t.00
hr. J Radiotim OncologyBiol.Phys..Vol. 19,pp. 401-407 Printed in the U.S.A. All rights reserved.
Copyright
0360-3016/90 $3.M) 0 1990 Pergamon Press plc
0 Phase I/II Clinical Trials PRELIMINARY RESULTS OF A PILOT STUDY OF PENTOXIFYLLINE IN THE TREATMENT OF LATE RADIATION SOFT TISSUE NECROSIS MARK W. DI:ON, M.D.,* DAVID H. HUSSEY, M.D.,* J. FRED DOORNBOS, M.D.,* ANTONIO P. VIGLIOTTI, M.D.,* B.-CHEN WEN, M.D.* AND BARRIE ANDERSON, M.D.? Universityof Iowa College of Medicine, Iowa City, IA BetweenSeptember1988 and August 1989, 12 patients with 15 sites of late radiationnecrosis of the soft tissues were treatedwith pentoxifylline,a hemorrheologicagent that has been used to treat a variety of vasculo-occlusive disorders. Four of these necroses were located in the oromucosa, four in the mucosa of the female genitalia, and seven in the skin. At the time of analysis, 87% (13/E) of the necroses had healed completely, and one was partially healed. Furthermore, the time-course of healing with pentoxifylline was significantly less than the duration of nonhealing prior to pentoxifylline (average: 9 weeks vs 304 weeks). All patients had pain relief. These results indicate that pentoxifylline can contribute to the healing of soft tissue radiation necrosis. They also support the concept that late radiation injury in skin and mucosa is at least partly due to vascular injury. Pentoxifylline,
Radliation therapy, Late radiation injury, Radiation therapy complications.
INTRODUCIION
which improve blood flow through narrowed microvasculature. One of the most effective of these is pentoxifylline*, a drug that is being used clinically to treat a variety of vasculo-occlusive disorders. Pentoxifylline is able to improve blood flow through small capillaries by increasing red blood cell deformability and by stimulating prostacyclin release. If vascular damage plays a major role in the pathogenesis of late radiation injury, pentoxifylline could be an effective means of preventing or treating late radiation therapy complications. Several years ago, a series of experiments was initiated at the University of Iowa to test the effect of pentoxifylline on healing in irradiated and unirradiated normal tissues. In these experiments, pentoxifylline was shown to reduce the incidence and severity of late radiation injury in the irradiated mouse extremity (4) and to enhance healing of full-thickness skin flaps in unirradiated pigskin (26). As an extension of this research, a pilot study was initiated in patients to evaluate the therapeutic effectiveness of pentoxifylline in the management of soft tissue radionecrosis. The specific aims of this pilot study were (a) to define a patient population that might be suitable for a
Late damage to normal tissues is the principal dose limiting factor in radiation .therapy today. This injury not only leads to significant sequelae, but the risk of late complications often causes the radiotherapist to limit the total dose delivered, thus compromising local tumor control. Late radiation effects usually become manifest months or years after radiation therapy has been completed, and consequently, little can be done to ameliorate the injury once damage has occurred. There is considerable controversy regarding the pathogenesis of late radiation injury. One theory is that radiation damage to late responding tissues results primarily from the depletion of parenchymal and stromal cells, and the time difference between acute and late radiation reactions is due to the kinetics of the various cell populations affected (25). A second theory is that, although acute effects are primarily caused by parenchymal cell damage, most late effects in normal tissues are due to vascular injury, especially to endothelial cells (7, 9, 18, 24). Recently, hemorrheologic agents have become available
Presentedat the 3 1st Annual Meetingof the American Society for Therapeutic Radiology and Oncology, San Francisco, CA, l-6 October 1989. * Division of Radiation Oncology, Department of Radiology. + Division of Gynecologic Oncology. Reprint requests to: David H. Hussey, M.D., Division of Radiation Oncology (Rm W189Z-GH), University of Iowa Hospitals and Clinics, Iowa City, IA 52242-1059.
Acknowledgements-The authors would like to thank HoechstRoussel Pharmaceuticals, Inc., for their support in this investigation and Ms. Terry Kirk for her assistance in the preparation of this manuscript. Accepted for publication 22 February 1990. * Hoechst-Roussel: Trental 400, Hoechst-Roussel Pharmaceuticals, Inc., Route 202-206 North, Somerville, NJ 08876. 401
402
1. J. Radiation Oncology 0 Biology 0 Physics
subsequent randomized clinical trial, (b) to evaluate dosage schedules and drug toxicity, and (c) to obtain preliminary information regarding the effectiveness of pentoxifylline in the treatment of late radiation injury. This paper is a preliminary report of that pilot study. METHODS
AND MATERIALS
Pentoxifylline Pentoxifylline (3,7-dimethy- 1(Soxyhexyl)-xanthin) is a methyl xanthine derivative which has been approved for the treatment of a variety of vasculo-occlusive disorders. It has been used primarily in the treatment of intermittent claudication (2,6, 16) but it has been reported to be effective in several other disease states, for example, proliferative diabetic retinopathy (2 1), venous stasis disease (17), and cerebrovascular insufficiency (15). Pentoxifylline has been shown to increase tissue oxygen levels significantly in patients with peripheral arterial disease (6) and to improve the survival of compromised surgical flaps and pedicle grafts (13, 23, 26). Mechanisms of action. There are two mechanisms by which pentoxifylline improves blood flow through compromised tissues: (a) by increasing red blood cell deformability (5, 6), and (b) by stimulating prostacyclin release (10, 12). Red blood cell deformability: Red blood cell deformability is necessary in most mammalian systems because erythrocytes are considerably larger than the capillaries through which they must travel. In man, the average erythrocyte measures 7-8 microns in diameter, whereas the capillaries can be as narrow as 3-5 microns. Red blood cell deformability is mainly dependent on the internal
August 1990. Volume 19, Number 2
viscosity of the erythrocyte and the flexibility of the cell membrane. The flexibility of the cell membrane is regulated by the spectrin-actin network which is dependent on pH, calcium levels, osmolarity, and adequate levels of intracellular ATP and CAMP. Through a complex series of chemical reactions, pentoxifylline intervenes in this system to increase intracellular levels of ATP and CAMP (Fig. 1) (14, 22), and this results in improved cell membrane flexibility. Prostacylin effects: Pentoxifylline stimulates the release of prostacyclin from normal endothelial cells (12, 17), and prostacyclin has a number of vascular effects. It is a potent vasodilator, an inhibitor of platelet aggregation (l), and a stimulator of thrombolysis (8). Prostacyclin also decreases fibrinogen levels and increases fibrinolytic activity, both of which increase the fluidity of the blood. Prostacyclin antagonizes the effects of thromboxane on platelets and the effects of platelet derived growth factor (PDGF) on the vessel wall ( 19). PDGF causes the migration and proliferation of vascular smooth muscle and endothelial cells, and as a result is thought to play a role in the etiology of late radiation vasculopathy ( 19). Eficts on irradiated tissues. A previous study from the University of Iowa showed that the prophylactic administration of pentoxifylline can prevent soft tissue radionecrosis in mice (4). In this experiment, C3H mice were allocated to eight groups of 13 mice each, and the right hind limbs irradiated with 4000,5000,6000, or 7000 cGy in 10 fractions over 12 days. Half of the animals at each dose level were treated with daily pentoxifylline and the other half with saline. Pentoxifylline had no effect on acute radiation reactions, but there was a significant difference between the pentoxifylline and the control animals with
Fig. 1. Pentoxifylline (PTX) improves red blood cell deformability through its action on three metabolic pathways: (a) PTX inhibits the action of phosphodiesterase. This delays the inactivation of c-AMP, leading to a build-up of ATP. ATP is needed for the phosphorylation of spectrin which is required for the contraction and relaxation of the spectrin-actin network. (b) PTX also increases the levels of 2,3-DPG which prevents the chelation of ATP by deoxygenated hemoglobin. This again leads to a build-up of ATP and enhanced phosphorylation of spectrin. (c) By increasing 2,3-DPG levels, PTX also indirectly blocks the inactivation of spectrin by dephosphorylation.
Pilot study of pentoxifylline ?? M. W. DION ef al.
regard to late radiation injury. Only 8% of the pentoxifylline treated animals had a late injury score as high as 3.0 and no scores greater than 3.0 (Table 1). In contrast, 42% (24/48) of the control group animals had a late injury score of 3.0 or greater, and some scored as high as 4.5. Side effects. Pentoxifylline, first marketed in Europe in 1972, has been approved for general clinical use in the U.S. since 1984. Consequently, there is considerable clinical experience with this drug. It has been used safely in elderly and chronically ill patients. There are no known drug interactions, and it has been used concurrently with antihypertensive drugs, beta blockers, anticoagulants, digitalis, and diuretics (I 1). Its side effects are mild and mainly involve the gastrointestinal tract (e.g., bloating, dyspepsia, and nausea)
hr. J Radiotim OncologyBiol.Phys..Vol. 19,pp. 401-407 Printed in the U.S.A. All rights reserved.
Copyright
0360-3016/90 $3.M) 0 1990 Pergamon Press plc
0 Phase I/II Clinical Trials PRELIMINARY RESULTS OF A PILOT STUDY OF PENTOXIFYLLINE IN THE TREATMENT OF LATE RADIATION SOFT TISSUE NECROSIS MARK W. DI:ON, M.D.,* DAVID H. HUSSEY, M.D.,* J. FRED DOORNBOS, M.D.,* ANTONIO P. VIGLIOTTI, M.D.,* B.-CHEN WEN, M.D.* AND BARRIE ANDERSON, M.D.? Universityof Iowa College of Medicine, Iowa City, IA BetweenSeptember1988 and August 1989, 12 patients with 15 sites of late radiationnecrosis of the soft tissues were treatedwith pentoxifylline,a hemorrheologicagent that has been used to treat a variety of vasculo-occlusive disorders. Four of these necroses were located in the oromucosa, four in the mucosa of the female genitalia, and seven in the skin. At the time of analysis, 87% (13/E) of the necroses had healed completely, and one was partially healed. Furthermore, the time-course of healing with pentoxifylline was significantly less than the duration of nonhealing prior to pentoxifylline (average: 9 weeks vs 304 weeks). All patients had pain relief. These results indicate that pentoxifylline can contribute to the healing of soft tissue radiation necrosis. They also support the concept that late radiation injury in skin and mucosa is at least partly due to vascular injury. Pentoxifylline,
Radliation therapy, Late radiation injury, Radiation therapy complications.
INTRODUCIION
which improve blood flow through narrowed microvasculature. One of the most effective of these is pentoxifylline*, a drug that is being used clinically to treat a variety of vasculo-occlusive disorders. Pentoxifylline is able to improve blood flow through small capillaries by increasing red blood cell deformability and by stimulating prostacyclin release. If vascular damage plays a major role in the pathogenesis of late radiation injury, pentoxifylline could be an effective means of preventing or treating late radiation therapy complications. Several years ago, a series of experiments was initiated at the University of Iowa to test the effect of pentoxifylline on healing in irradiated and unirradiated normal tissues. In these experiments, pentoxifylline was shown to reduce the incidence and severity of late radiation injury in the irradiated mouse extremity (4) and to enhance healing of full-thickness skin flaps in unirradiated pigskin (26). As an extension of this research, a pilot study was initiated in patients to evaluate the therapeutic effectiveness of pentoxifylline in the management of soft tissue radionecrosis. The specific aims of this pilot study were (a) to define a patient population that might be suitable for a
Late damage to normal tissues is the principal dose limiting factor in radiation .therapy today. This injury not only leads to significant sequelae, but the risk of late complications often causes the radiotherapist to limit the total dose delivered, thus compromising local tumor control. Late radiation effects usually become manifest months or years after radiation therapy has been completed, and consequently, little can be done to ameliorate the injury once damage has occurred. There is considerable controversy regarding the pathogenesis of late radiation injury. One theory is that radiation damage to late responding tissues results primarily from the depletion of parenchymal and stromal cells, and the time difference between acute and late radiation reactions is due to the kinetics of the various cell populations affected (25). A second theory is that, although acute effects are primarily caused by parenchymal cell damage, most late effects in normal tissues are due to vascular injury, especially to endothelial cells (7, 9, 18, 24). Recently, hemorrheologic agents have become available
Presentedat the 3 1st Annual Meetingof the American Society for Therapeutic Radiology and Oncology, San Francisco, CA, l-6 October 1989. * Division of Radiation Oncology, Department of Radiology. + Division of Gynecologic Oncology. Reprint requests to: David H. Hussey, M.D., Division of Radiation Oncology (Rm W189Z-GH), University of Iowa Hospitals and Clinics, Iowa City, IA 52242-1059.
Acknowledgements-The authors would like to thank HoechstRoussel Pharmaceuticals, Inc., for their support in this investigation and Ms. Terry Kirk for her assistance in the preparation of this manuscript. Accepted for publication 22 February 1990. * Hoechst-Roussel: Trental 400, Hoechst-Roussel Pharmaceuticals, Inc., Route 202-206 North, Somerville, NJ 08876. 401
402
1. J. Radiation Oncology 0 Biology 0 Physics
subsequent randomized clinical trial, (b) to evaluate dosage schedules and drug toxicity, and (c) to obtain preliminary information regarding the effectiveness of pentoxifylline in the treatment of late radiation injury. This paper is a preliminary report of that pilot study. METHODS
AND MATERIALS
Pentoxifylline Pentoxifylline (3,7-dimethy- 1(Soxyhexyl)-xanthin) is a methyl xanthine derivative which has been approved for the treatment of a variety of vasculo-occlusive disorders. It has been used primarily in the treatment of intermittent claudication (2,6, 16) but it has been reported to be effective in several other disease states, for example, proliferative diabetic retinopathy (2 1), venous stasis disease (17), and cerebrovascular insufficiency (15). Pentoxifylline has been shown to increase tissue oxygen levels significantly in patients with peripheral arterial disease (6) and to improve the survival of compromised surgical flaps and pedicle grafts (13, 23, 26). Mechanisms of action. There are two mechanisms by which pentoxifylline improves blood flow through compromised tissues: (a) by increasing red blood cell deformability (5, 6), and (b) by stimulating prostacyclin release (10, 12). Red blood cell deformability: Red blood cell deformability is necessary in most mammalian systems because erythrocytes are considerably larger than the capillaries through which they must travel. In man, the average erythrocyte measures 7-8 microns in diameter, whereas the capillaries can be as narrow as 3-5 microns. Red blood cell deformability is mainly dependent on the internal
August 1990. Volume 19, Number 2
viscosity of the erythrocyte and the flexibility of the cell membrane. The flexibility of the cell membrane is regulated by the spectrin-actin network which is dependent on pH, calcium levels, osmolarity, and adequate levels of intracellular ATP and CAMP. Through a complex series of chemical reactions, pentoxifylline intervenes in this system to increase intracellular levels of ATP and CAMP (Fig. 1) (14, 22), and this results in improved cell membrane flexibility. Prostacylin effects: Pentoxifylline stimulates the release of prostacyclin from normal endothelial cells (12, 17), and prostacyclin has a number of vascular effects. It is a potent vasodilator, an inhibitor of platelet aggregation (l), and a stimulator of thrombolysis (8). Prostacyclin also decreases fibrinogen levels and increases fibrinolytic activity, both of which increase the fluidity of the blood. Prostacyclin antagonizes the effects of thromboxane on platelets and the effects of platelet derived growth factor (PDGF) on the vessel wall ( 19). PDGF causes the migration and proliferation of vascular smooth muscle and endothelial cells, and as a result is thought to play a role in the etiology of late radiation vasculopathy ( 19). Eficts on irradiated tissues. A previous study from the University of Iowa showed that the prophylactic administration of pentoxifylline can prevent soft tissue radionecrosis in mice (4). In this experiment, C3H mice were allocated to eight groups of 13 mice each, and the right hind limbs irradiated with 4000,5000,6000, or 7000 cGy in 10 fractions over 12 days. Half of the animals at each dose level were treated with daily pentoxifylline and the other half with saline. Pentoxifylline had no effect on acute radiation reactions, but there was a significant difference between the pentoxifylline and the control animals with
Fig. 1. Pentoxifylline (PTX) improves red blood cell deformability through its action on three metabolic pathways: (a) PTX inhibits the action of phosphodiesterase. This delays the inactivation of c-AMP, leading to a build-up of ATP. ATP is needed for the phosphorylation of spectrin which is required for the contraction and relaxation of the spectrin-actin network. (b) PTX also increases the levels of 2,3-DPG which prevents the chelation of ATP by deoxygenated hemoglobin. This again leads to a build-up of ATP and enhanced phosphorylation of spectrin. (c) By increasing 2,3-DPG levels, PTX also indirectly blocks the inactivation of spectrin by dephosphorylation.
Pilot study of pentoxifylline ?? M. W. DION ef al.
regard to late radiation injury. Only 8% of the pentoxifylline treated animals had a late injury score as high as 3.0 and no scores greater than 3.0 (Table 1). In contrast, 42% (24/48) of the control group animals had a late injury score of 3.0 or greater, and some scored as high as 4.5. Side effects. Pentoxifylline, first marketed in Europe in 1972, has been approved for general clinical use in the U.S. since 1984. Consequently, there is considerable clinical experience with this drug. It has been used safely in elderly and chronically ill patients. There are no known drug interactions, and it has been used concurrently with antihypertensive drugs, beta blockers, anticoagulants, digitalis, and diuretics (I 1). Its side effects are mild and mainly involve the gastrointestinal tract (e.g., bloating, dyspepsia, and nausea)
