Case Report
Selective Efficacy of Temsirolimus on Bone Metastases in Chromophobe Renal Cell Carcinoma Lorel Huelsmann,1,2 D. Nathan W. Kim,1,2 Raquibul Hannan,1 Lori M. Watumull,3 James Brugarolas2,4 Clinical Practice Points Evidence on the use of various targeted therapies on
The potential difference in the bioavailability or
treatment of chromophobe renal cell carcinoma (chRCC) is lacking. We report a case of a patient with metastatic chRCC who experienced site-specific disease control in the bone with temsirolimus, but significant progression in the liver.
mechanism of action at the 2 sites by mammalian target of rapamycin complex 1 (mTORC1) inhibitors is hypothesized to cause this differential response. This hypothesis-generating case study supports further research on the mechanism of action of mTORC1 inhibitors to potentially preferentially affect bone metastases.
Clinical Genitourinary Cancer, Vol. 13, No. 4, e321-3 ª 2015 Elsevier Inc. All rights reserved. Keywords: Bone remodeling, Everolimus, Mammalian target of rapamycin (mTOR), Osteoclasts, Tuberous Sclerosis Complex 1 (TSC1)
Introduction Chromophobe (ch) renal cell carcinoma (RCC) patients have a reported 5-year survival rate of 87.9%, but median survival for metastatic disease is reported to be 29 months.1 chRCC is characterized by higher overall survival in a nonmetastatic setting, but with worse prognosis when metastatic compared with clear-cell RCC.2 Although evidence is limited, chRCCs are often treated with the vascular endothelial growth factor receptor tyrosine kinase inhibitors, sunitinib and sorafenib, and the mammalian target of rapamycin complex 1 (mTORC1) inhibitors, everolimus and temsirolimus.1 We report a case of a patient with metastatic Case review permitted by the internal review board-approved study “STU-032012-017: retrospective chart review of renal cell carcinoma patients treated from 1/1/2000-10/1/ 2013”. Lorel Huelsmann and D. Nathan W. Kim contributed equally to this work. 1
Department of Radiation Oncology Kidney Cancer Program, Simmons Comprehensive Cancer Center Department of Radiology 4 Internal Medicine, Medical Oncology Division/Developmental Biology The University of Texas Southwestern Medical Center, Dallas, TX 2 3
Submitted: Nov 22, 2014; Accepted: Dec 15, 2014; Epub: Dec 20, 2014 Address for correspondence: James Brugarolas, MD, PhD, Department of Internal Medicine, Oncology Division, Department of Developmental Biology, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9133 Fax: 214-648-1960; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2014.12.007
chRCC that seemingly experienced site-specific disease control in bone with temsirolimus, but progression elsewhere.
Case Report A 73-year-old Caucasian man without significant medical history presented with an episode of hematuria in March of 2009. A computed tomography (CT) scan of the abdomen and pelvis revealed a mass arising from the upper pole of the left kidney. The patient underwent a left-sided radical nephrectomy and ipsilateral adrenalectomy in April 2009. Pathology demonstrated a 6.6-cm high grade chRCC extending into the renal sinus and renal vein (pT3a), with no lymph node involvement (pN0; stage III). The patient was followed with periodic imaging studies and 19 months later was found to have extensive metastases to bone (iliac crest, thoracic and lumbar spine, and ribs) and the liver (Figure 1A). An ultrasound-guided biopsy of a rib lesion confirmed metastatic carcinoma, morphologically consistent with the previously diagnosed chRCC. The patient was started on temsirolimus (25 mg weekly intravenously) and zoledronate (once per month). Five months after the beginning of systemic therapy, imaging studies revealed responsiveness of bone metastases but progression in hepatic lesions (Figure 1B). Because of liver progression, temsirolimus was stopped and sunitinib (50 mg daily) was started at a conventional schedule of 4 weeks of treatment followed by a 2-week break. The patient continued with monthly zoledronate.
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Temsirolimus Effect on Chromophobe RCC Figure 1 (A) Representative Axial View of Computed Tomography (CT) Scan of a Rib and Liver Metastases That Developed 19 Months After Diagnosis of Localized Chromophobe Renal Cell Carcinoma. (B) Five Months After Initiation of Systemic Therapy (Temsirolimus and Zoledronate) CT Studies Demonstrated a Response of Rib Metastases But Progression of the Hepatic Lesion(s), Shown in These Representative Images. (C) Representative Axial CT Images Demonstrating Stable Rib Metastases, and Progressing Liver Metastases After the Patient Resumed Temsirolimus and Started Denosumab. (D) Representative Axial CT Images Demonstrate Extensive Liver Progression 19 Months After First Diagnosis of Metastatic Recurrence
He tolerated the sunitinib treatment well with some oral discomfort, dysgeusia, and occasional vomiting. Immediately after completion of the first cycle of sunitinib, the patient developed severe pain of acute onset in the right proximal lower extremity requiring hospitalization. Magnetic resonance imaging (MRI) of the right lower extremity and pelvis showed a nondisplaced pathologic fracture at the base of the lesser trochanter of the femur. In addition, there was progression of bone metastases in the pelvis, and lower lumbar spine. Sunitinib was stopped and the patient underwent radiation therapy to the right lesser trochanter lesion. Because of the morbidity associated with bone fractures and previous disease control in bone with temsirolimus, the patient elected, despite progression of liver metastases, to resume temsirolimus treatment. At that time, he was also switched from zoledronate to denosumab. Two months after reinitiation of temsirolimus, the patient had overall stable bone disease but significant liver progression (Figure 1C). As determined clinically and using CT scans there was no appreciable progression in his bone metastases for another 6 months and the patient did not have another pathologic fracture. However, at 6 months he developed pain in his lumbar spine and
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was treated with radiation to the L2-L4 metastases, which successfully resolved his pain. Two months later, he presented with headaches and an MRI of the brain showed 2 subcentimeter lesions in the right cerebellum concerning for metastases. Given the perception that temsirolimus might be a contributor to reduced progression of bone metastases, the patient decided to continue treatment. During the next 3 months, lesions in the liver continued to progress (Figure 1D) with worsening circulating liver enzyme levels. At this time, the patient was admitted to hospice and passed away shortly thereafter. Overall, the patient, who presented with poor prognostic factors including bone metastases and anemia, survived 20 months after diagnosis of metastatic chRCC.
Discussion Lack of large scale clinical trials for patients with noneclear-cell histology has led to little evidence on the use of various targeted therapies on treatment of these RCC subtypes.1 A multicenter study of treatment outcomes in 53 patients, 12 having metastatic chRCC resulted in only 3 of those 12 patients (25%) having a partial response to tyrosine kinase inhibitors (2 patients receiving sorafenib and 1 patient receiving sunitinib).3 This emphasizes the
Lorel Huelsmann et al need for targeting other signaling pathways in treatment of chRCC. Over the past several years, few case reports have been published on patients with chRCC treated with mTORC1 inhibitors. Most recently, Venugopal et al reported a case of a 36-year-old woman with metastatic chRCC who initially received 2 cycles of sunitinib with progression and subsequently had a durable response for 20 months with temsirolimus.4 Another case report describes a 45-year-old woman with metastatic chRCC who received 5 cycles of sunitinib with progressive disease and then had a partial response lasting several years with temsirolimus.5 A similar case report by Paule and Brion describes a 57-year-old man with metastatic chRCC who had 26 months of stable disease with temsirolimus after progression with interferon alfa and sorafenib.6 Overall, these reports suggest that temsirolimus might have activity at least in a subset of metastatic chRCC. Notably, mutations in Tuberous Sclerosis Complex 1 (TSC1) in RCC have been postulated to identify patients particularly susceptible to mTORC1 inhibitors7,8 and we have recently reported the presence of such mutations in a small subset of chRCC.9 Despite these findings, the recent phase II Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN) trial suggested limited activity of everolimus in noneclear-cell RCC, although only 11 patients had chRCC.10 The results of the ongoing randomized phase II trial of everolimus versus sunitinib in patients with metastatic non-clear cell renal cell carcinoma (ASPEN) might provide further insight on the use of mTORC1 inhibitors in the treatment of chRCC.11 The striking difference in liver versus bone response with temsirolimus treatment in our patient suggests a potential difference in the bioavailability or mechanism of action at the 2 sites. Liver dysfunction could affect the metabolism, dosing, and efficacy of targeted agents.12 It is also suggested that tumor cells that enter bone interfere with the homeostatic balance of bone formation and resorption and the release of cytokines from tumor cells result in activation of osteoclasts.13 mTORC1 signaling has a role in osteoclastogenesis and inhibition of mTORC1 can affect osteoclast survival.13 For example, it has been shown that combining everolimus in treatment of breast cancer leads to decreased bone progression and inhibits bone turnover by inhibiting osteoclastogenesis.13 This could be relevant in
explaining why using temsirolimus was efficacious in stabilizing our patient’s bone metastases.
Conclusion We present a patient with metastatic chRCC who had stable bone, but not liver metastases during temsirolimus treatment. This hypothesis-generating study suggests a need for consideration of further research on the mechanism of action of mTORC1 inhibitors to potentially preferentially affect bone metastases.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Albiges L, Molinie V, Escudier B. Non-clear cell renal cell carcinoma: does the mammalian target of rapamycin represent a rational therapeutic target? Oncologist 2012; 17:1051-62. 2. Klatte T, Han KR, Said JW, et al. Pathobiology and prognosis of chromophobe renal cell carcinoma. Urol Oncol 2008; 26:604-9. 3. Choueiri TK, Plantade A, Elson P, et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol 2008; 26: 127-31. 4. Venugopal B, Ansari J, Aitchison M, Tho LM, Campbell R, Jones RJ. Efficacy of temsirolimus in metastatic chromophobe renal cell carcinoma. BMC Urol 2013; 13:26. 5. Shuch B, Vourganti S, Friend JC, Zehngebot LM, Linehan WM, Srinivasan R. Targeting the mTOR pathway in chromophobe kidney cancer. J Cancer 2012; 3: 152-7. 6. Paule B, Brion N. Temsirolimus in metastatic chromophobe renal cell carcinoma after interferon and sorafenib therapy. Anticancer Res 2011; 31:331-4. 7. Kucejova B, Pena-Llopis S, Yamasaki T, et al. Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma. Mol Cancer Res 2011; 9: 1255-65. 8. Brugarolas J. Research Translation and Personalized Medicine. In: Figlin RA, Rathmell WK, Rini BI, eds. Renal Cell Carcinoma: Translational Biology, Personalized Medicine, and Novel Therapeutic Targets. New York: Springer; 2012. 9. Durinck S, Stawiski EW, Pavia-Jimenez A, et al. Spectrum of diverse genomic alterations define non-clear cell renal carcinoma subtypes. Nat Genet 2015; 47: 13-21. 10. Tannir NM, Jonasch E, Altinmakas E, et al. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (The ESPN Trial): a multicenter randomized phase 2 trial. Available at: http://meetinglibrary. asco.org/content/134866-144. Accessed: May 23, 2014. 11. Clinicaltrials.gov [Web site]. Phase II Study of Afinitor vs. Sutent in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma (ASPEN). Available at: www. clinicaltrials.gov/ct2/show/NCT01108445. Accessed: May 23, 2014. 12. McKay RR, Kroeger N, Xie W, et al. Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy. Eur Urol 2014; 65: 577-84. 13. Bertoldo F, Silvestris F, Ibrahim T, et al. Targeting bone metastatic cancer: role of the mTOR pathway. Biochim Biophys Acta 2014; 1845:248-54.
Clinical Genitourinary Cancer August 2015
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Selective Efficacy of Temsirolimus on Bone Metastases in Chromophobe Renal Cell Carcinoma Lorel Huelsmann,1,2 D. Nathan W. Kim,1,2 Raquibul Hannan,1 Lori M. Watumull,3 James Brugarolas2,4 Clinical Practice Points Evidence on the use of various targeted therapies on
The potential difference in the bioavailability or
treatment of chromophobe renal cell carcinoma (chRCC) is lacking. We report a case of a patient with metastatic chRCC who experienced site-specific disease control in the bone with temsirolimus, but significant progression in the liver.
mechanism of action at the 2 sites by mammalian target of rapamycin complex 1 (mTORC1) inhibitors is hypothesized to cause this differential response. This hypothesis-generating case study supports further research on the mechanism of action of mTORC1 inhibitors to potentially preferentially affect bone metastases.
Clinical Genitourinary Cancer, Vol. 13, No. 4, e321-3 ª 2015 Elsevier Inc. All rights reserved. Keywords: Bone remodeling, Everolimus, Mammalian target of rapamycin (mTOR), Osteoclasts, Tuberous Sclerosis Complex 1 (TSC1)
Introduction Chromophobe (ch) renal cell carcinoma (RCC) patients have a reported 5-year survival rate of 87.9%, but median survival for metastatic disease is reported to be 29 months.1 chRCC is characterized by higher overall survival in a nonmetastatic setting, but with worse prognosis when metastatic compared with clear-cell RCC.2 Although evidence is limited, chRCCs are often treated with the vascular endothelial growth factor receptor tyrosine kinase inhibitors, sunitinib and sorafenib, and the mammalian target of rapamycin complex 1 (mTORC1) inhibitors, everolimus and temsirolimus.1 We report a case of a patient with metastatic Case review permitted by the internal review board-approved study “STU-032012-017: retrospective chart review of renal cell carcinoma patients treated from 1/1/2000-10/1/ 2013”. Lorel Huelsmann and D. Nathan W. Kim contributed equally to this work. 1
Department of Radiation Oncology Kidney Cancer Program, Simmons Comprehensive Cancer Center Department of Radiology 4 Internal Medicine, Medical Oncology Division/Developmental Biology The University of Texas Southwestern Medical Center, Dallas, TX 2 3
Submitted: Nov 22, 2014; Accepted: Dec 15, 2014; Epub: Dec 20, 2014 Address for correspondence: James Brugarolas, MD, PhD, Department of Internal Medicine, Oncology Division, Department of Developmental Biology, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9133 Fax: 214-648-1960; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2014.12.007
chRCC that seemingly experienced site-specific disease control in bone with temsirolimus, but progression elsewhere.
Case Report A 73-year-old Caucasian man without significant medical history presented with an episode of hematuria in March of 2009. A computed tomography (CT) scan of the abdomen and pelvis revealed a mass arising from the upper pole of the left kidney. The patient underwent a left-sided radical nephrectomy and ipsilateral adrenalectomy in April 2009. Pathology demonstrated a 6.6-cm high grade chRCC extending into the renal sinus and renal vein (pT3a), with no lymph node involvement (pN0; stage III). The patient was followed with periodic imaging studies and 19 months later was found to have extensive metastases to bone (iliac crest, thoracic and lumbar spine, and ribs) and the liver (Figure 1A). An ultrasound-guided biopsy of a rib lesion confirmed metastatic carcinoma, morphologically consistent with the previously diagnosed chRCC. The patient was started on temsirolimus (25 mg weekly intravenously) and zoledronate (once per month). Five months after the beginning of systemic therapy, imaging studies revealed responsiveness of bone metastases but progression in hepatic lesions (Figure 1B). Because of liver progression, temsirolimus was stopped and sunitinib (50 mg daily) was started at a conventional schedule of 4 weeks of treatment followed by a 2-week break. The patient continued with monthly zoledronate.
Clinical Genitourinary Cancer August 2015
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Temsirolimus Effect on Chromophobe RCC Figure 1 (A) Representative Axial View of Computed Tomography (CT) Scan of a Rib and Liver Metastases That Developed 19 Months After Diagnosis of Localized Chromophobe Renal Cell Carcinoma. (B) Five Months After Initiation of Systemic Therapy (Temsirolimus and Zoledronate) CT Studies Demonstrated a Response of Rib Metastases But Progression of the Hepatic Lesion(s), Shown in These Representative Images. (C) Representative Axial CT Images Demonstrating Stable Rib Metastases, and Progressing Liver Metastases After the Patient Resumed Temsirolimus and Started Denosumab. (D) Representative Axial CT Images Demonstrate Extensive Liver Progression 19 Months After First Diagnosis of Metastatic Recurrence
He tolerated the sunitinib treatment well with some oral discomfort, dysgeusia, and occasional vomiting. Immediately after completion of the first cycle of sunitinib, the patient developed severe pain of acute onset in the right proximal lower extremity requiring hospitalization. Magnetic resonance imaging (MRI) of the right lower extremity and pelvis showed a nondisplaced pathologic fracture at the base of the lesser trochanter of the femur. In addition, there was progression of bone metastases in the pelvis, and lower lumbar spine. Sunitinib was stopped and the patient underwent radiation therapy to the right lesser trochanter lesion. Because of the morbidity associated with bone fractures and previous disease control in bone with temsirolimus, the patient elected, despite progression of liver metastases, to resume temsirolimus treatment. At that time, he was also switched from zoledronate to denosumab. Two months after reinitiation of temsirolimus, the patient had overall stable bone disease but significant liver progression (Figure 1C). As determined clinically and using CT scans there was no appreciable progression in his bone metastases for another 6 months and the patient did not have another pathologic fracture. However, at 6 months he developed pain in his lumbar spine and
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was treated with radiation to the L2-L4 metastases, which successfully resolved his pain. Two months later, he presented with headaches and an MRI of the brain showed 2 subcentimeter lesions in the right cerebellum concerning for metastases. Given the perception that temsirolimus might be a contributor to reduced progression of bone metastases, the patient decided to continue treatment. During the next 3 months, lesions in the liver continued to progress (Figure 1D) with worsening circulating liver enzyme levels. At this time, the patient was admitted to hospice and passed away shortly thereafter. Overall, the patient, who presented with poor prognostic factors including bone metastases and anemia, survived 20 months after diagnosis of metastatic chRCC.
Discussion Lack of large scale clinical trials for patients with noneclear-cell histology has led to little evidence on the use of various targeted therapies on treatment of these RCC subtypes.1 A multicenter study of treatment outcomes in 53 patients, 12 having metastatic chRCC resulted in only 3 of those 12 patients (25%) having a partial response to tyrosine kinase inhibitors (2 patients receiving sorafenib and 1 patient receiving sunitinib).3 This emphasizes the
Lorel Huelsmann et al need for targeting other signaling pathways in treatment of chRCC. Over the past several years, few case reports have been published on patients with chRCC treated with mTORC1 inhibitors. Most recently, Venugopal et al reported a case of a 36-year-old woman with metastatic chRCC who initially received 2 cycles of sunitinib with progression and subsequently had a durable response for 20 months with temsirolimus.4 Another case report describes a 45-year-old woman with metastatic chRCC who received 5 cycles of sunitinib with progressive disease and then had a partial response lasting several years with temsirolimus.5 A similar case report by Paule and Brion describes a 57-year-old man with metastatic chRCC who had 26 months of stable disease with temsirolimus after progression with interferon alfa and sorafenib.6 Overall, these reports suggest that temsirolimus might have activity at least in a subset of metastatic chRCC. Notably, mutations in Tuberous Sclerosis Complex 1 (TSC1) in RCC have been postulated to identify patients particularly susceptible to mTORC1 inhibitors7,8 and we have recently reported the presence of such mutations in a small subset of chRCC.9 Despite these findings, the recent phase II Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN) trial suggested limited activity of everolimus in noneclear-cell RCC, although only 11 patients had chRCC.10 The results of the ongoing randomized phase II trial of everolimus versus sunitinib in patients with metastatic non-clear cell renal cell carcinoma (ASPEN) might provide further insight on the use of mTORC1 inhibitors in the treatment of chRCC.11 The striking difference in liver versus bone response with temsirolimus treatment in our patient suggests a potential difference in the bioavailability or mechanism of action at the 2 sites. Liver dysfunction could affect the metabolism, dosing, and efficacy of targeted agents.12 It is also suggested that tumor cells that enter bone interfere with the homeostatic balance of bone formation and resorption and the release of cytokines from tumor cells result in activation of osteoclasts.13 mTORC1 signaling has a role in osteoclastogenesis and inhibition of mTORC1 can affect osteoclast survival.13 For example, it has been shown that combining everolimus in treatment of breast cancer leads to decreased bone progression and inhibits bone turnover by inhibiting osteoclastogenesis.13 This could be relevant in
explaining why using temsirolimus was efficacious in stabilizing our patient’s bone metastases.
Conclusion We present a patient with metastatic chRCC who had stable bone, but not liver metastases during temsirolimus treatment. This hypothesis-generating study suggests a need for consideration of further research on the mechanism of action of mTORC1 inhibitors to potentially preferentially affect bone metastases.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Albiges L, Molinie V, Escudier B. Non-clear cell renal cell carcinoma: does the mammalian target of rapamycin represent a rational therapeutic target? Oncologist 2012; 17:1051-62. 2. Klatte T, Han KR, Said JW, et al. Pathobiology and prognosis of chromophobe renal cell carcinoma. Urol Oncol 2008; 26:604-9. 3. Choueiri TK, Plantade A, Elson P, et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol 2008; 26: 127-31. 4. Venugopal B, Ansari J, Aitchison M, Tho LM, Campbell R, Jones RJ. Efficacy of temsirolimus in metastatic chromophobe renal cell carcinoma. BMC Urol 2013; 13:26. 5. Shuch B, Vourganti S, Friend JC, Zehngebot LM, Linehan WM, Srinivasan R. Targeting the mTOR pathway in chromophobe kidney cancer. J Cancer 2012; 3: 152-7. 6. Paule B, Brion N. Temsirolimus in metastatic chromophobe renal cell carcinoma after interferon and sorafenib therapy. Anticancer Res 2011; 31:331-4. 7. Kucejova B, Pena-Llopis S, Yamasaki T, et al. Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma. Mol Cancer Res 2011; 9: 1255-65. 8. Brugarolas J. Research Translation and Personalized Medicine. In: Figlin RA, Rathmell WK, Rini BI, eds. Renal Cell Carcinoma: Translational Biology, Personalized Medicine, and Novel Therapeutic Targets. New York: Springer; 2012. 9. Durinck S, Stawiski EW, Pavia-Jimenez A, et al. Spectrum of diverse genomic alterations define non-clear cell renal carcinoma subtypes. Nat Genet 2015; 47: 13-21. 10. Tannir NM, Jonasch E, Altinmakas E, et al. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (The ESPN Trial): a multicenter randomized phase 2 trial. Available at: http://meetinglibrary. asco.org/content/134866-144. Accessed: May 23, 2014. 11. Clinicaltrials.gov [Web site]. Phase II Study of Afinitor vs. Sutent in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma (ASPEN). Available at: www. clinicaltrials.gov/ct2/show/NCT01108445. Accessed: May 23, 2014. 12. McKay RR, Kroeger N, Xie W, et al. Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy. Eur Urol 2014; 65: 577-84. 13. Bertoldo F, Silvestris F, Ibrahim T, et al. Targeting bone metastatic cancer: role of the mTOR pathway. Biochim Biophys Acta 2014; 1845:248-54.
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