**8. Side effects of targeted therapies used in renal cell carcinoma**

The increasing use of novel anti-VEGF agents, and for longer periods of time for the treatment of RCC has raised challenges in the management of the associated toxicities or adverse effects. There are supportive interventions developed for their prevention and control. [96]

It has been identified in clinical trials and post marketing surveillance that the treatment toxicities associated with the new targeted therapies against cancer differ significantly from the toxicities seen with conventional chemotherapy. [96, 97]

Many of the anti-VEGF agents share similar toxicities, including hypertension, fatigue, gastrointestinal, skin and bone marrow effects. The mTOR inhibitors have unique adverse effects, which include metabolic alterations (hypercholesterolnaemia, hyperglycermia), gastrointestinal alterations and interstitial pneumonitis. Hypothyroidism is seen uniquely in patients on sunitinib, potentially sorafenib and pazopanib. [96]

### **8.1. Hyperension**

Arterial hypertension is commonly observed as an adverse event in patients treated with inhibitors of the VEGF pathway. [96, 98] The most common implicated anti-VEGF agents include axitinib, bevacizumab, sorafenib, sunitinib and pazopanib. [33, 41, 51, 99, 100] Prompt identification of arterial hypertension is essential to prevent serious consequences such as strokes and heart failure. [101, 102] The regular use of ambulatory BP monitoring may be valuable for early detection and accurate assessment of blood pressure (BP) changes. [103] Hypertension has occurred whether or not the patient has a history of high blood pressure, however incidence may be higher in patients with pre-existing cardiovascular disease. [33, 41, 50, 99] There are pre-existing algorithms to treat hypertension associated with targeted therapies [96] but it falls on the clinician's discretion to individualise treatment accordingly. [98] For example, the use of angiotensin-converting enzyme (ACE) inhibitor is a logical choice if bevacizumab is the underlying cause as they may improve the associated proteinuria. [104] Angiotensin II inhibitors, diuretics, dihydropyridine calcium channel blockers (CCBs), and βblockers are also considered as appropriate anti-hypertensive agents.

### *8.1.1. Hypertension as a biomarker*

Hypertension induced by sunitinib and bevacizumab is associated with improved clinical outcomes, supporting its use as an efficacious biomarker. In a retrospective analysis which included pooled efficacy and safety data (n=544, n=4917) from four trials of patients with metastatic RCC treated with sunitinib 50mg/d (4 week on / 2 week off), it was observed that patients who had a systolic BP ≥to 140mmHg and a diastolic blood pressure of ≥ 90mmHg had better outcomes compared to those without treatment induced hypertension The ORR were 54.8% in the treatment induced hypertension cohort vs. 8.7% in the normotensive patients. The median PFS was 12.5 vs. 2.5 months in the hypertensive and normotensive respectively and similarly the median OS was 30.9 months in the hypertensive group vs. 7.2 months in the normotensive group. [105] The rates of AEs were similar between patients with and without hypertension. However patients with high BP experienced more frequent renal adverse events (5% vs. 3%). [105] More importantly, no difference in outcome (PFS and ORR) was noted regardless of whether patients received treatment for their hypertension. [105]

Treatment induced arterial hypertension is also correlated with good clinical outcomes in patients treated with bevacizumab for metastatic colorectal cancer [106] but this has not been investigated widely in metastatic RCC.

### **8.2. Fatigue**

Collecting duct tumour is a very aggressive but rare variant of aggressive but rare variant of RCC. The largest data is derived from a phase II multi-centre trial of 23 treatment naïve patients who received platinum based chemotherapy with gemcitabine. The choice of chemotherapy is that of a platinum doublet based on some similarities to transitional cell carcinoma of the bladder. The ORR was 26% with a median PFS and OS of 7.1 months and 10.5 months

The increasing use of novel anti-VEGF agents, and for longer periods of time for the treatment of RCC has raised challenges in the management of the associated toxicities or adverse effects.

It has been identified in clinical trials and post marketing surveillance that the treatment toxicities associated with the new targeted therapies against cancer differ significantly from

Many of the anti-VEGF agents share similar toxicities, including hypertension, fatigue, gastrointestinal, skin and bone marrow effects. The mTOR inhibitors have unique adverse effects, which include metabolic alterations (hypercholesterolnaemia, hyperglycermia), gastrointestinal alterations and interstitial pneumonitis. Hypothyroidism is seen uniquely in

Arterial hypertension is commonly observed as an adverse event in patients treated with inhibitors of the VEGF pathway. [96, 98] The most common implicated anti-VEGF agents include axitinib, bevacizumab, sorafenib, sunitinib and pazopanib. [33, 41, 51, 99, 100] Prompt identification of arterial hypertension is essential to prevent serious consequences such as strokes and heart failure. [101, 102] The regular use of ambulatory BP monitoring may be valuable for early detection and accurate assessment of blood pressure (BP) changes. [103] Hypertension has occurred whether or not the patient has a history of high blood pressure, however incidence may be higher in patients with pre-existing cardiovascular disease. [33, 41, 50, 99] There are pre-existing algorithms to treat hypertension associated with targeted therapies [96] but it falls on the clinician's discretion to individualise treatment accordingly. [98] For example, the use of angiotensin-converting enzyme (ACE) inhibitor is a logical choice if bevacizumab is the underlying cause as they may improve the associated proteinuria. [104] Angiotensin II inhibitors, diuretics, dihydropyridine calcium channel blockers (CCBs), and β-

Hypertension induced by sunitinib and bevacizumab is associated with improved clinical outcomes, supporting its use as an efficacious biomarker. In a retrospective analysis which

respectively.[18] There is no data to support the use of TKI in this variant of tumour.

**8. Side effects of targeted therapies used in renal cell carcinoma**

There are supportive interventions developed for their prevention and control. [96]

the toxicities seen with conventional chemotherapy. [96, 97]

patients on sunitinib, potentially sorafenib and pazopanib. [96]

blockers are also considered as appropriate anti-hypertensive agents.

**8.1. Hyperension**

172 Renal Tumor

*8.1.1. Hypertension as a biomarker*

Fatigue is a very frequent side-effect seen with the targeted agents used in metastatic RCC [74, 96, 107] The incidence of fatigue in phase III studies ranged from 14% to 51% for all grades and up to 11% for grade 3–4.

There is no direct treatment available to alleviate treatment induced fatigue. Monitoring and treating patients for any aggravating or reversible factors (i.e. anaemia, anxiety, hypothyroid‐ ism, depression may help. If grade 3–4 fatigue persists, dose reduction or cessation of the treatment should be considered. [96, 108]

### *8.2.1. Fatigue as a biomarker*

Fatigue is another potential biomarker in patients with metastatic RCC treated with sunitinib. A retrospective analysis of pooled data from 770 patients who received sunitinib in 5 clinical trials for metastatic RCC revealed that the development of grade 1-2 fatigue was linked with significantly longer time to progression and improved overall survival. [109]

### **8.3. Hand and foot syndrome as biomarker**

In a retrospective registry of metastatic RCC, 705 and 365 patients treated with sunitinib and sorafenib respectively were assessed for outcomes of the disease in those who developed hand and foot syndrome. In the sunitinib group, the median OS was 43 months for those with the hand and foot syndrome vs. 31 months (p=0.027) in those without. The PFS in patients with the dermatological toxicity was 20.8 months vs. 11.1 months (p=0.007) in those without. In the sorafenib group, no differences was noted in median OS for those that did and did not experience hand foot syndrome (27.9 vs. 24.6 months (p=0.244). The PFS was 12.2 vs. 8.8 months (p=0.050) with a difference of 3.4 months in those that experienced hand foot syndrome. In multivariable cox regression analysis, hand and foot syndrome was associated with longer OS in the sunitinib group. In sorafenib, the survival benefits were less convincing. [110]

### **8.4. Other biomarkers**

Emerging data has also shown that other adverse effects such as hypothyroidism, myelosup‐ pression in addition to the aforementioned hypertension and hand foot syndrome were biomarkers for tumour control and OS when sunitinib is the agent in use. [111, 112] In mTOR inhibitors, serum LDH, elevated cholesterol and pneumonitis have been studied as predictive biomarkers. [113-115]

preference when assessed at 22 weeks revealed 70% of patients preferred pazopanib, 22% preferred sunitinib, and 8% expressed no preference. The magnitude of difference was 49.3% between pazopanib and sunitinib. Fewer patients received pazopanib required a dose reduc‐ tion (13% vs. 20%), prematurely discontinued treatment during the first study period (14% vs. 8%), or prematurely discontinued treatment during the second period (15% vs. 31%). [117, 118]

New Systemic Treatment Approaches for Metastatic Renal Cell Carcinoma

http://dx.doi.org/10.5772/55280

175

The discovery of anti-angiogenic (small molecule tyrosine kinase inhibitors and anti-VEGF agents) agents has altered the treatment landscape for patients with metastatic RCC. Their effective anti-neoplastic activities have provided hope of survival beyond six month, in contrast to that traditionally gained from IFN-α therapy. Different treatment strategies are being investigated vigorously, either in combination or in sequence with the aim of improving the pre-existing survival and response rates. Whilst the treatment algorithm for advanced clear-cell variant of renal cell carcinoma is constantly evolving with increasing treatment options, the non clear-cell counterpart remains an area in need of significant research. With improved understanding of the various molecular pathways, options for non clear-cell variants would hopefully become more established. The recognition of the potentially serious side-effects of targeted agents begs for vigilance in the clinician's part to improve treatment adherence and compliance. Close monitoring of these toxicities will also allow for better identification of their role as bio-markers of efficacy. The ultimate goal is to have an effective

We wish to express our gratitude to Ms. Judith Lees, Senior Cancer Pharmacist, RAH Cancer

[1] Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med. 2005 Dec 8;353(23):

agent that leads to durable response with a tolerable side-effect profile.

Centre, for assistance with new drugs information.

Thean Hsiang Tan, Sina Vatandoust and Michail Charakidis

RAH Cancer Centre, Royal Adelaide Hospital, Adelaide, Australia

**10. Conclusion**

**Acknowledgements**

**Author details**

**References**

2477-90
