- Email: [email protected]
Mitigating radiation-induced cognitive impairment
Reflection and Reaction
Panel: Conditions that can be associated with an increased serum CA-125 concentration (>35 U/mL) and ascites with or without pelvic masses Non-malignant disorders Pelvic-mass associated Multivisceral tuberculosis Meigs and pseudo-Meigs syndrome Ovarian hyperstimulation syndrome Non-pelvic mass associated Liver cirrhosis Tuberculosis peritonitis Uremia and renal failure Nephrotic syndrome Fulminant hepatic failure Pancreatitis Malignant disorders Primary pelvic tumour Ovarian cancer Advanced uterine cancer Advanced fallopian-tube cancer Advanced rectal or bladder cancer Secondary pelvic involvement Lymphoma with peritoneal involvement Pancreatic carcinoma Breast cancer with peritoneal metastasis Gastric cancer with peritoneal metastasis Advanced hepatocellular carcinoma
as well as in patients with ovarian cancer who have been in remission for more than 2 years, especially in the presence of ascites or in comorbid conditions, such as congestive heart failure. The presence of such conditions should raise the suspicion of a benign underlying pathology. We believe that benign conditions should also be ruled out in the case of asymptomatic marker recurrences, before further treatment is started. *Alper Sevinc, Mustafa Adli, Mehmet Emin Kalender, Celalettin Camci Department of Medical Oncology (AS, MEK, CC) and Department of Radiation Oncology (MA), School of Medicine, Gaziantep University, Gaziantep Oncology Hospital, Gaziantep, Turkey [email protected] The authors declared no conflicts of interest. 1
2
3
4
5 6
the past decade, we have undertaken several studies on increased serum CA-125 concentrations,2–6 and we believe the information summarised in the panel should have been provided in their Review.7,8 Increased serum CA-125 concentrations should be interpreted with caution in several benign conditions
7
8
Goonewardene TI, Hall MR, Rustin GJ. Management of asymptomatic patients on follow-up for ovarian cancer with rising CA-125 concentrations. Lancet Oncol 2007; 8: 813–21. Sevinc A, Buyukberber S, Sari R, Turk HM, Ates M. Elevated serum CA-125 levels in patients with nephrotic syndrome-induced ascites. Anticancer Res 2000; 20: 1201–04. Sevinc A, Buyukberber S, Sari R, Kiroglu Y, Turk HM, Ates M. Elevated serum CA-125 levels in hemodialysis patients with peritoneal, pleural, or pericardial fluids. Gynecol Oncol 2000; 77: 254–57. Sari R, Yildirim B, Sevinc A, Hilmioglu F. Sensitivity of CA-125 in patients with liver cirrhosis in the presence of ascites. Am J Gastroenterol 2001; 96: 253–54. Sevinc A, Buyukberber S, Sari R. Elevated serum CA-125 levels: hepatitis or ascites? Gynecol Oncol 2000; 76: 141–42. Sevinc A, Camci C, Turk HM, Buyukberber S. How to interpret serum CA 125 levels in patients with serosal involvement? A clinical dilemma. Oncology 2003; 65: 1–6. Ahmed AS, Long M, Donaldson D. Lessons to be learned: a case study approach: Ascites and elevated serum CA 125 due to a pancreatic carcinoma. A diagnostic dilemma. J R Soc Health 2000; 120: 47–51. Sevinc A, Sari R, Camci C, Buyukberber S. A secondary interpretation is needed on serum CA 125 levels in case of serosal involvement. J R Soc Health 2000; 120: 268–70.
Mitigating radiation-induced cognitive impairment The Keynote Comment on cognitive dysfunction in people with cancer by Shagen and Vardy in a recent issue of The Lancet Oncology1 brings to mind a particular question—is sufficient attention being paid to possible methods for mitigating cognitive impairment caused by cranial radiotherapy? Several possible candidate lines of enquiry exist. Angiotensin-receptor blockers and angiotensinconverting-enzyme inhibitors have been shown to decrease irradiation injury in the kidney, lung, brain, and optic chiasma in rats, and captopril is currently under http://oncology.thelancet.com Vol 8 December 2007
investigation in a clinical trial to ascertain whether it can decrease radiation damage to the lung.2 Additionally, because the renin–angiotensin system is active in the brain (where it modifies pain perception, cognition, and the blood-brain barrier),3 drugs targeting this system might have a beneficial role. Insulin sensitisers have also been studied, with pioglitazone showing a decrease in cognitive impairment in brain-irradiated rats.4 A treatment for lactic acidosis could be another possible method of preventing radiation-induced cognitive impairment. Dichloroacetate, which blocks the glucose1055
Reflection and Reaction
lactic acid cycle and is used clinically for the treatment of lactic acidosis, has been shown to decrease lactic acid in the brain in rats, thereby decreasing ischaemic damage.5 This drug improves lactic acidosis after experimental arterial blockade and might, therefore, also decrease neural damage due to ischaemia after radiotherapy. Dichloroacetate could also have a potential antitumour effect, because many cancers—eg, glioblastoma—use the glucose-lactic acid cycle in mitochondrial respiration.6 A phase II trial has now opened to test the safety and efficacy of dichloroacetate for the treatment of malignant gliomas.7 A drug used in the prevention of delayed bowel injury might also be useful in the prevention of cognitive impairment after radiotherapy. Haydont and co-workers8 have recently shown in rats that protection of the bowel from delayed radiation injury can be achieved by use of the anticholesterol drug pravastatin. However, this drug had limited benefit in acute-bowel injury. If cognitive impairment, which is likely to be a late reaction to radiotherapy in the brain, has a similar underlying mechanism to delayed-bowel injury, then this drug might have a use in the management of such injury in the brain. The prevention of neural impairment by other methods has also been assessed. Stem cells in the brain seem to be present on the undersurface of the dentate gyrus in the hippocampus and in the subventricular zone of the lateral ventricles. From these sites, stem cells can migrate to damaged areas elsewhere in the brain. Due to the fact that only a small percentage of brain metastases occur in the dentate gyrus, the shielding of this area during radiotherapy might, in many situations, be possible, thereby preventing the damage of these repair cells themselves.9 Clinical research on the prevention of neurological impairment after radiotherapy is already being done. For example, in a small study of 15 patients with brain tumours, bevacizumab was shown to decrease capillary leakage and radiation necrosis.10 Furthermore, erythropoietin has been used to modify irradiation damage to the spinal cord in patients with malignant
1056
spinal-cord compression,11 and, thus, might have a role in modifying radiation damage to the brain. Some of these drugs are already commonly used for other indications. However, in an ideal world, all patients who have radiotherapy to the brain should be given a drug to decrease the likelihood of subsequent cognitive impairment. There are obvious opportunities for trials. John Healy 5 Claremont Villas, Glenageary, County Dublin, Ireland [email protected] The author declared no conflicts of interest. 1
2
3
4
5 6
7
8
9
10 11
Schagen SB, Vardy J, on behalf of the Steering Committee of the International Cognition and Cancer Task Force. Cognitive dysfunction in people with cancer. Lancet Oncol 2007; 8: 852–53. Captopril in treating patients with non-small cell lung cancer or limitedstage small cell lung cancer that has been previously treated with radiation therapy with or without chemotherapy. http://www.clinicaltrials.gov/ct2/ show/NCT00077064?term=captopril+%2B+cancer&rank=1 (accessed Nov 19, 2007). Robbins ME, Diz DI. Pathogenic role of the renin-angiotensin system in modulating radiation-induced late effects. Int J Radiat Oncol Biol Phys 2006: 64: 6–12. Zhao W, Payne V, Tommasi E, Diz DI, Hsu FC, Robbins ME. Administration of the peroxisomal proliferator-activated receptor gamma agonist pioglitazone during fractionated brain irradiation prevents radiationinduced cognitive impairment. Int J Radiat Oncol Biol Phys 2007; 67: 6–9. Chandy MJ, Ravindra J. Effect of dichloroacetate on infarct size in a primate model of focal cerebral ischaemia. Neurol India 2000; 48: 227–30. Bonnet S, Archer SL, Allalunis-Turner J, et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 2007: 11: 37–51. The safety and efficacy of DCA for the treatment of brain cancer. http:// www.clinicaltrials.gov/ct2/show/NCT00540176?term=DCA+brain+cancer &rank=1 (accessed Nov 19, 2007). Haydont V, Gilliot O, et al. Successful mitigation of delayed intestinal radiation injury using pravastatin is not associated with acute injury improvement or tumor protection. Int J Radiat Oncol Biol Phys 2007: 68: 1471–82. Barani IJ, Benedict SH, Lin PS. Neural stem cells: implications for the conventional radiotherapy of central nervous system malignancies. Int J Radiat Oncol Biol Phys 2007: 68: 324–33. Gonzalez J, Kumar AJ, Conrad CA, Levin VA. Effect of bevacizumab on radiation necrosis of the brain. Int J Radiat Oncol Biol Phys 2007: 67: 323–26. Loblaw DA, Holden L, Xenocostas A, et al. Functional and pharmacokinetic outcomes after a single intravenous infusion of recombinant human erythropoietin in patients with malignant extradural spinal cord compression Clin Oncol (R Coll Radiol) 2007: 19: 63–70.
Erratum Paolino A. 49th Annual Meeting of the American Society for Therapeutic Radiology and Oncology; Oct 28–Nov 1, 2007; Los Angeles, CA, USA. Lancet Oncol 2007; 8: 970. Throughout the section entitled ‘Hyperfractionated ERBT better’, on each occasion ‘four fractions’ should have read ‘one fraction’.
http://oncology.thelancet.com Vol 8 December 2007
Panel: Conditions that can be associated with an increased serum CA-125 concentration (>35 U/mL) and ascites with or without pelvic masses Non-malignant disorders Pelvic-mass associated Multivisceral tuberculosis Meigs and pseudo-Meigs syndrome Ovarian hyperstimulation syndrome Non-pelvic mass associated Liver cirrhosis Tuberculosis peritonitis Uremia and renal failure Nephrotic syndrome Fulminant hepatic failure Pancreatitis Malignant disorders Primary pelvic tumour Ovarian cancer Advanced uterine cancer Advanced fallopian-tube cancer Advanced rectal or bladder cancer Secondary pelvic involvement Lymphoma with peritoneal involvement Pancreatic carcinoma Breast cancer with peritoneal metastasis Gastric cancer with peritoneal metastasis Advanced hepatocellular carcinoma
as well as in patients with ovarian cancer who have been in remission for more than 2 years, especially in the presence of ascites or in comorbid conditions, such as congestive heart failure. The presence of such conditions should raise the suspicion of a benign underlying pathology. We believe that benign conditions should also be ruled out in the case of asymptomatic marker recurrences, before further treatment is started. *Alper Sevinc, Mustafa Adli, Mehmet Emin Kalender, Celalettin Camci Department of Medical Oncology (AS, MEK, CC) and Department of Radiation Oncology (MA), School of Medicine, Gaziantep University, Gaziantep Oncology Hospital, Gaziantep, Turkey [email protected] The authors declared no conflicts of interest. 1
2
3
4
5 6
the past decade, we have undertaken several studies on increased serum CA-125 concentrations,2–6 and we believe the information summarised in the panel should have been provided in their Review.7,8 Increased serum CA-125 concentrations should be interpreted with caution in several benign conditions
7
8
Goonewardene TI, Hall MR, Rustin GJ. Management of asymptomatic patients on follow-up for ovarian cancer with rising CA-125 concentrations. Lancet Oncol 2007; 8: 813–21. Sevinc A, Buyukberber S, Sari R, Turk HM, Ates M. Elevated serum CA-125 levels in patients with nephrotic syndrome-induced ascites. Anticancer Res 2000; 20: 1201–04. Sevinc A, Buyukberber S, Sari R, Kiroglu Y, Turk HM, Ates M. Elevated serum CA-125 levels in hemodialysis patients with peritoneal, pleural, or pericardial fluids. Gynecol Oncol 2000; 77: 254–57. Sari R, Yildirim B, Sevinc A, Hilmioglu F. Sensitivity of CA-125 in patients with liver cirrhosis in the presence of ascites. Am J Gastroenterol 2001; 96: 253–54. Sevinc A, Buyukberber S, Sari R. Elevated serum CA-125 levels: hepatitis or ascites? Gynecol Oncol 2000; 76: 141–42. Sevinc A, Camci C, Turk HM, Buyukberber S. How to interpret serum CA 125 levels in patients with serosal involvement? A clinical dilemma. Oncology 2003; 65: 1–6. Ahmed AS, Long M, Donaldson D. Lessons to be learned: a case study approach: Ascites and elevated serum CA 125 due to a pancreatic carcinoma. A diagnostic dilemma. J R Soc Health 2000; 120: 47–51. Sevinc A, Sari R, Camci C, Buyukberber S. A secondary interpretation is needed on serum CA 125 levels in case of serosal involvement. J R Soc Health 2000; 120: 268–70.
Mitigating radiation-induced cognitive impairment The Keynote Comment on cognitive dysfunction in people with cancer by Shagen and Vardy in a recent issue of The Lancet Oncology1 brings to mind a particular question—is sufficient attention being paid to possible methods for mitigating cognitive impairment caused by cranial radiotherapy? Several possible candidate lines of enquiry exist. Angiotensin-receptor blockers and angiotensinconverting-enzyme inhibitors have been shown to decrease irradiation injury in the kidney, lung, brain, and optic chiasma in rats, and captopril is currently under http://oncology.thelancet.com Vol 8 December 2007
investigation in a clinical trial to ascertain whether it can decrease radiation damage to the lung.2 Additionally, because the renin–angiotensin system is active in the brain (where it modifies pain perception, cognition, and the blood-brain barrier),3 drugs targeting this system might have a beneficial role. Insulin sensitisers have also been studied, with pioglitazone showing a decrease in cognitive impairment in brain-irradiated rats.4 A treatment for lactic acidosis could be another possible method of preventing radiation-induced cognitive impairment. Dichloroacetate, which blocks the glucose1055
Reflection and Reaction
lactic acid cycle and is used clinically for the treatment of lactic acidosis, has been shown to decrease lactic acid in the brain in rats, thereby decreasing ischaemic damage.5 This drug improves lactic acidosis after experimental arterial blockade and might, therefore, also decrease neural damage due to ischaemia after radiotherapy. Dichloroacetate could also have a potential antitumour effect, because many cancers—eg, glioblastoma—use the glucose-lactic acid cycle in mitochondrial respiration.6 A phase II trial has now opened to test the safety and efficacy of dichloroacetate for the treatment of malignant gliomas.7 A drug used in the prevention of delayed bowel injury might also be useful in the prevention of cognitive impairment after radiotherapy. Haydont and co-workers8 have recently shown in rats that protection of the bowel from delayed radiation injury can be achieved by use of the anticholesterol drug pravastatin. However, this drug had limited benefit in acute-bowel injury. If cognitive impairment, which is likely to be a late reaction to radiotherapy in the brain, has a similar underlying mechanism to delayed-bowel injury, then this drug might have a use in the management of such injury in the brain. The prevention of neural impairment by other methods has also been assessed. Stem cells in the brain seem to be present on the undersurface of the dentate gyrus in the hippocampus and in the subventricular zone of the lateral ventricles. From these sites, stem cells can migrate to damaged areas elsewhere in the brain. Due to the fact that only a small percentage of brain metastases occur in the dentate gyrus, the shielding of this area during radiotherapy might, in many situations, be possible, thereby preventing the damage of these repair cells themselves.9 Clinical research on the prevention of neurological impairment after radiotherapy is already being done. For example, in a small study of 15 patients with brain tumours, bevacizumab was shown to decrease capillary leakage and radiation necrosis.10 Furthermore, erythropoietin has been used to modify irradiation damage to the spinal cord in patients with malignant
1056
spinal-cord compression,11 and, thus, might have a role in modifying radiation damage to the brain. Some of these drugs are already commonly used for other indications. However, in an ideal world, all patients who have radiotherapy to the brain should be given a drug to decrease the likelihood of subsequent cognitive impairment. There are obvious opportunities for trials. John Healy 5 Claremont Villas, Glenageary, County Dublin, Ireland [email protected] The author declared no conflicts of interest. 1
2
3
4
5 6
7
8
9
10 11
Schagen SB, Vardy J, on behalf of the Steering Committee of the International Cognition and Cancer Task Force. Cognitive dysfunction in people with cancer. Lancet Oncol 2007; 8: 852–53. Captopril in treating patients with non-small cell lung cancer or limitedstage small cell lung cancer that has been previously treated with radiation therapy with or without chemotherapy. http://www.clinicaltrials.gov/ct2/ show/NCT00077064?term=captopril+%2B+cancer&rank=1 (accessed Nov 19, 2007). Robbins ME, Diz DI. Pathogenic role of the renin-angiotensin system in modulating radiation-induced late effects. Int J Radiat Oncol Biol Phys 2006: 64: 6–12. Zhao W, Payne V, Tommasi E, Diz DI, Hsu FC, Robbins ME. Administration of the peroxisomal proliferator-activated receptor gamma agonist pioglitazone during fractionated brain irradiation prevents radiationinduced cognitive impairment. Int J Radiat Oncol Biol Phys 2007; 67: 6–9. Chandy MJ, Ravindra J. Effect of dichloroacetate on infarct size in a primate model of focal cerebral ischaemia. Neurol India 2000; 48: 227–30. Bonnet S, Archer SL, Allalunis-Turner J, et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 2007: 11: 37–51. The safety and efficacy of DCA for the treatment of brain cancer. http:// www.clinicaltrials.gov/ct2/show/NCT00540176?term=DCA+brain+cancer &rank=1 (accessed Nov 19, 2007). Haydont V, Gilliot O, et al. Successful mitigation of delayed intestinal radiation injury using pravastatin is not associated with acute injury improvement or tumor protection. Int J Radiat Oncol Biol Phys 2007: 68: 1471–82. Barani IJ, Benedict SH, Lin PS. Neural stem cells: implications for the conventional radiotherapy of central nervous system malignancies. Int J Radiat Oncol Biol Phys 2007: 68: 324–33. Gonzalez J, Kumar AJ, Conrad CA, Levin VA. Effect of bevacizumab on radiation necrosis of the brain. Int J Radiat Oncol Biol Phys 2007: 67: 323–26. Loblaw DA, Holden L, Xenocostas A, et al. Functional and pharmacokinetic outcomes after a single intravenous infusion of recombinant human erythropoietin in patients with malignant extradural spinal cord compression Clin Oncol (R Coll Radiol) 2007: 19: 63–70.
Erratum Paolino A. 49th Annual Meeting of the American Society for Therapeutic Radiology and Oncology; Oct 28–Nov 1, 2007; Los Angeles, CA, USA. Lancet Oncol 2007; 8: 970. Throughout the section entitled ‘Hyperfractionated ERBT better’, on each occasion ‘four fractions’ should have read ‘one fraction’.
http://oncology.thelancet.com Vol 8 December 2007