Biological therapies in breast cancer: Common toxicities and management strategies

The Breast 22 (2013) 1009e1018

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The Breast journal homepage: www.elsevier.com/brst

Review

Biological therapies in breast cancer: Common toxicities and management strategies Romualdo Barroso-Sousa, Iuri A. Santana, Laura Testa, Débora de Melo Gagliato, Max S. Mano* Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Arnaldo, 251, 5
andar, CEP 01246-000 São Paulo, SP, Brazil

a r t i c l e i n f o

a b s t r a c t

Article history: Received 21 May 2013 Received in revised form 14 September 2013 Accepted 21 September 2013

In recent years, a number of new molecules e commonly known as biological therapies e have been approved or are in late stages of regulatory evaluation for the treatment of advanced breast cancer. These innovative compounds have improved treatment efficacy and have probably contributed to the increase in survival length observed in some breast cancer subtypes. However, these agents are not deprived of toxicity, which can impair quality of life and may occasionally be life-threatening. In this article, we reviewed the most common toxicities associated with these drugs and provided a number of practical recommendations on their optimal clinical management. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: Breast cancer Adverse events Trastuzumab Pertuzumab Lapatinib Bevacizumab Trastuzumab-emtansine Everolimus

Introduction Currently, six drugs entitled targeted or ‘biological’ agents are approved for clinical use in distinct disease scenarios in breast cancer (BC) management. The medications include trastuzumab, pertuzumab, lapatinib, trastuzumab-emtansine, bevacizumab and everolimus. These drugs are changing survival outcomes in metastatic BC patients and are largely used in clinical practice. However, treating patients for longer periods with potentially toxic agents raises new challenges, such as managing their potential adverse events (AEs). Clinicians must be aware that gains in disease control and/or survival must be weighed against potential detrimental effects in quality of life (QoL). Some of these molecules

can cause unusual AEs even for an experienced oncologist. Also, potentially life-threatening AEs can also occur. A recent metaanalysis showed that new anticancer agents approved since 2000 increased morbidity and treatment-related mortality [1]. Therefore, community oncologists must become fully familiar with the potential toxicity associated with these agents and must have the expertise for their appropriate management. The objectives of this review are to provide 1) an updated description of the safety profile of novel targeted agents used in the management of breast cancer; 2) practical recommendations on the management of these AEs and patient monitoring.

Search criteria Abbreviations: ABC, advanced breast cancer; QoL, quality of life; AE, adverse event; HER2, human epidermal growth factor receptor type 2; LVEF, left ventricular ejection fraction; EGFR, epidermal growth factor receptor; T-DM1, Trastuzumab emtansine; FDA, Food and Drug Administration; VEGF, vascular endothelial growth factor; mTOR, the mammalian target of rapamycin; CT, computed tomography; RCC, renal cell cancer. * Corresponding author. Tel.: þ55 11 3893 2686; fax: þ55 11 3893 2690. E-mail addresses: [email protected], [email protected] (M.S. Mano). 0960-9776/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.breast.2013.09.009

We conducted an English-language MEDLINE (last 10 years) and proceedings of ASCO Annual Meetings and San Antonio Annual Meeting (last 5 years). We gave priority to phase III studies when those were available, but also included Phase II trials, when Phase III were not available. The search terms included six agents now approved or under evaluation from regulatory authorities. The last search was updated on 03 March 2013.

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Trastuzumab Risk of cardiac dysfunction Approximately 15e20% of breast cancers have amplification or overexpression of the human epidermal growth factor receptor type 2 (HER2) and are characterized by an aggressive clinical behavior and a worse prognosis [2]. Trastuzumab, a humanized monoclonal antibody against HER2 was proven to be effective in several clinical trials in the neoadjuvant, adjuvant and metastatic setting [3]. However, in the Pivotal Trial that evaluated this drug, Trastuzumab use was associated with cardiac dysfunction, especially in the cohort of patients that were treated concurrently with anthracyclines [3]. Of note, cardiac monitoring was not mandatory in this trial and the actual risk of trastuzumab-related cardiac dysfunction remained unclear. Subsequent studies demonstrated symptomatic heart failure (HF) in approximately 4% of patients [4e6]. An important adjuvant trial evaluated trastuzumab given sequentially to anthracyclines (4 cycles of Doxorubicin plus Cyclophosphamide followed by Docetaxel and Trastuzumab: AC-TH). This study included an arm of patients treated with Docetaxel plus Carboplatin plus Trastuzumab (TCH) and a third one with AC-T. The actual risk of symptomatic congestive heart failure was 2% for the AC-TH group and 0.7% for the TCH group of patients (p < 0.001). A subclinical asymptomatic loss of mean LVEF (defined as >10% relative loss) was found in 18.6% and 9.4% for the group that received AC-TH and TCH, respectively. This is showed in Table 1 [7]. Of note, Quality of Life data was collected in a portion of the patients from BCIRG006. Patients answered The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and BR-23 at baseline, in cycle 4 and in the end of chemotherapy. The questionnaire was also answered at month 6, 12, and 24 after chemotherapy. Systemic side effect change scores were significantly improved for the group treated with TCH, compared with AC-TH and AC-T. All patients recovered from deterioration of systemic side effects by one year. This analysis suggests TCH as a more tolerable treatment [8]. Although TCH was associated with few cardiac events and better quality of life, one cannot conclude that this is a preferable regimen over AC-TH, as the trial was not designed to demonstrate it. Asymptomatic impairment of left ventricular ejection fraction (LVEF) of 10e15% or more was seen in up 18% of patients as summarized in Table 1 [7,9e11]. The clinical significance of this finding remains unknown. Whether or not the cardiac toxicity rates can be generalized to the real world is still a matter of debate, since women included in these clinical trials were usually highly selected, with limited comorbidities. In addition, many studies simply excluded patients with suboptimal cardiac function. For instance, two recent retrospective studies performed in patients treated in the community setting suggested that risk of trastuzumab-associated cardiac dysfunction could be slightly Table 1 Reported asymptomatic LVEF and CHF in pivotal trastuzumab-based adjuvant trials in breast cancer. Trial

Number of patients

LVEF decreasing

CHF

NSABP-31 [11,16] NCCTG 9831 [11] HERA [10] BCIRG 006a [7] FinHer [9]

1736 1633 3387 3222 332

14.0% NR 7.1% 18.6%  9.4% 3.5%

4.1% 2.9% 1.7% 2.0%  0.4% 0.0%

Abbreviations: LVEF, left ventricular ejection fraction (defined as a drop in Left Ventricular Ejection Fraction of more than 10 units percent or a drop below 50%); CHF, congestive heart failure. a Trastuzumab-based chemotherapy including or not anthracyclines.

higher than reported in the adjuvant trials [12,13]. It is also important to point out that LVEF decrease criteria can vary and the methods currently used to evaluate LVEF are quite heterogeneous among the clinical trials, As a consequence Trastuzumab Cardiac Toxicity can be over or underestimated depending on the criteria adopted. Trastuzumab-related cardiotoxicity, differently from anthracycline-related, commonly presents as asymptomatic impairment of LVEF, does not appear to be related to cumulative dose and is often partially reversible with treatment interruption. Resuming treatment with trastuzumab after cardiac function recovery is often feasible. However it can also be associated with relapse of LVEF decrease [14]. To date, other anti-HER2 targeted agents have not been associated with significant cardiotoxicity. Recommendations for the management of trastuzumab-related cardiotoxicity The most important risk factors for trastuzumab-related cardiotoxicity are previous or concurrent use of anthracycline and age greater than 50 years [12,15,16]. Elderly patients (70 years), which have been traditionally excluded from clinical trials, are at especially high risk for Trastuzumab related Cardiotoxity. A retrospective study that evaluated patients with 70 years old or more treated with Trastuzumab, showed an incidence of 8.9% in the development of symptomatic congestive heart failure for the metastatic patients cohort [17]. Other risk factors include decreased baseline LVEF, increased body mass index and previous hypertension [14]. A recent study evaluated troponin 1 levels before and after each Trastuzumab cycle in women with early stage or advanced BC. Trastuzumab Cardiac Event, defined as LVEF decrease of 10 units and below 50%, was more commonly seen in patients with elevated levels of troponin 1 (62% versus 5%; p < 0.001). Also, LVEF recovery occurred less frequently in patients with elevated troponin 1 (35% versus 100%; P < 0.001) [18]. Surveillance for trastuzumab-related cardiotoxicity is largely empirical [19,20]. Cardiac function should be assessed prior to trastuzumab therapy. Clinical Oncologists should determine previous cardiac events and risk factors for each patient. Also, we feel that a 12-lead electrocardiogram (ECG) e looking for possible markers of structural heart disease is recommended. Additionally, a baseline exam to obtain the Left ventricular ejection fraction measurement, using echocardiogram or radionucleotide multiplegated acquisition (MUGA) scan is also extremely important. Repeat echocardiogram or MUGA every three months of therapy and also at the end of Adjuvant Trastuzumab treatment. For the metastatic patients, we recommend repeating echo or MUGA every 3 months. Patients with a normal baseline LVEF and no signs or symptoms of heart failure are able to start therapy. Patients with a modestly increased risk for cardiotoxicity (include those with borderline LVEF between 50 and 55 percent, age >50 years and hypertension) should also be considered for treatment with trastuzumab, after careful consideration of the potential harms and benefits. In this group of patients, one should consider the use of non-anthracycline containing trastuzumab schedules [7]. Although the late onset of cardiac dysfunction seems to be uncommon, it is advisable to continue LVEF assessments every 6 months for at least 2 years after completion of treatment [14,16]. In the metastatic setting, the routine assessment is less clearly defined. Nevertheless, we believe that there is no reason not to propose the same schedule as in the adjuvant setting. Some of these patients can become long-term survivors, and cardiac function is an important part of the quality of life [18].

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If a Cardiac Event related to Trastuzumab use occurs, this agent should be initially halted for 4 weeks. Cardiac dysfunction should be managed according to established guidelines for treatment of heart failure [19]. Treatment should include anti-hypertensive drugs (especially angiotensin converting enzyme inhibitors or angiotensin receptors blocks) until LVEF recovery [19,21]. Since most cases of trastuzumab-related cardiotoxicity are reversible and LVEF improves after treatment withdrawal, it is recommended that a new assessment of LVEF be performed after 4 weeks. If cardiac function restores to the previous normal baseline from the patient, re-challenge with trastuzumab can be considered [22e24]. If a second event occurs, trastuzumab should be permanently discontinued. Table 2 summarizes the recommendations for patient monitoring and management of cardiac dysfunction during treatment with anti-HER2 therapies. Trastuzumab-related infusion reactions Common trastuzumab related AE include infusional reactions, can be occasionally severe and are described in up to 40% of the patients receiving the drug. However, they rarely lead to treatment discontinuation and tend not to recur with repeated exposure. Caution is recommended in patients with severe pulmonary conditions and/or tumor involvement especially those with clinically relevant dyspnea and hypoxemia. Other side effects have been described but are usually mild with no clinical impact. Lapapatinib and pertuzumab Lapatinib is an orally administered small-molecule inhibitor of the tyrosine kinase domains of both HER2 and HER1/epidermal growth factor receptor type 1 (EGFR). The Phase I trial that evaluated lapatinib demonstrated that the most common side effects associated with this drug are diarrhea, rash, nausea, and fatigue. The great majority of side effects were grade 1 or 2 (135 from 140 drug-related AE) [25]. Table 3 shows the common clinically relevant toxicity in lapatinib treated patients. From the patient’s perspective, one of the most compromising AE is the skin rash, manifested by an erythematous papular

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eruption, most often seen on the face, chest, and back. In the large phase III trial of lapatinib plus capecitabine versus capecitabine alone for metastatic BC patients, 28% of patients in the combination arm experienced rash, versus 15% in the capecitabine alone arm [26]. This type of rash is an AE typically seen in drugs that target the ErbB-1 receptor. The possible mechanism of skin rash is not fully completely understood. One possible explanation is the inhibition of EGFR receptor from the keratinocytes in the skin itself [27]. Also, a systemic immunological reaction is another possible theory for the rash, as a neutrophilic infiltrate is often seen in the skin tissue and corticosteroids are usually effective in the rash treatment [28]. Although skin rash can considerably compromise QoL, the Phase III Trial that evaluated capecitabine and Lapatinib versus capecitabine alone published an important QoL assessment [27]. Patients completed Functional Assessment of Cancer Therapy Breast (FACTB) and EuroQoL (EQ-5D) questionnaires during efficacy and safety assessment visits. Surprisingly, the combination group had better Qol scores, although not statistically significant. Patients with an objective response rate or stable disease had clinically meaningful differences in QoL scores compared to patients with progressive disease. This may have contributed to the better QoL scores found in the combination group, as this treatment was associated with a better Progression Free survival. Thus, this combination proved that QoL was not compromised with the addition of the biological agent [29]. Nevertheless, the toxicity profile from lapatinib is not negligible and a new drug was proven better tolerated. A recent randomized Phase III study evaluated the combination of lapatinib and capecitabine against a novel drug in this setting, Trastuzumab emtansine (T-DM1). This trial demonstrated that T-DM1 significantly prolonged progression-free and overall survival compared to lapatinib and capecitabine. Also, it was associated with a more favorable toxicity profile. Grade 3 or above AE were much higher with lapatinib plus capecitabine, compared with T-DM1 (57% vs. 41%). Lapatinib treated patients experienced more diarrhea, nausea, vomiting, and palmareplantar erythro-dysesthesia. After data from this study, T-DM1 is the preferable option over capecitabine and lapatinib combination in the second line treatment of metastatic BC patients with overexpression of HER2 [30].

Table 2 Monitoring and management of cardiac dysfunction in patients undergoing adjuvant anti-HER2 therapy. Therapy phase

Recommendations

Patient profile

Recommendations

Before starting treatment

Clinical assessment with detailed history and physical examination

No risk factors with normal LVEF Positive cardiac history and/or risk factor with normal LVEF Impaired LVEF

1. Start trastuzumab-based therapy 1. Start trastuzumab-based therapy

First decrease in LVEFa

1. Interrupt trastuzumab for 4 weeks 2. Start treatment for heart failure and after 4 weeks reassess LVEF - If LVEF returns to baseline, resume trastuzumab if clinically appropriate. - If LVEF remains impaired, trastuzumab should be discontinued 1. Discontinue trastuzumab

During treatment

Monitoring LVEF repeated at 3-months intervals until the end of anti-HER2 therapy or when clinically indicated

Second decrease in LVEF or onset of cardiac symptoms* After completion of treatment

Repeat LVEF at 6-months intervals until at least 2 years have elapsed since the last dose of trastuzumab

No change in LVEF Decrease in LVEF or cardiovascular symptoms

1. Treat heart failure with standard therapies (ACE-1 or ARB, BB). 2. Reassess LVEF to decide if starting therapy will be possible/appropriate.

1. Stop monitoring after 2 years 1. Start treatment for heart failure 2. After 4 weeks reassess LVEF

LVEF: left ventricular ejection fraction. a Decrease in LVEF was defined as a decrease in the ejection fraction of 10 percentage points or more from baseline to an LVEF of less than 50 percent at any time [10,19]; *the onset of cardiac symptoms including: symptoms (dyspnea, orthopnea, pedal edema) and/or objective findings (elevated jugular venous pressure, sinus tachycardia, tachypnea, S3 gallop, crackles) and concomitant LVEF decline or chest radiograph findings of pulmonary edema or increased vascular markings.

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Table 3 Reported adverse events in pivotal phase III of biological therapies in advanced breast cancer. Pertuzumab (plus trastuzumab and docetaxel; n ¼ 402) [Baselga et al. [32]]

Lapatinib (plus capecitabine; n ¼ 163) [Geyer et al. [26]]

Lapatinib (plus capecitabine; n ¼ 496) [Verma et al. [30]]

TD-M1 (n ¼ 495) [Verma et al. [30]]

Bevacizumab (plus Bevacizumab (plus Bevacizumab (plus paclitaxel; n ¼ 722) docetaxel; n ¼ 736) chemotherapya; n ¼ 1237) [Miles et al. [41]] [Miller et al. [40]] [Robert et al. [39]]

All grades

All grades

Grade 3 or 4

All grades

All grades

All grades

Grade 3 or 4

37 e e e

3 e e e

18 e e e

e e e

28 e e e

e e e

35 e e e

e e e

e e

e

e

e

e

e

e

e

e

e e e e e e e e

e 2.8 e e e e 2 e

e e e e e e 11 e

e e e e e e e

e e e e e e e e

e e e e e e e e

e e e e e e e e

e e e e e e e e

50 8 e e

46 8 4 e

e e e e

e e e e

9 e 8 3

26 e 42 e 46 25 e e e e

e e e e 5

15

<1

e

e 24

Grade 3 or 4

General (%) Fatigue 33 4 Decreased weight 19 1 Pyrexia 14 <1 Infections e e Metabolic disorders (%) Hyperglycemia 13 5 Cardiovascular and pulmonary toxicities (%) Hypertension e e LVEF decreasing Peripheral edema 14 1 Hemorrhage e e Thrombosis/embolism e e Cerebral ischemia e e Dyspnea 18 4 Pneumonitis 12 3 Hematological, % Neutropenia e e Febrile Neutropenia e e Anemia 16 6 Thrombocytopenia 12 3 Gastrointestinal and hepatic toxicities (%) Anorexia 29 1 Dysgeusia 21 <1 Nausea 27 1 Vomiting 14 1 Diarrhea 30 3 Constipation 13 <1 Proteinuria e e Perforation e e ALT level increased 11 3 AST level increased 13 3 Dermatological toxicity (%) Stomatitis 56 8 Rash 36 1

Grade 3 or 4 2

3

e e e e

44 26 60 10 e e e e

2 2 13 0 e e e e

e e

15 27

0 1

Grade 3 or 4 4

4 2 <1

6 e 10 28

e

e

e

Grade 3 or 4

Grade 3 or 4

Grades 2e5

7 e e <1

e e e e

e

e

e

15 <1 e <1 2 2 e e

e e <1 e e e 3 e

8.9e10.5 1.5e6.2 e 0.2e5.4 2e5 0.5e1.5 e e

<1 e <1 0

e e

1.2e9.4 0e8.4 e e

3

9

9

2 e 3 13 e

45 29 80 e e e 9 9

3 5 21 e e e 1 <1

39 19 23 e e e 17 22

<1 <1 2 e e e 3 4

<1 e 3 3 e e 4 <1 e 2

e e

e e

e e

e e

e

1

2 e 2 e 2 2 7 e e e e e 3 2

e e e e e e 2.2e3.9 0e2.5 e e e e

Abbreviations:LVEF: left ventricular ejection fraction; ALT: alanine aminotrasferase; AST: aspartate aminotransferase. a chemotherapy regimens were choosed by investigators and included: capecitabine (Cape; 2000 mg/m2 for 14 days), taxane (Tax) -based (nab-paclitaxel 260 mg/m2, docetaxel 75 or 100 mg/m2), or anthracycline (Anthra) -based (doxorubicin or epirubicin combinations [doxorubicin/cyclophosphamide, epirubicin/cyclophosphamide, fluorouracil/epirubicin/cyclophosphamide, or fluorouracil/doxorubicin/cyclophosphamide]) chemotherapy administered every 3 weeks [39].

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Everolimus (plus exemestane; n ¼ 485) [Baselga et al. [56]]

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Pertuzumab is a humanized monoclonal antibody that binds to HER 2 receptor domain II (dimerization domain), differently from trastuzumab, that binds HER2 at subdomain IV [31]. Recently, CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) phase III trial has confirmed the benefit of pertuzumab, trastuzumab and docetaxel combination as first-line therapy in HER2positive metastatic breast cancer patients compared with the standard combination of trastuzumab and docetaxel [32]. The most common AE (any grade) were diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin (Table 3). The events were mostly grade 1 or 2 and occurred during the period of docetaxel administration. Grade 3 or higher febrile neutropenia and diarrhea were also more frequently seen in the pertuzumab group. Neoadjuvant trials demonstrated similar results: Pertuzumab use was associated with markedly increased efficacy, with a good safety track [33,34]. Currently, a registration phase III study is ongoing in the adjuvant setting with patients newly diagnosed with HER2positive breast cancer [35]. Management of diarrhea associated to lapatinib and pertuzumab Management of lapatinib or pertuzumab-associated diarrhea is empirical. Practical management recommendations are similar to those established for diarrhea associated to capecitabine. If a patient experiences mild to moderate (grade 1 or 2) diarrhea, a lactose-containing free diet should be oriented, as well as oral fluids intake and small portions meals. Anti diarrheal drugs are indicated, such as loperamide. Start with an initial dose of 4 mg followed by 2 mg every 4 h or after every unformed stool until the patient is free from diarrhea for at least 12 h [36]. If a patient experiences moderate to severe diarrhea or has signs of potential complications, such as severe cramping, nausea, vomiting, fever, or dehydration, further doses of lapatinib or pertuzumab should be held. Intravenous fluids and inpatient hospitalization should be considered. Repeat administration of the anti-HER2 drugs should be delayed until the patient recovers and subsequent doses should be decreased. Management of rash associated to lapatinib and pertuzumab There are no clear evidence-based recommendations for the management of lapatinib or pertuzumab-associated rash. However, there is considerable experience in managing dermatologic eruptions from other EGFR-targeted agents. In most patients, rash attributable to lapatinib resolves during treatment, following a temporary interruption in treatment, or after treatment cessation. Clindamycin phosphate 1% gel can be used with good effect for inflammatory pustular lesions. A combination of clindamycin 1% and benzoyl peroxide 5% gel can also be effective. Oral antibiotics

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can also be used, including doxycycline (100 mg twice daily) or tetracycline (500 mg twice daily). Colloidal oatmeal lotion has also been shown to be effective. Emollients should be used to reduce dry skin component of this. The treatment for cutaneous toxicities needs to be maintained even when EGFRI therapy is decreased or is interrupted as EGFRI-associated toxicities can last a very long duration period. Patients with extensive or persistent skin involvement should be referred to a dermatologist [36]. Trastuzumab-DM1 Trastuzumab emtansine (T-DM1) is an antibodyedrug conjugate that incorporates the HER2- targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubuleinhibitory agent DM1 (derivative of maytansine) [37]. T-DM1 was developed to deliver the intracellular drug specifically to HER2overexpressing cells, thereby improving the therapeutic index and minimizing exposure of normal tissue. The pivotal phase 3 study ‘EMILIA’ was described above, in the lapatinib section [30]. As mentioned, T-DM1 treatment was associated with fewer grade 3 or higher AE, compared with Lapatinib and Capecitabine. Although with a more favorable toxicity profile, grade 3 or 4 thrombocytopenia (12.9%), elevated serum concentrations of aspartate aminotransferase (4.3%) and alanine aminotransferase (2.9%) were important side effects associated with T-DM1 use. However, the great majority of patients were able to continue the treatment after briefly interruption of T-DM1, when returning to normal levels of platelets and serum aminotransferases. Table 3 shows AE associated with T-DM1. The hepatoxicity associated with T-DM1 administration raises serious concerns. It was previously reported two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy. Thus, the packet insert of T-DM1 contains a boxed warning regarding the risk of serious liver injury. There is a formal recommendation for monitoring serum transaminases and bilirubin before each dose. Table 4 summarizes the dose adjustments in TDM1 regimen in the case of hepatotoxicity exhibited as increases in serum transaminases and/or hyperbilirubinemia. Anti-VEGF monoclonal antibody e bevacizumab Angiogenesis plays a critical role in progression of breast cancer. After publication of E2100 trial, the Food and Drug Administration (FDA) approved the bevacizumab in combination with paclitaxel for the first-line treatment of metastatic HER-2 negative breast cancer. Of note, bevacizumab is a humanized monoclonal antibody directed against circulating vascular endothelial growth factor A (VEGF-A).

Table 4 Graduation and management of hepatotoxicity associated to T-DM1. Grade 1 Increased Serum Transaminases (AST/ALT) - Definition: 2.5  ULN - Intervention recommended: None

Hyperbilirubinemia - Definition: - Intervention recommended:

<1.5  ULN None

Grade 2

Grade 3

Grade 4

>2.5 to 5  ULN Treat at same dose level.

>5 to 20  ULN Do not administer T-DM1 until AST/ALT recovers to Grade 2, and then reduce one dose levela

>20  ULN Discontinue treatment

>1.5 to 3  ULN Do not administer T-DM1 until total bilirubin recovers to Grade 1, and then treat at same dose levela

>3 to 10  ULN Do not administer T-DM1 until total bilirubin recovers to Grade 1, and then reduce one dose levela

>10  ULN Discontinue treatment

a Starting dose: 3.6 mg/kg; first dose reduction: 3.0 mg/kg; second dose reduction: 2.4 mg/kg; requirement for further dose reduction: discontinue treatment. ALT: alanine transaminase; AST: aspartate transferase; ULN: upper limit of normality.

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However, ever since its approval for the management of metastatic BC, bevacizumab has generated discussion and controversies. On July 2010 the Oncologic Drugs Advisory Committee voted against its use in BC. At the same year, FDA revoked the approval of bevacizumab for this indication [38]. Despite that, bevacizumab remains approved and is used in many countries in combination with chemotherapy for metastatic BC treatment. Safety analyses from the three phase III randomized clinical trials that evaluated bevacizumab in the first line treatment for metastatic BC demonstrated an expected AE profile. The most common side effects were hypertension, proteinuria, bleeding disorders, cardiovascular events, gastrointestinal perforation and thromboembolic events [39e41] (Table 3). It is important to point out that in view of the borderline efficacy gains and safety issues, the license for bevacizumab in combination with docetaxel has been withheld in many countries. Hypertension Hypertension is by far the most common AE associated with bevacizumab. Previous studies have shown its multifactorial cause. However, the inhibition of nitric oxide production causing vasoconstriction is the major pathway. Other described mechanism is the reduction of density in the microvascular beds, increasing systemic vascular resistance [42]. There are two meta-analyses showing a raise in the risk of hypertension of 3e7.5 fold for patients receiving bevacizumab [43,44]. Management of antiangiogenic related hypertension is frequently based on the current guidelines from the American Heart Association [45], but should be individualized for each patient. Women should be advised to periodically monitor blood pressure during bevacizumab use. This may detect early changes and should promptly trigger treatment [46]. There are no clear recommendations for specific antihypertensive agents, but one should consider that Angiotensin Conversion Enzyme Inhibitors and Angiotensin Receptor Blockers are able to reduce proteinuria, which may contribute for renal function protection. Drugs that increase nitric oxide, such as nitrates, nebivolol and phophodiesterase inhibitors, might be of particular interest and should be evaluated in prospective clinical trials. Among Calcium Channel Blockers, verapamil and diltiazem inhibit CYP3A4 and nifedipine induces VEGF. However, amlodipine and felodipine do not share those issues and can be used safely [47]. Thiazide diuretics should be used cautiously, particularly in patients prone to dehydration or hypercalcemia. A panel expert from the National Cancer Institute published a guideline for the management of hypertension induced by VEGF signaling pathway inhibitors. It can be summarized in four recommendations: (1) conduct and document a formal risk assessment for potential cardiovascular complications; (2) recognize that preexisting hypertension will be common in cancer patients and should be identified and addressed before initiation of VSP inhibitor therapy; (3) actively monitor BP throughout treatment with more frequent assessments during the first cycle of treatment; (4) manage BP with a goal of less than 140/90 mmHg for most patients

(and to lower, pre specified goals in patients with specific preexisting cardiovascular risk factors [48]. Proteinuria Proteinuria is a common dose-related AE occurring with inhibition of VEGF signaling and may reflect glomerular damage. Hypertension is a strong risk factor for bevacizumab-associated proteinuria, leading to the hypothesis that increasing intraglomerular pressure secondary to hypertension produces this proteinuria. Besides, it is well known that VEGF is responsible for maintaining glomerular integrity. Podocytes constitutively express VEGF and are found on glomerular capillary endothelial cells [49]. Since there are no interventional studies addressing the management of proteinuria, no evidence-based recommendations can be made at the present time. However, following specialists’ orientations all patients prior to the start of an anti-VEGF drug should be evaluated for existing kidney disease. This includes a screening urine analysis for proteinuria, blood pressure measurement and an estimated renal function. After bevacizumab initiation, all patients should have their urine analyzed by dipstick before each infusion. Key recommendations for management of bevacizumab-associated proteinuria are summarized in Table 5 [49]. Bleeding disorders Minor hemorrhagic events are relatively common in patients treated with targeted agents. The most common event reported in patients treated with bevacizumab is epistaxis, which usually resolves without medical attention [50,51]. Life-threatening hemorrhagic events are very rare in breast cancer patients. The risk of serious hemorrhage can be minimized by good control of hypertension. Clearly, with any agent that increases the risk of bleeding, care should be taken in patients who require concomitant treatment with anticoagulants or who for any reason develop thrombocytopenia. Thromboembolic events Two meta-analyses showing an increased risk of arterial and venous thromboembolic events are published. Patients with different types of solid tumors using bevacizumab were included [52,53]. Whether this increased risk requires some form of prophylaxis remains unclear. The great issue of this discussion is finding a balance of risk between thromboembolic and hemorrhagic complications. For now, there is no evidence to support the indication of primary prophylactic anticoagulation for patients receiving bevacizumab. When a patient develops a venous thromboembolism while on Bevacizumab therapy, it is of extreme importance graduation of the event. If a deep vein thrombosis with intervention necessity occurs, or a pulmonary embolus is incidentally discovered, bevacizumab should be held for at least two weeks while anticoagulant treatment is initiated. The decision to continue the drug should be individualized. If the patient has a clinically meaningful benefit

Table 5 Graduation and management of proteinuria related to bevacizumab. Proteinuria

Grade 1

Grade 2

Grade 3 or higher

- Definition:

1þ proteinuria; urinary protein <1.0 g/24 h Dose adjustment: No intervention is required

2þ proteinuria; 24 h urinary protein analysis indicated; Urinary protein 1.0e3.4 g/24 h Dose adjustment: Hold dose until recovery to 2 g/24 h

Urinary protein 3.5 g/24 h

- Intervention recommended:

Dose adjustment: Discontinue treatment

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with the treatment, is clinically stable and adequate anticoagulation is achieved, bevacizumab may be re started. We do not recommend Bevacizumab use if any life-threatening thromboembolism occurs. If an arterial thromboembolism occurs, such as cerebrovascular accident, myocardial infarction, unstable angina, transient ischemic attack or any other arterial embolic events, we recommend bevacizumab discontinuation. Cardiotoxicity Another rare but serious AE related to bevacizumab is cardiotoxicity. Heart failure has been rarely reported in some trials with bevacizumab use in different tumors. However, this is of special importance in patients with BC due to prior or concurrent exposure to other cardiotoxic agents. In a meta-analysis, Choueiri and cols demonstrated an overall relative risk of development of high-grade congestive heart failure for patients receiving bevacizumab of 4.74 (95% CI, 1.84 to 12.19 p ¼ 0.001) compared to those who did not receive bevacizumab [54]. Guidelines for the management of cardiotoxicity related to bevacizumab are not well defined. However, it is recommended holding the drug and a cardiologist evaluation [54]. Everolimus Everolimus is an oral sirolimus (formerly called rapamycin) derivative that inhibits the mammalian target of rapamycin (mTOR). This complex is located at a central point for a number of intracellular signaling pathways, linking growth factors, nutrients and energy availability to cell survival, growth, proliferation, and motility [55]. Recently, BOLERO-2 (the Breast Cancer Trials of Oral Everolimus2), a multicenter, phase III, randomized, placebo-controlled clinical trial confirmed the substantial benefit of mTOR blockage in postmenopausal women with advanced estrogen receptorepositive BC. Of note, this was a cohort of patients resistant to first-line endocrine therapy with anastrozole or letrozole [56]. Of relevance, the addition of everolimus to hormonal therapy treatment was accompanied by a significant increase in side effects. A higher percentage of patients discontinued everolimus in the combination-therapy group than discontinued placebo in the control group. This was mostly due to AE (19% vs. 4%). The main grade 3 or 4 AE were stomatitis, anemia, dyspnea, hyperglycemia, fatigue and pneumonitis. In clinical practice, we recommend a careful monitoring of patients receiving exemestane with everolimus, since there are some important and potentially serious AE associated with this drug combination. Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin analogues, including everolimus, and is characterized by a nonmalignant infiltration of the lungs. The exact mechanism from the pneumonitis related to mTOR inhibitors remains unclear, although data suggests that is immunologically mediated [57]. The experience acquired with everolimus use in renal cell cancer (RCC) patients, reveals that the typical onset of pneumonitis (any grade) occurred within 2e6 months of treatment initiation with a median time to occurrence of 108 days [58]. The majority of patients were asymptomatic despite the radiographic abnormalities. The most frequent radiological findings observed were ground-glass opacities, parenchymal consolidation and pleural effusion. When symptomatic, patients typically present with dyspnea on exertion

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and dry cough. Systemic symptoms of fever and fatigue can be present in some cases. BOLERO2 trial demonstrated that approximately 12% of patients in the everolimus arm had a diagnosis consistent with noninfectious pneumonitis (3% had a grade 3 and none of them had a grade 4 event). This diagnosis was determined by routine computed tomography (CT) scans performed every 6 weeks, as recommended in the study protocol for tumor assessment. A central radiology panel reviewed those CT scans [56]. The frequency of this pneumonitis in the everolimus arm was consistent with previous clinical experience [59]. The use of systemic corticosteroids is recommended in severe cases. Thus, it is important to rule out alternative diagnoses, such as infection and tumor progression before starting treatment. Key recommendations for the management of everolimus-related pneumonitis are summarized in Table 6. The appropriate monitoring of patients receiving everolimus is currently unclear. Chest X-rays have low sensitive and are probably unhelpful. In a retrospective analysis from CT scans of the ‘RECORD1’ trial, up to 50% of the exams were found to fulfill criteria for noninfectious pneumonitis. The reported incidence of clinical pneumonitis was much lower, suggesting that routine monitoring of these patients with serial CTs may be excessive [58]. However, physicians should be aware that even minimal symptoms potentially indicative of pneumonitis (usually dry cough and dyspnea on exertion e sometimes described by patients as ‘fatigue’) should be promptly investigated. Stomatitis/mucositis Although oral AE associated with everolimus are sometimes underestimated, stomatitis is one of the most frequent doselimiting toxicities in practice. The clinical findings resemble a thrush stomatitis rather than the mucositis seen with conventional cytotoxic chemotherapy [60]. Although the etiology of this stomatitis is not fully understood, some data suggest involvement of Tcell mediated inflammatory reaction [61]. It generally presents as an inflammation of the mucous membranes in the oral cavity, inner surface of the lips, or tongue. Most cases are associated with erythema, edema, burning sensation and occasionally bleeding. In addition, other symptoms can also be present, such as oral mucosal pain, dysgeusia, and dysphagia, in the absence of clinical lesions. The stomatitis has a rapid onset being usually seen within the first week therapy, however, the incidence decreases with subsequent cycles [60]. In BOLERO-2 trial, the incidence of stomatitis in the everolimus group was 56% (grade 3, 8%; none grade 4) [56]. The management of everolimus-associated stomatitis is empirical and derives from the experience with cytotoxic chemotherapy. A good oral hygiene and treatment of anticipated infectious foci (e.g. periodontal diseases) should be encouraged. Patients should also be evaluated for herpes and/or fungal infections, with an antiviral agent (e.g. acyclovir) or antifungal agent (e.g. fluconazole) treatment. Laser therapy can be considered for the occasional cases of severe stomatitis. Key recommendations for the management of everolimus-associated stomatitis are summarized in Table 6. In clinical practice, physicians are used to empirical manage those side effects with dose reductions to 5 mg or they start treatment with half of the recommended dose. Nevertheless, the Phase Ib study that evaluated letrozol in combination with 5 or 10 mg of everolimus recommended the dose of 10 mg. Also, this was the dose used in BOLERO2 and in the neoadjuvant Phase II trial that evaluated everolimus in combination with letrozol [59,62]. Therefore, we recommend initiating with a 10 mg dose of everolimus. Dose reducing is acceptable in clinical practice, but is not grounded by clinical trials.

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Table 6 Graduation and management of adverse events related to everolimus.

Pneumonitis - Definition:

Grade 1

Grade 2

Grade 3

Grade 4

Asymptomatic;

Symptomatic; medical intervention indicated; limiting instrumental ADL

Severe symptoms; limiting self care ADL; oxygen indicated

 Consult pulmonologist as appropriate Consider diagnostic procedures to rule out infectious causes or tumor progression  Consider corticosteroids

 High dose corticosteroids if infectious cause ruled out For impending respiratory distress: concomitant treatment with antibiotics and corticosteroids is recommended

Life-threatening respiratory compromise; urgent intervention indicated (tracheotomy or intubation)  Same as grade 3

- Intervention No intervention required recommended: clinical and/or radiologic surveillance only

Dose adjustment:  Hold dose until recovery to grade 1 and consider reescalation  If no recovery to grade 1, discontinue treatment Stomatitis - Definition:

Asymptomatic or mild symptoms; - Intervention  Non-alcoholic mouth wash recommended: or 0.9% saline solution (Avoid agents containing hydrogen peroxide, iodine and thyme derivatives) Dose adjustment: Not required

Rash - Definition:

- Intervention recommended:

Moderate pain; not interfering with oral intake; modified diet Indicated  Same as Grade 1 plus:  Topical analgesic mouth treatments  Topical corticosteroids  Antiviral therapy if herpetic infection confirmed  Antifungal therapy (topical preferred), if fungal infection suspected Dose adjustment: Maintain dose if tolerable  Hold dose if intolerable until recovery to grade 1, then restart at same dose

Dose adjustment:  Hold dose until recovery to grade 1, then restart at reduced dose Severe pain; interfering with oral intake  Same as Grade 2

Life-threatening consequences

Dose adjustment: Hold dose until recovery to grade 1, then restart at reduced dose

Dose adjustment: Discontinue treatment

 Same as Grade 2

 Papules and/or pustules covering any % BSA, which may or may not be associated with symptoms of pruritus or tenderness and are associated with extensive superinfection with IV antibiotics indicated; life-threatening consequences  Proceed the same  Proceed the same interventions cited for grade 2 interventions cited for grade 2  Papules and/or pustules covering >30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; limiting self care ADL; associated with local superinfection with oral antibiotics indicated

 Papules and/or pustules covering <10% BSA, which may or may not be associated with symptoms of pruritus or tenderness

 Papules and/or pustules covering 10e30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; associated with psychosocial impact; limiting instrumental ADL

 Mild lesions may resolve spontaneously; no specific therapy

 Topical treatment with corticosteroids and products containing benzoyl peroxide and antibiotic initially  Some patients with acne before starting Dose adjustment: everolimus benefit from topical as well  Everolimus dose modification: as oral antibiotic therapy (i.e., tetracycline; Interrupt dose until recovery avoid strong CYP3A4 inhibitors such to grade 1, then restart at as clarithromycin) lower dose level

Dose adjustment:  No change

Dose adjustment:  Discontinue treatment

Dose adjustment:  Everolimus dose modification: discontinue everolimus

Dose adjustment:  If patient is able to tolerate the toxicity, maintain same dose;  If patient is unable to tolerate the toxicity, hold dose until recovery to grade 1, then restart at same dose;  If toxicity returns to grade 2, hold dose until recovery to grade 1, then restart at lower dose level. Metabolic abnormalities Glucose: >160e250 mg/dL - Definition: Glucose: >ULN e 160 mg/dL Colesterol: >ULN e 300 mg/dL Colesterol: >300e400 mg/dL TGC: >2.5e5.0  ULN TGC: >ULN e 2.5  ULN - Intervention None intervention is required  Treat hyperglycaemia and hyperlipidemia recommended: according to the ADA and EASD consensus  Triglycerides 500 mg/dL present risk of pancreatitis; treat urgently with fibrates Dose adjustment: Maintain dose if tolerable  Hold dose if intolerable until recovery to grade 1, then restart at same dose

Glucose: >250e500 mg/dL Colesterol:>400e500 mg/dL TGC: >5.0e10$ULN  Same as Grade 2

Glucose: >500 mg/dL Colesterol: >500 mg/dL TGC:>10$ULN  Same as Grade 2

Dose adjustment: Hold dose until recovery to grade 1, then restart at reduced dose or discontinue as per clinical judgment

Dose adjustment: Discontinue treatment

ADL: Activities of Daily Living; ULN: Upper Limit of Normal; TGC: Triglycerides; ADA: American Diabetes Association; EASD: European Association for the Study of Diabetes.

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Metabolic abnormalities e hyperglycemia and dyslipidemia

Conclusion

Hyperglycemia is a class effect common to all mTOR inhibitors. Most cases occur in patients with abnormal fasting glucose levels before treatment. Insulin-induced up-regulation of GLUT1 mRNA translation is reduced by mTOR inhibitors, resulting in the failure of insulin to stimulate glucose uptake [63]. Hyperglycemia was observed in BOLERO-2 in 13% of patients (grade 3, 4%; grade 4, <1%) who received everolimus. Although hypercholesterolemia is another potential AE of mTOR inhibitors, there was no mention about it in BOLERO-2. This AE has been probably underestimated, as serum lipid checks were not planned in most trials. In the RCC trial RECORD-1, the incidence of hypercholesterolemia was based on laboratory results instead of a record by investigators. In this trial the incidence was higher and occurred approximately in 75% of patients that used everolimus. However, this side effect is generally marked by mild increases in cholesterol levels [60,64]. Patients with preexistent lipid metabolic abnormalities should be adequately treated according to general practice guidelines to achieve optimal glycemic and lipids control before starting everolimus. Patients with underlying diabetes require careful monitoring and may require modifications of their anti-hyperglycemic regimen. Treatment of hyperglycemia and hypercholesterolemia should follow the established guidelines, such as the American Diabetes Association and American Heart Association. Key recommendations for the management of everolimus-associated metabolic abnormalities are summarized in Table 6.

The development of novel targeted agents represents a major progress to patients with BC. Survival outcomes have been markedly improved of these agents. However, many of them are also associated with a wide range of side effects, and specific management is required. The resulting side effects can also be associated with potential detrimental effects in QoL and decrease treatment compliance, making the management of side effects a key component of treatment. In this review, we illustrated the main toxic profile related with each target agent and provided a number of practical recommendations in this regard.

Rash Everolimus has been associated with a high incidence of skin rash (39% all grades) in BOLERO-2. This AE is defined as druginduced acneiform dermatitis and usually starts as an inflammatory lesion (papule or pustule), while comedones (blackheads) may appear thereafter [65,66]. The distribution is frequently unusual, typically in acne-free areas (e.g., upper extremities, trunk, neck) [65e68]. There are no evidence-based guidelines for its management. Treatment includes topical treatments (with products containing corticosteroids, benzoyl peroxide, and antibiotics), systemic antibiotics, and dose adjustments. Key recommendations for the management of everolimus-associated metabolic abnormalities are summarized in Table 6. Patients with extensive or persistent skin involvement should be referred to a dermatologist. Infections Everolimus has been associated with a higher risk of infection due to its immunosuppressive properties. Everolimus can predispose patients to opportunistic infections and/or reactivation of latent infections. Thereby, patients should be screened for active or latent infections at baseline and when possible, should be appropriately treated prior to treatment initiation. In some circumstances, everolimus treatment might not be appropriate, such as in patients with a history of hepatitis B/C, HIV, tuberculosis and fungal infections. Local endemic infections should also be considered. Contrary to the phase III trials in renal and neuroendocrine cancer, no increase in the rate of severe infections was reported in ABC (BOLERO-2 trial) [56]. The rationale for this discrepancy is unclear but may reflect the severity from the underlying malignant disease. Of note, an earlier phase II trial evaluated two schedules of everolimus (daily vs. weekly) in heavily pretreated patients, the authors reported an incidence of infections of 11% (2% grades 3e4) [69]. Therefore, we recommend an aggressive and early infection treatment in patients being treated with everolimus and a clinical suspicion of infection.

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