- Email: [email protected]
Does amifostine have a role in chemoradiation treatment?
Debate
Amifostine
other evidence came from a few very small, mostly inconclusive studies and some in which the methods and description of analyses were flawed. My research therefore highlights the simple truth that ASCO’s recommendations make claims of evidence that does not exist and are consequently misleading to clinicians. So, does the preclinical evidence concur with the manufacturers claims that amifostine is selectively taken up by normal tissues and does not provide protection to tumour cells? In the blood, amifostine is converted to the prodrug WR1065, which acts as a scavenger to reduce the radiation damage to DNA.3,4 It is claimed that this prodrug is selectively taken up by normal tissues, especially in salivary glands. This process is thought to be facilitated by differences in the Jens Overgaard concetrations of alkaline phosphatases, but recently this theory has been challenged.3,4,8 A high concentration of the JO is at the Department of Experimental Clinical Oncology, Aarhus University prodrug can indeed be detected in some normal tissues, but Hospital, Denmark the preclinical data quite clearly show that there is no selective Email: [email protected] normal-tissue radioprotection. Most normal tissues have I do not disagree with the statement shown varying degrees of protection depending on the dose that amifostine offers some salivary- of drug, radiation, type of tissue, and endpoint—but so has gland protection during radiation, tumour tissue. This topic was extensively studied in the mid and I am not going to spend time disscussing some of the 1980s and the scientific community reached the conclusion increasing evidence that this agent has severe side-effects that there was no virtue in pursuing amifostine in clinical which may lead to interruption of treatment.1,2 Instead, I shall practice.3,4,9–11 I believe the only reason that amifostine has simply focus on what I consider the most important issue: can continued to be investigated is that a new manufacturer has amifostine be given with radiotherapy without risk of tumour taken on the drug and is eager to explore its commercial protection? potential. Two reviews have reported Without consideration of the that the extent of protection of normal historical background of the tissue and tumour tissue in preclinical development of this drug,1,3,4 or the studies are of the same magnitude and extensive preclinical research that has that no clear selectivity has been been done, it is easy to believe that shown.3,4 The topic was analysed in detail by Denekamp who reported amifostine dose not protect tumour shortly before her death in an tissue from radiation. The manufacturer unpublished paper that more than 90% has put substantial effort in promoting of all preclinical studies with amifostine the product, claiming that it is effective, showed tumour radioprotection. Thus, selective, of true benefit for patients, and there is no preclinical basis whatsoever that it carries no risk of tumour for the argument of selective protection. But, the question I want to radioprotection of normal tissue. ask is: are these claims are justified? Is there clinical evidence to support There is a jungle of published Xerostomia in the mouth of a patient who has the use of amifostine? In reality, only the information about amifostine, but the recieved radiation therapy for head and neck study by Brizel and colleagues7 reports recommendations from the American cancer. some conclusive evidence. The trial has Society for Clinical Oncology (ASCO) do not seem to provide any clarification. ASCO’s most recent been used for registration of amifostine and is widely used by recommendation in 2002 was no different from their the manufacturer as proof of evidence. However, the study is statement in 1999, which said that ASCO “recommends that a hybrid of two scenarios—a full course of radiotherapy given amifostine may be considered to decrease the incidence of with conventional fractionation (given to one-third of the acute and late xerostomia (figure) in patients who undergo patients) and postoperative therapy with a lower dose (given fractionated radiation therapy in the head and neck region”. to the remainder). Originally, the trial was designed to assess This statement was, according to ASCO, supported by level I how well the salivary glands were protected; tumour evidence, meaning it was based on the results of a meta- radiosensitivity was not a primary endpoint and was not analysis of multiple, well-designed, controlled studies of high considered when the study size was planned. A short-term statistical power.6 However, when I searched for the meta- evaluation of 303 patients showed less severe xerostomia in analysis referred to by ASCO’s recommendations, and for the those who had received amifostine, but the trial did not have trials it included, I found that the evidence was not of a sufficient number of events to rule out the risk of tumour sufficient quality to justify a level I classification. The only trial protection. The fact that no significant difference in tumour of any significance was the study by Brizel and colleagues7 and outcome was observed between the two groups can not be Courtesy of NL. Rhodus
amifostine to prevent radiochemotherapy-induced mucositis and xerostomia in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002; 52: 739–47. 18 Antonadou D, Coliarakis N, Synodinou M, et al. Randomized phase III trial of radiation treatment +/- amifostine in patients with advanced-stage lung cancer. Int J Radiat Oncol Biol Phys 2001; 51: 915–22. 19 Koukourakis MI, Romanidis K, Froudarakis M, et al. Concurrent administration of Docetaxel and stealth liposomal doxorubicin with radiotherapy in non-small cell lung cancer: excellent tolerance using subcutaneous amifostine for cytoprotection. Br J Cancer 2002; 87: 385–92. 20 Koukourakis MI, Kyrias G, Kakolyris S, et al. Subcutaneous administration of amifostine during fractionated radiotherapy: a randomized phase II study. J Clin Oncol 2000; 18: 2226–33.
380
THE LANCET Oncology Vol 4 June 2003
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Debate
Amifostine
used as an argument because this question can only be addressed in a study aimed at rejecting the zero hypothesis, which, to reach a reliable conclusion, would require inclusion of enough patients to generate more than 500 events—five times the number of events in this trial. Thus, there is no clinical evidence that amifostine is not tumour protective and it is unlikely that such evidence can be generated. This is a catch-22 situation: we do not have enough clinical data to rule out tumour protection and we are unable to generate sufficient clinical data to answer the question. Therefore, the clinical trials have not been able to show selectivity and the claims of the manufacturers and Brizel have not been substantiated. When these points are taken into consideration, the question of why this drug is allowed to be marketed becomes paramount. The simple answer is that it’s not—at least not to the extent that it has been. Interesting information on this topic can be found in a transcript of the FDA Advisory Committee’s 62nd meeting, June 8, 1999 (http://www. accessdata.fda.gov/scripts/cder/onctools/druglist.cfm). At this meeting, the manufacturer of amifostine presented its data supporting the use of this drug as a radioprotector. However, the data were severely criticised, mainly because the number of events was insufficient to rule out tumour protection. As a consequence, the permission and indication was strictly limited, as shown by the following statement: amifostine should be reserved for “postoperative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands…there are at present only limited data on the effects of Ethyol [amifostine] on the efficacy of chemotherapy or radiotherapy in other settings. Ethyol should not be administered to patients in other settings where chemotherapy can produce a significant survival benefit or cure, or in patients receiving definitive radiotherapy, except in the context of a clinical study…since there are at present insufficient data to exclude a tumour-protective effect in this setting.” In Europe, amifostine’s manufacturers have managed to obtain a broader indication than in the USA, This Debate was presented in a Controversy session at the 27th Congress of the European Society for Medical Oncology in Nice, France, 18-22 October, 2002.
THE LANCET Oncology Vol 4 June 2003
possibly because the European regulatory boards are less aware of this drug’s history. The bottom line is that amifostine has not yet been proved safe and effective for use alongside chemoradiotherapy, outside experimental protocols. Although this drug is promoted by the manufacturers, preclinical data are against it, statistics do not support it, and the FDA advises against it. There are insufficient data to establish whether the use of amifostine in chemoradiotherapy decreases the rate of cure and is harmful to patients. Therefore, the answer to the question of whether amifostine has a role in chemoradiation should be a resounding “No”. We should not forget that absence of evidence is not evidence of absence. Conflict of interest
I have no conflicts to declare. References
1 Lindegaard JC. Has the time come for routine use of amifostine in clinical radiotherapy practice? Acta Oncol 2003; 42: 2–3. 2 Lindegaard JC, Grau C. Has the outlook improved for amifostine as a clinical radioprotector? Radiother Oncol 2000; 57: 113–18. 3 Bourhis J, De Crevoisier R, Abdulkarim B, et al. A randomized study of very accelerated radiotherapy with and without amifostine in head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2000; 46: 1105–08. 4 Andreassen CN, Grau C, Lindegaard JC. Chemical radioprotection: A critical review of amifostine as a cytoprotector in radiotherapy. Semin Radiat Oncol 2003; 13: 62–72. 5 Schuchter LM, Hensley ML, Meropol NJ, Winer EP. 2002 update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2002; 20: 2895–903. 6 Hensley ML, Schuchter LM, Lindley C, et al. American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol 1999; 17: 3333–55. 7 Brizel DM, Wasserman TH, Henke M, et al. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 2000; 18: 3339–45. 8 Thompson DC, Wyrick SD, Holbrook DJ, Chaney SG. Effect of the chemoprotective agent WR-2721 on disposition and biotransformations of ormaplatin in the Fischer 344 rat bearing a fibrosarcoma. Cancer Res 1995; 55: 2837–46. 9 Denekamp J, Stewart FA, Rojas A. Is the outlook grey for WR-2721 as a clinical radioprotector? Int J Radiat Oncol Biol Phys 1983; 9: 1247–49. 10 Rojas A, Stewart FA, Soranson JA, et al. Fractionation studies with WR-2721: normal tissues and tumour. Radiother Oncol 1986; 6: 51–60. 11 McChesney SL, Gillette EL, Dewhirst MW, Withrow SJ. Influence of WR 2721 on radiation response of canine soft tissue sarcomas. Int J Radiat Oncol Biol Phys 1986; 12: 1957–63.
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
381
Amifostine
other evidence came from a few very small, mostly inconclusive studies and some in which the methods and description of analyses were flawed. My research therefore highlights the simple truth that ASCO’s recommendations make claims of evidence that does not exist and are consequently misleading to clinicians. So, does the preclinical evidence concur with the manufacturers claims that amifostine is selectively taken up by normal tissues and does not provide protection to tumour cells? In the blood, amifostine is converted to the prodrug WR1065, which acts as a scavenger to reduce the radiation damage to DNA.3,4 It is claimed that this prodrug is selectively taken up by normal tissues, especially in salivary glands. This process is thought to be facilitated by differences in the Jens Overgaard concetrations of alkaline phosphatases, but recently this theory has been challenged.3,4,8 A high concentration of the JO is at the Department of Experimental Clinical Oncology, Aarhus University prodrug can indeed be detected in some normal tissues, but Hospital, Denmark the preclinical data quite clearly show that there is no selective Email: [email protected] normal-tissue radioprotection. Most normal tissues have I do not disagree with the statement shown varying degrees of protection depending on the dose that amifostine offers some salivary- of drug, radiation, type of tissue, and endpoint—but so has gland protection during radiation, tumour tissue. This topic was extensively studied in the mid and I am not going to spend time disscussing some of the 1980s and the scientific community reached the conclusion increasing evidence that this agent has severe side-effects that there was no virtue in pursuing amifostine in clinical which may lead to interruption of treatment.1,2 Instead, I shall practice.3,4,9–11 I believe the only reason that amifostine has simply focus on what I consider the most important issue: can continued to be investigated is that a new manufacturer has amifostine be given with radiotherapy without risk of tumour taken on the drug and is eager to explore its commercial protection? potential. Two reviews have reported Without consideration of the that the extent of protection of normal historical background of the tissue and tumour tissue in preclinical development of this drug,1,3,4 or the studies are of the same magnitude and extensive preclinical research that has that no clear selectivity has been been done, it is easy to believe that shown.3,4 The topic was analysed in detail by Denekamp who reported amifostine dose not protect tumour shortly before her death in an tissue from radiation. The manufacturer unpublished paper that more than 90% has put substantial effort in promoting of all preclinical studies with amifostine the product, claiming that it is effective, showed tumour radioprotection. Thus, selective, of true benefit for patients, and there is no preclinical basis whatsoever that it carries no risk of tumour for the argument of selective protection. But, the question I want to radioprotection of normal tissue. ask is: are these claims are justified? Is there clinical evidence to support There is a jungle of published Xerostomia in the mouth of a patient who has the use of amifostine? In reality, only the information about amifostine, but the recieved radiation therapy for head and neck study by Brizel and colleagues7 reports recommendations from the American cancer. some conclusive evidence. The trial has Society for Clinical Oncology (ASCO) do not seem to provide any clarification. ASCO’s most recent been used for registration of amifostine and is widely used by recommendation in 2002 was no different from their the manufacturer as proof of evidence. However, the study is statement in 1999, which said that ASCO “recommends that a hybrid of two scenarios—a full course of radiotherapy given amifostine may be considered to decrease the incidence of with conventional fractionation (given to one-third of the acute and late xerostomia (figure) in patients who undergo patients) and postoperative therapy with a lower dose (given fractionated radiation therapy in the head and neck region”. to the remainder). Originally, the trial was designed to assess This statement was, according to ASCO, supported by level I how well the salivary glands were protected; tumour evidence, meaning it was based on the results of a meta- radiosensitivity was not a primary endpoint and was not analysis of multiple, well-designed, controlled studies of high considered when the study size was planned. A short-term statistical power.6 However, when I searched for the meta- evaluation of 303 patients showed less severe xerostomia in analysis referred to by ASCO’s recommendations, and for the those who had received amifostine, but the trial did not have trials it included, I found that the evidence was not of a sufficient number of events to rule out the risk of tumour sufficient quality to justify a level I classification. The only trial protection. The fact that no significant difference in tumour of any significance was the study by Brizel and colleagues7 and outcome was observed between the two groups can not be Courtesy of NL. Rhodus
amifostine to prevent radiochemotherapy-induced mucositis and xerostomia in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002; 52: 739–47. 18 Antonadou D, Coliarakis N, Synodinou M, et al. Randomized phase III trial of radiation treatment +/- amifostine in patients with advanced-stage lung cancer. Int J Radiat Oncol Biol Phys 2001; 51: 915–22. 19 Koukourakis MI, Romanidis K, Froudarakis M, et al. Concurrent administration of Docetaxel and stealth liposomal doxorubicin with radiotherapy in non-small cell lung cancer: excellent tolerance using subcutaneous amifostine for cytoprotection. Br J Cancer 2002; 87: 385–92. 20 Koukourakis MI, Kyrias G, Kakolyris S, et al. Subcutaneous administration of amifostine during fractionated radiotherapy: a randomized phase II study. J Clin Oncol 2000; 18: 2226–33.
380
THE LANCET Oncology Vol 4 June 2003
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Debate
Amifostine
used as an argument because this question can only be addressed in a study aimed at rejecting the zero hypothesis, which, to reach a reliable conclusion, would require inclusion of enough patients to generate more than 500 events—five times the number of events in this trial. Thus, there is no clinical evidence that amifostine is not tumour protective and it is unlikely that such evidence can be generated. This is a catch-22 situation: we do not have enough clinical data to rule out tumour protection and we are unable to generate sufficient clinical data to answer the question. Therefore, the clinical trials have not been able to show selectivity and the claims of the manufacturers and Brizel have not been substantiated. When these points are taken into consideration, the question of why this drug is allowed to be marketed becomes paramount. The simple answer is that it’s not—at least not to the extent that it has been. Interesting information on this topic can be found in a transcript of the FDA Advisory Committee’s 62nd meeting, June 8, 1999 (http://www. accessdata.fda.gov/scripts/cder/onctools/druglist.cfm). At this meeting, the manufacturer of amifostine presented its data supporting the use of this drug as a radioprotector. However, the data were severely criticised, mainly because the number of events was insufficient to rule out tumour protection. As a consequence, the permission and indication was strictly limited, as shown by the following statement: amifostine should be reserved for “postoperative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands…there are at present only limited data on the effects of Ethyol [amifostine] on the efficacy of chemotherapy or radiotherapy in other settings. Ethyol should not be administered to patients in other settings where chemotherapy can produce a significant survival benefit or cure, or in patients receiving definitive radiotherapy, except in the context of a clinical study…since there are at present insufficient data to exclude a tumour-protective effect in this setting.” In Europe, amifostine’s manufacturers have managed to obtain a broader indication than in the USA, This Debate was presented in a Controversy session at the 27th Congress of the European Society for Medical Oncology in Nice, France, 18-22 October, 2002.
THE LANCET Oncology Vol 4 June 2003
possibly because the European regulatory boards are less aware of this drug’s history. The bottom line is that amifostine has not yet been proved safe and effective for use alongside chemoradiotherapy, outside experimental protocols. Although this drug is promoted by the manufacturers, preclinical data are against it, statistics do not support it, and the FDA advises against it. There are insufficient data to establish whether the use of amifostine in chemoradiotherapy decreases the rate of cure and is harmful to patients. Therefore, the answer to the question of whether amifostine has a role in chemoradiation should be a resounding “No”. We should not forget that absence of evidence is not evidence of absence. Conflict of interest
I have no conflicts to declare. References
1 Lindegaard JC. Has the time come for routine use of amifostine in clinical radiotherapy practice? Acta Oncol 2003; 42: 2–3. 2 Lindegaard JC, Grau C. Has the outlook improved for amifostine as a clinical radioprotector? Radiother Oncol 2000; 57: 113–18. 3 Bourhis J, De Crevoisier R, Abdulkarim B, et al. A randomized study of very accelerated radiotherapy with and without amifostine in head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2000; 46: 1105–08. 4 Andreassen CN, Grau C, Lindegaard JC. Chemical radioprotection: A critical review of amifostine as a cytoprotector in radiotherapy. Semin Radiat Oncol 2003; 13: 62–72. 5 Schuchter LM, Hensley ML, Meropol NJ, Winer EP. 2002 update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2002; 20: 2895–903. 6 Hensley ML, Schuchter LM, Lindley C, et al. American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol 1999; 17: 3333–55. 7 Brizel DM, Wasserman TH, Henke M, et al. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 2000; 18: 3339–45. 8 Thompson DC, Wyrick SD, Holbrook DJ, Chaney SG. Effect of the chemoprotective agent WR-2721 on disposition and biotransformations of ormaplatin in the Fischer 344 rat bearing a fibrosarcoma. Cancer Res 1995; 55: 2837–46. 9 Denekamp J, Stewart FA, Rojas A. Is the outlook grey for WR-2721 as a clinical radioprotector? Int J Radiat Oncol Biol Phys 1983; 9: 1247–49. 10 Rojas A, Stewart FA, Soranson JA, et al. Fractionation studies with WR-2721: normal tissues and tumour. Radiother Oncol 1986; 6: 51–60. 11 McChesney SL, Gillette EL, Dewhirst MW, Withrow SJ. Influence of WR 2721 on radiation response of canine soft tissue sarcomas. Int J Radiat Oncol Biol Phys 1986; 12: 1957–63.
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
381