Neratinib (PB-272; Puma Biotechnology Inc, Los Angeles, CA, USA) is a potent small-molecule kinase inhibitor of human epidermal growth factor receptors HER1 (or EGFR1), HER2, and HER4.1,2
It binds irreversibly to the intracellular ATP-binding pocket of the HER2 receptor and reduces receptor autophosphorylation.2 In vitro
studies show that neratinib blocks downstream signal transduction and cell cycle regulatory pathways in cancer cell lines, ultimately leading to decreased cell proliferation.2
In animal studies, neratinib inhibits the growth of EGFR– and HER2–dependent tumor xenograft models when given orally on a once-daily schedule.2
Neratinib is currently in late-stage clinical development, with regulatory submission planned in 2016. It has been investigated extensively in the treatment of metastatic HER2–positive breast cancer both as a single agent3-5
and in combination with chemotherapeutic and targeted agents.6-11
Overall response rates in phase II studies ranged from 29% to 40% with neratinib monotherapy in women with metastatic HER2–positive breast cancer who had previously been treated with chemotherapy and trastuzumab.3-5
Considerably higher response rates were observed when neratinib was combined with chemotherapeutic agents, for example, 63% with capecitabine8
and 72% to 75% with neratinib plus paclitaxel.6,10
Of note, neratinib showed clinical activity in women who had been previously treated with trastuzumab,4,8
suggesting that it may be able to circumvent trastuzumab resistance.
Neratinib is also being investigated in early-stage HER2– positive breast cancer. In a phase III trial of neratinib (ExteNET), a 12-month course of treatment improved invasive disease-free survival after 2 years of follow-up compared with placebo in women with early-stage HER2–positive breast cancer after trastuzumab-containing adjuvant therapy (hazard ratio 0.67, 95% CI 0.50–0.91; 1-sided P
Diarrhea was the most common adverse event with neratinib (grade 3, 40%; grade 4, <0.1%).12
As previous efforts to improve outcomes with extended adjuvant therapy with trastuzumab have been unsuccessful,13
neratinib is the first agent to significantly prolong disease-free survival in women with trastuzumab-treated early-stage breast cancer. Longer term follow-up and assessment of overall survival in the ExteNET trial is ongoing.
Neratinib is taken orally at a dosage of 240 mg once daily on a continuous schedule.4
At this dosage, neratinib is generally well tolerated with a low incidence of grade 3/4 adverse events.4
The most commonly reported adverse event and dose-limiting toxicity of neratinib is diarrhea,3,4
a known class effect of EGFR-directed tyrosine kinase inhibitors.14
In this article, we will discuss the incidence, severity and patterns of occurrence of diarrhea with neratinib, and how this may be effectively managed with initiation of intensive loperamide prophylaxis at the beginning of treatment.
Cancer Treatment-Related Diarrhea
The standard tool most commonly used for grading the severity of diarrhea is the National Cancer Institute Common Toxicity Criteria (NCI-CTC) for Adverse Events.15
According to version 4.0 of these criteria, grade 1 (mild) diarrhea is defined as an increase of <4 stools per day from baseline (or mild increase in ostomy output), with asymptomatic or mild symptoms such that intervention is not indicated.15
Grade 2 (moderate) diarrhea is defined as an increase of four to six stools per day from baseline (or moderate increase in ostomy output), requiring minimal, local, or non-invasive interventions only.15
Grade 3 (severe or medically significant) diarrhea is defined as an increase of ≥7 stools per day from baseline (or severe increase in ostomy output), incontinence, hospitalization (or prolongation of hospitalization) limiting self-care activities of daily living.15
Grade 4 events are deemed to be life-threatening requiring urgent intervention.15
In clinical practice, patient symptom diaries are also generally used as an additional assessment tool in conjunction with the NCI-CTC criteria.
Diarrhea is a common side effect of manyn cancer treatments,including chemotherapeutic agents, molecularly targeted agents and pelvic radiotherapy. EGFR-directed tyrosine kinase inhibitors are associated with high frequencies of clinically important diarrhea, and depending on the agent, up to 95% of patients may experience some grade of diarrhea, although the risk of grade 3/4 events tends to be lower (<15%) (Table 1
). Diarrhea is also common with several multi-agent HER2–directed regimens used in the treatment of HER2–positive breast cancer (Table 1
). Further, it fluoropyrimidines and irinotecan, carry a high is recognized that regimens used for the treatment of colorectal cancer, particularly those involving risk of diarrhea.50
Data from randomized trials suggest that up to 80% of patients treated with regimens involving these agents may experience diarrhea, and 20% will commonly experience grade 3 or 4 diarrhea (Table 1
Diarrhea caused by cancer treatments requires early intervention to prevent complications such s dehydration, electrolyte imbalances, and renal insufficiency.51
If left unmanaged, persistent diarrhea can require additional resources beyond oral antidiarrheal agents (fluid replacement, octreotide, antibiotics, unplanned clinic visits, hospitalization) and can be costly to manage.52,53
Severe diarrhea can also lead to changes in treatment, including dose reductions and treatment discontinuation.52-54
These alterations may have a negative effect on tumor control, although the consequences of diarrhea-driven treatment modifications and discontinuations on clinical outcomes have never been formally investigated.
Effective management should involve a continuous process of assessment, reassessment, and appropriate dietetic and pharmacological interventions, with an increase in aggressive stepwise management as needed. There are several sets of guidelines for the management of cancer treatment-related diarrhea,50,51,55-59
although there is little consensus between them on the details of care. Treatment is often empirical and the guidelines have served to highlight that there are few clinically relevant studies on which to base decisions relating to the management of cancer treatment-related diarrhea.5
Pharmacological treatment of cancer treatment-related diarrhea is based primarily on the empirical use of opioids. Loperamide, a synthetic opiate, is the standard first-line treatment for chemotherapy-induced diarrhea.50,59
It acts as an agonist on opioid receptors in the gastrointestinal tract to decrease gut motility.51
Systemic absorption of loperamide and systemic adverse events are minimal, although high-dose therapy can lead to paralytic ileus.55
Alternative opioids recommended for cancer treatment-related diarrhea include deodorized tincture of opium50,59
and diphenoxylate plus atropine (Lomotil®
Octreotide is the other main pharmacologic intervention for cancer treatment-related diarrhea. It is generally reserved for use in complicated cases or as a second-line treatment for persistent diarrhea after loperamide.50
Octreotide is a somatostatin analogue that decreases hormone secretion to prolong intestinal transit time, promote intestinal absorption of electrolytes, and decrease mesenteric blood flow.51
It is well tolerated, with the most common adverse events being mild abdominal pain and injection site pain.60
Other than the use of atropine for early cholinergic diarrhea associated with irinotecan infusion,61
prophylactic anti-diarrheal therapy is not standard for any cancer treatment. Several small studies have investigated the utility of different prophylactic anti-diarrheal regimens to reduce the frequency and severity of cancer treatment-related diarrhea. Activated charcoal62
and oral alkalinization63
may be beneficial for irinotecan-associated diarrhea, and probiotics may have a role in preventing 5-fluorouracil (5-FU)-related diarrhea.64
However, studies of prophylactic octreotide65-67
and an intestinal adsorbent68
did not show benefit.
Many studies have investigated potential risk factors for the development of cancer treatment-related diarrhea (ie, genotype, clinical characteristics), although prospective studies are lacking and no predictors are used in clinical practice. Readers are referred to Andreyev et al55
for a more detailed discussion of this subject.
Occurrence of Diarrhea with Neratinib
Studies with No or Suboptimal Antidiarrheal Prophylaxis
Diarrhea management in initial trials of neratinib involved treatment with antidiarrheal agents and/or dose modifications only after diarrheal symptoms became apparent. A few studies included antidiarrheal prophylaxis, but the doses of loperamide used were proven to be suboptimal (ie, 2 or 4 mg/day).7,69,70
For example, in the Translational Breast Cancer Research Consortium 022 phase II study, the incidence of grade 3 diarrhea was 33% before the introduction of prophylaxis compared with 21% with low-dose loperamide prophylaxis (2 mg/day).69
Diarrhea is a common side effect of many cancer treatments and can lead to severe complications and treatment modifications if left unmanaged. Diarrhea is the most common adverse event of neratinib, a novel irreversible pan-HER tyrosine kinase inhibitor.
Most higher-grade diarrhea with neratinib occurs during the first cycle of treatment.
For effective management, neratinib should be used in conjunction with an intensive regimen of loperamide prophylaxis for the first cycle of treatment.
From the studies with no or suboptimal prophylaxis, it was evident that most diarrhea events with neratinib occurred in the first month of treatment. For example, in the ExteNET trial, the overall incidence of grade 3 or higher diarrhea was 40%; however, 73% of these patients experienced grade 3 events during the first month of treatment. After the third month of treatment, grade 3 diarrhea was relatively infrequent with approximately 6% of patients on treatment or fewer experiencing grade 3 diarrhea after month 3. The rate of grade 2 diarrhea also declined from about 30% in the first month to 18% to 19% in months 2 and 3, and to 12% in month 12 (data on file, Puma Biotechnology Inc.).
In studies with no or suboptimal prophylaxis, treatment-emergent diarrhea with neratinib was generally of mild-to-moderate severity; grade 1/2 events occurred in 56% to 67% of patients (Table 2
The incidence of grade 3 diarrhea ranged from 30% to 53% (Table 2
with an incidence of 40% in the largest study performed to date (ExteNET).12
Where details of grade 4 events were available, these events were rare (0% to 3% of patients).3,4,6,7,9,10,12,69
The median duration of all grade events was 7 to 14 days per episode as reported in two studies (Table 2
Diarrhea resolved in most patients either spontaneously or with standard management involving antidiarrheal medications and/or dose modifications.5
Neratinib dose reductions because of diarrhea were documented in 10% to 15% of patients.5,8,10
Most patients continued treatment despite the occurrence of diarrhea, and treatment discontinuation as a result of diarrhea was uncommon (0% to 14% of patients).3-6,8,10,12,71
Studies with Intensive Loperamide Prophylaxis
The mainstay of management for neratinib-associated diarrhea is intensive prophylaxis with loperamide. An intensive prophylactic regimen was first instigated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) FB-8 study after the investigators noted a high occurrence of diarrhea in the first week of neratinib therapy despite early treatment with loperamide.9
Prophylaxis was initiated with the first dose of neratinib and given for the first cycle of treatment. Although the patient numbers in the NSABP FB-8 study were small, the introduction of intensive loperamide prophylaxis reduced the occurrence of grade 3 diarrhea from 53% (8 of 15 patients) before its introduction to 0% (0 of 6 patients).9
Based on the early success of this regimen, intensive antidiarrheal prophylaxis with loperamide for the first cycle of treatment has been introduced as a mandatory measure in new and ongoing trials of neratinib. The precise loperamide regimen used in these studies has evolved over the past 2 years to improve patient compliance. However, the initial dose of loperamide has remained constant (ie, 4 mg with the first dose of neratinib), and all regimens have tapered to a lower dose of loperamide over the course of the first cycle. The recommended loperamide prophylactic regimen for use with neratinib is shown in Figure 1
Safety data from trials that included intensive loperamide prophylaxis show a marked reduction in the incidence of grade 3 diarrhea to 0% to 17%, even though many of the patients who experienced grade 3 diarrhea did not receive the full prophylactic regimen due to compliance issues (Table 2
This compares with rates of 30% to 53% in studies with no or suboptimal prophylaxis (Table 2
). The median duration of all-grade treatment-emergent diarrheal events was also reduced from 7 to 14 days to 2 days with loperamide prophylaxis (Table 2
A detailed management algorithm for treatment-emergent diarrhea during neratinib therapy is shown in Figure 2
. Any new-onset diarrhea may be managed with the maximum dose of loperamide (ie, 16 mg/day), with the addition of diphenoxylate plus atropine (Lomotil®
) or octreotide according to severity. Dietetic changes, such as the BRAT diet (ie, low-fat diet enriched with bananas, rice, applesauce, and toast), increased fluid intake, stopping all lactose-containing products, and frequent small meals, should also be encouraged. Treatment interruptions or dose reductions are recommended only if patients have significant persistent diarrhea and are unresponsive to the above-mentioned interventions.
Future Research With Neratinib
A comprehensive clinical development program of neratinib is currently ongoing (Table 3
). In a recently reported phase III trial (ExteNET), treatment with neratinib demonstrated a statistically significant improvement in invasive disease-free survival compared with placebo in patients with early-stage HER2– positive breast cancer who had previously received adjuvant trastuzumab. However, because no antidiarrheal prophylaxis was given in ExteNET, the rate of grade 3 (or higher) diarrhea was high (40%).12
To better understand the ability of high-dose loperamide prophylaxis to reduce neratinib-related diarrhea, a phase II study (PUMA-NER 6201) has been initiated to formally investigate the effectiveness of this loperamide prophylaxis regimen. Similar to ExteNET, the study is enrolling women with early-stage HER2–positive breast cancer following trastuzumab-based adjuvant therapy. All patients are receiving neratinib 240 mg/day plus intensive loperamide prophylaxis (ie, 4 mg with the first dose of neratinib, 4 mg 3-times daily for 2 weeks, then 4 mg twice daily). The primary outcome of the study is the incidence and severity of diarrhea, and secondary outcomes include the incidence and severity of diarrhea by loperamide exposure.
In addition, there are several other phase II and III trials of neratinib with loperamide prophylaxis in patients with early-stage and metastatic HER2–positive breast cancer (Table 3). NALA (PUMA-NER-1301) is a randomized phase III trial that is comparing neratinib plus capecitabine with lapatinib plus capecitabine as third-line therapy in patients with HER2–positive metastatic breast cancer. The study was prompted by the findings of an earlier phase II study that reported notable activity with neratinib plus capecitabine.8 NALA will enroll approximately 600 patients from centers in Europe, Asia-Pacific, and North and South America. The coprimary study endpoints are progression-free survival and overall survival. Further phase II studies are testing neratinib alone or as part of a combination in tumors with HER2 or HER3 mutations, or EGFR-amplified tumors.
The precise molecular mechanism of neratinib-induced diarrhea is unknown, but is postulated to be due to EGFR inhibition and resultant secretory diarrhea.55
Preclinical studies are ongoing to better characterize the histopathology, clinical symptoms, and blood biochemistry of neratinib-induced diarrhea, and to understand the on-target effects of neratinib on the gastrointestinal system and the specific mechanisms of the neratinib-related diarrhea.
Diarrhea is a recognized adverse event of many cancer treatments and a side effect well understood by most oncologists. Once diarrhea occurs, it should be managed promptly and aggressively to prevent an escalation in severity and patient morbidity, and to maintain full-dose therapy. Diarrhea is a class effect of EGFR-directed tyrosine kinase inhibitors, and the most common toxicity of neratinib, a novel irreversible pan-HER tyrosine kinase inhibitor. For patients receiving neratinib, preventive management with intensive loperamide prophylaxis is required to reduce the severity and duration of diarrhea. Loperamide prophylaxis should be started with the first dose of treatment and continued until the end of the first cycle, regardless of the presence or absence of diarrhea. Any treatment-emergent diarrhea should be managed according to standard guidelines.
Initial trials with neratinib were all performed without the support of effective antidiarrheal prophylaxis. Intensive loperamide prophylaxis has been implemented and refined in ongoing and new trials of the drug. Preliminary safety data from these trials suggest that active management with intensive loperamide prophylaxis reduces the incidence, severity, and duration of neratinib-associated diarrhea. The frequency of grade 3 diarrhea when neratinib is given with intensive loperamide prophylaxis (0% to 17%) is similar to rates observed with other EGFR-directed tyrosine kinase inhibitors (1% to 14%), and considerably lower than rates observed with many chemotherapy regimens used in routine oncology practice (Table 1
Intensive loperamide prophylaxis provides an effective means of reducing the incidence, severity and duration of neratinib-associated diarrhea. It should be given for the first cycle of treatment in all patients receiving neratinib. Current diarrhea prophylaxis recommendations are 4 mg with the first dose of neratinib, then 4 mg 3 times on day 1 (for a total of 16 mg on day 1), 4 mg 3-times daily (for a total of 12 mg/day) on days 2 and 3, reducing to 2 mg 3- or 4-times daily (for a total of 6-8 mg/day) for the remainder of the first cycle. Nonpharmacologic interventions, including dietetic changes and increased fluid intake, are recommended for new-onset uncomplicated diarrhea.
Federico Ustaris, MD, Richard Bryce, MBChB, MRCGP, MFPM, Susan Moran, MD, Linda Neuman, MD, and Rolando Ruiz, MD, are from Puma Biotechnology Inc, Los Angeles, CA, USA. Cristina Saura, MD, Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Jack Di Palma, MD, Division of Gastroenterology, University of South Alabama College of Medicine, Mobile, Alabama, USA.
Dr Saura declares consultancy work and involvement in paid advisory boards. Dr Di Palma is involved in an independent data management committee. Drs Bryce, Moran, Neuman, Ruiz, and Ustaris are employees of Puma Biotechnology Inc, and Drs Bryce and Neuman also declare stock ownership in the company.
Source of Funding:
Puma Biotechnology Inc was involved in the collection, analysis, and interpretation of safety data, and provided funding for editorial assistance. Drs Bryce, Moran, Neuman, Ruiz, and Ustaris are employees of Puma Biotechnology Inc. All authors revised the manuscript for intellectual content and approved the final version.
Address Correspondence to:
Dr Federico Ustaris; Phone: 424-248-6500; fax: 424-248-6501; email: RUstaris@ pumabiotechnology.com
Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PK. Comprehensive analysis of kinase inhibitor selectivity. Nature Biotechnol. 2011:29(11):1046-1051.
Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E, Reich MF, Shen R, Shi X, Tsou HR, Wang YF, Wissner A. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 2004;64(11):3958-3965.
Wong KK, Fracasso PM, Bukowski RM, Lynch TJ, Munster PN, Shapiro GI, Jänne PA, Eder JP, Naughton MJ, Ellis MJ, Jones SF, Mekhail T, Zacharchuk C,Vermette J, Abbas R, Quinn S, Powell C, Burris HA. A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin Cancer Res. 2009;15(7):2552-2558.
Burstein HJ, Sun Y, Dirix LY, Jiang Z, Paridaens R, Tan AR, Awada A, Ranade A, Jiao S, Schwartz G, Abbas R, Powell C, Turnbull K, Vermette J, Zacharchuk C, Badwe R. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010;28(8):1301-1307.
Martin M, Bonneterre J, Geyer CE Jr, Ito Y, Ro J, Lang I, Kim SB, Germa C, Vermette J, Wang K, Wang K, Awada A. A phase two randomised trial of neratinib monotherapy versus lapatinib plus capecitabine combination therapy in patients with HER2+ advanced breast cancer. Eur J Cancer. 2013;49(18):3763-3772.
Chow LW, Xu B, Gupta S, Freyman A, Zhao Y, Abbas R, Vo Van ML, Bondarenko I. Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. Br J Cancer. 2013;108(10):1985-1993.
Awada A, Colomer R, Bondarenko I, et al. Efficacy and CNS progression analysis from the randomized phase 2 trial of neratinib + paclitaxel vs trastuzumab + paclitaxel as first-line treatment for HER2+ metastatic breast cancer (NEfERTT). J Clin Oncol. 2015;33 (suppl; abstract 610).
Saura C, Garcia-Saenz JA, Xu B, Harb W, Moroose R, Pluard T, Cortés J, Kiger C, Germa C, Wang K, Martin M, Baselga J, Kim SB. Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2014;32(32):3626-3633.
Jankowitz RC, Abraham J, Tan AR, Limentani SA, Tierno MB, Adamson LM, Buyse M, Wolmark N, Jacobs SA. Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2‑positive breast cancer: an NSABP Foundation Research Program phase I study.
Cancer Chemother Pharmacol. 2013;72(6):1205-1212.
Awada A, Dirix L, Manso Sanchez L, Xu B, Luu T, Diéras V, Hershman DL, Agrapart V, Ananthakrishnan R, Staroslawska E. Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy. Ann Oncol. 2013;24(1):109-116.
Swaby R, Blackwell K, Jiang Z, et al. Neratinib in combination with trastuzumab for the treatment of advanced breast cancer: A phase I/II study. J Clin Oncol. 2009;27:15s (suppl; abstract 1004).
Chan A, Delaloge S, Holmes GA, et al. Neratinib after adjuvant chemotherapy and trastuzumab in HER2-positive early breast cancer: Primary analysis at 2 years of a phase 3, randomized, placebo-controlled trial (ExteNET). J Clin Oncol. 33,2015 (suppl; abstract 508).
Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013;382(9897):1021-1028.
Hirsh V , Blais N, Burkes R, et al. Management of diarrhea induced by epidermal growth factor receptor tyrosine kinase inhibitors. Curr Oncol. 2014;21(6):329-336.
US Department of Health and Human Services. National Institutes of Health National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0. v4.03: June 14, 2010. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed August 20, 2015.
Shepherd FA, Rodrigues Pereira J, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353(2):123-132.
Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380-2388.
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957.
Boehringer Ingelheim International GmbH. GILOTRIF® (afatinib) tablets, for oral use. 2015. http://bidocs. boehringer-ingelheim.com/BIWebAccess/ViewServlet. ser?docBase=renetnt&folderPath=/Prescribing+Information/ PIs/Gilotrif/Gilotrif.pdf. Accessed August 20, 2015.
Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28(7):1124-1130.
Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-1018.
GlaxoSmithKline TYKERB (lapatinib) tablets, for oral use 2015. http://www.pharma.us.novartis.com/product/pi/pdf/ tykerb.pdf. Accessed August 20, 2015.
O’Shaughnessy J, Miles D, Vukelja S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase 3 trial results. J Clin Oncol. 2002;20(12):2812-2823.
Poole CJ, Earl HM, Hiller L, et al. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006;355(18):1851-1862.
Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-119.
Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase 2 cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278-2284.
San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15(11):1195-1206.
Fuchs CS, Moore MR, Harker G, et al. Phase 3 comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003;21(5):807-814.
Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase 3 trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(14):2311-2319.
Cunningham D, Pyrhönen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998;352(9138):1413-1418.
Cassidy J, Twelves C, Van Cutsem E, et al. Capecitabine Colorectal Cancer Study Group. First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol. 2002;13(4):566-575.
Haller DG, Catalano PJ, Macdonald JS, et al. Phase 3 study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 2005;23(34):8671-8678.
Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352(26):2696-2704.
Köhne CH, Bedenne L, Carrato A, et al. A randomised phase 3 intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/ folinic acid in the adjuvant treatment of stage III colon cancer: the Pan-European Trial in Adjuvant Colon Cancer 2 study. Eur J Cancer. 2013;49(8):1868-1875.
Lembersky BC, Wieand HS, Petrelli NJ, et al. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 2006;24(13):2059-2064.
André T, Colin P, Louvet C, et al. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol. 2003;21(15):2896-2903.
André T, Boni C, Mounedji-Boudiaf L, et al. Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350(23):2343-2351.
Goldberg RM, Sargent DJ, Morton RF, et al. Randomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan or infused fluorouracil plus leucovorin and oxaliplatin in patients with previously untreated metastatic colorectal cancer: a North American Intergroup Trial. J Clin Oncol. 2006;24(21):3347-3353.
Cassidy J, Clarke S, Díaz-Rubio E, et al. Randomized phase 3 study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008;26(12):2006-2012.
de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000;18(16):2938-2947.
Colucci G, Gebbia V, Paoletti G, et al. Phase 3 randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol. 2005;23(22):4866-4875.
Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22(2):229-237.
Peeters M, Price TJ, Cervantes A, et al. Randomized phase 3 study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28(31):4706-4701.
Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25(30):4779-4786.
Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408-1417.
Falcone A, Ricci S, Brunetti I, et al. Phase 3 trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007;25(13):1670-1676.
Schmoll HJ, Cartwright T, Tabernero J, et al. Phase 3 trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007;25(1):102-109.
Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1065-1075.
Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337-345.
Benson AB 3rd, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 2004;22(14):2918-2926.
Kornblau S, Benson AB, Catalano R, et al. Management of cancer treatment-related diarrhea. Issues and therapeutic strategies. J Pain Symptom Manage. 2000;19(2):118-129.
Arbuckle RB, Huber SL, Zacker C. The consequences of diarrhea occurring during chemotherapy for colorectal cancer: a retrospective study. Oncologist. 2000;5(3):250-259.
Dranitsaris G, Maroun J, Shah A. Estimating the cost of illness in colorectal cancer patients who were hospitalized for severe chemotherapy-induced diarrhea. Can J Gastroenterol. 2005;19(2):83-87.
Arnold RJ, Gabrail N, Raut M, et al. Clinical implications of chemotherapy-induced diarrhea in patients with cancer. J Support Oncol. 2005;3(3):227-232.
Andreyev J, Ross P, Donnellan C, et al. Guidance on the management of diarrhoea during cancer chemotherapy. Lancet Oncol. 2014;15:e447-460.
Andreyev HJ, Davidson SE, Gillespie C, et al. Practice guidance on the management of acute and chronic gastrointestinal problems arising as a result of treatment for cancer. Gut. 2012;61(2):179-192.
Maroun JA, Anthony LB, Blais N, et al. Prevention and management of chemotherapy-induced diarrhea in patients with colorectal cancer: a consensus statement by the Canadian Working Group on Chemotherapy-Induced Diarrhea. Curr Oncol. 2007;14(1):13-20.
Wadler S, Benson AB 3rd, Engelking C, et al. Recommended guidelines for the treatment of chemotherapy-induced diarrhea. J Clin Oncol. 1998;16(9):3169-3178.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Palliative Care, version 2 2015. http://www.nccn.org/professionals/physician_gls/pdf/ palliative.pdf. Accessed August 27, 2015.
Gebbia V, Carreca I, Testa A, et al. Subcutaneous octreotide versus oral loperamide in the treatment of diarrhea following chemotherapy. Anticancer Drugs. 1993;4(4):443-445.
CAMPTOSAR irinotecan hydrochloride injection, solution. Pfizer injectables, Revised 12/2014. Available from: http:// labeling.pfizer.com/ShowLabeling.aspx?id=533. Accessed October 30, 2015.
Michael M, Brittain M, Nagai J, et al. Phase II study of activated charcoal to prevent irinotecan-induced diarrhea. J Clin Oncol. 2004; 22(21):4410-4417.
Takeda Y, Kobayashi K, Akiyama Y, et al. Prevention of irinotecan (CPT-11)-induced diarrhea by oral alkalization combined with control of defecation in cancer patients. Int J Cancer. 2001; 92(2):269-75.
Osterlund P, Ruotsalainen T, Korpela R, et al. Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study. Br J Cancer. 2007; 97(8):1028-34.
Meropol NJ, Blumenson LE, Creaven PJ. Octreotide does not prevent diarrhea in patients treated with weekly 5-fluorouracil plus high-dose leucovorin. Am J Clin Oncol. 1998; 21(2):135-8.
Rosenoff SH, Gabrail NY, Conklin R, et al. A multicenter, randomized trial of long-acting octreotide for the optimum prevention of chemotherapy-induced diarrhea: results of the STOP trial. J Support Oncol. 2006; 4(6):289-94. prevention of chemotherapy-induced diarrhea: results of the STOP trial. J Support Oncol. 2006; 4(6):289-94.
Hoff PM, Saragiotto DF, Barrios CH, et al. Randomized phase III trial exploring the use of long-acting release octreotide in the prevention of chemotherapy-induced diarrhea in patients with colorectal cancer: the LARCID trial. J Clin Oncol. 2014;32(10):1006-1011.
Kee BK, Morris JS, Slack RS, et al. A phase II, randomized, double blind trial of calcium aluminosilicate clay versus placebo for the prevention of diarrhea in patients with metastatic colorectal cancer treated with irinotecan. Support Care Cancer. 2015; 23(3):661-70.
Freedman RA, Gelman RS, Wefel JS, et al. TBCRC 022: Phase II trial of neratinib for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer and brain metastases (BCBM). J Clin Oncol. 2014;32:5s (suppl; abstract 528).
Gajria D, Modi S, Saura C, et al. A phase I/II study of neratinib plus temsirolimus in HER2+ metastatic breast cancer reveals ongoing HER2 pathway dependence in many patients despite several lines of HER2 targeted therapy. http://cancerres. aacrjournals.org/content/75/9_Supplement/P5-19-04. short?rss=1. Accessed August 20, 2015.
Gandhi L, Bahleda R, Tolaney SM, et al. Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors. J Clin Oncol. 2014;32(2):68-75.
Besse B, Soria J, Yao B, et al. Neratinib with or without temsirolimus in patients with non-small cell lung cancer (NSCLC) carrying HER2 somatic mutations: An international randomized phase II study. Ann Oncol. 2014;25:1-41 (abstract A39).