- Email: [email protected]
Bravo for PRAVO
Reflection and Reaction
In conclusion, Van Hemelrijck and colleagues provide an important population-based analysis of clotting in a large cohort of Swedish men with prostate cancer. The data should increase clinical suspicion for venous thromboembolism in men with prostate cancer, and stimulate further study of the potential interactions between androgen deprivation and blood coagulation. Philip J Saylor*, Annemarie E Fogerty Division of Hematology-Oncology, Massachusetts General Hospital Cancer Center, Lawrence House, 55 Fruit Street, Boston, MA, USA [email protected]
5
6
7
8
9
10
11 The authors declared no conflicts of interest. 1 2
3 4
Donati MB. Cancer and thrombosis: from Phlegmasia alba dolens to transgenic mice. Thromb Haemostasis 1995; 74: 278–81. Levitan N, Dowlati A, Remick SC, et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine 1999; 78: 285–91. Varki A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood 2007; 110: 1723–29. Rickles FR, Falanga A. Molecular basis for the relationship between thrombosis and cancer. Thromb Res 2001; 102: V215–24.
12
13
Lippi G, Plebani M, Franchini M, Guidi GC, Favaloro EJ. Prostate-specific antigen, prostate cancer, and disorders of hemostasis. Sem Thromb Hemostasis 2009; 35: 654–64. Zwicker JI, Liebman HA, Neuberg D, et al. Tumor-derived tissue factorbearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res 2009; 15: 6830–40. Van Hemelrijck M, Adolfsson J, Garmo H, et al. Risk of thromboembolic diseases in men with prostate cancer: results from the population-based PCBaSe Sweden. Lancet Oncol 2010; published online April 14. DOI: 10.1016/S1470-2045(10)70063-2. Khorana AA, Francis CW, Culakova E, Fisher RI, Kuderer NM, Lyman GH. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol 2006; 24: 484–90. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer 2007; 110: 2339–46. Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab 2006; 91: 1305–8. Smith MR, Finkelstein JS, McGovern FJ, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab 2002; 87: 599–603. Alibhai SM, Duong-Hua M, Sutradhar R, et al. Impact of androgen deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol 2009; 27: 3452–58. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006; 24: 4448–56.
Two decades ago, amidst predictions that novel molecularly targeted cancer therapies would sweep away the old treatments, many believed that radiotherapy was living on borrowed time. Regrettably, the optimism surrounding targeted therapies has now been tempered by knowledge that, apart from notable exceptions like imatinib in gastrointestinal stromal tumour, most new agents achieve only modest, short-term responses followed by rapid emergence of drug resistance. Thus, radiotherapy retains its central role in cancer management—given to about half of all patients. Thankfully, rather than heeding forecasts of its imminent demise, physicists and clinical oncologists have revolutionised clinical radiotherapy in the past two decades. This technical renaissance has given us threedimensional conformal, intensity-modulated, and imageguided radiotherapy (collectively technical radiotherapy), and we are now equipped to deliver higher radiation doses to tumour masses while limiting the dose to critical normal structures. Despite these achievements, technical radiotherapy results in only modest improvements in tumour control.1 Combining radiotherapy with standard cytotoxic drugs (eg, cisplatin) can lead to incremental gains, but at www.thelancet.com/oncology Vol 11 May 2010
the cost of increased acute and late toxic effects so that further treatment intensification is difficult.2 Given the hurdles facing targeted drugs, radiotherapy, and chemoradiotherapy, and the fact that most targeted therapies interact with key pathways in the cellular response to radiation, it is logical to combine these approaches to try to maximise therapeutic benefit.3 Histone deacetylase (HDAC) inhibitors modulate gene transcription and upregulate or downregulate many target genes, and are therefore appropriate to investigate alongside radiotherapy. As single-agent therapies, HDAC inhibitors affect cell-cycle distribution, DNA repair, apoptosis, angiogenesis, and immune function. In this issue of The Lancet Oncology, Ree and colleagues’ study4 of pelvic radiation and vorinostat (PRAVO) represents the first clinical combination of HDAC inhibitors with therapeutic radiation, and builds on the investigators’ previous preclinical experience with this combination. By recruiting more or less homogeneous patient cohorts for palliative pelvic radiotherapy (fixed dose of 30 Gy in 10 fractions), and by escalating the dose of vorinostat, the researchers confirmed the safety and tolerability of the combination and recommend a vorinostat dose
Marc Phares/Science Photo Library
Bravo for PRAVO
See Articles page 459
407
Reflection and Reaction
of 300 mg/day for phase 2 studies. These data will also underpin future studies of vorinostat combined with technical radiotherapy in the curative setting. Ree and colleagues’ decision to include additional biomarker studies is commendable and raises this report above the level of a standard phase 1 trial; however, with hindsight, they will acknowledge that more might have been achieved with the biopsy material. Changes in levels of acetylated histone H3 and H4 confirm that the drug reached its target, but the substantial variability of the loading controls hinders data analysis. Unfortunately, there was insufficient biopsy material to assess more biologically relevant processes (eg, apoptosis [caspase cleavage], cell-cycle progression [P21 levels], and DNA damage [ -H2AX foci]). Future studies should learn from this shortcoming and use technologies, such as the duplex meso-scale discovery immunoassay, that allow simultaneous analysis of many proteins and phosphoproteins in the same sample to maximise data yield from small samples. The serial diffusion-weighted MRI generated interesting data and allowed the investigators to correlate changes in apparent diffusion coefficients with tumour volume measurements. In future studies of combining novel agents with curative technical radiotherapy, pharmacodynamic data derived from functional imaging are likely to become increasingly important as alternatives to serial biopsies. This is particularly relevant where biopsies from deepseated tumours are hazardous and, if associated with
complications, will delay curative therapy. The PRAVO study is a valuable template for combining molecularly targeted drugs with palliative radiation. The study answered important safety questions, but was flexible enough to allow the investigators to generate preliminary biomarker data. The challenge for clinical oncologists in the next decade is to seize the initiative, and integrate drugs that target the radiation response with curative doses of radiotherapy delivered using state-of-the-art techniques.5 This work will ensure that radiotherapy remains at the heart of cancer treatment for the foreseeable future. Kevin J Harrington*, Christopher M Nutting The Institute of Cancer Research, Chester Beatty Laboratories, Section of Cell and Molecular Biology, London SW3 6JB, UK (KJH); and Head and Neck Unit, The Royal Marsden Hospital, London SW3 6JJ, UK (KJH, CMN) [email protected] The authors declared no conflicts of interest. 1
2
3
4
5
Dearnaley DP, Hall E, Lawrence D, et al. Phase III pilot study of dose escalation using conformal radiotherapy in prostate cancer: PSA control and side effects. Br J Cancer 2005; 92: 488–98. Harrington KJ, Nutting CM. Interactions between ionizing radiation and drugs in head and neck cancer: how can we maximize the therapeutic index? Curr Opin Investig Drugs 2002; 3: 807–11. Harrington K, Jankowska P, Hingorani M. Molecular biology for the radiation oncologist: the 5Rs of radiobiology meet the hallmarks of cancer. Clin Oncol (R Coll Radiol) 2007; 19: 561–71. Ree AH, Dueland S, Folkvord S, et al. Vorinostat, a histone deacetylase inhibitor, in pelvic palliative radiotherapy for gastrointestinal carcinoma: a phase 1 study. Lancet Oncol 2010; 11: 459–64. Maughan TS. A new opportunity for radiotherapy research in the UK. Clin Oncol (R Coll Radiol) 2009; 21: 157–58.
Exercise research: early promise warrants further investment Tony Mcconnell/Science Photo Library
In a world where over 11·4 million are diagnosed with cancer and over 7·4 million individuals succumb to this disease annually,1 a widely available and relatively inexpensive intervention that could not only improve quality of life following diagnosis, but potentially aid in prevention and treatment of disease would prove welcome indeed. In fact, such an intervention might be available, and not in the form of a new multi-targeted small-molecule tyrosine kinase inhibitor, but instead, in exercise. The benefits of exercise have been recognised since antiquity, although the first exercise guidelines for health promotion and disease prevention were only established over the past few decades. Since that time, regular 408
exercise has become established as the cornerstone of primary and secondary disease prevention in many areas of clinical medicine. By contrast, investigation of the role of exercise following a diagnosis of cancer has, until recently, received scant attention. The precise reasons for this are not known, but probably reflect the prevailing dogma that a cancer diagnosis and associated therapeutic management precludes participation in and benefit from exercise therapy. Such attitudes are now passé, with exercise research in oncology now increasingly recognised as an emerging and legitimate field. The rising interest in exercise following the diagnosis and treatment for cancer probably results from the alignment of several factors, including the www.thelancet.com/oncology Vol 11 May 2010
In conclusion, Van Hemelrijck and colleagues provide an important population-based analysis of clotting in a large cohort of Swedish men with prostate cancer. The data should increase clinical suspicion for venous thromboembolism in men with prostate cancer, and stimulate further study of the potential interactions between androgen deprivation and blood coagulation. Philip J Saylor*, Annemarie E Fogerty Division of Hematology-Oncology, Massachusetts General Hospital Cancer Center, Lawrence House, 55 Fruit Street, Boston, MA, USA [email protected]
5
6
7
8
9
10
11 The authors declared no conflicts of interest. 1 2
3 4
Donati MB. Cancer and thrombosis: from Phlegmasia alba dolens to transgenic mice. Thromb Haemostasis 1995; 74: 278–81. Levitan N, Dowlati A, Remick SC, et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine 1999; 78: 285–91. Varki A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood 2007; 110: 1723–29. Rickles FR, Falanga A. Molecular basis for the relationship between thrombosis and cancer. Thromb Res 2001; 102: V215–24.
12
13
Lippi G, Plebani M, Franchini M, Guidi GC, Favaloro EJ. Prostate-specific antigen, prostate cancer, and disorders of hemostasis. Sem Thromb Hemostasis 2009; 35: 654–64. Zwicker JI, Liebman HA, Neuberg D, et al. Tumor-derived tissue factorbearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res 2009; 15: 6830–40. Van Hemelrijck M, Adolfsson J, Garmo H, et al. Risk of thromboembolic diseases in men with prostate cancer: results from the population-based PCBaSe Sweden. Lancet Oncol 2010; published online April 14. DOI: 10.1016/S1470-2045(10)70063-2. Khorana AA, Francis CW, Culakova E, Fisher RI, Kuderer NM, Lyman GH. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol 2006; 24: 484–90. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer 2007; 110: 2339–46. Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab 2006; 91: 1305–8. Smith MR, Finkelstein JS, McGovern FJ, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab 2002; 87: 599–603. Alibhai SM, Duong-Hua M, Sutradhar R, et al. Impact of androgen deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol 2009; 27: 3452–58. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006; 24: 4448–56.
Two decades ago, amidst predictions that novel molecularly targeted cancer therapies would sweep away the old treatments, many believed that radiotherapy was living on borrowed time. Regrettably, the optimism surrounding targeted therapies has now been tempered by knowledge that, apart from notable exceptions like imatinib in gastrointestinal stromal tumour, most new agents achieve only modest, short-term responses followed by rapid emergence of drug resistance. Thus, radiotherapy retains its central role in cancer management—given to about half of all patients. Thankfully, rather than heeding forecasts of its imminent demise, physicists and clinical oncologists have revolutionised clinical radiotherapy in the past two decades. This technical renaissance has given us threedimensional conformal, intensity-modulated, and imageguided radiotherapy (collectively technical radiotherapy), and we are now equipped to deliver higher radiation doses to tumour masses while limiting the dose to critical normal structures. Despite these achievements, technical radiotherapy results in only modest improvements in tumour control.1 Combining radiotherapy with standard cytotoxic drugs (eg, cisplatin) can lead to incremental gains, but at www.thelancet.com/oncology Vol 11 May 2010
the cost of increased acute and late toxic effects so that further treatment intensification is difficult.2 Given the hurdles facing targeted drugs, radiotherapy, and chemoradiotherapy, and the fact that most targeted therapies interact with key pathways in the cellular response to radiation, it is logical to combine these approaches to try to maximise therapeutic benefit.3 Histone deacetylase (HDAC) inhibitors modulate gene transcription and upregulate or downregulate many target genes, and are therefore appropriate to investigate alongside radiotherapy. As single-agent therapies, HDAC inhibitors affect cell-cycle distribution, DNA repair, apoptosis, angiogenesis, and immune function. In this issue of The Lancet Oncology, Ree and colleagues’ study4 of pelvic radiation and vorinostat (PRAVO) represents the first clinical combination of HDAC inhibitors with therapeutic radiation, and builds on the investigators’ previous preclinical experience with this combination. By recruiting more or less homogeneous patient cohorts for palliative pelvic radiotherapy (fixed dose of 30 Gy in 10 fractions), and by escalating the dose of vorinostat, the researchers confirmed the safety and tolerability of the combination and recommend a vorinostat dose
Marc Phares/Science Photo Library
Bravo for PRAVO
See Articles page 459
407
Reflection and Reaction
of 300 mg/day for phase 2 studies. These data will also underpin future studies of vorinostat combined with technical radiotherapy in the curative setting. Ree and colleagues’ decision to include additional biomarker studies is commendable and raises this report above the level of a standard phase 1 trial; however, with hindsight, they will acknowledge that more might have been achieved with the biopsy material. Changes in levels of acetylated histone H3 and H4 confirm that the drug reached its target, but the substantial variability of the loading controls hinders data analysis. Unfortunately, there was insufficient biopsy material to assess more biologically relevant processes (eg, apoptosis [caspase cleavage], cell-cycle progression [P21 levels], and DNA damage [ -H2AX foci]). Future studies should learn from this shortcoming and use technologies, such as the duplex meso-scale discovery immunoassay, that allow simultaneous analysis of many proteins and phosphoproteins in the same sample to maximise data yield from small samples. The serial diffusion-weighted MRI generated interesting data and allowed the investigators to correlate changes in apparent diffusion coefficients with tumour volume measurements. In future studies of combining novel agents with curative technical radiotherapy, pharmacodynamic data derived from functional imaging are likely to become increasingly important as alternatives to serial biopsies. This is particularly relevant where biopsies from deepseated tumours are hazardous and, if associated with
complications, will delay curative therapy. The PRAVO study is a valuable template for combining molecularly targeted drugs with palliative radiation. The study answered important safety questions, but was flexible enough to allow the investigators to generate preliminary biomarker data. The challenge for clinical oncologists in the next decade is to seize the initiative, and integrate drugs that target the radiation response with curative doses of radiotherapy delivered using state-of-the-art techniques.5 This work will ensure that radiotherapy remains at the heart of cancer treatment for the foreseeable future. Kevin J Harrington*, Christopher M Nutting The Institute of Cancer Research, Chester Beatty Laboratories, Section of Cell and Molecular Biology, London SW3 6JB, UK (KJH); and Head and Neck Unit, The Royal Marsden Hospital, London SW3 6JJ, UK (KJH, CMN) [email protected] The authors declared no conflicts of interest. 1
2
3
4
5
Dearnaley DP, Hall E, Lawrence D, et al. Phase III pilot study of dose escalation using conformal radiotherapy in prostate cancer: PSA control and side effects. Br J Cancer 2005; 92: 488–98. Harrington KJ, Nutting CM. Interactions between ionizing radiation and drugs in head and neck cancer: how can we maximize the therapeutic index? Curr Opin Investig Drugs 2002; 3: 807–11. Harrington K, Jankowska P, Hingorani M. Molecular biology for the radiation oncologist: the 5Rs of radiobiology meet the hallmarks of cancer. Clin Oncol (R Coll Radiol) 2007; 19: 561–71. Ree AH, Dueland S, Folkvord S, et al. Vorinostat, a histone deacetylase inhibitor, in pelvic palliative radiotherapy for gastrointestinal carcinoma: a phase 1 study. Lancet Oncol 2010; 11: 459–64. Maughan TS. A new opportunity for radiotherapy research in the UK. Clin Oncol (R Coll Radiol) 2009; 21: 157–58.
Exercise research: early promise warrants further investment Tony Mcconnell/Science Photo Library
In a world where over 11·4 million are diagnosed with cancer and over 7·4 million individuals succumb to this disease annually,1 a widely available and relatively inexpensive intervention that could not only improve quality of life following diagnosis, but potentially aid in prevention and treatment of disease would prove welcome indeed. In fact, such an intervention might be available, and not in the form of a new multi-targeted small-molecule tyrosine kinase inhibitor, but instead, in exercise. The benefits of exercise have been recognised since antiquity, although the first exercise guidelines for health promotion and disease prevention were only established over the past few decades. Since that time, regular 408
exercise has become established as the cornerstone of primary and secondary disease prevention in many areas of clinical medicine. By contrast, investigation of the role of exercise following a diagnosis of cancer has, until recently, received scant attention. The precise reasons for this are not known, but probably reflect the prevailing dogma that a cancer diagnosis and associated therapeutic management precludes participation in and benefit from exercise therapy. Such attitudes are now passé, with exercise research in oncology now increasingly recognised as an emerging and legitimate field. The rising interest in exercise following the diagnosis and treatment for cancer probably results from the alignment of several factors, including the www.thelancet.com/oncology Vol 11 May 2010