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Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx
Targeted therapy-induced diarrhea: A review of the literature M.A. Pessi a , N. Zilembo b , E.R. Haspinger b , L. Molino b , S. Di Cosimo b , M. Garassino b , C.I. Ripamonti a,∗ a
Supportive Care in Cancer Unit, Department of Hematology and Pediatric Onco-Hematology, Milano, Italy b Medical Oncology 1 Unit. Fondazione IRCCS, Istituto Nazionale Tumori di Milano, Milan, Italy Accepted 28 November 2013
Contents 1. 2. 3.
4. 5.
∗
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Type of research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diarrhea: definition, pathophysiology, assessment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Incidence of diarrhea induced by biological agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Gefitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Erlotinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Afatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Lapatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Trastuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Pertuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Cetuximab and panitumumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. Imatinib mesylate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9. Pazopanib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10. Regorafenib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.11. Cabozantinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.12. Sunitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.13. Sorafenib. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.14. Ziv-aflibercept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.15. Axitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16. Bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.17. Vandetanib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.18. Temsirolimus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.19. Everolimus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.20. Mek—Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.20.1. Vemurafenib and dabrafenib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.20.2. Trametinib and selumetinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.21. Crizotinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.22. Ipilimumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Corresponding author at: Tel.: +39 2 23903644; fax: +39 2 23904847. E-mail address: [email protected] (C.I. Ripamonti).
1040-8428/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2013.11.008
Please cite this article in press as: Pessi MA, et al. Targeted therapy-induced diarrhea: A review of the literature. Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.11.008
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Abstract Purpose of research: Revision of the literature on targeted therapy-induced diarrhea (TT-ID). Principal results: TT-ID is frequent; the mechanisms are mainly secretive, followed by ischemic or autoimmune ones. The duration of TT-ID is protracted over time. Its intensity is of grade G1–G3 but may be fatal in patients with diffuse colitis or on ipilimumab. However, no specific guidelines are available on management of different grades of TT-ID. Preventive measures with antibiotics, probiotics or activated charcoal should be further investigated. Loperamide is the first choice drug followed by octreotide. The role of corticosteroids is controversial. Conclusion: Early assessment and management of TT-ID is essential to prevent the worsening of this side-effect, patients’ hospitalization and dose reduction or oncological treatment discontinuation. Future research is needed to better understand the pathophysiological mechanisms of TT-ID and it should also be investigated whether a specific pharmacological and/or non pharmachological approach is indicated. © 2013 Elsevier Ireland Ltd. All rights reserved. Keywords: Targeted therapy; Diarrhea; Incidence; Assessment; Treatment
1. Introduction Diarrhea is a common and serious side-effect associated with radiation therapy to the abdomen and with a variety of chemotherapy (CT) agents, in particular fluoropyrimidines and irinotecan. It may have a negative impact on the patients’ health as well as on their quality of life (QoL), causing dehydration, renal insufficiency, electrolyte imbalance, metabolic acidosis, malnutrition, fatigue, sleep disturbance; in some rare cases it can even be life-threatening. Furthermore diarrhea can alter treatment schedules, leading to dose reduction and treatment discontinuation [1–3]. Despite the availability of recommendations and guidelines for the treatment of CTinduced diarrhea, there are still few data reported by patients on targeted-therapy. Results of toxicity profiles obtained from clinical trials show that diarrhea is frequent, of mild-moderate grade and protracted over time in a large number of patients. This paper aims to review the available evidence on: (1) the incidence and intensity of diarrhea induced by targeted agents, (2) the possible pathophysiological mechanisms and (3) the prophylactic and therapeutic measures to prevent and reduce its severity and its duration. 1.1. Type of research PubMed, Cancer-Lit, Embase databases and Cochrane Library were searched for Randomized Controlled Trials in March 2013. Search terms were “Diarrhea” [Substance Name] and “Target Therapy” [Substance Name]. The proceedings from 2008 to 2013 conferences of the American Society of Clinical Oncology, European Society of Medical Oncology and International Society for the Study of Lung Cancer World Conference were also searched for relevant abstracts through EMBASE. Authors of primary studies were not contacted to identify additional studies. No language or date limits were applied.
2. Diarrhea: definition, pathophysiology, assessment Diarrhea is generally defined as the frequent passage of loose stools with urgency, commonly more than three
unformed stools in 24 h [4]. Although a practical definition is lacking, diarrhea is commonly diagnosed when an abnormal increase in daily stool weight [5], water content more than 75%, and frequency, whether or not accompanied by urgency, perianal discomfort, or incontinence, is present as a consequence of incomplete absorption of electrolytes and water from luminal content [6,7]. Normally an average solid stool of 50–200 g/day passes through the colon; it is formed by bacteria, non-absorbed carbohydrates, water, electrolytes and short chain fatty acids. Diarrhea is classified according to the duration: acute if 4 weeks. Stool consistency probably best defines diarrhea, but it cannot be easily measured [8]. The specific different pathophysiological mechanisms of diarrhea induced by targeted therapy have not been adequately investigated up to now. The different classes of biological agents, but also a single agent in a specific class may cause diarrhea through different mechanisms which are distinguished in: (1). Secretive (i.e. most of the Anti EGFR agents) [9,10], (2). Direct Ischemic mucosal damage (i.e. sorafenib) [11] and (3). Immuno-related (i.e. ipilimumab) [12,13]. Table 1 shows the assessment of the patient: physical examination, subjective report, pain related to frequent evacuation, vital signs, grading, laboratory tests and imaging studies. The most commonly used method for assessing the severity of diarrhea is the National Cancer Institute Common Toxicity Criteria (NCI CTC). The last version includes 5 grades where 5 corresponds to death [14]. Even though the NCI CTC is a helpful tool, clinicians need to be rigorous in the assessment of every sign and symptom presented by the patient: they have to assess the frequency of stools evacuation, the stool composition and the presence of coexisting systemic signs and symptoms, such as fever, neutropenia, abdominal pain/cramping, nausea and vomiting, weakness, dizziness, hydration status, malnutrition and Performance Status deterioration. Complicated patients are described as having grade 3–4 diarrhea or lower grade diarrhea with multiple other symptoms, while uncomplicated patients are those
Please cite this article in press as: Pessi MA, et al. Targeted therapy-induced diarrhea: A review of the literature. Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.11.008
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M.A. Pessi et al. / Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx Table 1 Cancer treatment-related diarrhea assessment.
Please cite this article in press as: Pessi MA, et al. Targeted therapy-induced diarrhea: A review of the literature. Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.11.008
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with grade 1–2 diarrhea without any other exacerbating signs or symptoms [15]. A regular assessment of patients ‘physical status as well as subjective symptoms, is mandatory to prevent and to avoid complications in patients on targeted-therapy. Moreover, laboratory examinations should be regularly monitored.
Therefore EGFR mutations may essentially influence the efficacy of EGFR-TKI in NSCLC and lead to molecular selection of patients who would likely benefit from that treatment. Recently a strong association between the ABCG2-15622C/T polymorphism and ABCG2 haplotype has been demonstrated with grade 2–3 diarrhea induced by Gefitinib [31].
3. Incidence of diarrhea induced by biological agents
3.2. Erlotinib
Epidermal growth factor (EGF) is crucial for tumor cell proliferation, inhibition of apoptosis, angiogenesis, invasion and metastasis. Targeting the epidermal growth factor receptor (EGFR) is one of cancer therapy goals and has been proposed on the basis of its ubiquitary expression in several epithelial cancers [16,17]. EGFR is a trans-membrane receptor belonging to a super family of four structurally related receptors ErbB1 (HER1), ErbB2 (HER2/neu), ErbB3 (HER3), ErbB4 (HER4). It has been associated with carcinogenesis and tumour progression via multiple different mechanisms, such as an over-expression of receptor or mutations which activate distinct pathways. EGFR targeting can be achieved using small-molecule tyrosine kinase inhibitors (TKIs), which bind reversibly or irreversibly to the intracellular receptor domain. Diarrhea induced by EGFR- TKIs is thought to be a result of excess chloride secretion, which causes a secretive form of diarrhea [11,12]. It is more common in patients receiving TKIs. Occurrence of diarrhea is up to 60% for all grades. Grade 3 diarrhea develops in about 6–9% of the cases, which often results in dose reductions. In addition, diarrhea could be a serious event during treatment with EGFR-TKIs in combination with radiotherapy [18]. During treatment with monoclonal antibodies (mAb), such as cetuximab or panitumumab, grade 2 diarrhea is observed in up to 21% of the cases and grade 3 in about 1–2% [19–21].
Erlotinib is an oral anilinoquinazoline derivative, highly selective and reversible EGFR-TKI. It has been approved for the treatment of NSCLC after the publication of the phase III trial BR 21 [32], which demonstrated an increase in RR, progression free survival (PFS) and OS in patients treated with erlotinib. Diarrhea was one of the most commonly reported AEs (54%) in the erlotinib arm, but most cases were grade 1–2 (48%). Dose reductions in the erlotinib arm were performed in 19% of patients, including 1% due to diarrhea. Only 1% of patients discontinued the study due to toxicity. Erlotinib as second line treatment [33] obtained similar OS compared with standard second line CT, either docetaxel or pemetrexed. The safety profile was similar to that registered in other studies, reporting diarrhea and rash as the most common AEs (diarrhea 18% for all grades, 3% for G3–4). Large phase III trials [34,35] compared erlotinib to standard first line platinum-based CT. Diarrhea grade 3 was reported in 3.7% of patients. The efficacy and safety of erlotinib as maintenance treatment has been explored in a large randomized phase III study [36] where diarrhea was identified as one of the most common AE (18%), mostly G1–2 (2% G3). In the erlotinib group 3% of patients received dose modification due to diarrhea and 50 mg daily. The LUX Lung 1 trial [38] compared afatinib vs. placebo in patients pre-treated either with gefitinib or erlotinib and CT. The most common grade 3 AEs were diarrhea, rash, stomatitis and nail disorders. LUX Lung 2 [39] is a phase II trial for patients with stage IV lung adenocarcinoma with EGFR mutations, not pre-treated with other EGFR-TKIs. The most common AEs
Please cite this article in press as: Pessi MA, et al. Targeted therapy-induced diarrhea: A review of the literature. Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.11.008
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were diarrhea (22% G3) and skin rash (28% G3) in patients treated with afatinib 50 mg/day; both percentages decreased at around 7% when the dose was reduced to 40 mg/day. Finally the drug was compared with CT in first line [40]. Afatinib was superior to CT in terms of median PFS and RR; however the toxicity was significantly higher with an incidence of diarrhea G1–2 and G3–4 around 95% and 14.4%, respectively. 3.4. Lapatinib Lapatinib is a an oral, small-molecule, reversible inhibitor of both EGFR and HER2/neu, approved in combination with capecitabine for the treatment of metastatic breast cancer (mBC). Gastrointestinal AEs, such as diarrhea and vomiting are often seen during the association of therapy with this drug. In the registration study grade 3–4 diarrhea compromised therapy in 9.7% of patients [41]. Lapatinib is also used with letrozole in postmenopausal women with HER2/neu and estrogen receptor positive mBC. In this case, the reported incidence of lapatinib-related grade 3–4 diarrhea and all grades was 10% vs. 2 diarrhea was reported in up to 1.6% of patients treated with CT plus trastuzumab; by contrast no case was found among patients treated with CT alone (Data on file. Genentech, Inc). The BCIRG 006 study recruited patients with operable breast cancer, node positive or node negative with high risk and HER2/neu overexpression, who were randomized to three arms: adriamycin and cyclophosphamide followed by docetaxel ± trastuzumab (AC-T or AC-TH) or carboplatin + docetaxel + trastuzumab (TCH). The incidence of Grade >2 diarrhea was higher among patients treated with trastuzumab regardless of the type of CT (5.6% AC-TH, 5.4% TCH vs. 3.0% AC-T) [48]. The HERA Trial randomly assigned women to one year, two years of treatment with trastuzumab, or observation after at least 4 cycles of CT. Overall, grade 1–4 diarrhea occurred in 7% and 1% of patients randomized to trastuzumab or control arm, respectively [49]. Among patients with mBC the reported incidence of diarrhea is 3.7% with single agent trastuzumab [50], 19% for the combination with hormonotherapy and up to 47% with CT [51,52]. 3.6. Pertuzumab Pertuzumab is a recombinant humanized mAb that targets the extracellular dimerization domain (subdomain II) of HER2/neu, and thereby blocks liganddependent heterodimerization of HER2/neu with other HER family members, including EGFR, HER3 and HER4 [53]. The incidence of diarrhea G3–G4 in the openlabel study with pertuzumab + trastuzumab + docetaxel vs. trastuzumab + docetaxel was 7.9% vs. 5%, respectively [54]; in monotherapy this incidence decreased to 3% [55].
Please cite this article in press as: Pessi MA, et al. Targeted therapy-induced diarrhea: A review of the literature. Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.11.008
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3.7. Cetuximab and panitumumab
3.10. Regorafenib
Cetuximab is a chimeric mouse/human mAb highly selective for the EGFR in the treatment of advanced head and neck cancer, NSCLC and metastatic colorectal cancer (mCRC); whereas panitumumab is a fully human IgG2 mAb, approved for the treatment of mCRC [56–58]. EGFR is overexpressed by 25–80% of mCRC and associated with advanced disease [58]. Panitumumab and cetuximab have shown promising results for the treatment of mCRC, when EGFR is overexpressed, in monotherapy as well as when added to standard CT regimens. Diarrhea is a frequently reported AE: when cetuximab is given as monotherapy, approximately 13–28% of patients with mCRC experience diarrhea of any grade, with 2% of these events classified as severe. Comparable rates have been reported for panitumumab with diarrhea of all grades in 21% of patients and 2% of those classified as grade 3 or 4 [59–61]. Diarrhea occurs more often with cetuximab or panitumumab given in combination with CT than with monotherapy. The overall incidence of diarrhea is about 80% (with 6–28% grade 3 and 4) in patients treated with cetuximab and CT [62–64] and 70% (with 8–20% grade 3 and 4) in patients treated with panitumumab and CT [65,66]. The EXTREME study [57] showed that in patients with metastatic or recurrent squamous head and neck cancer the addition of cetuximab to a standard CT regimen and the continuation of cetuximab as maintenance therapy in the case of tumor response or disease stabilization significantly improved median OS, PFS, and RR, compared with CT alone. The toxicity profile confirmed a notable incidence of diarrhea [57,61].
Regorafenib is a novel oral diphenylurea based multikinase inhibitor that simultaneously targets angiogenic and stromal TKIs, including kinases involved in the regulation of tumor angiogenesis (VEGFR1, VEGFR2, VEGFR3, TIE2), oncogenesis (KIT, RET, RAF1, BRAF) and the tumor microenvironment (PDGFR, FGFR). Regorafenib has shown promising results in patients with TKI- resistant GIST or heavily pretreated advanced CRC, for whom there is currently no other therapy approved by any regulatory authority. Diarrhea is a frequent AE observed during the treatment with regorafenib. The incidence of diarrhea reported from two phase III trials is about 34–40% with 5–8% of G3 or G4 events [70,71].
3.8. Imatinib mesylate Imatinib mesylate is a highly selectively inhibitor of the protein tyrosine kinase family comprising Abl, the chimeric bcR-Abl, the platelet-derived growth factor receptor alfa and beta, and the product of the c-Kit proto-oncogene. Diarrhea is one of the most important AEs observed during the treatment with imatinib mesylate. Approximately 20–26% of patients experienced diarrhea during therapy with 1% of these events classified as severe [67,68]
3.9. Pazopanib Pazopanib is an oral antiangiogenic inhibitor targeting VEGFR-1, -2, and -3, PDGFR alfa and beta, c-KIT, that is indicated for the first line treatment of metastatic renal cell carcinoma (mRCC) and for patients who have received prior cytokine therapy for advanced disease. 435 patients were enrolled in a trial which demonstrated its efficacy as therapy in mRCC and 52% presented diarrhea which was of grade 3 and 4 in
ARTICLE IN PRESS
Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx
Targeted therapy-induced diarrhea: A review of the literature M.A. Pessi a , N. Zilembo b , E.R. Haspinger b , L. Molino b , S. Di Cosimo b , M. Garassino b , C.I. Ripamonti a,∗ a
Supportive Care in Cancer Unit, Department of Hematology and Pediatric Onco-Hematology, Milano, Italy b Medical Oncology 1 Unit. Fondazione IRCCS, Istituto Nazionale Tumori di Milano, Milan, Italy Accepted 28 November 2013
Contents 1. 2. 3.
4. 5.
∗
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Type of research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diarrhea: definition, pathophysiology, assessment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Incidence of diarrhea induced by biological agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Gefitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Erlotinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Afatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Lapatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Trastuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Pertuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Cetuximab and panitumumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. Imatinib mesylate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9. Pazopanib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10. Regorafenib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.11. Cabozantinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.12. Sunitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.13. Sorafenib. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.14. Ziv-aflibercept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.15. Axitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16. Bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.17. Vandetanib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.18. Temsirolimus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.19. Everolimus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.20. Mek—Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.20.1. Vemurafenib and dabrafenib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.20.2. Trametinib and selumetinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.21. Crizotinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.22. Ipilimumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Corresponding author at: Tel.: +39 2 23903644; fax: +39 2 23904847. E-mail address: [email protected] (C.I. Ripamonti).
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Abstract Purpose of research: Revision of the literature on targeted therapy-induced diarrhea (TT-ID). Principal results: TT-ID is frequent; the mechanisms are mainly secretive, followed by ischemic or autoimmune ones. The duration of TT-ID is protracted over time. Its intensity is of grade G1–G3 but may be fatal in patients with diffuse colitis or on ipilimumab. However, no specific guidelines are available on management of different grades of TT-ID. Preventive measures with antibiotics, probiotics or activated charcoal should be further investigated. Loperamide is the first choice drug followed by octreotide. The role of corticosteroids is controversial. Conclusion: Early assessment and management of TT-ID is essential to prevent the worsening of this side-effect, patients’ hospitalization and dose reduction or oncological treatment discontinuation. Future research is needed to better understand the pathophysiological mechanisms of TT-ID and it should also be investigated whether a specific pharmacological and/or non pharmachological approach is indicated. © 2013 Elsevier Ireland Ltd. All rights reserved. Keywords: Targeted therapy; Diarrhea; Incidence; Assessment; Treatment
1. Introduction Diarrhea is a common and serious side-effect associated with radiation therapy to the abdomen and with a variety of chemotherapy (CT) agents, in particular fluoropyrimidines and irinotecan. It may have a negative impact on the patients’ health as well as on their quality of life (QoL), causing dehydration, renal insufficiency, electrolyte imbalance, metabolic acidosis, malnutrition, fatigue, sleep disturbance; in some rare cases it can even be life-threatening. Furthermore diarrhea can alter treatment schedules, leading to dose reduction and treatment discontinuation [1–3]. Despite the availability of recommendations and guidelines for the treatment of CTinduced diarrhea, there are still few data reported by patients on targeted-therapy. Results of toxicity profiles obtained from clinical trials show that diarrhea is frequent, of mild-moderate grade and protracted over time in a large number of patients. This paper aims to review the available evidence on: (1) the incidence and intensity of diarrhea induced by targeted agents, (2) the possible pathophysiological mechanisms and (3) the prophylactic and therapeutic measures to prevent and reduce its severity and its duration. 1.1. Type of research PubMed, Cancer-Lit, Embase databases and Cochrane Library were searched for Randomized Controlled Trials in March 2013. Search terms were “Diarrhea” [Substance Name] and “Target Therapy” [Substance Name]. The proceedings from 2008 to 2013 conferences of the American Society of Clinical Oncology, European Society of Medical Oncology and International Society for the Study of Lung Cancer World Conference were also searched for relevant abstracts through EMBASE. Authors of primary studies were not contacted to identify additional studies. No language or date limits were applied.
2. Diarrhea: definition, pathophysiology, assessment Diarrhea is generally defined as the frequent passage of loose stools with urgency, commonly more than three
unformed stools in 24 h [4]. Although a practical definition is lacking, diarrhea is commonly diagnosed when an abnormal increase in daily stool weight [5], water content more than 75%, and frequency, whether or not accompanied by urgency, perianal discomfort, or incontinence, is present as a consequence of incomplete absorption of electrolytes and water from luminal content [6,7]. Normally an average solid stool of 50–200 g/day passes through the colon; it is formed by bacteria, non-absorbed carbohydrates, water, electrolytes and short chain fatty acids. Diarrhea is classified according to the duration: acute if 4 weeks. Stool consistency probably best defines diarrhea, but it cannot be easily measured [8]. The specific different pathophysiological mechanisms of diarrhea induced by targeted therapy have not been adequately investigated up to now. The different classes of biological agents, but also a single agent in a specific class may cause diarrhea through different mechanisms which are distinguished in: (1). Secretive (i.e. most of the Anti EGFR agents) [9,10], (2). Direct Ischemic mucosal damage (i.e. sorafenib) [11] and (3). Immuno-related (i.e. ipilimumab) [12,13]. Table 1 shows the assessment of the patient: physical examination, subjective report, pain related to frequent evacuation, vital signs, grading, laboratory tests and imaging studies. The most commonly used method for assessing the severity of diarrhea is the National Cancer Institute Common Toxicity Criteria (NCI CTC). The last version includes 5 grades where 5 corresponds to death [14]. Even though the NCI CTC is a helpful tool, clinicians need to be rigorous in the assessment of every sign and symptom presented by the patient: they have to assess the frequency of stools evacuation, the stool composition and the presence of coexisting systemic signs and symptoms, such as fever, neutropenia, abdominal pain/cramping, nausea and vomiting, weakness, dizziness, hydration status, malnutrition and Performance Status deterioration. Complicated patients are described as having grade 3–4 diarrhea or lower grade diarrhea with multiple other symptoms, while uncomplicated patients are those
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M.A. Pessi et al. / Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx Table 1 Cancer treatment-related diarrhea assessment.
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with grade 1–2 diarrhea without any other exacerbating signs or symptoms [15]. A regular assessment of patients ‘physical status as well as subjective symptoms, is mandatory to prevent and to avoid complications in patients on targeted-therapy. Moreover, laboratory examinations should be regularly monitored.
Therefore EGFR mutations may essentially influence the efficacy of EGFR-TKI in NSCLC and lead to molecular selection of patients who would likely benefit from that treatment. Recently a strong association between the ABCG2-15622C/T polymorphism and ABCG2 haplotype has been demonstrated with grade 2–3 diarrhea induced by Gefitinib [31].
3. Incidence of diarrhea induced by biological agents
3.2. Erlotinib
Epidermal growth factor (EGF) is crucial for tumor cell proliferation, inhibition of apoptosis, angiogenesis, invasion and metastasis. Targeting the epidermal growth factor receptor (EGFR) is one of cancer therapy goals and has been proposed on the basis of its ubiquitary expression in several epithelial cancers [16,17]. EGFR is a trans-membrane receptor belonging to a super family of four structurally related receptors ErbB1 (HER1), ErbB2 (HER2/neu), ErbB3 (HER3), ErbB4 (HER4). It has been associated with carcinogenesis and tumour progression via multiple different mechanisms, such as an over-expression of receptor or mutations which activate distinct pathways. EGFR targeting can be achieved using small-molecule tyrosine kinase inhibitors (TKIs), which bind reversibly or irreversibly to the intracellular receptor domain. Diarrhea induced by EGFR- TKIs is thought to be a result of excess chloride secretion, which causes a secretive form of diarrhea [11,12]. It is more common in patients receiving TKIs. Occurrence of diarrhea is up to 60% for all grades. Grade 3 diarrhea develops in about 6–9% of the cases, which often results in dose reductions. In addition, diarrhea could be a serious event during treatment with EGFR-TKIs in combination with radiotherapy [18]. During treatment with monoclonal antibodies (mAb), such as cetuximab or panitumumab, grade 2 diarrhea is observed in up to 21% of the cases and grade 3 in about 1–2% [19–21].
Erlotinib is an oral anilinoquinazoline derivative, highly selective and reversible EGFR-TKI. It has been approved for the treatment of NSCLC after the publication of the phase III trial BR 21 [32], which demonstrated an increase in RR, progression free survival (PFS) and OS in patients treated with erlotinib. Diarrhea was one of the most commonly reported AEs (54%) in the erlotinib arm, but most cases were grade 1–2 (48%). Dose reductions in the erlotinib arm were performed in 19% of patients, including 1% due to diarrhea. Only 1% of patients discontinued the study due to toxicity. Erlotinib as second line treatment [33] obtained similar OS compared with standard second line CT, either docetaxel or pemetrexed. The safety profile was similar to that registered in other studies, reporting diarrhea and rash as the most common AEs (diarrhea 18% for all grades, 3% for G3–4). Large phase III trials [34,35] compared erlotinib to standard first line platinum-based CT. Diarrhea grade 3 was reported in 3.7% of patients. The efficacy and safety of erlotinib as maintenance treatment has been explored in a large randomized phase III study [36] where diarrhea was identified as one of the most common AE (18%), mostly G1–2 (2% G3). In the erlotinib group 3% of patients received dose modification due to diarrhea and 50 mg daily. The LUX Lung 1 trial [38] compared afatinib vs. placebo in patients pre-treated either with gefitinib or erlotinib and CT. The most common grade 3 AEs were diarrhea, rash, stomatitis and nail disorders. LUX Lung 2 [39] is a phase II trial for patients with stage IV lung adenocarcinoma with EGFR mutations, not pre-treated with other EGFR-TKIs. The most common AEs
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were diarrhea (22% G3) and skin rash (28% G3) in patients treated with afatinib 50 mg/day; both percentages decreased at around 7% when the dose was reduced to 40 mg/day. Finally the drug was compared with CT in first line [40]. Afatinib was superior to CT in terms of median PFS and RR; however the toxicity was significantly higher with an incidence of diarrhea G1–2 and G3–4 around 95% and 14.4%, respectively. 3.4. Lapatinib Lapatinib is a an oral, small-molecule, reversible inhibitor of both EGFR and HER2/neu, approved in combination with capecitabine for the treatment of metastatic breast cancer (mBC). Gastrointestinal AEs, such as diarrhea and vomiting are often seen during the association of therapy with this drug. In the registration study grade 3–4 diarrhea compromised therapy in 9.7% of patients [41]. Lapatinib is also used with letrozole in postmenopausal women with HER2/neu and estrogen receptor positive mBC. In this case, the reported incidence of lapatinib-related grade 3–4 diarrhea and all grades was 10% vs. 2 diarrhea was reported in up to 1.6% of patients treated with CT plus trastuzumab; by contrast no case was found among patients treated with CT alone (Data on file. Genentech, Inc). The BCIRG 006 study recruited patients with operable breast cancer, node positive or node negative with high risk and HER2/neu overexpression, who were randomized to three arms: adriamycin and cyclophosphamide followed by docetaxel ± trastuzumab (AC-T or AC-TH) or carboplatin + docetaxel + trastuzumab (TCH). The incidence of Grade >2 diarrhea was higher among patients treated with trastuzumab regardless of the type of CT (5.6% AC-TH, 5.4% TCH vs. 3.0% AC-T) [48]. The HERA Trial randomly assigned women to one year, two years of treatment with trastuzumab, or observation after at least 4 cycles of CT. Overall, grade 1–4 diarrhea occurred in 7% and 1% of patients randomized to trastuzumab or control arm, respectively [49]. Among patients with mBC the reported incidence of diarrhea is 3.7% with single agent trastuzumab [50], 19% for the combination with hormonotherapy and up to 47% with CT [51,52]. 3.6. Pertuzumab Pertuzumab is a recombinant humanized mAb that targets the extracellular dimerization domain (subdomain II) of HER2/neu, and thereby blocks liganddependent heterodimerization of HER2/neu with other HER family members, including EGFR, HER3 and HER4 [53]. The incidence of diarrhea G3–G4 in the openlabel study with pertuzumab + trastuzumab + docetaxel vs. trastuzumab + docetaxel was 7.9% vs. 5%, respectively [54]; in monotherapy this incidence decreased to 3% [55].
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3.7. Cetuximab and panitumumab
3.10. Regorafenib
Cetuximab is a chimeric mouse/human mAb highly selective for the EGFR in the treatment of advanced head and neck cancer, NSCLC and metastatic colorectal cancer (mCRC); whereas panitumumab is a fully human IgG2 mAb, approved for the treatment of mCRC [56–58]. EGFR is overexpressed by 25–80% of mCRC and associated with advanced disease [58]. Panitumumab and cetuximab have shown promising results for the treatment of mCRC, when EGFR is overexpressed, in monotherapy as well as when added to standard CT regimens. Diarrhea is a frequently reported AE: when cetuximab is given as monotherapy, approximately 13–28% of patients with mCRC experience diarrhea of any grade, with 2% of these events classified as severe. Comparable rates have been reported for panitumumab with diarrhea of all grades in 21% of patients and 2% of those classified as grade 3 or 4 [59–61]. Diarrhea occurs more often with cetuximab or panitumumab given in combination with CT than with monotherapy. The overall incidence of diarrhea is about 80% (with 6–28% grade 3 and 4) in patients treated with cetuximab and CT [62–64] and 70% (with 8–20% grade 3 and 4) in patients treated with panitumumab and CT [65,66]. The EXTREME study [57] showed that in patients with metastatic or recurrent squamous head and neck cancer the addition of cetuximab to a standard CT regimen and the continuation of cetuximab as maintenance therapy in the case of tumor response or disease stabilization significantly improved median OS, PFS, and RR, compared with CT alone. The toxicity profile confirmed a notable incidence of diarrhea [57,61].
Regorafenib is a novel oral diphenylurea based multikinase inhibitor that simultaneously targets angiogenic and stromal TKIs, including kinases involved in the regulation of tumor angiogenesis (VEGFR1, VEGFR2, VEGFR3, TIE2), oncogenesis (KIT, RET, RAF1, BRAF) and the tumor microenvironment (PDGFR, FGFR). Regorafenib has shown promising results in patients with TKI- resistant GIST or heavily pretreated advanced CRC, for whom there is currently no other therapy approved by any regulatory authority. Diarrhea is a frequent AE observed during the treatment with regorafenib. The incidence of diarrhea reported from two phase III trials is about 34–40% with 5–8% of G3 or G4 events [70,71].
3.8. Imatinib mesylate Imatinib mesylate is a highly selectively inhibitor of the protein tyrosine kinase family comprising Abl, the chimeric bcR-Abl, the platelet-derived growth factor receptor alfa and beta, and the product of the c-Kit proto-oncogene. Diarrhea is one of the most important AEs observed during the treatment with imatinib mesylate. Approximately 20–26% of patients experienced diarrhea during therapy with 1% of these events classified as severe [67,68]
3.9. Pazopanib Pazopanib is an oral antiangiogenic inhibitor targeting VEGFR-1, -2, and -3, PDGFR alfa and beta, c-KIT, that is indicated for the first line treatment of metastatic renal cell carcinoma (mRCC) and for patients who have received prior cytokine therapy for advanced disease. 435 patients were enrolled in a trial which demonstrated its efficacy as therapy in mRCC and 52% presented diarrhea which was of grade 3 and 4 in
