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A novel method to control severe upper GI bleeding from metastatic cancer with a hemostatic sealant: The CoStasis surgical hemostat
GI bleeding (metastatic cancer): control by hemostatic sealant
CASE REPORTS A novel method to control severe upper GI bleeding from metastatic cancer with a hemostatic sealant: the CoStasis surgical hemostat
D Milkes, S Friedland, O Lin, et al.
be used at the time of diagnosis would be beneficial. The application of a hemostatic sealant over the surface of bleeding tumors may be an effective method to achieve hemostasis. This is a report of the successful treatment of 2 patients with severe bleeding from metastatic lung cancer to the upper GI tract by using the CoStasis Surgical Hemostat (Cohesion, Inc., Palo Alto, Calif.), a novel collagen-fibrin sealant. CASE REPORTS
David E. Milkes, MD, Shai Friedland, MD, Otto S. Lin, MD, Tony R. Reid, MD, PhD, Roy M. Soetikno, MD, MS
Control of diffuse bleeding from primary and metastatic cancers in the GI tract is often difficult.13 Although surgery is an option, it is infrequently performed in patients with metastatic cancer who are often debilitated and have limited life expectancy. Angiography with embolization of feeding vessels can be used for brisk bleeding, but this may be difficult when multiple lesions are present. Endotherapy by injection, Nd:YAG laser photocoagulation, microwave coagulation, and electrocoagulation have been used with limited efficacy.2-7 Because endoscopy is the standard modality for the diagnosis of bleeding metastatic tumors in the GI tract, a simple, safe, and effective endoscopic treatment that could Current affiliations: Department of Medicine, Veterans Affairs Palo Alto Health Care System and Stanford University School of Medicine, Palo Alto, California. Reprint requests: Roy M. Soetikno, MD, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., GI 111, Palo Alto, CA 94305. 37/4/122796 doi:10.1067/mge.2002.122796 VOLUME 55, NO. 6, 2002
The CoStasis Surgical Hemostat is a Food and Drug Administration–approved device that is packaged in a kit. CoStasis is comprised of 2 separate components. One component, supplied in a syringe, is a sterile suspension of bovine fibrillar collagen (20 mg/mL) and bovine thrombin (500 U/mL) in a calcium chloride buffer (40 mmol/L). The other component is prepared from the patient’s blood immediately before the procedure. Fifteen milliliters of blood are drawn into a supplied centrifuge container, which is then spun at 1380g for 2 minutes with a portable centrifuge. The resultant platelet-rich plasma is transferred to a syringe. A support adaptor holds the plasma syringe and the collagen-thrombin syringe barrels together, and a special mixing nozzle is attached (Fig. 1). Depression of the plungers results in equal rates of delivery from each syringe such that the components are evenly mixed by the special nozzle. Because the CoStasis delivery system is designed for use during open surgical procedures, it was necessary to modify the device for endoscopic use. For the first patient, a standard ERCP cannulation catheter (Microvasive Endoscopy, Inc., Natick, Mass.) was attached to the mixing nozzle and passed through the accessory channel of a colonoscope (CF2T140, Olympus America, Inc., Melville, N.Y.). For the second patient, a 10F Oasis stent delivery GASTROINTESTINAL ENDOSCOPY
735
D Milkes, S Friedland, O Lin, et al.
GI bleeding (metastatic cancer): control by hemostatic sealant
A
Figure 1. CoStasis Surgical Hemostat. Collagen/thrombin suspension is stored at 40°C until needed. Patient’s plasma can be collected and prepared up to several hours before use. Depression of plungers provides equal rates of delivery of components from each syringe, which are mixed together by the special nozzle. This nozzle is attached to an endoscopic catheter. catheter sheath (Wilson-Cook Medical, Inc., WinstonSalem, N.C.) was used with an upper endoscope (GIF2T100, Olympus). Informed consent was obtained from both patients before the CoStasis Surgical Hemostat was used, and the proposed treatment was discussed with our institutional review board. Case 1 A 64-year-old man with metastatic adenocarcinoma of the lung was admitted with melena. Two months before admission, a diagnosis of metastases to the brain and spine was made for which the patient was treated with corticosteroids, external beam radiation, and chemotherapy. His medical history was notable only for diabetes mellitus. On admission, examination was remarkable for cachexia and melena. The admission hematocrit was 17% (39%-51%). Enteroscopy revealed a 1-cm ulcerated mass in the duodenum, and 3 other irregular masses that measured up to 2 cm in the proximal jejunum. Fresh blood was slowly oozing from the lesions in the jejunum. Biopsies of the masses confirmed adenocarcinoma. Despite 2 separate endoscopies involving epinephrine injections into the masses and argon plasma coagulation, the patient continued to have melena daily and was transfused a total of 24 units of packed red blood cells over 2 weeks. The patient was considered by consultants to be a poor candidate for surgery and for arterial embolization. The patient primarily wanted palliative therapy and discharge home; placement in an inpatient hospice ward with frequent blood transfusions was unacceptable. The 736
GASTROINTESTINAL ENDOSCOPY
B Figure 2. A, Endoscopic view of delivery catheter positioned at site of large lesion in proximal jejunum. B, Endoscopic view after application of CoStasis showing entire lesion covered by viscous solution. patient agreed to another enteroscopy with use of CoStasis on a compassionate basis. Enteroscopy revealed oozing of blood from the surface of 2 of the 4 lesions. Approximately 30 mL of CoStasis were applied, starting with the most distal lesion, such that all 4 lesions were completely covered. All of the sealant was delivered within 2 minutes to prevent premature cross-linking and clogging of the catheter. Minimal resistance was noted while depressing the plungers of the delivery system. CoStasis was successfully delivered through the endoscope (Fig. 2) without complication. Initial hemostasis was achieved with the formation of an opaque gelatinous coagulum covering the lesions. Treatment with orally administered lansoprazole, 30 mg twice daily, was continued. The hematocrit remained stable and the patient was discharged home 2 days after application of CoStasis. He had no further episodes of melena or overt GI bleeding until death 6 weeks later. During the 30 days before CoStasis application the patient received 24 units of blood versus 4 units during the 30 days after the treatment. VOLUME 55, NO. 6, 2002
GI bleeding (metastatic cancer): control by hemostatic sealant
D Milkes, S Friedland, O Lin, et al.
A
B
C
D
Figure 3. A, Endoscopic view of multiple large friable masses in stomach. Large mass on anterior wall has central ulceration; smaller masses with whitish exudates present on posterior wall. B, Generous application of CoStasis to surface of mass. C and D, Endoscopic views 4 weeks later showing absence of frank ulcerations. Case 2 A 55-year-old man with metastatic squamous cell carcinoma of the lung was admitted with melena. He had a metastatic subcutaneous mass on his back and had been treated with carboplatin and taxol chemotherapy, as well as external beam radiation. There was no significant comorbid condition. Examination was remarkable for tachycardia and melena. The admission hematocrit was 17% and he was transfused 7 units of packed red blood cells over the ensuing 5 days. Upper endoscopy revealed three 2 to 3 cm nodular masses and one 4.5-cm × 7-cm nodular mass in the proximal body of the stomach; blood was oozing diffusely from all 4 lesions. An oozing central ulcer in the largest mass was injected with 3 mL of epinephrine solution (1:10,000), and all visible oozing areas were treated with argon plasma coagulation. Initial hemostasis was achieved, and biopsies of the masses confirmed squamous cell carcinoma. However, the patient had recurrent bleeding requiring transfer to the intensive care unit VOLUME 55, NO. 6, 2002
and transfusion of 5 units of packed red blood cells. He refused surgery. Consultants concluded that the patient was not a suitable candidate for arterial embolization and was too unstable to receive chemotherapy. Because the endoscopic treatments had been unsuccessful, the patient agreed to endoscopic application of CoStasis. Endoscopy again revealed slow oozing of blood diffusely from all 4 gastric masses. Approximately 30 mL of CoStasis were applied, starting with the most distal lesion, such that all lesions were completely covered. The sealant was applied easily within 2 minutes and there was no complication. Initial hemostasis was achieved with an opaque coagulum coating the masses. Treatment was continued with orally administered lansoprazole, 30 mg twice daily. The patient remained hemodynamically stable with no overt GI bleeding and was able to undergo additional chemotherapy with gemcitabine starting 3 days after treatment with CoStasis. There was no recurrent melena or overt GI bleeding during 9 weeks of follow-up. Endoscopy 4 weeks after CoStasis demonstrated a GASTROINTESTINAL ENDOSCOPY
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D Milkes, S Friedland, O Lin, et al.
Figure 4. Hematocrit values in second patient before and after application of CoStasis (asterisk). Before treatment, 12 units of packed red blood cells (red drop = 1 unit) were transfused. After application of CoStasis, patient underwent chemotherapy and was treated with an iron supplement. decrease in size of the largest gastric mass to 3.5 × 5.5 cm and complete resolution of the central ulcer (Fig. 3). The metastatic subcutaneous mass was also measurably smaller after chemotherapy, having decreased from 5 cm to 2.5 cm. The anemia improved with iron supplementation. During the 30 days before CoStasis application the patient was transfused 12 units of blood versus no further transfusions after treatment (Fig. 4).
DISCUSSION This is the first report of the endoscopic use of CoStasis to successfully control bleeding in 2 patients with metastatic lung cancer to the upper GI tract. Both patients had continuous bleeding from the surface of multiple metastatic lesions and had no other satisfactory treatment option. The lack of therapeutic options for these 2 patients led us to seek novel treatments and subsequently to develop the technique necessary to deliver the hemostatic sealant effectively through the endoscope. These 2 cases clearly demonstrate the feasibility of delivering CoStasis endoscopically. Because CoStasis dramatically stopped the bleeding in the first case, it can be concluded that this treatment was responsible for the long-term hemostatic control rather than spontaneous resolution of bleeding. In the second case, CoStasis provided short-term hemostatic control that enabled effective chemotherapy, and CoStasis may have contributed to ulcer healing and long-term hemostasis. The respective contributions of CoStasis, chemotherapy, and treatment with a proton pump inhibitor to the control of bleeding cannot be determined. However, the control of bleeding achieved in these 2 cases highlights the potential benefits of this novel treatment. CoStasis, a hemostatic agent for use during surgical procedures, is composed of a sterile suspension of bovine fibrillar collagen and thrombin that is mixed with the patient’s own platelet-rich plasma during its application. The CoStasis suspension pro738
GASTROINTESTINAL ENDOSCOPY
GI bleeding (metastatic cancer): control by hemostatic sealant
vides activated thrombin and microfibrillar collagen, whereas the patient’s own plasma acts as a source of platelets and fibrinogen. The mixing of these components enables the bovine thrombin to convert fibrinogen to fibrin and leads to formation of a collagen-reinforced fibrin clot at the bleeding surface.8 The resultant clot adheres to the bleeding site and acts as a sealant that prevents further bleeding.8 The components in CoStasis efficiently activate both the intrinsic and the extrinsic coagulation pathways, whereas the platelet aggregation effect of collagen and thrombin serves as an additional mechanism of hemostasis.8 Several studies have demonstrated the ability of CoStasis to control diffuse bleeding in patients undergoing various types of surgery.9-12 In a randomized, controlled prospective trial of 318 patients undergoing general, hepatic, orthopedic, and cardiac operations, control of bleeding was more effective in CoStasis-treated patients (>90%) compared with treatment with a collagen sponge and tamponade in a control group of patients (58%).9 There were no adverse reactions in the treatment group. CoStasis has also performed well in animal models in comparison with fibrin sealants.8 Studies in animals have even demonstrated the efficacy of CoStasis in the setting of aspirin-mediated platelet dysfunction and heparin anticoagulation.13 Fibrin sealants have been injected endoscopically to stop active bleeding from peptic ulcers, but to our knowledge they have not been used to treat bleeding GI tumors.14,15 CoStasis offers several theoretical advantages over other available fibrin sealants. By using autologous plasma, CoStasis carries no risk of transmission of bloodborne disease whereas fibrin sealants, which contain factors from pooled human blood, may transmit disease.15 The collagen and platelets in CoStasis reinforce the coagulum, and may therefore provide a more durable seal than traditional fibrin sealants. Although the CoStasis mixture is viscous, it is still easily delivered through a standard ERCP catheter. Fibrin sealants are substantially more viscous and difficult to deliver through a similar catheter.16 Formation of microthrombi on the surface of bleeding lesions covered with CoStasis has been demonstrated in animal studies, and it is likely that immediate hemostasis occurs through this mechanism. However, the precise mechanism by which CoStasis provided long-term hemostasis in our first patient is unclear. In animal studies, the application of CoStasis has been shown to lead to formation of granulation tissue over the cut surface. In our 2 patients, follow-up biopsies were not performed, but the endoscopic appearance 4 weeks after treatment VOLUME 55, NO. 6, 2002
GI bleeding (metastatic cancer): control by hemostatic sealant
in our second patient (Fig. 3) suggests that CoStasis may have contributed to ulcer healing, although this occurred during treatment with a proton pump inhibitor and chemotherapy, and thus the contribution of CoStasis is unclear. Other endotherapies have been found to have limited efficacy in the treatment of patients bleeding from upper GI malignant lesions. Loftus et al.2 used a variety of endoscopic therapies including epinephrine injection, heat probe coagulation, Nd:YAG laser photocoagulation, and sclerosant injection to treat 15 patients. Hemostasis was achieved initially in 10 patients (67%); however, there was persistent or recurrent bleeding in 13 patients (87%). The treatment did not change the transfusion requirement significantly. Five major complications occurred in relation to 32 endoscopic procedures (16%) including perforation in two patients who underwent heat probe coagulation, iatrogenic hemorrhage in two others, and cardiac arrest in one. These investigators cautioned specifically against the use of the heat probe in this setting because of the high rate of perforation, and consequently argon plasma coagulation was tried in our two patients in an attempt to produce a more controlled, superficial coagulation. Savides et al.3 treated 42 patients, 7 by thermal probe, epinephrine injection, or both. All 7 patients had active, focal oozing from a single site and endoscopic hemostasis was accomplished in all 7 patients (100%). However, the rates of recurrent bleeding were similar in treated and untreated patients, 34% and 29%, respectively. MathusVliegen and Tytgat5 described 16 patients with gastric carcinoma, most with bleeding, who underwent Nd:YAG photocoagulation, with effective palliation in 81% and a major bleeding complication rate of 13%. Suzuki et al.4 used a Nd:YAG laser to treat 17 patients with bleeding gastric malignancies; the hemostasis rate was 94% and rate of recurrent bleeding 19%. Application of CoStasis to achieve hemostasis in bleeding GI lesions has several potential advantages. Diffusely bleeding lesions such as tumors are easily covered by the viscous solution. Delayed ulceration, associated with cautery and sclerosants, is avoided. No bulky and expensive equipment, such as the Nd:YAG laser, is required. And no special training is necessary. The CoStasis system has been demonstrated to be effective for the control of bleeding in major surgical procedures and in various animal models. The unique collagen-thrombin matrix strengthens the sealant and may also promote wound healing. Because of the limited efficacy and high frequency of complications associated with current endoVOLUME 55, NO. 6, 2002
D Milkes, S Friedland, O Lin, et al.
scopic treatments for bleeding GI tumors, our preliminary experience in two patients suggests that CoStasis may be valuable in this patient group. CoStasis may be particularly suited to diffusely bleeding lesions and large ulcers. In addition, CoStasis might also become a useful adjunct to standard techniques for treatment of common lesions such as bleeding ulcer, in which it could potentially aid in wound healing. Further studies with CoStasis to determine the optimal method of delivery through the endoscope, exact mechanism of action, and efficacy in the treatment of various types of GI bleeding are needed. ACKNOWLEDGEMENTS We thank Frank DeLustro, PhD, and Marcee Maroney, MS, of Cohesion Technologies, Inc., Palo Alto, California for their advice on use of CoStasis and the materials used in this report. DISCLOSURE The authors of this manuscript have no financial interest in Cohesion Technologies and have not received financial support from the company. REFERENCES 1. Randall GM, Jensen DM. Diagnosis and management of bleeding from upper gastrointestinal neoplasms. Gastrointest Endosc Clin N Am 1991;1:401-27. 2. Loftus EV, Alexander GL, Ahlquist DA, Balm RK. Endoscopic treatment of major bleeding from advanced gastroduodenal malignant lesions. Mayo Clin Proc 1994;69:736-40. 3. Savides TJ, Jensen DM, Cohen J, Randall GM, Kovacs TO, Pelayo S, et al. Severe upper gastrointestinal tumor bleeding: endoscopic findings, treatment, and outcome. Endoscopy 1996;28:244-8. 4. Suzuki H, Miho O, Watanabe Y, Kohyama M, Nagao F. Endoscopic laser therapy in the curative and palliative treatment of upper gastrointestinal cancer. World J Surg 1989; 13:158-64. 5. Mathus-Vliegen EM, Tytgat GN. Analysis of failures and complications of Neodymium:YAG laser photocoagulation in gastrointestinal tract tumors: a retrospective survey of 8 years’ experience. Endoscopy 1990;22:17-23. 6. Tajika M, Kato T, Nagaki M, Kato M, Fukutomi Y, Ninomiya M, et al. Endoscopic injection of gelatin solution for severe hemorrhagic gastric cancer. Gastrointest Endosc 1996;43: 247-50. 7. Tabuse K, Katsumi M, Nagai Y, Kobayashi Y, Noguchi H, Egawa H, et al. Microwave tissue coagulation applied clinically in endoscopic surgery. Endoscopy 1985;17:139-44. 8. Prior JJ, Wallace DG, Harner A, Powers N. A sprayable hemostat containing fibrillar collagen, bovine thrombin, and autologous plasma. Ann Thorac Surg 1999;68:479-85. 9. The CoStasis Multi-center Collaborative Writing Committee. A novel collagen-based composite offers effective hemostasis for multiple surgical indications: results of a randomized controlled trial. Surgery 2001;129:445-50. 10. Chapman WC, Clavien PA, Fung J, Khanna A, Bonham A. Effective control of hepatic bleeding with a novel collagenGASTROINTESTINAL ENDOSCOPY
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based composite combined with autologous plasma: results of a randomized controlled trial. Arch Surg 2000;135:1200-4. 11. Buncke GM, Sherman R. CoStasis provides superior control of diffuse bleeding at muscle-flap donor sites, compared to manual compression. J Reconstructr Microsurg 2000;16:557-61. 12. Turley K. Aortic homograft root replacement for failed freehand homograft aortic valve: effectiveness of a collagen/ thrombin/plasma composite hemostat in the setting of technically complicated homograft to root anastomosis. Heart Surg Forum 1999;2:143-6. 13. Prior JJ, Powers N, DeLustro F. Efficacy of a novel hemostat-
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ic agent in animal models of impaired hemostasis. J Biomed Material Res 2000;53:252-7. 14. Rutgeerts P, Rauws E, Wara P, Swain P, Hoos A, Solleder E, et al. Randomized trial of single and repeated fibrin glue compared with injection of polidocanol in treatment of bleeding peptic ulcer. Lancet 1997;350:692-6. 15. Dunn CJ, Goa KL. Fibrin sealant: a review of its use in surgery and endoscopy. Drugs 1999;58:863-86. 16. Nagelschmidt M. Endoscopic use of fibrin adhesives: problems when injecting through long catheters. Surg Endosc 1999;13:80-2.
VOLUME 55, NO. 6, 2002
CASE REPORTS A novel method to control severe upper GI bleeding from metastatic cancer with a hemostatic sealant: the CoStasis surgical hemostat
D Milkes, S Friedland, O Lin, et al.
be used at the time of diagnosis would be beneficial. The application of a hemostatic sealant over the surface of bleeding tumors may be an effective method to achieve hemostasis. This is a report of the successful treatment of 2 patients with severe bleeding from metastatic lung cancer to the upper GI tract by using the CoStasis Surgical Hemostat (Cohesion, Inc., Palo Alto, Calif.), a novel collagen-fibrin sealant. CASE REPORTS
David E. Milkes, MD, Shai Friedland, MD, Otto S. Lin, MD, Tony R. Reid, MD, PhD, Roy M. Soetikno, MD, MS
Control of diffuse bleeding from primary and metastatic cancers in the GI tract is often difficult.13 Although surgery is an option, it is infrequently performed in patients with metastatic cancer who are often debilitated and have limited life expectancy. Angiography with embolization of feeding vessels can be used for brisk bleeding, but this may be difficult when multiple lesions are present. Endotherapy by injection, Nd:YAG laser photocoagulation, microwave coagulation, and electrocoagulation have been used with limited efficacy.2-7 Because endoscopy is the standard modality for the diagnosis of bleeding metastatic tumors in the GI tract, a simple, safe, and effective endoscopic treatment that could Current affiliations: Department of Medicine, Veterans Affairs Palo Alto Health Care System and Stanford University School of Medicine, Palo Alto, California. Reprint requests: Roy M. Soetikno, MD, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., GI 111, Palo Alto, CA 94305. 37/4/122796 doi:10.1067/mge.2002.122796 VOLUME 55, NO. 6, 2002
The CoStasis Surgical Hemostat is a Food and Drug Administration–approved device that is packaged in a kit. CoStasis is comprised of 2 separate components. One component, supplied in a syringe, is a sterile suspension of bovine fibrillar collagen (20 mg/mL) and bovine thrombin (500 U/mL) in a calcium chloride buffer (40 mmol/L). The other component is prepared from the patient’s blood immediately before the procedure. Fifteen milliliters of blood are drawn into a supplied centrifuge container, which is then spun at 1380g for 2 minutes with a portable centrifuge. The resultant platelet-rich plasma is transferred to a syringe. A support adaptor holds the plasma syringe and the collagen-thrombin syringe barrels together, and a special mixing nozzle is attached (Fig. 1). Depression of the plungers results in equal rates of delivery from each syringe such that the components are evenly mixed by the special nozzle. Because the CoStasis delivery system is designed for use during open surgical procedures, it was necessary to modify the device for endoscopic use. For the first patient, a standard ERCP cannulation catheter (Microvasive Endoscopy, Inc., Natick, Mass.) was attached to the mixing nozzle and passed through the accessory channel of a colonoscope (CF2T140, Olympus America, Inc., Melville, N.Y.). For the second patient, a 10F Oasis stent delivery GASTROINTESTINAL ENDOSCOPY
735
D Milkes, S Friedland, O Lin, et al.
GI bleeding (metastatic cancer): control by hemostatic sealant
A
Figure 1. CoStasis Surgical Hemostat. Collagen/thrombin suspension is stored at 40°C until needed. Patient’s plasma can be collected and prepared up to several hours before use. Depression of plungers provides equal rates of delivery of components from each syringe, which are mixed together by the special nozzle. This nozzle is attached to an endoscopic catheter. catheter sheath (Wilson-Cook Medical, Inc., WinstonSalem, N.C.) was used with an upper endoscope (GIF2T100, Olympus). Informed consent was obtained from both patients before the CoStasis Surgical Hemostat was used, and the proposed treatment was discussed with our institutional review board. Case 1 A 64-year-old man with metastatic adenocarcinoma of the lung was admitted with melena. Two months before admission, a diagnosis of metastases to the brain and spine was made for which the patient was treated with corticosteroids, external beam radiation, and chemotherapy. His medical history was notable only for diabetes mellitus. On admission, examination was remarkable for cachexia and melena. The admission hematocrit was 17% (39%-51%). Enteroscopy revealed a 1-cm ulcerated mass in the duodenum, and 3 other irregular masses that measured up to 2 cm in the proximal jejunum. Fresh blood was slowly oozing from the lesions in the jejunum. Biopsies of the masses confirmed adenocarcinoma. Despite 2 separate endoscopies involving epinephrine injections into the masses and argon plasma coagulation, the patient continued to have melena daily and was transfused a total of 24 units of packed red blood cells over 2 weeks. The patient was considered by consultants to be a poor candidate for surgery and for arterial embolization. The patient primarily wanted palliative therapy and discharge home; placement in an inpatient hospice ward with frequent blood transfusions was unacceptable. The 736
GASTROINTESTINAL ENDOSCOPY
B Figure 2. A, Endoscopic view of delivery catheter positioned at site of large lesion in proximal jejunum. B, Endoscopic view after application of CoStasis showing entire lesion covered by viscous solution. patient agreed to another enteroscopy with use of CoStasis on a compassionate basis. Enteroscopy revealed oozing of blood from the surface of 2 of the 4 lesions. Approximately 30 mL of CoStasis were applied, starting with the most distal lesion, such that all 4 lesions were completely covered. All of the sealant was delivered within 2 minutes to prevent premature cross-linking and clogging of the catheter. Minimal resistance was noted while depressing the plungers of the delivery system. CoStasis was successfully delivered through the endoscope (Fig. 2) without complication. Initial hemostasis was achieved with the formation of an opaque gelatinous coagulum covering the lesions. Treatment with orally administered lansoprazole, 30 mg twice daily, was continued. The hematocrit remained stable and the patient was discharged home 2 days after application of CoStasis. He had no further episodes of melena or overt GI bleeding until death 6 weeks later. During the 30 days before CoStasis application the patient received 24 units of blood versus 4 units during the 30 days after the treatment. VOLUME 55, NO. 6, 2002
GI bleeding (metastatic cancer): control by hemostatic sealant
D Milkes, S Friedland, O Lin, et al.
A
B
C
D
Figure 3. A, Endoscopic view of multiple large friable masses in stomach. Large mass on anterior wall has central ulceration; smaller masses with whitish exudates present on posterior wall. B, Generous application of CoStasis to surface of mass. C and D, Endoscopic views 4 weeks later showing absence of frank ulcerations. Case 2 A 55-year-old man with metastatic squamous cell carcinoma of the lung was admitted with melena. He had a metastatic subcutaneous mass on his back and had been treated with carboplatin and taxol chemotherapy, as well as external beam radiation. There was no significant comorbid condition. Examination was remarkable for tachycardia and melena. The admission hematocrit was 17% and he was transfused 7 units of packed red blood cells over the ensuing 5 days. Upper endoscopy revealed three 2 to 3 cm nodular masses and one 4.5-cm × 7-cm nodular mass in the proximal body of the stomach; blood was oozing diffusely from all 4 lesions. An oozing central ulcer in the largest mass was injected with 3 mL of epinephrine solution (1:10,000), and all visible oozing areas were treated with argon plasma coagulation. Initial hemostasis was achieved, and biopsies of the masses confirmed squamous cell carcinoma. However, the patient had recurrent bleeding requiring transfer to the intensive care unit VOLUME 55, NO. 6, 2002
and transfusion of 5 units of packed red blood cells. He refused surgery. Consultants concluded that the patient was not a suitable candidate for arterial embolization and was too unstable to receive chemotherapy. Because the endoscopic treatments had been unsuccessful, the patient agreed to endoscopic application of CoStasis. Endoscopy again revealed slow oozing of blood diffusely from all 4 gastric masses. Approximately 30 mL of CoStasis were applied, starting with the most distal lesion, such that all lesions were completely covered. The sealant was applied easily within 2 minutes and there was no complication. Initial hemostasis was achieved with an opaque coagulum coating the masses. Treatment was continued with orally administered lansoprazole, 30 mg twice daily. The patient remained hemodynamically stable with no overt GI bleeding and was able to undergo additional chemotherapy with gemcitabine starting 3 days after treatment with CoStasis. There was no recurrent melena or overt GI bleeding during 9 weeks of follow-up. Endoscopy 4 weeks after CoStasis demonstrated a GASTROINTESTINAL ENDOSCOPY
737
D Milkes, S Friedland, O Lin, et al.
Figure 4. Hematocrit values in second patient before and after application of CoStasis (asterisk). Before treatment, 12 units of packed red blood cells (red drop = 1 unit) were transfused. After application of CoStasis, patient underwent chemotherapy and was treated with an iron supplement. decrease in size of the largest gastric mass to 3.5 × 5.5 cm and complete resolution of the central ulcer (Fig. 3). The metastatic subcutaneous mass was also measurably smaller after chemotherapy, having decreased from 5 cm to 2.5 cm. The anemia improved with iron supplementation. During the 30 days before CoStasis application the patient was transfused 12 units of blood versus no further transfusions after treatment (Fig. 4).
DISCUSSION This is the first report of the endoscopic use of CoStasis to successfully control bleeding in 2 patients with metastatic lung cancer to the upper GI tract. Both patients had continuous bleeding from the surface of multiple metastatic lesions and had no other satisfactory treatment option. The lack of therapeutic options for these 2 patients led us to seek novel treatments and subsequently to develop the technique necessary to deliver the hemostatic sealant effectively through the endoscope. These 2 cases clearly demonstrate the feasibility of delivering CoStasis endoscopically. Because CoStasis dramatically stopped the bleeding in the first case, it can be concluded that this treatment was responsible for the long-term hemostatic control rather than spontaneous resolution of bleeding. In the second case, CoStasis provided short-term hemostatic control that enabled effective chemotherapy, and CoStasis may have contributed to ulcer healing and long-term hemostasis. The respective contributions of CoStasis, chemotherapy, and treatment with a proton pump inhibitor to the control of bleeding cannot be determined. However, the control of bleeding achieved in these 2 cases highlights the potential benefits of this novel treatment. CoStasis, a hemostatic agent for use during surgical procedures, is composed of a sterile suspension of bovine fibrillar collagen and thrombin that is mixed with the patient’s own platelet-rich plasma during its application. The CoStasis suspension pro738
GASTROINTESTINAL ENDOSCOPY
GI bleeding (metastatic cancer): control by hemostatic sealant
vides activated thrombin and microfibrillar collagen, whereas the patient’s own plasma acts as a source of platelets and fibrinogen. The mixing of these components enables the bovine thrombin to convert fibrinogen to fibrin and leads to formation of a collagen-reinforced fibrin clot at the bleeding surface.8 The resultant clot adheres to the bleeding site and acts as a sealant that prevents further bleeding.8 The components in CoStasis efficiently activate both the intrinsic and the extrinsic coagulation pathways, whereas the platelet aggregation effect of collagen and thrombin serves as an additional mechanism of hemostasis.8 Several studies have demonstrated the ability of CoStasis to control diffuse bleeding in patients undergoing various types of surgery.9-12 In a randomized, controlled prospective trial of 318 patients undergoing general, hepatic, orthopedic, and cardiac operations, control of bleeding was more effective in CoStasis-treated patients (>90%) compared with treatment with a collagen sponge and tamponade in a control group of patients (58%).9 There were no adverse reactions in the treatment group. CoStasis has also performed well in animal models in comparison with fibrin sealants.8 Studies in animals have even demonstrated the efficacy of CoStasis in the setting of aspirin-mediated platelet dysfunction and heparin anticoagulation.13 Fibrin sealants have been injected endoscopically to stop active bleeding from peptic ulcers, but to our knowledge they have not been used to treat bleeding GI tumors.14,15 CoStasis offers several theoretical advantages over other available fibrin sealants. By using autologous plasma, CoStasis carries no risk of transmission of bloodborne disease whereas fibrin sealants, which contain factors from pooled human blood, may transmit disease.15 The collagen and platelets in CoStasis reinforce the coagulum, and may therefore provide a more durable seal than traditional fibrin sealants. Although the CoStasis mixture is viscous, it is still easily delivered through a standard ERCP catheter. Fibrin sealants are substantially more viscous and difficult to deliver through a similar catheter.16 Formation of microthrombi on the surface of bleeding lesions covered with CoStasis has been demonstrated in animal studies, and it is likely that immediate hemostasis occurs through this mechanism. However, the precise mechanism by which CoStasis provided long-term hemostasis in our first patient is unclear. In animal studies, the application of CoStasis has been shown to lead to formation of granulation tissue over the cut surface. In our 2 patients, follow-up biopsies were not performed, but the endoscopic appearance 4 weeks after treatment VOLUME 55, NO. 6, 2002
GI bleeding (metastatic cancer): control by hemostatic sealant
in our second patient (Fig. 3) suggests that CoStasis may have contributed to ulcer healing, although this occurred during treatment with a proton pump inhibitor and chemotherapy, and thus the contribution of CoStasis is unclear. Other endotherapies have been found to have limited efficacy in the treatment of patients bleeding from upper GI malignant lesions. Loftus et al.2 used a variety of endoscopic therapies including epinephrine injection, heat probe coagulation, Nd:YAG laser photocoagulation, and sclerosant injection to treat 15 patients. Hemostasis was achieved initially in 10 patients (67%); however, there was persistent or recurrent bleeding in 13 patients (87%). The treatment did not change the transfusion requirement significantly. Five major complications occurred in relation to 32 endoscopic procedures (16%) including perforation in two patients who underwent heat probe coagulation, iatrogenic hemorrhage in two others, and cardiac arrest in one. These investigators cautioned specifically against the use of the heat probe in this setting because of the high rate of perforation, and consequently argon plasma coagulation was tried in our two patients in an attempt to produce a more controlled, superficial coagulation. Savides et al.3 treated 42 patients, 7 by thermal probe, epinephrine injection, or both. All 7 patients had active, focal oozing from a single site and endoscopic hemostasis was accomplished in all 7 patients (100%). However, the rates of recurrent bleeding were similar in treated and untreated patients, 34% and 29%, respectively. MathusVliegen and Tytgat5 described 16 patients with gastric carcinoma, most with bleeding, who underwent Nd:YAG photocoagulation, with effective palliation in 81% and a major bleeding complication rate of 13%. Suzuki et al.4 used a Nd:YAG laser to treat 17 patients with bleeding gastric malignancies; the hemostasis rate was 94% and rate of recurrent bleeding 19%. Application of CoStasis to achieve hemostasis in bleeding GI lesions has several potential advantages. Diffusely bleeding lesions such as tumors are easily covered by the viscous solution. Delayed ulceration, associated with cautery and sclerosants, is avoided. No bulky and expensive equipment, such as the Nd:YAG laser, is required. And no special training is necessary. The CoStasis system has been demonstrated to be effective for the control of bleeding in major surgical procedures and in various animal models. The unique collagen-thrombin matrix strengthens the sealant and may also promote wound healing. Because of the limited efficacy and high frequency of complications associated with current endoVOLUME 55, NO. 6, 2002
D Milkes, S Friedland, O Lin, et al.
scopic treatments for bleeding GI tumors, our preliminary experience in two patients suggests that CoStasis may be valuable in this patient group. CoStasis may be particularly suited to diffusely bleeding lesions and large ulcers. In addition, CoStasis might also become a useful adjunct to standard techniques for treatment of common lesions such as bleeding ulcer, in which it could potentially aid in wound healing. Further studies with CoStasis to determine the optimal method of delivery through the endoscope, exact mechanism of action, and efficacy in the treatment of various types of GI bleeding are needed. ACKNOWLEDGEMENTS We thank Frank DeLustro, PhD, and Marcee Maroney, MS, of Cohesion Technologies, Inc., Palo Alto, California for their advice on use of CoStasis and the materials used in this report. DISCLOSURE The authors of this manuscript have no financial interest in Cohesion Technologies and have not received financial support from the company. REFERENCES 1. Randall GM, Jensen DM. Diagnosis and management of bleeding from upper gastrointestinal neoplasms. Gastrointest Endosc Clin N Am 1991;1:401-27. 2. Loftus EV, Alexander GL, Ahlquist DA, Balm RK. Endoscopic treatment of major bleeding from advanced gastroduodenal malignant lesions. Mayo Clin Proc 1994;69:736-40. 3. Savides TJ, Jensen DM, Cohen J, Randall GM, Kovacs TO, Pelayo S, et al. Severe upper gastrointestinal tumor bleeding: endoscopic findings, treatment, and outcome. Endoscopy 1996;28:244-8. 4. Suzuki H, Miho O, Watanabe Y, Kohyama M, Nagao F. Endoscopic laser therapy in the curative and palliative treatment of upper gastrointestinal cancer. World J Surg 1989; 13:158-64. 5. Mathus-Vliegen EM, Tytgat GN. Analysis of failures and complications of Neodymium:YAG laser photocoagulation in gastrointestinal tract tumors: a retrospective survey of 8 years’ experience. Endoscopy 1990;22:17-23. 6. Tajika M, Kato T, Nagaki M, Kato M, Fukutomi Y, Ninomiya M, et al. Endoscopic injection of gelatin solution for severe hemorrhagic gastric cancer. Gastrointest Endosc 1996;43: 247-50. 7. Tabuse K, Katsumi M, Nagai Y, Kobayashi Y, Noguchi H, Egawa H, et al. Microwave tissue coagulation applied clinically in endoscopic surgery. Endoscopy 1985;17:139-44. 8. Prior JJ, Wallace DG, Harner A, Powers N. A sprayable hemostat containing fibrillar collagen, bovine thrombin, and autologous plasma. Ann Thorac Surg 1999;68:479-85. 9. The CoStasis Multi-center Collaborative Writing Committee. A novel collagen-based composite offers effective hemostasis for multiple surgical indications: results of a randomized controlled trial. Surgery 2001;129:445-50. 10. Chapman WC, Clavien PA, Fung J, Khanna A, Bonham A. Effective control of hepatic bleeding with a novel collagenGASTROINTESTINAL ENDOSCOPY
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based composite combined with autologous plasma: results of a randomized controlled trial. Arch Surg 2000;135:1200-4. 11. Buncke GM, Sherman R. CoStasis provides superior control of diffuse bleeding at muscle-flap donor sites, compared to manual compression. J Reconstructr Microsurg 2000;16:557-61. 12. Turley K. Aortic homograft root replacement for failed freehand homograft aortic valve: effectiveness of a collagen/ thrombin/plasma composite hemostat in the setting of technically complicated homograft to root anastomosis. Heart Surg Forum 1999;2:143-6. 13. Prior JJ, Powers N, DeLustro F. Efficacy of a novel hemostat-
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ic agent in animal models of impaired hemostasis. J Biomed Material Res 2000;53:252-7. 14. Rutgeerts P, Rauws E, Wara P, Swain P, Hoos A, Solleder E, et al. Randomized trial of single and repeated fibrin glue compared with injection of polidocanol in treatment of bleeding peptic ulcer. Lancet 1997;350:692-6. 15. Dunn CJ, Goa KL. Fibrin sealant: a review of its use in surgery and endoscopy. Drugs 1999;58:863-86. 16. Nagelschmidt M. Endoscopic use of fibrin adhesives: problems when injecting through long catheters. Surg Endosc 1999;13:80-2.
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