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Heart Failure: A Paraneoplastic Manifestation of Renal Cell Carcinoma – Reversed With Pazopanib
Accepted Manuscript Heart Failure : A Paraneoplastic Manifestation of Renal Cell Carcinoma – Reversed with Pazopanib Manu Pandey, Shipra Gandhi, Saby George PII:
S1558-7673(17)30048-4
DOI:
10.1016/j.clgc.2017.02.005
Reference:
CLGC 799
To appear in:
Clinical Genitourinary Cancer
Received Date: 28 January 2017 Accepted Date: 19 February 2017
Please cite this article as: Pandey M, Gandhi S, George S, Heart Failure : A Paraneoplastic Manifestation of Renal Cell Carcinoma – Reversed with Pazopanib, Clinical Genitourinary Cancer (2017), doi: 10.1016/j.clgc.2017.02.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
HEART FAILURE : A PARANEOPLASTIC MANIFESTATION OF RENAL CELL CARCINOMA – REVERSED WITH PAZOPANIB Manu Pandey1, Shipra Gandhi2, Saby George2 State University of New York at Buffalo Roswell Park Cancer Institute
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2
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1
M AN U
Clinical Practice point
Introduction
TE D
Pazopanib is now a first line therapy for Metastatic renal cell carcinoma(RCC). Several trials have excluded patients with heart failure, NYHA Grade III and IV. Heart failure is also a known complication of Pazopanib . We report a case of a patient with Ejection fraction(EF) of 20-25% at the time of diagnosis which we believe was due to paraneoplastic syndrome from RCC. Patient’s EF dramatically improved with treatment of his RCC. This case raises the question, whether low EF should preclude patient from treatement with pazopanib , or such patients can be started on a low dose of pazopanib , uptitrating the dose and carefully monitoring them for heart failure symptoms
AC C
EP
An estimated 62,700 new cases of kidney and renal pelvis cancers were projected to be diagnosed in 2016, leading to an estimated 14,240 deaths [1]. About 16% of these tumors are metastatic at the time of presentation [2]. Tyrosine kinase inhibitors (TKI), form the backbone of treatment for most cases of metastatic renal cell carcinoma. Cardiac toxicity such as congestive heart failure (CHF), hypertension, left ventricular systolic dysfunction, myocardial ischemia and infarction are known complications of TKI. A meta-analysis showed that the overall incidence of all grade and high grade (NYHA grade 3 and 4) CHF associated with vascular endothelial growth factor receptor –tyrosine kinase inhibitor (VEGFR-TKI) was 3.2% (95% CI 1.8%-5.8%) and 1.4% (95% CI 0.9%-2.3%), respectively. The sub-group analysis didn’t find significant differences in odds ratio (OR) of developing all grade or high-grade CHF among different VEGFR-TKI [3]. Majority of the studies with pazopanib have excluded patient with NYHA grade 3 and 4 heart failure [4, 5]. We report the case of a patient with metastatic renal cell carcinoma (mRCC), who was found to have heart failure with reduced ejection of 20-25 % at presentation. The patient was started on low dose pazopanib, which was slowly up-titrated to the recommended dose of 800 mg daily with good tolerance
ACCEPTED MANUSCRIPT
and surprisingly an improvement in the EF, a factor that has limited the use of pazopanib in this scenario. Case Report
TE D
M AN U
SC
RI PT
A 47-year-old man with no significant past medical history was worked up for cough and pneumonia-like symptoms and was found to have multiple lung nodules with parenchymal edema, pleural effusion, and a 12 cm left renal mass. Figure 1 represents the renal cell carcinoma with renal vein thrombosis.
EP
FIGURE 1 : Figure depicting renal cell carcinoma with renal vein thrombosis.
AC C
At presentation, labs showed hypercalcemia with total calcium of 10.8 mg/dl, thrombocytosis with platelet count of 806,000 /ml and anemia with hemoglobin of 10.9 gram/dl - all the above likely secondary to the inflammatory response to the disease burden or could be paraneoplastic manifestations of renal cell carcinoma. Figure 2 shows multiple cannon ball lung metastasis with parenchymal edema at the time of presentation.
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
FIGURE 2: Multiple cannon ball lung metastasis with parenchymal edema
AC C
EP
TE D
The patient underwent a cytoreductive / debulking surgery and pathology confirmed clear cell renal cell carcinoma Fuhrman grade 4, pT3aN0M1, invading into the renal vein and perinephric adipose tissue. Immediate improvement in total calcium to 9.4 was observed after the nephrectomy. Figure 3 shows a follow up CT Chest which showed resolution of the parenchymal edema surrounding the cannon ball lung metastasis within 2 days post nephrectomy.
ACCEPTED MANUSCRIPT
FIGURE 3: Resolution of the parenchymal edema surrounding the pulmonary nodules ona follow up CT chest post nephrectomy
RI PT
The patient was initially planned to be started on Interleukin-2 (IL-2), given his young age, good performance score and no comorbidities. However, an echocardiogram performed as initial pretreatment IL-2 workup showed an ejection fraction (EF) of 20-25% with global hypokinesis of the left ventricle. Right ventricular function was normal, and valves were morphologically intact. This was followed by a pharmacological stress test which revealed an EF of 27% with stress and 41% at rest. A multi-gated acquisition (MUGA) scan done later that month confirmed a EF of 35%, with inferior and inferoseptal hypokinesis. The patient was started on Carvedilol.
M AN U
SC
Given the reduced ejection fraction, the patient was not a candidate for the IL-2 therapy. Thus, the plan was to start him on a low dose of pazopanib 400 mg daily to be gradually titrated up to 600 mg daily as opposed to the recommended dose of 800 mg daily. Patient remained asymptomatic and was thus uptitrated up to the recommended dose of pazopanib, 800 mg daily, within three weeks of starting treatment. Improvement in anemia and thrombocytosis was noted after initiation of pazopanib. The patient had a repeat echocardiogram, around 10 weeks after starting pazopanib with the EF remaining stable at 20-25% with global hypokinesis. A repeat CT scans about three months after starting treatment showed a good response with 32% shrinkage in the tumor load. He was continued on pazopanib 800mg daily.
TE D
The patient remained asymptomatic during pazopanib treatment, with repeat scans seven months and ten months after starting pazopanib treatment continuing to show a partial response to the treatment. His cardiac function showed improvement with a repeat MUGA scan reporting an EF of 43% after seven months of starting pazopanib.
AC C
EP
Nearly a year after starting treatment with pazopanib, the patient started complaining of abdominal pain. Subsequent CT showed increasing size of hilar and mediastinal lymph nodes with increase in size of mass adjacent to the psoas muscle suggestive of the progressive disease. Anti-PD1 antibody nivolumab was started thereafter with good response. The patient continued on nivolumab for 14 months, at which time it was discontinued due to grade 4 pneumonitis and metastatic disease to the brain, treated with open resection and gamma knife radiation. Following treatments included sorafenib for about five months and then everolimus for three months. Patient eventually progressed and was rechallenged with pazopanib 800 mg daily. The patient tolerated pazopanib without any cardiovascular symptoms, although disease progression was noted within eight months of restarting pazopanib. Cabozantinib 40 mg daily was then started on which the patient continues. Patient’s last echocardiography was about 33 months post initial diagnosis which showed an EF of 55-60%.
Discussion According to NCCN guidelines, pazopanib, sunitinib are the two VEGFR-TKIs which have category one recommendations as first-line therapy for metastatic renal cell carcinoma. Pazopanib was found to be non-inferior to sunitinib in progression-free survival (PFS) (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22) and no statistical significance was
ACCEPTED MANUSCRIPT
found in the overall survival (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08) (4). A better safety profile and quality of life favor pazopanib over sunitinib [4,11]
RI PT
Pazopanib is a VEGFR –TKI which acts on multiple targets, including Vascular endothelial growth factor (VEGF) receptors 1, 2, and 3; PDGFRα and β, c-KIT [6]. The RR of hypertension with VEGF – TKIs has been shown to range between 1.71 and 8.06 [ 7]. Hypertension is a known risk factor for CHF and VEGF-TKIs increase the risk of CHF through this mechanism [8]. Another mechanism for cardiotoxicity is through the inhibition of the VEGF signal pathway. Mice studies have showed that inhibition of endogenous VEGF could lead to a reduction in the net capillary density, impaired cardiac hypertrophy and loss of contractile function after pressure overload in mice [9]. Also, inhibition of the PDGFR-beta in cardiomyocytes has also shown to induce heart failure in mice exposed to high vascular pressures. [10].
TE D
M AN U
SC
Congestive heart failure is a relatively uncommon side effect of pazopanib. A meta-analysis which included three trials with pazopanib (two Renal cell carcinoma and one Inflammatory breast cancer ), doses ranging between 400 mg to 800 mg daily showed the OR of 2.40 (95 %CI=1.01, 5.69) of all grade CHF [left ventricular ejection fraction (LVEF) decline] or dysfunction and CHF not otherwise specified as CHF-related adverse events, according to National Cancer Institute's common terminology criteria for adverse events (CTCAE)) although the OR for high-grade CHF (CHF events, >grade 2 , according to CTCAE grading ) was non-significant 4.52 (95% CI=0.41, 50.16) [3]. The incidence of CHF didn’t vary with tumor type [3].In PALETTE study, a soft tissue sarcoma trial; 16 out of 239 patients in the pazopanib group had a fall in the EF during or after treatment, out of which three patients were symptomatic [5]. A recent study has shown that a lower dose (most patients received 400 mg) of pazopanib (versus 800 mg used in PALLETTE trial), has the same progression-free survival (PFS) when compared to the PALLETTE trial [12], thereby concluding that a patient may be started on a low dose of pazopanib, with increase in dose depending on the side effect profile of the patient.
AC C
EP
This case could represent heart failure secondary to mRCC. There have been reports of patients with renal cell carcinoma who presented with heart failure (13,14) which has been hypothesized to be due to catecholamine-mediated myocardial stunning. In our case, there are several hypotheses to explain the CHF at presentation. It could be due to decreased venous return secondary to sequestration of blood in the lungs around the lung nodules (cannon ball metastasis). Improvement in the EF alongwith resolution of the pulmonary edema consolidates the above hypothesis. Second hypothesis is that CHF could represent a paraneoplastic phenomenon as improvement was noted in the patient’s EF after starting systemic treatment, along with resolution of hypercalcemia, anemia and thrombocytosis. Another possible hypothesis of CHF is decreased cardiac return due to Inferior vena cava (IVC) thrombosis. Patient’s IVC thrombus resolved after starting therapy which would lead to improved cardiac return leading to improved EF. Hence, concluding from the above that CHF is not a contraindication to treatment with pazopanib, on the contrary, patient’s underlying CHF improved with pazopanib treatment along with a good clinical and radiological response. To our knowledge, this is the only case of renal cell carcinoma wherein the patient was started on pazopanib with an EF as low as 25 % with good tolerance and CHF reversal. Only a small percentage of patients on pazopanib develop heart failure or worsening of EF. Majority of these patients don’t have high grade CHF. Patients with low EF can be started on low dose pazopanib which can be up-titrated as tolerated by the patient. Simultaneously such patients should also be started on an appropriate regimen for CHF. Their EF and symptoms should be regularly monitored. Reduced EF shouldn’t preclude treatment with pazopanib. Prospective studies are required to establish the safety of this approach.
ACCEPTED MANUSCRIPT
CONCLUSION
References
SC
RI PT
CHF can be a paraneoplastic manifestation of renal cell carcinoma and can be reversed with surgical and systemic treatment. CHF at presentation should not preclude treatment with pazopanib which can be started at a lower dose and slowly up-titrated if patient remains asymptomatic.
1.Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2016. CA Cancer J Clin, 2016. 66(1): p. 7-30.
M AN U
2. https://seer.cancer.gov/statfacts/html/kidrp.html
3.Qi, W.X., et al., Congestive heart failure risk in cancer patients treated with vascular endothelial growth factor tyrosine kinase inhibitors: a systematic review and meta-analysis of 36 clinical trials. Br J Clin Pharmacol, 2014. 78(4): p. 748-62. 4.Motzer, R.J., et al., Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med, 2013. 369(8): p. 722-31.
TE D
5.van der Graaf, W.T., et al., Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet, 2012. 379(9829): p. 1879-86. 6.Boudou-Rouquette, P., et al., Clinical pharmacology, drug-drug interactions and safety of pazopanib: a review. Expert Opin Drug Metab Toxicol, 2016: p. 1-12.
EP
7.Incidence and risk of hypertension with pazopanib in patients with cancer: a meta- analysis. Qi WX, Lin F, Sun YJ, Tang LN, He AN, Yao Y, Shen Z Cancer Chemother Pharmacol. 2013 Feb; 71(2):431-9.
AC C
8.Prevention of disease progression, left ventricular hypertrophy and congestive heart failure in hypertension treatment trials. Moser M, Hebert PR. J Am Coll Cardiol. 1996 Apr; 27(5):1214-8. 9. Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload.Izumiya Y, Shiojima I, Sato K, Sawyer DB, Colucci WS, Walsh K Hypertension. 2006 May; 47(5):887-93. 10. Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress.Chintalgattu V, Ai D, Langley RR, Zhang J, Bankson JA, Shih TL, Reddy AK, Coombes KR, Daher IN, Pati S, Patel SS, Pocius JS, Taffet GE, Buja LM, Entman ML, Khakoo AY J Clin Invest. 2010 Feb; 120(2):472-84.
ACCEPTED MANUSCRIPT
11. Escudier, Bernard, et al. "Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES study." Journal of Clinical Oncology (2014): JCO-2013.
RI PT
12.Abe, K., et al., Balancing Prolonged Survival with QoL Using Low-dose Pazopanib Maintenance: A Comparison with the PALETTE Study. Anticancer Res, 2016. 36(6): p. 2893-7. Lee CM, Sim A, Kurugulasigamoney G, Ng LG. Heart failure as the first manifestation of renal cell carcinoma. Korean J Urol. 2015 Jan;56(1):82-5. doi: 10.4111/kju.2015.56.1.82. Epub 2015 Jan 6
14.
Vieira MS1, Antunes N, Carvalho H, Torres S. Renal cell carcinoma presenting as a stress cardiomyopathy.Eur Heart J Cardiovasc Imaging. 2013 Feb;14(2):192. doi: 10.1093/ehjci/jes168. Epub 2012 Aug 24.
AC C
EP
TE D
M AN U
SC
13.
S1558-7673(17)30048-4
DOI:
10.1016/j.clgc.2017.02.005
Reference:
CLGC 799
To appear in:
Clinical Genitourinary Cancer
Received Date: 28 January 2017 Accepted Date: 19 February 2017
Please cite this article as: Pandey M, Gandhi S, George S, Heart Failure : A Paraneoplastic Manifestation of Renal Cell Carcinoma – Reversed with Pazopanib, Clinical Genitourinary Cancer (2017), doi: 10.1016/j.clgc.2017.02.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
HEART FAILURE : A PARANEOPLASTIC MANIFESTATION OF RENAL CELL CARCINOMA – REVERSED WITH PAZOPANIB Manu Pandey1, Shipra Gandhi2, Saby George2 State University of New York at Buffalo Roswell Park Cancer Institute
RI PT
2
SC
1
M AN U
Clinical Practice point
Introduction
TE D
Pazopanib is now a first line therapy for Metastatic renal cell carcinoma(RCC). Several trials have excluded patients with heart failure, NYHA Grade III and IV. Heart failure is also a known complication of Pazopanib . We report a case of a patient with Ejection fraction(EF) of 20-25% at the time of diagnosis which we believe was due to paraneoplastic syndrome from RCC. Patient’s EF dramatically improved with treatment of his RCC. This case raises the question, whether low EF should preclude patient from treatement with pazopanib , or such patients can be started on a low dose of pazopanib , uptitrating the dose and carefully monitoring them for heart failure symptoms
AC C
EP
An estimated 62,700 new cases of kidney and renal pelvis cancers were projected to be diagnosed in 2016, leading to an estimated 14,240 deaths [1]. About 16% of these tumors are metastatic at the time of presentation [2]. Tyrosine kinase inhibitors (TKI), form the backbone of treatment for most cases of metastatic renal cell carcinoma. Cardiac toxicity such as congestive heart failure (CHF), hypertension, left ventricular systolic dysfunction, myocardial ischemia and infarction are known complications of TKI. A meta-analysis showed that the overall incidence of all grade and high grade (NYHA grade 3 and 4) CHF associated with vascular endothelial growth factor receptor –tyrosine kinase inhibitor (VEGFR-TKI) was 3.2% (95% CI 1.8%-5.8%) and 1.4% (95% CI 0.9%-2.3%), respectively. The sub-group analysis didn’t find significant differences in odds ratio (OR) of developing all grade or high-grade CHF among different VEGFR-TKI [3]. Majority of the studies with pazopanib have excluded patient with NYHA grade 3 and 4 heart failure [4, 5]. We report the case of a patient with metastatic renal cell carcinoma (mRCC), who was found to have heart failure with reduced ejection of 20-25 % at presentation. The patient was started on low dose pazopanib, which was slowly up-titrated to the recommended dose of 800 mg daily with good tolerance
ACCEPTED MANUSCRIPT
and surprisingly an improvement in the EF, a factor that has limited the use of pazopanib in this scenario. Case Report
TE D
M AN U
SC
RI PT
A 47-year-old man with no significant past medical history was worked up for cough and pneumonia-like symptoms and was found to have multiple lung nodules with parenchymal edema, pleural effusion, and a 12 cm left renal mass. Figure 1 represents the renal cell carcinoma with renal vein thrombosis.
EP
FIGURE 1 : Figure depicting renal cell carcinoma with renal vein thrombosis.
AC C
At presentation, labs showed hypercalcemia with total calcium of 10.8 mg/dl, thrombocytosis with platelet count of 806,000 /ml and anemia with hemoglobin of 10.9 gram/dl - all the above likely secondary to the inflammatory response to the disease burden or could be paraneoplastic manifestations of renal cell carcinoma. Figure 2 shows multiple cannon ball lung metastasis with parenchymal edema at the time of presentation.
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
FIGURE 2: Multiple cannon ball lung metastasis with parenchymal edema
AC C
EP
TE D
The patient underwent a cytoreductive / debulking surgery and pathology confirmed clear cell renal cell carcinoma Fuhrman grade 4, pT3aN0M1, invading into the renal vein and perinephric adipose tissue. Immediate improvement in total calcium to 9.4 was observed after the nephrectomy. Figure 3 shows a follow up CT Chest which showed resolution of the parenchymal edema surrounding the cannon ball lung metastasis within 2 days post nephrectomy.
ACCEPTED MANUSCRIPT
FIGURE 3: Resolution of the parenchymal edema surrounding the pulmonary nodules ona follow up CT chest post nephrectomy
RI PT
The patient was initially planned to be started on Interleukin-2 (IL-2), given his young age, good performance score and no comorbidities. However, an echocardiogram performed as initial pretreatment IL-2 workup showed an ejection fraction (EF) of 20-25% with global hypokinesis of the left ventricle. Right ventricular function was normal, and valves were morphologically intact. This was followed by a pharmacological stress test which revealed an EF of 27% with stress and 41% at rest. A multi-gated acquisition (MUGA) scan done later that month confirmed a EF of 35%, with inferior and inferoseptal hypokinesis. The patient was started on Carvedilol.
M AN U
SC
Given the reduced ejection fraction, the patient was not a candidate for the IL-2 therapy. Thus, the plan was to start him on a low dose of pazopanib 400 mg daily to be gradually titrated up to 600 mg daily as opposed to the recommended dose of 800 mg daily. Patient remained asymptomatic and was thus uptitrated up to the recommended dose of pazopanib, 800 mg daily, within three weeks of starting treatment. Improvement in anemia and thrombocytosis was noted after initiation of pazopanib. The patient had a repeat echocardiogram, around 10 weeks after starting pazopanib with the EF remaining stable at 20-25% with global hypokinesis. A repeat CT scans about three months after starting treatment showed a good response with 32% shrinkage in the tumor load. He was continued on pazopanib 800mg daily.
TE D
The patient remained asymptomatic during pazopanib treatment, with repeat scans seven months and ten months after starting pazopanib treatment continuing to show a partial response to the treatment. His cardiac function showed improvement with a repeat MUGA scan reporting an EF of 43% after seven months of starting pazopanib.
AC C
EP
Nearly a year after starting treatment with pazopanib, the patient started complaining of abdominal pain. Subsequent CT showed increasing size of hilar and mediastinal lymph nodes with increase in size of mass adjacent to the psoas muscle suggestive of the progressive disease. Anti-PD1 antibody nivolumab was started thereafter with good response. The patient continued on nivolumab for 14 months, at which time it was discontinued due to grade 4 pneumonitis and metastatic disease to the brain, treated with open resection and gamma knife radiation. Following treatments included sorafenib for about five months and then everolimus for three months. Patient eventually progressed and was rechallenged with pazopanib 800 mg daily. The patient tolerated pazopanib without any cardiovascular symptoms, although disease progression was noted within eight months of restarting pazopanib. Cabozantinib 40 mg daily was then started on which the patient continues. Patient’s last echocardiography was about 33 months post initial diagnosis which showed an EF of 55-60%.
Discussion According to NCCN guidelines, pazopanib, sunitinib are the two VEGFR-TKIs which have category one recommendations as first-line therapy for metastatic renal cell carcinoma. Pazopanib was found to be non-inferior to sunitinib in progression-free survival (PFS) (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22) and no statistical significance was
ACCEPTED MANUSCRIPT
found in the overall survival (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08) (4). A better safety profile and quality of life favor pazopanib over sunitinib [4,11]
RI PT
Pazopanib is a VEGFR –TKI which acts on multiple targets, including Vascular endothelial growth factor (VEGF) receptors 1, 2, and 3; PDGFRα and β, c-KIT [6]. The RR of hypertension with VEGF – TKIs has been shown to range between 1.71 and 8.06 [ 7]. Hypertension is a known risk factor for CHF and VEGF-TKIs increase the risk of CHF through this mechanism [8]. Another mechanism for cardiotoxicity is through the inhibition of the VEGF signal pathway. Mice studies have showed that inhibition of endogenous VEGF could lead to a reduction in the net capillary density, impaired cardiac hypertrophy and loss of contractile function after pressure overload in mice [9]. Also, inhibition of the PDGFR-beta in cardiomyocytes has also shown to induce heart failure in mice exposed to high vascular pressures. [10].
TE D
M AN U
SC
Congestive heart failure is a relatively uncommon side effect of pazopanib. A meta-analysis which included three trials with pazopanib (two Renal cell carcinoma and one Inflammatory breast cancer ), doses ranging between 400 mg to 800 mg daily showed the OR of 2.40 (95 %CI=1.01, 5.69) of all grade CHF [left ventricular ejection fraction (LVEF) decline] or dysfunction and CHF not otherwise specified as CHF-related adverse events, according to National Cancer Institute's common terminology criteria for adverse events (CTCAE)) although the OR for high-grade CHF (CHF events, >grade 2 , according to CTCAE grading ) was non-significant 4.52 (95% CI=0.41, 50.16) [3]. The incidence of CHF didn’t vary with tumor type [3].In PALETTE study, a soft tissue sarcoma trial; 16 out of 239 patients in the pazopanib group had a fall in the EF during or after treatment, out of which three patients were symptomatic [5]. A recent study has shown that a lower dose (most patients received 400 mg) of pazopanib (versus 800 mg used in PALLETTE trial), has the same progression-free survival (PFS) when compared to the PALLETTE trial [12], thereby concluding that a patient may be started on a low dose of pazopanib, with increase in dose depending on the side effect profile of the patient.
AC C
EP
This case could represent heart failure secondary to mRCC. There have been reports of patients with renal cell carcinoma who presented with heart failure (13,14) which has been hypothesized to be due to catecholamine-mediated myocardial stunning. In our case, there are several hypotheses to explain the CHF at presentation. It could be due to decreased venous return secondary to sequestration of blood in the lungs around the lung nodules (cannon ball metastasis). Improvement in the EF alongwith resolution of the pulmonary edema consolidates the above hypothesis. Second hypothesis is that CHF could represent a paraneoplastic phenomenon as improvement was noted in the patient’s EF after starting systemic treatment, along with resolution of hypercalcemia, anemia and thrombocytosis. Another possible hypothesis of CHF is decreased cardiac return due to Inferior vena cava (IVC) thrombosis. Patient’s IVC thrombus resolved after starting therapy which would lead to improved cardiac return leading to improved EF. Hence, concluding from the above that CHF is not a contraindication to treatment with pazopanib, on the contrary, patient’s underlying CHF improved with pazopanib treatment along with a good clinical and radiological response. To our knowledge, this is the only case of renal cell carcinoma wherein the patient was started on pazopanib with an EF as low as 25 % with good tolerance and CHF reversal. Only a small percentage of patients on pazopanib develop heart failure or worsening of EF. Majority of these patients don’t have high grade CHF. Patients with low EF can be started on low dose pazopanib which can be up-titrated as tolerated by the patient. Simultaneously such patients should also be started on an appropriate regimen for CHF. Their EF and symptoms should be regularly monitored. Reduced EF shouldn’t preclude treatment with pazopanib. Prospective studies are required to establish the safety of this approach.
ACCEPTED MANUSCRIPT
CONCLUSION
References
SC
RI PT
CHF can be a paraneoplastic manifestation of renal cell carcinoma and can be reversed with surgical and systemic treatment. CHF at presentation should not preclude treatment with pazopanib which can be started at a lower dose and slowly up-titrated if patient remains asymptomatic.
1.Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2016. CA Cancer J Clin, 2016. 66(1): p. 7-30.
M AN U
2. https://seer.cancer.gov/statfacts/html/kidrp.html
3.Qi, W.X., et al., Congestive heart failure risk in cancer patients treated with vascular endothelial growth factor tyrosine kinase inhibitors: a systematic review and meta-analysis of 36 clinical trials. Br J Clin Pharmacol, 2014. 78(4): p. 748-62. 4.Motzer, R.J., et al., Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med, 2013. 369(8): p. 722-31.
TE D
5.van der Graaf, W.T., et al., Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet, 2012. 379(9829): p. 1879-86. 6.Boudou-Rouquette, P., et al., Clinical pharmacology, drug-drug interactions and safety of pazopanib: a review. Expert Opin Drug Metab Toxicol, 2016: p. 1-12.
EP
7.Incidence and risk of hypertension with pazopanib in patients with cancer: a meta- analysis. Qi WX, Lin F, Sun YJ, Tang LN, He AN, Yao Y, Shen Z Cancer Chemother Pharmacol. 2013 Feb; 71(2):431-9.
AC C
8.Prevention of disease progression, left ventricular hypertrophy and congestive heart failure in hypertension treatment trials. Moser M, Hebert PR. J Am Coll Cardiol. 1996 Apr; 27(5):1214-8. 9. Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload.Izumiya Y, Shiojima I, Sato K, Sawyer DB, Colucci WS, Walsh K Hypertension. 2006 May; 47(5):887-93. 10. Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress.Chintalgattu V, Ai D, Langley RR, Zhang J, Bankson JA, Shih TL, Reddy AK, Coombes KR, Daher IN, Pati S, Patel SS, Pocius JS, Taffet GE, Buja LM, Entman ML, Khakoo AY J Clin Invest. 2010 Feb; 120(2):472-84.
ACCEPTED MANUSCRIPT
11. Escudier, Bernard, et al. "Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES study." Journal of Clinical Oncology (2014): JCO-2013.
RI PT
12.Abe, K., et al., Balancing Prolonged Survival with QoL Using Low-dose Pazopanib Maintenance: A Comparison with the PALETTE Study. Anticancer Res, 2016. 36(6): p. 2893-7. Lee CM, Sim A, Kurugulasigamoney G, Ng LG. Heart failure as the first manifestation of renal cell carcinoma. Korean J Urol. 2015 Jan;56(1):82-5. doi: 10.4111/kju.2015.56.1.82. Epub 2015 Jan 6
14.
Vieira MS1, Antunes N, Carvalho H, Torres S. Renal cell carcinoma presenting as a stress cardiomyopathy.Eur Heart J Cardiovasc Imaging. 2013 Feb;14(2):192. doi: 10.1093/ehjci/jes168. Epub 2012 Aug 24.
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EP
TE D
M AN U
SC
13.