- Email: [email protected]
Quantifying hypertension in patients with cancer treated with sorafenib
Reflection and Reaction
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Pfreundschuh M, Trumper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004; 104: 634–41. Sonneveld P, Putten Wv, Biesma D, et al. Phase III Trial of 2-Weekly CHOP with rituximab for aggressive B-cell non-Hodgkin’s lymphoma in elderly patients. Blood 2006; 108: 66a (abstr 210). Tholstrup D, de Nully Brown P, Jurlander J, Hansen M. Feasibility, efficacy and safety of CHOP-14 in elderly patients with very high-risk diffuse large B-cell lymphoma. Eur J Haematol 2007; 79: 100–06. Brusamolino E, Rusconi C, Montalbetti L, et al. Dose-dense R-CHOP-14 supported by pegfilgrastim in patients with diffuse large B-cell lymphoma: a phase II study of feasibility and toxicity. Haematologica 2006; 91: 496–502.
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US National Institutes of Health. R-CHOP-14 versus R-CHOP-21 and darbepoetin alpha in patients aged 60–80 years with diffuse large B-cell lymphoma. A GELA study. http://clinicaltrials.gov/ ct2/show/NCT00144755?term=lnh+03-6B&rank=1 (accessed Jan 3, 2008). UK Clinical Research Network. A phase III multicentre randomised clinical trial comparing rituximab with CHOP given every 14 days and rituximab with CHOP given every 21 days for the treatment of patients with newly diagnosed diffuse large B cell non-Hodgkin’s lymphoma. UKCRN ID 1437. http://pfsearch.ukcrn.org.uk/StudyDetail.aspx?TopicID=1&StudyID=1437 (accessed June 18, 2007).
Quantifying hypertension in patients with cancer treated with sorafenib See Articles page 117
Treatment targeted against vascular endothelial growth factor (VEGF) is a robust antitumour strategy, most notably in renal-cell carcinoma, and also increasingly across a wide range of solid tumours. In view of the fact that VEGF is a protein that is important in normal physiology in addition to cancer pathophysiology, cardiovascular effects, including hypertension, have emerged as an important toxic effect of drugs that inhibit VEGF. In this issue of The Lancet Oncology, the article by Wu and colleagues1 on the incidence of hypertension with sorafenib treatment is a timely and important contribution to the published work. The researchers did a systematic review and meta-analysis of clinical trials that used standard-dose sorafenib in patients with cancer, to look at the incidence and relative risk of hypertension. They appropriately argue that an awareness of
Sorafenib is associated with an increased risk of hypertension
86
hypertension is important so that early management can be instituted to prevent further cardiovascular toxic effects. An incidence of about 23% for all-grade hypertension and 6% for high-grade hypertension was noted with sorafenib, with a six-times greater relative risk for the development of all-grade hypertension compared with controls. This analysis, however, has many limitations that must be taken into account when interpreting these data. Foremost, the major renal-cell carcinoma trial included in this analysis, which contributed over 70% of the total patients, was the expanded-access programme. This trial did an assessment of toxic effects according to the local standard of care for each country and institution where patients were treated, and, therefore, variability in the recording of toxicity data limits the quality of the data collected. Also, for this and many of the trials included in the analysis, different degrees of baseline hypertension existed and are not accounted for in the analysis. Variability is relevant in the measurement of hypertension due to the mechanics of cuff size, manual versus automated measurement, the person taking the measure (ie, patient versus health-care provider), and the setting in which it is done. Furthermore, as the researchers appropriately note in the discussion, the Common Terminology Criteria definition of grade 3 hypertension can be variably interpreted and can be largely overlapping with the definition of grade 2 hypertension. Grade 3 hypertension is defined as needing more than one medication or more intense treatment than previously used. Therefore, http://oncology.thelancet.com Vol 9 February 2008
Reflection and Reaction
hypertension that needs a minor increase in the dose of a single medication could be considered as grade 3, as could hypertension that needs maximum doses of many antihypertensives. Clearly, these two scenarios represent different degrees of hypertension, but are both captured as grade 3 in the current definition. When looking at the forest plots of individual trials, a higher incidence of hypertension was noted in the trial by Ratain and colleagues, which represents the earliest experience with sorafenib.2 In early clinical trials of sorafenib, as well as of other contemporary VEGFtargeted drugs, such as sunitinib and bevacizumab, hypertension might have been under-recognised. Therefore, the recording of toxic effects in early trials was probably not uniform with the recording of these effects in more recent trials and, certainly, early and aggressive management of hypertension was not undertaken as it has been more recently. Nonetheless, the data in the trial by Wu and colleagues broadly represent a finding that will be clinically appreciated; mainly, that VEGF-targeting drugs, including sorafenib, cause hypertension in a substantial proportion of patients with cancer. Recognition and management of this toxic effect is important to prevent further complications. However, an explanation for the causative mechanism(s) behind this effect is still absent. The researchers cite the only existing publication on the mechanism of sorafenib-associated hypertension, from a study that was limited to 20 patients and did not find significant changes in humoral factors or another obvious mechanistic explanation.3 Nitric oxide has also been implicated, although there is very little published data offering an insight into its effect. The mechanisms of hypertension with sorafenib and other VEGF-targeted drugs need to be prospectively investigated so that the most appropriate class of antihypertensives can be instituted. At present, management of hypertension in patients assigned these drugs is largely empiric. The analysis by Wu and colleagues was limited to clinical trials in which sorafenib was given at the standard dose, approved by the US Food and Drug Administration, of 400 mg twice a day. More recent data suggest that higher doses of this drug in renalcell carcinoma might enhance the clinical effect of sorafenib.4 This enhanced clinical effect might be due, in part, to a greater inhibitory effect on the http://oncology.thelancet.com Vol 9 February 2008
VEGF receptor, but might also result in increased hypertension and other toxic effects. Additionally, other drugs that more potently target the VEGF receptor, such as axitinib, are associated with an increased incidence of hypertension.5 Therefore, the use of higher doses of sorafenib or the use of more potent VEGF-targeting drugs might result in an even higher incidence and severity of hypertension, which would be potentially balanced against greater efficacy in certain tumour types. Additionally, hypertension might be a useful and easily measured biomarker of response to sorafenib and other VEGF-targeted drugs. There is, as yet, little, if any, published data on this possibility. In an era of investigative biomarkers, such as dynamic contrast-enhanced MRI and circulating endothelial cells, which are not as easily measured, a simple biomarker such as hypertension, and its relation to therapeutic outcome with these drugs, deserves further investigation. Wu and colleagues have provided a valuable contribution in describing the incidence and relative risk of hypertension with sorafenib and other VEGFtargeted drugs. Although limited by the quality of individual trials, including the large proportion of patients treated on an expanded access trial, the conclusions are, nonetheless, robust. This toxic effect should be carefully monitored by patients and physicians on institution of VEGF-targeted treatment, and early and aggressive management of hypertension should be undertaken to avoid further toxic complications. Brian I Rini Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA [email protected] The author has received research funding from Bayer (West Haven, CT, USA) and Onyx (Richmond, CA, USA) who manufacture sorafenib. 1
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Wu S, Chen JJ, Kudelka A, Lu J, Zhu X. Incidence and risk if hypertension with sorafenib in patients with cancer: a systemic review and metaanalysis. Lancet Oncol 9: 117–23. Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006; 24: 2505–12. Veronese ML, Mosenkis A, Flaherty KT, et al. Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol 2006; 24: 1363–69. Amato RJ, P Harris, Dalton M, et al, A phase II trial of intra-patient doseescalated sorafenib in patients (pts) with metastatic renal cell cancer (MRCC). Proc Am Soc Clin Oncol 2007; 25: (abstr 5026). Rixe O, Bukowski RM, Michaelson MD, et al. Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol 2007; 8: 975–84.
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Pfreundschuh M, Trumper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004; 104: 634–41. Sonneveld P, Putten Wv, Biesma D, et al. Phase III Trial of 2-Weekly CHOP with rituximab for aggressive B-cell non-Hodgkin’s lymphoma in elderly patients. Blood 2006; 108: 66a (abstr 210). Tholstrup D, de Nully Brown P, Jurlander J, Hansen M. Feasibility, efficacy and safety of CHOP-14 in elderly patients with very high-risk diffuse large B-cell lymphoma. Eur J Haematol 2007; 79: 100–06. Brusamolino E, Rusconi C, Montalbetti L, et al. Dose-dense R-CHOP-14 supported by pegfilgrastim in patients with diffuse large B-cell lymphoma: a phase II study of feasibility and toxicity. Haematologica 2006; 91: 496–502.
9
10
US National Institutes of Health. R-CHOP-14 versus R-CHOP-21 and darbepoetin alpha in patients aged 60–80 years with diffuse large B-cell lymphoma. A GELA study. http://clinicaltrials.gov/ ct2/show/NCT00144755?term=lnh+03-6B&rank=1 (accessed Jan 3, 2008). UK Clinical Research Network. A phase III multicentre randomised clinical trial comparing rituximab with CHOP given every 14 days and rituximab with CHOP given every 21 days for the treatment of patients with newly diagnosed diffuse large B cell non-Hodgkin’s lymphoma. UKCRN ID 1437. http://pfsearch.ukcrn.org.uk/StudyDetail.aspx?TopicID=1&StudyID=1437 (accessed June 18, 2007).
Quantifying hypertension in patients with cancer treated with sorafenib See Articles page 117
Treatment targeted against vascular endothelial growth factor (VEGF) is a robust antitumour strategy, most notably in renal-cell carcinoma, and also increasingly across a wide range of solid tumours. In view of the fact that VEGF is a protein that is important in normal physiology in addition to cancer pathophysiology, cardiovascular effects, including hypertension, have emerged as an important toxic effect of drugs that inhibit VEGF. In this issue of The Lancet Oncology, the article by Wu and colleagues1 on the incidence of hypertension with sorafenib treatment is a timely and important contribution to the published work. The researchers did a systematic review and meta-analysis of clinical trials that used standard-dose sorafenib in patients with cancer, to look at the incidence and relative risk of hypertension. They appropriately argue that an awareness of
Sorafenib is associated with an increased risk of hypertension
86
hypertension is important so that early management can be instituted to prevent further cardiovascular toxic effects. An incidence of about 23% for all-grade hypertension and 6% for high-grade hypertension was noted with sorafenib, with a six-times greater relative risk for the development of all-grade hypertension compared with controls. This analysis, however, has many limitations that must be taken into account when interpreting these data. Foremost, the major renal-cell carcinoma trial included in this analysis, which contributed over 70% of the total patients, was the expanded-access programme. This trial did an assessment of toxic effects according to the local standard of care for each country and institution where patients were treated, and, therefore, variability in the recording of toxicity data limits the quality of the data collected. Also, for this and many of the trials included in the analysis, different degrees of baseline hypertension existed and are not accounted for in the analysis. Variability is relevant in the measurement of hypertension due to the mechanics of cuff size, manual versus automated measurement, the person taking the measure (ie, patient versus health-care provider), and the setting in which it is done. Furthermore, as the researchers appropriately note in the discussion, the Common Terminology Criteria definition of grade 3 hypertension can be variably interpreted and can be largely overlapping with the definition of grade 2 hypertension. Grade 3 hypertension is defined as needing more than one medication or more intense treatment than previously used. Therefore, http://oncology.thelancet.com Vol 9 February 2008
Reflection and Reaction
hypertension that needs a minor increase in the dose of a single medication could be considered as grade 3, as could hypertension that needs maximum doses of many antihypertensives. Clearly, these two scenarios represent different degrees of hypertension, but are both captured as grade 3 in the current definition. When looking at the forest plots of individual trials, a higher incidence of hypertension was noted in the trial by Ratain and colleagues, which represents the earliest experience with sorafenib.2 In early clinical trials of sorafenib, as well as of other contemporary VEGFtargeted drugs, such as sunitinib and bevacizumab, hypertension might have been under-recognised. Therefore, the recording of toxic effects in early trials was probably not uniform with the recording of these effects in more recent trials and, certainly, early and aggressive management of hypertension was not undertaken as it has been more recently. Nonetheless, the data in the trial by Wu and colleagues broadly represent a finding that will be clinically appreciated; mainly, that VEGF-targeting drugs, including sorafenib, cause hypertension in a substantial proportion of patients with cancer. Recognition and management of this toxic effect is important to prevent further complications. However, an explanation for the causative mechanism(s) behind this effect is still absent. The researchers cite the only existing publication on the mechanism of sorafenib-associated hypertension, from a study that was limited to 20 patients and did not find significant changes in humoral factors or another obvious mechanistic explanation.3 Nitric oxide has also been implicated, although there is very little published data offering an insight into its effect. The mechanisms of hypertension with sorafenib and other VEGF-targeted drugs need to be prospectively investigated so that the most appropriate class of antihypertensives can be instituted. At present, management of hypertension in patients assigned these drugs is largely empiric. The analysis by Wu and colleagues was limited to clinical trials in which sorafenib was given at the standard dose, approved by the US Food and Drug Administration, of 400 mg twice a day. More recent data suggest that higher doses of this drug in renalcell carcinoma might enhance the clinical effect of sorafenib.4 This enhanced clinical effect might be due, in part, to a greater inhibitory effect on the http://oncology.thelancet.com Vol 9 February 2008
VEGF receptor, but might also result in increased hypertension and other toxic effects. Additionally, other drugs that more potently target the VEGF receptor, such as axitinib, are associated with an increased incidence of hypertension.5 Therefore, the use of higher doses of sorafenib or the use of more potent VEGF-targeting drugs might result in an even higher incidence and severity of hypertension, which would be potentially balanced against greater efficacy in certain tumour types. Additionally, hypertension might be a useful and easily measured biomarker of response to sorafenib and other VEGF-targeted drugs. There is, as yet, little, if any, published data on this possibility. In an era of investigative biomarkers, such as dynamic contrast-enhanced MRI and circulating endothelial cells, which are not as easily measured, a simple biomarker such as hypertension, and its relation to therapeutic outcome with these drugs, deserves further investigation. Wu and colleagues have provided a valuable contribution in describing the incidence and relative risk of hypertension with sorafenib and other VEGFtargeted drugs. Although limited by the quality of individual trials, including the large proportion of patients treated on an expanded access trial, the conclusions are, nonetheless, robust. This toxic effect should be carefully monitored by patients and physicians on institution of VEGF-targeted treatment, and early and aggressive management of hypertension should be undertaken to avoid further toxic complications. Brian I Rini Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA [email protected] The author has received research funding from Bayer (West Haven, CT, USA) and Onyx (Richmond, CA, USA) who manufacture sorafenib. 1
2
3 4
5
Wu S, Chen JJ, Kudelka A, Lu J, Zhu X. Incidence and risk if hypertension with sorafenib in patients with cancer: a systemic review and metaanalysis. Lancet Oncol 9: 117–23. Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006; 24: 2505–12. Veronese ML, Mosenkis A, Flaherty KT, et al. Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol 2006; 24: 1363–69. Amato RJ, P Harris, Dalton M, et al, A phase II trial of intra-patient doseescalated sorafenib in patients (pts) with metastatic renal cell cancer (MRCC). Proc Am Soc Clin Oncol 2007; 25: (abstr 5026). Rixe O, Bukowski RM, Michaelson MD, et al. Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol 2007; 8: 975–84.
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