent phase III clinical trial investigating sunitinib reported an objective remission rate of 47% and progression-free survival (PFS) of 11 months. Because of the long duration of dosing, adverse reactions can occur at any time during treatment, affecting continued dosing and patient safety, and therefore require special attention. Adverse reactions occur in the majority of patients and result in dose reductions in 32% of patients and treatment interruptions in 8% of patients. Obviously, in order to maintain good patient compliance, clinicians are required to manage adverse reactions appropriately, and many have provided advice based on clinical experience. However, the extent to which these recommendations are accepted is unclear and has not been evaluated. In this study, the available literature evidence was collected, reviewed by 12 German experts in this field, and then reviewed. This paper lists the recommendations for the management of side effects that have received more than 70% expert consensus for monitoring, prevention and treatment, which may provide some insight into the daily treatment of patients. Materials and methods The sources of reference for this article were: articles published in peer-reviewed journals listed in PubMed, EmBase, and Current Contents through November 2008; recommendations given by the Oncology Society; and content available online (last updated August 9, 2008, PubMed last updated October 17, 2008). 17, 2008). The information collected was compiled and referred to each clinical expert for independent evaluation of these treatments based on his or her own experience. The assessment was conducted in the form of a questionnaire of 60 pages containing approximately 450 treatment recommendations. To avoid bias in the assessment, the source of all treatment recommendations was omitted. Attitudes toward each treatment recommendation were rated on a four-point scale from “strongly agree” to “completely disagree”. In addition, two open-ended modules were included for experts to make a general assessment and to give specific treatment measures based on their own experience. A total of 12 experts, each with at least 30 cases of clinical experience (as of November 26, 2008), were involved in the independent evaluation. The management method that was approved by at least 70% of the experts was considered expert consensus and is described in detail in the text. Results Hypertension Definition and symptoms As a class reaction arising from VEGF or VEGFR inhibitors, hypertension is one of the most common toxic side effects of VEGF or VEGFR inhibitors. The pivotal clinical trial investigating sunitinib as first-line therapy reported a 24% incidence of hypertension, with grade 3 and 4 hypertension accounting for 8% of cases. Elevated blood pressure may return to normal within a 2-week period between doses and recur after dosing. In patients with pre-existing hypertension, blood pressure may rise further, requiring more intensive antihypertensive therapy. The mechanism by which sunitinib causes hypertension is not fully understood. Some studies suggest that inhibition of VEGFR leads to a concomitant decrease in nitric oxide in blood vessels, which in turn leads to hypertension. A recent retrospective article examining cardiovascular events in patients with RCC reported changes in patients’ electrocardiograms and arrhythmias. In addition, it has also been found that cardiac myocytes are directly damaged, further exacerbating the damage caused by hypertension to the myocardium. Therefore, some scholars recommend mandatory blood pressure monitoring prior to administration of sunitinib, but the frequency of monitoring is not clearly specified. Some scholars recommend close monitoring of blood pressure, even daily. There is no optimal strategy for lowering blood pressure, and the patient’s antihypertensive medication is usually prescribed by the local physician. Prevention and adjunctive blood pressure control methods More than 90% of experts agree that patients should undergo ambulatory blood pressure measurement and evaluation of signs and symptoms associated with hypertension. Blood pressure monitoring should begin before medication is administered and continue throughout the course of treatment. There are a number of complementary approaches to blood pressure control, including regular exercise, weight control, and a low-salt diet; in addition, more than 80% of experts agree that alcohol consumption should be reduced. Table 1 National Cancer Institute’s Common Terminology Criteria for Adverse Effects (CTCAE) Classification of Hypertension Severity Classification Hypertension Ⅰ Diastolic blood pressure elevation greater than 20 mmHg, or blood pressure >150/100 mmHg when previously normal; asymptomatic, transient (<24h); no treatment required Ⅱ Diastolic blood pressure elevation greater than 20 mmHg, or blood pressure >150/100 mmHg when previously normal; no treatment required Ⅱ Diastolic blood pressure elevation greater than 20 mmHg, or blood pressure >150/100 mmHg when previously normal; no treatment required mmHg and previously normal blood pressure; recurrent, or persistent (>24h), or symptomatic; may require monotherapy Ⅲ More than one antihypertensive drug is required, or stronger antihypertensive therapy than previously required Ⅳ Life-threatening (e.g., hypertensive crisis) Medication In principle, early intervention should be performed according to the relevant local guidelines when blood pressure is significantly elevated. Pre-existing hypertension should be controlled to a normal level (>90% expert agreement) even before sunitinib treatment is started. Antihypertensive therapy should be initiated when hypertension reaches a grade 2 level, and antihypertensive medication should be discontinued or reduced during the interval (2 weeks) between sunitinib doses (high expert agreement). In the event of uncontrolled grade 3 hypertension or untreated severe hypertension, sunitinib dosing should be temporarily discontinued until blood pressure is satisfactorily controlled (expert agreement >90%). The choice of antihypertensive drug may follow national guidelines and take into account the patient’s risk of cardiovascular events (>90% expert agreement). Mild hypertension should be controlled with a single drug, while severe or poorly controlled hypertension should be controlled with a combination of drugs (>90% expert agreement). When choosing antihypertensive drugs, attention should be paid to whether they affect the liver enzymes CYP3A4 and QT interval (expert agreement >90%). If antihypertensive drugs affecting CYP3A4 are used, the dose of sunitinib should be adjusted accordingly (80% – 90% expert agreement), e.g., if CYP3A4 inhibitors are used, the dose of sunitinib should be reduced to 37.5 mg. Weakness Definition and symptoms Weakness refers to a range of discomfort such as exertion, fatigue or decreased physical strength, and is often associated with tumors, endocrine diseases, systemic diseases and treatment of tumors. In addition, mental and physical stress can also lead to malaise symptoms. Clinical manifestations do not predict the underlying cause of malaise. Clinical trials have reported that sunitinib causes malaise in 65.2-73.0% of patients, with grade 3 and 4 malaise in 14.4-17.5% and 0.2-1.1%, respectively [15]. Other factors contributing to malaise should not be overlooked, as the presence of malaise may indicate the need for intervention, such as hypothyroidism. Prevention and adjunctive measures For patients receiving sunitinib, it is crucial to have a thorough understanding of their basic information and to assess the underlying causes of their fatigue. Patients should assess and actively seek out the causes of their weakness, such as: hypothyroidism, anemia, depression, malnutrition, adverse stress, sleep disturbances, activity level, pain, combination medications, etc. (expert agreement >90%). Patients can keep a daily record of their fatigue, which will help monitor the onset of severe fatigue (70%-80% expert agreement). During the first few cycles of treatment, staff should provide close support and assistance to the patient, especially by emphasizing the need to consult with the physician about how to cope with fatigue and stay motivated (>90% expert agreement). Physicians should make patients fully aware of the different levels of severity of malaise and how to deal with the different causes of malaise. By and large, it is recommended that patients be given relevant reading material to guide them on how to adjust their daily activities to conserve energy. There are many ways to keep patients active in their daily activities (>90% expert agreement), including maintaining normal social and physical activity and a regular routine. Moderate activity should be based on the individual’s physical condition and should not be excessive to the point of significant fatigue or even to the point of interfering with activity throughout the day; weight should be routinely monitored. Distraction methods (e.g., reading) are beneficial, while short periods of sleep during the day are not very useful (80-90% expert agreement). Table 2 CTCAE Weakness Classification Severity Classification Side effects Dose adjustment Ⅰ Mild weakness No adjustment required Ⅱ Moderate weakness with partial limitation of daily activities No adjustment required Ⅲ Severe weakness with significant interference with daily activities Dose reduction or discontinuation; restart from lower dose Ⅳ Life-threatening (e.g., hypertensive crisis) Dose reduction or discontinuation; restart from lower dose Medication If weakness is secondary to a clear cause such as hypothyroidism, depression, anemia, or pain. If the weakness is secondary to a clear cause such as hypothyroidism, depression, anemia, or pain, then the drug should be used to treat these related conditions (>90% expert agreement). Sunitinib dose adjustment In general, if sunitinib reduces the patient’s quality of life, a dose reduction should be considered (>90% expert agreement) (see Table 2). Oral adverse reactions Definitions and symptoms Oral adverse reactions due to sunitinib are varied and include stomatitis, mucositis, mucosal hypersensitivity, mouth ulcers, labyrinthitis, and altered taste sensation. In many cases, patients present with oral dysfunction without a definite lesion, and symptoms may resolve spontaneously during a 2-week treatment interval. Prophylaxis and adjunctive measures Oral lesions are one of the most common adverse effects due to sunitinib, for which various prophylactic measures such as mucosal protection and gentle oral care are often taken, but these measures are prone to infectious complications and need to be closely monitored (>90% expert agreement). However, only 80-90% of experts agreed to perform bacterial testing of oral rinses. To reduce oral side effects, patients should avoid irritating foods or beverages in their diet (>90% agreement), such as spicy foods, foods or beverages that are too hot or too cold, and dry and hard foods. In addition, care should be taken to protect the lips (>90% of experts agree). When the sense of taste is altered, patients may benefit from trying to associate food with a tasty experience (expert agreement >90%). Patients who suffer from a metallic or bitter taste in the mouth may find it easiest to mouth a sugar cube or chew sugar-free mint-flavored gum (>90% expert agreement) or consult a dietitian (70-80% expert agreement). Panthenol tablets or ointments (>90% expert opinion) can be used to protect the oral mucosa, but oral hygiene is also essential (>90% expert opinion). Dental care helps to reduce oral mucosal discomfort and should be performed gently and delicately with a very soft toothbrush and without the use of mouthwashes containing alcohol (80-90% expert opinion) or toothpastes containing peroxide (70-80% expert opinion). If possible, try not to wear dentures (80-90% of experts agree). Medication Early intervention should be made as soon as oral problems appear, such as surface anesthesia, steroids, or anti-infective treatment. Topical pain relief can be provided by lidocaine gels (>90% agreement), which are superior to some formulations of rinses. Steroids can also be used topically (70-80% expert agreement), preferably in combination with panthenolics (>90% expert agreement). If there is evidence of infection, topical antibiotics are recommended (>90% expert agreement). Of note, systemic antifungal therapy involves drug interactions and has a slightly lower expert agreement (80-90%). Oral side effects resulting in sunitinib dose reduction or discontinuation were less common, unless symptoms were very pronounced (80-90% expert agreement) or interfered with eating (>90% expert agreement). Diarrhea is also a common complication of sunitinib (42.5-59.9%), mostly mild to moderate, but the severity may increase with the duration of treatment. The presentation of diarrhea varies from person to person and there is no fixed pattern. The CTCAE grading of diarrhea is shown in Table 4. Prevention and adjunctive measures Diarrhea should be detected and treated early, which requires the patient’s cooperation, attention to changes in his or her bowel habits, and active search for other possible causes of diarrhea (>90% expert agreement). It is important to prevent worsening of diarrhea, and patients may be advised to eat small and frequent meals daily (expert agreement >90%). The diet should include adequate fluid intake and avoid spices (>90% agreement). Recommended foods include bananas, ripe apples, toast or potatoes; spicy, high-fat, gas-producing or fried foods are not recommended, and large amounts of fruit or juice should not be consumed (>90% agreement). Laxatives should not be taken (expert approval >90%), it is advisable to avoid hyperosmolar dietary additives (expert approval 70-80%), and the temperature of drinking water should be close to room temperature (expert approval 70-80%). For mild diarrhea, electrolyte supplementation is appropriate (80-90% expert approval), and for severe diarrhea, intravenous hydration and electrolytes are indicated (>90% expert approval). Early treatment of diarrhea is recommended with medications such as lupronate (>90% expert approval). dose adjustment of sunitinib is not required for grade 1 to 2 diarrhea (80-90% expert approval), and dose reduction is required for grade 3 to 4 diarrhea (>90% expert approval). Table 4 CTCAE diarrhea grading Severity grading Side effects Impact on sunitinib treatment Ⅰ Increase in bowel movements <4 times per day; mild increase in enterostomy discharge No adjustment needed Ⅱ Increase in bowel movements 4-6 times per day; rehydration time <24 hours; moderate increase in enterostomy discharge; does not affect daily activities No adjustment needed Ⅲ Increase in bowel movements ≥7 times per day; intravenous rehydration time ≥24 hours Ⅲ Increased number of bowel movements per day ≥ 7; duration of intravenous rehydration ≥ 24 hours; hospitalization required; significant increase in enterostomy output; interferes with daily activities Interruption of therapy, consider dose reduction; intravenous rehydration as necessary Ⅳ Life-threatening events Interruption of therapy, consider dose reduction; intravenous rehydration as necessary Nausea and vomiting Definition, classification and incidence Sunitinib can cause the development of upper gastrointestinal symptoms such as decreased appetite, nonspecific epigastric pain or nausea and vomiting. Nausea and vomiting are often present at the beginning of treatment and are manageable. The National Cancer Institute (NCI) classification of diarrhea is shown in Table 5. Based on available literature, the probability of varying degrees of nausea due to sunitinib is 36.6-53.3%, with grade III accounting for 3.4-3.5%. The probability of vomiting was 32.7%, with grade III accounting for 1.6-3.1%. Prevention and medication According to available studies and expert recommendations, a mild, non-irritating diet should be consumed and a doctor should be consulted as soon as digestive symptoms appear. In fact, early treatment of discomfort is important for the continuity of sunitinib medication. A mild diet requires the patient to eat small, frequent meals and to avoid a diet that is too hot, too greasy and too salty (>90% agreement by experts). According to the available studies and expert recommendations, antiemetic and acid suppressant drugs should be used as early as possible. Antiemetics such as metoclopramide or alizapride are recommended, and acid suppressants such as proton pump inhibitors are recommended to protect the gastric mucosa (>90% agreement). Sunitinib dosing adjustments Clinical studies have shown a significant correlation between sunitinib dosing and antitumor effects. Therefore, dose reductions or intermittent discontinuations should be avoided (>90% expert agreement) and a dose reduction of 12.5 mg should only be considered when symptoms reach grade 3 or 4 and are poorly controlled (>90% expert agreement). Table 5 Severity grading of nausea and vomiting by the National Cancer Institute (NCI) Severity grading Nausea Vomiting Ⅰ Decreased appetite, no change in eating habits Occurrence within 1 time Ⅱ Decreased intake; no significant weight loss, no dehydration or malnutrition; intravenous rehydration time <24 hours Occurrence within 2-5 times within hours; intravenous rehydration time <24 hours Ⅲ Malnutrition or dehydration; intravenous nutrition, rehydration Life threatening Rash and depigmentation Definition, probability and classification Rash and depigmentation are common side effects of sunitinib and are usually temporary and reversible. However, these side effects are aesthetically displeasing and have a negative impact on the patient's subjective perception. Sunitinib inhibits the c-Kit gene, which in turn affects melatonin production, resulting in depigmentation 3-5 weeks after the start of treatment. Crossed streaks can even occur due to periodic discontinuation of the drug during sunitinib treatment. Yellowish skin staining due to drug administration does not usually affect the sclera and mucous membranes and therefore should not be misdiagnosed as jaundice (>90% expert agreement). The current NCI grading system classifies this type of side effect into four classes: clear or limited margins (class I), marked or more widely distributed (class II), and undefined (class III/IV). According to the information provided by the drug manufacturer, the incidence of color change was 15.2-18.9% in hair and 26.5-33.2% in skin. Severe rash (grade III) occurred in only 0.0-0.2% of patients. Treatment and patient information Patients should be fully informed of the potential for rash and depigmentation due to sunitinib, including the specific changes that may occur in the hair and skin, and, if they occur, the appropriate makeup for each individual based on their condition (>90% expert agreement). Patients should also be informed that the yellowing of the skin is not a sign of liver damage, but is due to the color of the drug itself. However, once jaundice is present, liver function should be investigated (expert agreement >90%). Hand-foot syndrome Definition, probability and classification The so-called hand-foot syndrome (HFS) is a side effect of chemotherapy, which can also be caused by tyrosine kinase inhibitors (mainly sunitinib). Hand-foot syndrome mainly presents as a painful rash on the palms of the hands and soles of the feet, accompanied by dullness of sensation. In addition, hyperkeratosis, edema and desquamation of the skin tend to occur in areas subjected to mechanical strain, sometimes without significant skin changes. However, severe hand-foot syndrome can sometimes lead to functional limitations that may resolve within 2 weeks of discontinuation of the drug. Hand-foot syndrome is classified into three classes according to severity: mild skin changes and dermatitis (Class I); significant skin changes (e.g., desquamation) without pain or with functional limitations (Class II); and a combination of ulceration or other changes with functional limitations in daily activities (Class III). The incidence of hand-foot syndrome due to sunitinib is 24.1-26.5%, with 6.1-8.5% of the more severe ones (grade III). Prevention and pharmacological treatment Clinical studies and expert recommendations for prevention and treatment include systematic patient education, prevention of mechanical irritation of the skin, and fine and regular daily care of the skin. Patients should be fully informed of every possible manifestation of hand-foot syndrome and should inform their physicians as soon as they notice the corresponding condition for early treatment. In addition, patients should avoid mechanical irritation such as pressure and friction, wear soft and comfortable shoes (even orthopedic-specific shoes), and refrain from engaging in a particular sport on a regular basis (expert agreement >90%). Both hands and feet should avoid contact with high heat or hot water, and ice packs can relieve swelling and pain. Finally, experts recommend using moisturizing, lanolin- or urea-based skin care products to protect the skin, and appropriate trimming or medical care for hyperkeratotic areas. Table 6 Recommendations for the management of hand-foot syndrome (HFS) Treatment Specific instructions, medications, and procedures Early prevention strategies Early management of symptoms can prevent the appearance of severe HFS. Ointments should be used at the first sign of symptoms rather than when symptoms become apparent Basic treatment Use ointment or lotion with 10% urea content If hyperkeratosis occurs, ointments with 35-40% urea content should be used for effective exfoliation Anti-inflammatory medications Systemic anti-inflammatory medications are necessary in some cases Anti-infective medications Topical antifungal medications may be used for local fungal infections Analgesia May be given orally Analgesics such as ibuprofen, paracetamol Rash Rash is a common adverse effect of sunitinib, manifested as dry skin, erythema-like changes (especially on the face and extremities), or seborrheic dermatitis with sagging skin. The rash usually appears 3-8 weeks after the start of sunitinib treatment and is indistinguishable from allergy. The rash is classified into four classes according to severity: maculopapular rash/papular rash or erythema without other symptoms (Class I); rash or erythema followed by localized flaking and lesions involving <50% of the body surface area (Class II); extensive rash and flaking involving >50% of the body surface area (Class III); and herpetic ichthyosis-like hyperkeratosis (Class IV). The probability of skin rash due to sunitinib is 14.5-22.2%, with a higher severity of 0.7% (grade III/IV). Prevention and medication According to the available studies and expert recommendations, in order to prevent and control the rash, patients should be informed about it, avoid sun exposure, and practice regular and careful skin care. It is recommended to use sunscreens with UV-protective ingredients (sunscreen strength 15-30) and to wear a hat for shade (80-90% expert approval). Based on clinical experience, it is recommended to avoid irritating skin care products and not to scratch when the skin is itchy. Finally, patients are advised to use ester-based creams or ointments to prevent dryness or flaking of the skin after bathing. Sunitinib dose adjustment Clinical evidence suggests that sunitinib dosing is significantly associated with antitumor efficacy. Therefore, dose reduction or discontinuation due to drug reactions should be avoided as much as possible. For grade I side effects, dose reduction or discontinuation is usually not necessary (>90% expert agreement). If patients experience grade II-IV side effects, temporary discontinuation may be considered (8 out of 12 experts agreed, 66% agreement). Table 7 Treatment recommendations for rash Treatment Description, medication and steps Basic treatment Skin lotion with 5-10% urea Anti-inflammatory treatment Steroids and, if itchy, antihistamines Broad recommendations If symptoms are severe, consultation with a dermatologist is recommended Discussion Early detection and treatment of complications during sunitinib treatment is important to ensure the patient’s quality of life and continuity of medication. Implementing good countermeasures can improve the safety of TKI-based drug therapy and reduce the number of cases in which effective treatment is interrupted due to improper management of side effects. Previous advice given was based on expert opinion within the field and was not supported by clinical controlled trials. This article summarizes the available literature on how to manage side effects of sunitinib and organizes an evaluation by experts in this field. We believe that this study is fairly representative and is a summary of the results available in Germany and can be used as a guideline for clinical work.