Vascular Toxicity of Antineoplastic Agents

Vascular Toxicity of Antineoplastic Agents Nasir Shahab, Syed Haider, and Donald C. Doll Among the various deleterious effects of cancer chemotherapy, vascular toxicity is the least well recognized. This lack of recognition may be because the vasculotoxic phenomena are not unique to antineoplastic agents, can occur in patients without exposure to these agents, and the fact cancer itself may produce a hypercoagulable state. As a result, many vascular events either go unnoticed, are ignored, and/or are attributed to the underlying malignancy. Many antineoplastic therapies are associated with various vascular phenomena that range from simple phelibitis to lethal microangiopathy. Recognition of these events is important to minimize the morbidity and even prevent unnecessary deaths. Herein we review the vascular syndromes that have been reported in association with antineoplastic agents. Semin Oncol 33:121-138 © 2006 Elsevier Inc. All rights reserved.

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he association of venous thromboembolism with underlying malignancy is well known, thus screening for an occult malignancy in patients with unexplained venous thromboembolism has always been tempting and has been the subject of much discussion in the medical literature.1,2. In addition, various other vascular events have been reported as complications of underlying malignancy.3 However, it is now apparent that the administration of chemotherapy, hormones, and immunotherapy may contribute to vascular conditions that encompasses a heterogeneous group of disorders, ranging from asymptomatic phlebitis to potentially lethal syndromes such as hepatic veno-occlusive disease (HVOD) or thrombotic microangiopathic syndrome (TMAS).4,5 The precise pathogenesis of these toxic effects has not been elucidated. Herein we review various syndromes of vascular toxicity that are reported to be associated with chemotherapy/hormonal therapy (Table 1) and discuss the putative pathogenic mechanisms.

Pulmonary Veno-occlusive Disease The diagnosis of pulmonary veno-occlusive disease (PVOD) is made on a lung tissue examination. Histologic findings include occlusion or narrowing of pulmonary veins and venules by loose to paucicellular fibrous material or, less Department of Medicine, Division of Hematology-Medical Oncology, Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO. Address correspondence to Nasir Shahab, MD, Assistant Professor, Ellis Fischel Cancer Center, 115 Business Loop 70 W, Columbia, MO 65203. E-mail: [email protected]

0093-7754/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2005.11.006

often, collagen-rich connective tissue.6 Although the pathogenesis of PVOD is not clear, exposure to inhaled toxins, respiratory infections, immunologic disorders, and a genetic predisposition have been proposed.6-8 Several cases of PVOD associated with chemotherapy have been described.9-12 The clinical scenario of PVOD consists of increasing dyspnea, hypoxia, respiratory failure, and pulmonary hypertension, which may culminate in death. Although there are only a few anecdotal reports of PVOD associated with chemotherapy, such findings may be related to a failure to recognize this complication and/or underuse of elastic tissue stain on histologic examinations. Rose9 reported two lymphoma patients with PVOD after treatment with bleomycin and prednisone. Joselson and Warnock10 described a case of PVOD in a patient with cervical carcinoma who had been treated with bleomycin, mitomycin, and cisplatin. Each patient had pulmonary interstitial fibrosis at autopsy, and the investigators stressed the importance of using elastic tissue stains to improve the accuracy of the pathologic diagnosis. Waldhorn et al11 documented PVOD associated with microangiopathic hemolytic anemia after treatment with 5-fluorouracil (5-FU), mitomycin, and doxorubicin for gastric cancer, although no autopsy findings of interstitial lung disease or microangiopathic blood changes were observed. In addition, Lombard et al12 reported PVOD in two patients after carmustine [1,3-bis (2-d-doroethyl)-lnitrosourea] (BCNU) therapy for malignant gliomas and in one patient after radiation and mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) chemotherapy for Hodgkin’s disease. PVOD has also been reported in a patient with untreated Hodgkin’s disease13 and after preparative regimens for stem cell transplantation 121

N. Shahab, S. Haider, and D.C. Doll

122 Table 1 Vascular Complications of Antineoplastic Agents Complication Pulmonary veno-occlusive disease

Hepatic veno-occlusive disease

Budd-Chiari syndrome

Raynaud’s phenomenon Myocardial ischemia and infarction

Thrombotic microangiopathy

Thromboembolic disease

Hypotension

Hypertension

Palmar plantar erythrodysesthesia

Drug Bleomycin Carmustine (BCNU) Cyclophosphamide Procarbazine Azathioprine Busulfan Carmustine (BCNU) Cyclophosphamide Cisplatin Dacarbazine Dactinomycin Etoposide Gemcitabine Gemtuzumab ozogamicin Mitomycin 6-Thioguanine Dacarbazine Cytarabine Methotrexate 6-Thioguanine Bleomycin Cisplatin Bleomycin Carboplatin Cisplatin Etoposide 5-Fluorouracil Vinblastine Bleomycin Carboplatin Cisplatin Mitomycin Bleomycin Cisplatin Cyclophosphamide Etoposide 5-Fluorouracil Methotrexate Tamoxifen Vinblastine Vincristine Carmustine (BCNU) Dacarbazine Etoposide Paclitaxel Tamoxifen Teniposide Vincristine Bleomycin Cisplatin Mitomycin Procarbazine Vinblastine Capecitabine Cytarabine Docetaxel Etoposide 5-Fluorouracil Hydroxyurea Irinotecan

Table 1 Continued Complication

Leukocytoclastic vasculitis

Retinal toxicity

Capillary leak syndrome

Drug Infusional doxorubicin Liposomal doxorubicin Methotrexate 6-Mercaptopurine Paclitaxel Vinorelbine All-trans retinoic acid (ATRA) Busulfan Cytarabine Gemcitabine Hydroxyurea Interferon Methotrexate Pentostatin Trastuzumab Vincristine Carmustine (BCNU) Carboplatin Cisplatin Aldesleukin (IL-2) Docetaxel Gemcitabine Vinorelbine

(SCT).14,15 In children with malignant infantile osteoporosis who undergo SCT after conditioning with cyclophosphamide and busulfan chemotherapy, there is an increased incidence of pulmonary hypertension due to PVOD.16,17 No standard effective therapy is available for PVOD.7 If a diagnosis is established antemortem, the offending drug should be discontinued. Azathioprine, by suppressing autoimmune vasculitis, has been effective in an isolated case of PVOD (but not one related to chemotherapy18). In addition, decreased pulmonary artery pressure after hydralazine therapy was helpful in one patient.13

Hepatic Veno-occlusive Disease Hepatic veno-occlusive disease (HVOD), also now known as sinusoidal obliteration syndrome, is a clinical syndrome characterized by painful liver enlargement, fluid retention, weight gain, and jaundice. Histologically there is nonthrombotic obliteration of the small intrahepatic branches of the hepatic veins by collagenous and reticular intimal thickening19-21 and hence the new name. By comparison, thrombotic occlusion of the large hepatic veins has been used to define the Budd-Chiari syndrome.19,22 However, the clinical and pathologic findings may overlap in these syndromes, and distinctions may thus be superfluous. Major causes of HVOD are hepatic irradiation23 and toxic pyrolizidine alkaloids.20 Several chemotherapeutic agents, including urethane,24 6-thioguanine,25-27 cytarabine,28,29 BCNU,30 busulfan,31 dimethylbusulfan,32 mitomycin,33,34 cyclophosphamide,32 dacarbazine,35 azathioprine,36,37 dactinomycin,38-43 gemcitabine,44,45 and gemtuzumab ozogamicin,46-48 have been im-

Vascular toxicity of antineoplastic agents plicated in HVOD. Regarding dactinomycin, there is a higher incidence of hepatic toxicity with the higher single-dose schedule than with divided doses.39 Isolated thrombocytopenia after dactinomycin administration may be a risk factor for subsequent development of full-blown HVOD.40 The Intergroup Rhabdomyosarcoma Study reported an overall incidence of HVOD of 1.2%.41 It is noteworthy that this complication only developed in patients treated with vincristine, dactinomycin, and cyclophosphamide. No patient who was treated with only vincristine and dactinomycin experienced this problem. HVOD was also strongly associated with escalated doses of cyclophosphamide. In several cases combination chemotherapy had been administered as preparative regimens for SCT.15,27,28,30,34,35 Indeed, essentially all preparative regimens have been implicated in HVOD, and HVOD is now a major early complication of SCT.49 In an early study at the University of Washington of 255 consecutive patients who underwent SCT, the incidence of HVOD was 21%.50 However, HVOD subsequently developed in 109 of 355 consecutive patients (54%) undergoing SCT at their institution.51 Fifty-four patients had severe HVOD, and 136 had mild or moderate HVOD. Factors that were predictive of severe HVOD included vancomycin treatment during cytoreductive therapy, elevated serum transaminase levels before transplantation, cytoreductive therapy with a high-dose regimen, acyclovir therapy before transplantation, mismatched or unrelated donor marrow, and prior radiation to the abdomen.51 The use of methotrexate for graft-versus-host disease prophylaxis,52 increased plasma levels of busulfan,53 low protein C levels before transplantation,54 and hepatitis C virus infection55 have also been implicated as risk factors for HVOD. Despite these observations, no single clinical factor is definitely predictive of HVOD in an individual patient.56-61 Investigators at John Hopkins also reported HVOD in approximately 20% of their patients undergoing SCT.56 They noted this complication only with preparative regimens that used either busulfan or BCNU in combination with cyclophosphamide. In contrast, the Dana-Farber group described HVOD in only 12 of 291 (4.1%) patients who underwent autologous SCT.57 In their study, evidence of metastatic liver disease was the only pretreatment factor that was predictive of HVOD. No individual preparative agent had a significant effect on the development of HVOD. A single 2-hour infusion of BCNU led to a higher frequency of HVOD than the same dose administered in a fractionated schedule. Gemtuzumab ozogamicin, a novel immunotoxic monoclonal antibody used in the treatment of acute myeloid leukemia, has also been associated with the development of HVOD.47 It was also shown to be associated with the development of potentially fatal HVOD in patients with leukemia who had not received SCT and who also had not received any prior chemotherapeutic agents.46 This finding is of concern because many patients with acute leukemia are also potential candidates for other hepatotoxic chemotherapeutic agents and prior gemtuzumab exposure may increase the likelihood of subsequent HVOD. Exposure of hepatic sinusoids to unconjugated calicheamicin (the active ingredient of gemtu-

123 zumab ozogamicin), nonspecific uptake of the antibody-calicheamicin complex by Kupffer cells, and receptor mediated uptake of antibody-calicheamicin complex through CD33 expression on one or more of the liver cell populations are the possible mechanisms of liver toxicity.48 As noted above, HVOD may appear as weight gain, ascites, painful hepatomegaly, and elevated liver function tests. Persistent thrombocytopenia and refractoriness to platelet transfusions may be early signs of HVOD.58-62 The diagnosis can be established by percutaneous or transvenous liver biopsy.19 Hepatic venography may be of benefit, because fine and tortuous hepatic vessels replace the large hepatic veins. Color Doppler ultrasonography of a segmental branch of the portal vein is useful for early diagnosis and even monitoring of the veno-occulsive disease. The change in blood flow can be detected 5 to 6 days before the clinical diagnostic criteria are fulfilled.63 Usually the disease manifests early after receiving chemotherapy but may occur late in a subset of patients.64,65 The myeloablative regimens dictate the onset and clinical course of the HVOD in patients undergoing SCT. Stoneham et al reported HVOD in 12% of patients with acute lymphoblastic leukemia who were receiving maintenance 6-thioguanine.66 Maintenance with 6-mercatopurine has also resulted in similar pathology.67 HVOD may vary from mild and reversible to life-threatening and lethal.68 Bearman et al69 developed a mathematical model for predicting a fatal outcome after SCT, based on serum bilirubin levels and weight gain from day 7 before transplantation through day 16 after transplantation. This model may be useful when deciding potential therapeutic interventions for HVOD. Another mode of monitoring HVOD after SCT might be the serum concentration of an aminopeptide of type III procollagen.70,71 Elevated serum concentration of this factor may identify patients in whom HVOD may later develop. In addition, an increased level of type M procollagen may be helpful in the diagnosis of HVOD and can be used to monitor disease activity.70 Anscher et al58 reported that measuring plasma levels of transforming growth factor P (TGF-P) might be worthwhile as a screening test for the development of HVOD or idiopathic interstitial pneumonitis associated with high-dose chemotherapy and SCT in patients with breast cancer. These investigators showed that the predictive value for the development of either condition was 90% or more when pretransplantation TGF-P levels were more than 2 SD above the mean established in the control subjects. However, they found no relationship between plasma TGF-P levels and HVOD in patients with leukemia and lymphoma who were treated in a similar manner.59 Hence, the role, if any, of TGF-P as a screening test for HVOD has not yet been determined. Also, elevated levels of tumor necrosis factor-alpha60 and plasminogen activators61 as a predictive test for HVOD need confirmation. More recently, plasminogen activator inhibitor-1 was reported to diagnose as well as predict the severity of the disease after allogenic transplantation following cyclophosphamide and busulfan conditioning.72 Because severe HVOD is lethal in most patients, successful interventions would be most welcome. In this regard, continuous low-dose heparin,73,74 pentoxifyline,75-77 and prostaglandin

124 E78,79have all been used as prophylaxis for HVOD. Unfortunately, none of these agents has been shown to be definitely effective in the prevention of HVOD after SCT. Ursodeoxycholic acid prophylaxis against hepatic complications warrants additional investigation.80 However, Ruutu et al recently reported a survival advantage in patients pretreated with ursodeoxycholic acid despite no difference in the incidence of HVOD following allogenic SCT.81 These authors suggested a role for ursodeoxycholic acid in the prevention of transplant-related HVOD. Other than supportive care, there is no standard effective therapy for HVOD. Treatment for severe HVOD with recombinant human tissue plasminogen activator has produced conflicting results.82-85 Further studies of tissue plasminogen activator and similar agents are necessary before any definitive conclusions can be drawn. Neither the administration of anti-thrombin III (ATIII) nor the use of activated protein C has been successful in a number of studies.86,87 Once fibrosis occurs, there is no treatment that can reverse the pathology, but liver transplantation has resulted in some success in extending survival.88 Defibrotide is a novel agent that by reactivating tissue plasminogen activator (tPA) and tissue factor pathway inhibitor (TFPI), decreases thrombin generation, inhibits fibrin generation, and modulates fibronectin release.89,90 In a series of studies, defibrotide has resulted in complete resolution in 42%, 52%, and 36% of patients, respectively.64,91,92 Further trials are underway to determine the effective dose and role of defibrotide in HVOD.

Budd-Chiari Syndrome Occlusion of the large hepatic veins, manifested clinically as the Budd-Chiari syndrome, has been reported in association with several chemotherapeutic agents. Dacarbazine, alone93,94 and in combination with other cytotoxic drugs,95,96 and 6-thioguanine plus cytarabine97 or methotrexate98 have been described. Scintiscan of the liver in Budd-Chiari syndrome may show caudate sparing and may be helpful in the diagnosis of this condition.99 Fatal hepatic necrosis with widespread thrombotic occlusion of the small hepatic veins has been observed in patients who are treated with dacarbazine.100-104 This disorder usually occurs during the second cycle of treatment and is characterized by the sudden onset of nausea, vomiting, and right upper quadrant pain, progressing rapidly to circulatory shock and death.101-104

Raynaud’s Phenomenon Raynaud’s phenomenon is characterized by transient episodes of vasoconstriction accompanied by changes in color of the affected digits. Exposures to cold and emotional stress are common precipitating factors for vasospastic attacks. Raynaud’s phenomenon has been documented after the administration of bleomycin, either alone105-107 or in combinations with a vinca alkaloid,108-113 cisplatin and a vinca alkaloid,108,113-126 etoposide and cisplatin,127 and doxorubicin and vincristine.128-130 In addition, Raynaud’s phenomenon and digital vasculitis have been reported with interferon therapy131-135 and tamoxifen.136 Vogel-

N. Shahab, S. Haider, and D.C. Doll zang et al108 initially noted Raynaud’s phenomenon in 21% of patients with testicular cancer who were treated with vinblastine and bleomycin and in 41% of patients also treated with cisplatin. Symptoms of painful digital ischemia on cold exposure were present in all patients and occurred a mean of 10 months after the initiation of chemotherapy. The Raynaud’s phenomenon was usually chronic and persistent for five or more years. Although 50% of the patients had clinical improvement over time, 12 had to make lifestyle changes because of intractable digital ischemia. Arteriograms in two of the patients revealed diffuse arterial narrowing that was consistent with vasculitis or arteritis.108 Subsequent reports by others noted Raynaud’s phenomenon or persistent digital cold sensitivity after cisplatin, bleomycin, and vinblastine sulfate in 2.6% to 49.0% of patients.113,118,122-124,137,138 Every reported patient with Raynaud’s phenomenon has been treated with bleomycin, either alone or in combination regimens. This fact strongly suggests that bleomycin is the primary drug responsible for this disorder. In some patients, Raynaud’s phenomenon is of minor or no clinical concern; in others, it is a severe, debilitating chronic problem. Rarely, it progresses to digital gangrene128-131,136 that may require amputation.130,131,139,140 Few data are available regarding the management of therapy-induced Raynaud’s phenomenon. Topical nitroglycerin and oral tolazoline hydrochloride were of no value in two patients.108 Nifedipine or other calcium channel blockers might be of benefit in some individuals.141-143 A decision to discontinue chemotherapy should depend on the severity of the complaints and the type and curability of the tumor that is being treated.

Myocardial Ischemia and Infarction Acute myocardial infarction has been reported to occur in association with vinca alkaloids,144-146 etoposide,147,148 cisplatin,149 gemcitabine,45 vinblastine and bleomycin,150,151 vinblastine, bleomycin, and cisplatin,152–155 cisplatin, cyclophosphamide, and doxorubicin,156 cisplatin, etoposide, and bleomycin,157 and in combination chemotherapy regimens for Hodgkin’s disease157,158 and metastatic colorectal cancer.159 Mediastinal irradiation,147,155,160 pre-existing coronary artery disease,148,152 smoking,151 and age older than 40 years153 were coexisting factors in some patients. Several patients had no known risk factors for heart disease and had normal coronary angiograms.150,153-155,158 Three patients had a prior history of Raynaud’s phenomenon,151,155 and in one patient ergonovine maleate precipitated diffuse coronary spasm and chest pain.155 In another case, coronary artery occlusion by fibrous intimal proliferation was demonstrated at autopsy.153 These results should be tempered by the data of the Testicular Cancer Intergroup Study.161 No greater degree of major cardiovascular complications was found in patients treated with cisplatin-based chemotherapy for testicular cancer than in an untreated control group. Cardiac ischemia has been reported in association with

Vascular toxicity of antineoplastic agents vinca alkaloids,162-164 cisplatin,165 cyclophosphamide,166 bleomycin infusions,167 carboplatin and etoposide,168 and the combiniation of cisplatin, etoposide, and bleomycin.169 Of note is the increasing number of reports of cardiac toxicity associated with 5-FU.170-193 Such toxicity has ranged from asymptomatic electrocardiographic changes to angina pectoris and myocardial infarction with cardiogenic shock and death. In one prospective study of 367 patients treated with continuous infusions of 5-FU, the incidence of cardiac toxicity was 7.6%.189 Although the mechanism is unknown, these events appear to be more likely to occur when 5-FU is administered in a high dose by continuous infusion in the presence of pre-existing coronary artery disease.189-191 In a large review of 262 patients, 76% of cardiac events occurred during, or within, the first 72 hours of the first cycle of the 5-FU infusion.194 Angina occurred in 48%, myocardial infarction in 23%, arrhythmias in 16%, acute pulmonary edema in 7%, and cardiac arrest and pericarditis in 7%.194 Symptoms were reproducible when patients were rechallenged with 5-FU or capecitabine. Nineteen percent of these rechallanged patients died. In some cases prophylaxis with calcium channel blockers was effective in preventing angina.180-183 Physicians should be aware of the potential cardiotoxic properties of 5-FU and capecitabine, and treatment should be discontinued immediately if any coronary symptoms develop. Rechallenging should not be done. Prophylactic telemetry monitoring during 5-FU administration does not detect vasospasm and therefore is not recommended.195 Cardiovascular disease as a long-term complication of treatment in survivors of testicular cancer is now a wellknown phenomenon.196,197 Huddart et al. reported data on 992 patients. After a median follow-up of 10.2 years, there was a twofold or greater risk of developing cardiovascular disease. The risk was approximately 10% for patients who received radiation and 6.7% for those patients who received chemotherapy.197

Thrombotic Microangiopathic Syndrome A thrombotic microangiopathic syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal insufficiency has been reported after treatment with several chemotherapeutic agents.198 Mitomycin, the drug that most commonly causes this condition, has accounted for at least 150 published cases of this event.199-243 Approximately 90% of the patients have had adenocarcinomas, with breast, colorectal, and gastric cancers occurring most frequently.243 The median age of patients with mitomycin-induced thrombotic microangiopathy is 52 years, with a range of 21 to 86 years.198 Clinically, virtually all patients have the triad of anemia, thrombocytopenia, and renal dysfunction.243 The anemia is usually severe, and the peripheral blood film reveals schistocytes and helmet cells that are typical of microangiopathic hemolysis. Most patients show no evidence of consumptive coagulopathy. Less common features include hematuria, congestive heart failure, pulmonary edema, pro-

125 teinuria, interstitial pneumonitis, rash, fever, hypertension, neurologic changes, and pericarditis.199 –243 Most patients with this syndrome have died of renal failure within a few months after the diagnosis was established.243 The cardinal histologic features in patients with this syndrome have been abnormalities in the renal vasculature. The principal light microscopic findings have been fibrin deposition and endothelial proliferation of the glomerular capillaries and afferent arterioles. In addition, glomerular basement membrane thickening or glomerular infarcts and necrosis have been described.200,201,203,209,211,216-218,229,231,234,236,238,239,242 Electron microscopy reveals marked expansion of the glomerular subendothelial space with electron lucent material. Similar histologic findings have been noted in patients with nephrotoxicity (but without thrombotic microangiopathy) associated with mitomycin.200,244-247 Histologic findings that are observed in the mitomycin-associated microangiopathy syndrome are similar to those reported in hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura (TTP).217 The incidence of mitomycin-associated thrombotic microangiopathy has been variable. Of 281 patients treated with mitomycin and 5-FU by the British Stomach Cancer Group, this complication developed in 24 (8.5%).220 In addition, 32 other patients (11.4%) experienced renal insufficiency. This syndrome did not develop in any of the 130 placebo-treated control subjects, and only four had renal insufficiency.220 Hanna et al200 reported renal dysfunction in 14 (9.8%) of 143 patients treated with mitomycin and 5-FU, two of whom had evidence of microangiopathy. Death from renal failure occurred in nine of the 14 patients. Pavy et al209 documented renal insufficiency in four of 94 patients (4.2%) treated with mitomycin, two of whom had microangiopathic hemolysis with renal failure. Valvaara and Nordman232 observed renal toxicity in 10 (8.5%) of 118 patients treated with mitomycin, five of whom had microangiopathic hemolytic anemia. These results suggest that there may be two types of mitomycininduced renal disorders: (1) a mild to severe renal insufficiency without microangiopathic hemolytic anemia; and (2) renal failure as part of a more generalized thrombotic microangiopathic syndrome. The onset of thrombotic microangiopathy associated with mitomycin is usually within 4 to 9 weeks from the last dose of chemotherapy, although it may occur, on occasion, 4 to 15 months after discontinuation of treatment.204,208,211,221,243 It appears that this complication is dose related, with most patients having received a cumulative dose of mitomycin greater than 60 mg.243 Clinicians should be aware of the fact that the syndrome may develop at any time while the patient is receiving mitomycin and for months after treatment is discontinued. In general, corticosteroids, antiplatelet agents, and blood transfusions have been ineffective as treatment of thrombotic microangiopathic syndrome. In fact, blood transfusions may actually exacerbate the renal failure and microangiopathic hemolysis and may precipitate acute pulmonary edema.203,208,210,213,216,218,28,230,235 Hence, blood transfusions should be given with caution. Such progression after blood transfusions may be caused by activation of intravascular clotting.248 Plasma exchange or plasmapheresis in

126 combination with other therapeutic modalities have been used in several patients.199,212,213,218,219,233-235,249 Although the hemolytic anemia has improved in some patients, renal failure was usually progressive and required maintenance dialysis. Cyclophosphamide, vincristine, and azathioprine have been tried in a few cases.243,250,251 Protein A immunoadsorption of plasma has been used in the treatment of chemotherapy-associated microangiopathy syndrome.252,253 Response to this therapy was observed in 25 of 55 patients, with an estimated 1-year survival of 61% in responders. Clinical responses were correlated with normalization of serum levels of circulating immune complexes and complement components C3c and C4. This new modality may be the preferred treatment in patients with chemotherapy-induced thrombotic microangiopathic syndrome. Thrombotic microangiopathy has also been described with other types of chemotherapy, including cisplatin and bleomycin regimens254-261 and carboplatin262 and after combination chemotherapy for lymphoma258,263,264 and acute leukemia.265 Recently, gemcitabine and pentostatin have also been implicated with this syndrome.266-269 The clinical course is similar to that described with mitomycin. Thrombotic microangiopathy associated with alfa-interferon has also been reported.270 Preparative regimens used for SCT may be complicated by a thrombotic microangiopathy analogous to the hemolyticuremic syndrome.271-274 Several factors, including irradiation, cyclosporine, graft-versus-host disease, infection, and intensive conditioning chemotherapy, may be involved in the pathogenesis of this syndrome. Of 581 patients with breast cancer treated with high-dose chemotherapy consisting of cyclophosphamide, cisplatin, and carmustine, symptoms similar to those of the hemolytic-uremic syndrome developed in 15 (2.6%).271 The mortality was an impressive 73%. In another study of 168 patients with non-Hodgkin’s lymphoma and other hematologic malignancies who underwent autologous or allogenic SCT, hemolytic-uremic syndrome developed in 16 patients.274 In this study all patients survived. Although plasmapheresis has been used for this problem, in contrast to classic TTP, it is generally not as responsive to treatment. Mortality is very high after allogenic transplantation. Fuge et al reported 86% mortality with TTP associated with SCT.275 Cyclosporine has been noted to induce remission of TTP in several patients after SCT, even after failure of plasmapheresis.276 Thus, cyclosporine may be an attractive agent for post-autologous SCT-microangiopathy syndrome.

Thrombosis and Thromboembolic Complications The relationship between cancer and a hypercoagulable state has been well recognized for more than a century.277 Chemotherapy or hormonal therapy may also be associated with thromboembolic phenomena, including venous and arterial thrombosis, cerebrovascular accidents, pulmonary embolism, and intestinal infarction. Such complications have been

N. Shahab, S. Haider, and D.C. Doll described primarily with combination chemotherapy regimens for the treatment of head and neck cancer,227,246-248 genitourinary tract tumors,131,133,249-255 lymphoma,256-259 and breast cancer.260-277 Kukla et al278 reported five patients with squamous cell carcinoma of the head and neck who developed cerebrovascular accidents associated with cisplatinbased chemotherapy. Each of the patients was at least 50 years old, and three had a prior history of heart disease or stroke. Licciardello et al254 described acute cerebrovascular events in two patients with head and neck cancer after cisplatin and bleomycin or vindesine. Pretreatment levels of von Willebrand factor (vWF) antigen were elevated in each patient in whom acute strokes developed and showed further elevation after the administration of chemotherapy. On the other hand, none of 11 patients with normal pretreatment vWF antigen levels experienced thrombotic events. Fallon et al279 documented 21 vascular complications during 400 cycles of cisplatin-based neoadjuvant chemotherapy for advanced squamous cell carcinoma of the head and neck. Every patient with these complications had at least two risk factors for cardiovascular disease. Pulmonary emboli, deep venous thrombosis, arterial thrombosis and embolus, cerebrovascular accidents, and mesenteric infarction have all been observed during cisplatin combination chemotherapy for testicular cancer and urothelial transitional cell carcinoma.153,155,157,280-310 Ten of 52 (19%) newly diagnosed patients with germ cell tumors treated with cisplatin combinations by Cantwell et al281 had vascular events (three arterial and seven venous or pulmonary). These investigators noted a higher frequency of retroperitoneal metastases in patients with vascular complications than in those without such metastases. As mentioned in the section Myocardial Ischemia and Infarction, however, the Testicular Cancer Intergroup Study138 found no increased risk of cardiovascular events in patients with early-stage testicular cancer treated with cisplatin-based chemotherapy. On the other hand, Weil et al presented data on 179 patients and found an increased risk of developing thromboembolic complications.311 Nonetheless, many patients who have testicular cancer are young and have no risk factors for vascular disease. Hence, one should be cognizant of potential vascular complications that may occur during or shortly after treatment. Czaykowski et al284 reported vascular events that occurred in 35 of 271 consecutive patients (12.9%) who received cisplatin-based combination chemotherapy for transitional cell carcinoma. Such events included 18 instances of deep vein thromboses, nine pulmonary emboli, seven arterial thromboses, three cerebrovascular events, one superficial phlebitis, and one angina pectoris. Overall, 3.6% of the chemotherapy cycles were complicated by vascular events, with 27 events (77%) occurring during the first two cycles. Risk factors for these complications included a large pelvic mass and concomitant peripheral vascular or coronary artery disease. Such vascular problems were associated with significant morbidity and in three cases were fatal. Lynch et al312 described two cases of myocardial infarction, one case of lethal pulmonary em-

Vascular toxicity of antineoplastic agents bolism, and one case of cerebrovascular accident following treatment with cisplatin, etoposide, and 5-FU infusion for non–small cell lung cancer. In addition, Mathews et al313 reported arterial occlusion in five patients with lung cancer treated with cisplatin combination chemotherapy. Although each patient had risk factors for vascular disease, the authors suggested that the chemotherapy itself may have been a major factor in the thrombotic events. Mortimer et al149 documented seven thromboembolic disorders during 57 cycles of intra-arterial cisplatin and radiation therapy for primary brain tumors. The thrombotic disorders included pulmonary embolism, deep venous thrombosis, myocardial infarction, septic phlebitis, and hemorrhagic infarction. Several reports have been published of arterial and venous thrombosis in patients with breast cancer treated with chemotherapy protocols based on cyclophosphamide, methotrexate, and 5-FU regimens, with or without vincristine, prednisone, tamoxifen, and doxorubicin.292,295,297,306-313 Weiss et al292 initially documented a 5% incidence of thrombosis in 433 postmastectomy patients with breast cancer treated with adjuvant chemotherapy. These investigators subsequently reported arterial thrombosis in 13 of 1,014 (1.3%) patients with stage II or III breast cancer that were treated with combination chemotherapy. These results were later confirmed by others.294,301,304,305 The Eastern Cooperative Oncology Group297 noted a frequency of venous and arterial thrombosis of 5.4% among 2,352 patients who were treated with adjuvant chemotherapy or chemotherapy plus tamoxifen compared to a rate of only 1.6% (P ⫽ .0002) among 321 patients who were observed without treatment. The European Organization for Research and Treatment of Breast Cancer304 reported thromboembolic events in 27 (2.1%) of 1,292 patients who were assigned to chemotherapy compared with 10 (0.8%) of 1,332 patients on an observation arm (P ⫽ .004). The National Cancer Institute of Canada Breast Cancer Site Group306 observed thrombotic events in 48 (13.6%) of 353 women who were allocated to receive tamoxifen plus chemotherapy in comparison to five (2.6%) of 352 women randomized to receive tamoxifen alone (P ⬍.0001). The Southwest Oncology Group also noted an increased incidence of thromboembolic complications in patients with breast cancer who were treated with combination chemotherapy and tamoxifen.301 Of note, the thrombotic events in all of the aforementioned studies always occurred while the patients were being treated with chemotherapy, with or without hormone therapy. Very–low-dose warfarin may prevent such vascular complications in breast cancer patients who are receiving chemotherapy.305 Thromboses and thromboembolic phenomena have also been described in patients who are undergoing chemotherapy for lymphoma,288-291 prostate cancer,314 osteogenic sarcoma,315 and esophageal cancer.316 Paclitaxel,317 alfa-interferon,318 and colony-stimulating factors319-322 also have been implicated as causative factors in thrombotic events. In the combination regimen that includes irinotecan, 5-FU, and leucovorin, an independent panel found that sudden death in

127 the study patients was in part due to unexpected thromboembolic events that were characterized as a vascular syndrome.159 A clinical trial of flavopiridol, a cyclin-dependent kinase inhibitor, was associated with vascular thromboembolic events, including transient ischemic attacks, deep venous thrombosis, pulmonary embolism, and myocardial infarction.323 With the emergence of thalidomide in studies of cancers such as multiple myeloma, an increased incidence of deep venous thrombosis has been observed.324,325 The risk is low when thalidomide is used alone but increases when it is combined with dexamethasone,324 darbepoietin-alpha,326 or gemcitabine plus 5-FU.327 Finally, it has been suggested that tamoxifen is a risk factor for thromboembolic disease,297,328,329 but Rutqvist and Mattsson330 found no increase in thrombotic events among patients with breast cancer treated with tamoxifen alone or in combination with chemotherapy compared with a no-treatment control arm.

Hypotension and Hypertension Hypotension associated with chemotherapy may be due to excipients present in the pharmaceutical formulation, rapid infusion of the drug, or alterations of the autonomic nervous system or it may be part of a hypersensitivity reaction. Rapid infusion of etoposide331 or teniposide332 can cause hypotension. However, infusion over 30 to 60 minutes is usually not associated with this problem. It has been suggested that the diluent or other additives can cause the hypotension associated with etoposide.333 Hypotension may be a dose-limiting complication associated with high-dose dacarbazine,334 high-dose BCNU,335 and homoharringtonine.336-338 The citric acid present in the pharmaceutical preparation can cause the hypotension that occurs with dacarbazine.334 Although orthostatic hypotension is a well-known complication of vincristine,339,340 it is uncommon, with an incidence of only 4% (one of 26 patients) in one prospective study.34 Such hypotension may be due to drug-induced impairment in norepinephrine secretion,339 or it may represent a neurotoxic reaction.340 Sustained hypertension has been reported after intra-arterial administration of cisplatin.341 In addition, accelerated hypertension was noted in a patient after treatment with cisplatin, vinblastine, and bleomycin.342 Renal biopsy revealed narrowing of the interlobular arteries and fibrin thrombosis of the afferent arterioles. Hypertension has been documented in 16% to 17% of patients with testicular cancer treated with cisplatin, bleomycin, and vinblastine.343 Hypertension may also develop in patients who receive procarbazine after ingestion of foods with a high tyramine content,344 as part of a hypersensitivity reaction to chemotherapy,345,346 and as a manifestation of the thrombotic microangiopathy syndrome.198 Novel agents such as SU5416, an anti-VEGF agent, when given with cisplatin and gemcitabine also have resulted in hypertention.347

128

Palmar-Plantar Erythrodysesthesia Palmar-plantar erythrodysesthesia or acral erythema is a distinct entity characterized by a painful, sharply demarcated, and intense erythema of the palms, fingers, and soles of the feet that is followed by bullae formation, desquamation, and healing.348 High-dose cytarabine,349-351 standard-dose cytarabine,351 hydroxyurea,352 5-FU (especially prolonged and continuous infusions),353-359 methotrexate,360 6-mercaptopurine,361 high-dose etoposide,362 capecitabine,363 irinotecan,364 vinorelbine,365 paclitaxel,366 docetaxel,367,368 tegafur,369,370 liposomal doxorubicin,371 and combination chemotherapy349,372-374 have all been reported to cause acral erythema. The pain associated with this disorder may be so intense that intravenous narcotics are necessary for patient relief. The pain may be worsened by cyclosporine infusions348 and may be alleviated by pyridoxine.355,368,375 Doses of 200 mg per day of pyrodoxine were associated with greater symptomatic relief.376 Application of 12% percent urea containing keratolytic ointment also effectively treated palmarplantar dysesthesia and prevented it when used prophylactically for some patients in one study.377 Nicotine patches may act as prophylaxis for 5-FU–associated dermatitis.378

Leukocytoclastic Vasculitis Leukocytoclastic vasculitis is a disorder of small cutaneous vessels with typical histologic features of fibrinoid degeneration and destruction of the blood vessel wall, with predominantly neutrophilic infiltration into the vessel wall perivascular region, hemorrhage, and leukocytosis.379 Palpable purpura of the lower extremities is the most common manifestation, but urticarial, infarctive, ulcerative, or livedoid lesions, nodules, vesicles, pustules, or bullae may be evident in affected patients.379 Leukocytoclastic vasculitis has been associated with the use of hydroxyurea,346,380 methotrexate,380-383 busulfan,346 hexamethylene bisacetamide,384 cytarabine,380,385,386 5-FU,387 vincristine,380 gemcitabine,388 trastuzumab,389 alfa-interferon,380 all-trans retinoic acid,390 and pentostatin.391 Such vasculitis is probably due to a hypersensitivity reaction.346

Retinal-Vessel Toxicity Retinal toxicity, manifested by unilateral fundal hemorrhages and exudates, was reported by Greenberg et al392 in four of six patients after receiving intra-arterial BCNU chemotherapy for malignant brain tumors. Blindness developed in three of the four patients. Fluorescein angiography disclosed an arterial phase leak that was consistent with a toxic retinal vasculitis in two patients. Corneal opacities and blindness were previously observed in laboratory animals after intracarotid BCNU.393 Bernauer et al394 documented an ocular microvasculopathy in 13 of 127 patients (10%) after SCT. All patients had cotton-wool spots in the fundus of both eyes, and three patients had bilateral optic disc edema. The authors attrib-

N. Shahab, S. Haider, and D.C. Doll uted these ischemic lesions to cyclosporine and total body irradiation. Optic neuropathy, maculopathy, blurred vision, and altered color perceptions have been reported in association with high-dose intravenous cisplatin,395 intracarotid infusion of cisplatin,396 and carboplatin.397 Ophthalmologic examination is warranted in patients who are undergoing treatment with these agents if ocular complaints are noted.

Capillary-Leak Syndrome Systemic capillary-leak syndrome is a rare disorder with a high mortality rate, characterized by rapidly developing edema, weight gain, hypotension, hematologic concentration and hypoproteinemia. This syndrome is caused by sudden reversible capillary hyperpermeability with a rapid extravasation of plasma from the intravascular to the interstitial space.398 A number of antineoplastic agents have been associated with development of this syndrome. These include aldesleukin,399 gemcitabine,400,401 vinorelbine,402 and docetaxel.398 If the offending drug is not discontinued immediately, patients may develop acute pulmonary edema and acute renal tubular necrosis with possible death.

Pathogenesis of Vascular Disorders Related to Chemotherapy The precise pathogenesis of vascular disorders associated with antineoplastic agents is not clear, and the role of specific drugs in the development of all of these phenomena is speculative. Nevertheless, there are several putative mechanisms. One possible mechanism is endothelial cell damage secondary to antineoplastic agents and/or one of their metabolites.403,404 In this regard, bleomycin causes a direct toxic effect on endothelial cells, capillaries, and small arterioles.405 Histologic studies of tumor specimens obtained after treatment with bleomycin have shown endothelial lesions that range from vacuolization to detachment and necrosis.405 Further, bleomycin stimulates collagen production and fibroblast proliferation in vitro, and scleroderma has been reported after bleomycin treatment.406-408 Nitrosoureas, vincristine, doxorubicin, cyclophosphamide, and mitomycin can induce endothelial cell alterations in animal models and in vitro cultured endothelial cells.404,409,410 Endothelial cell injury may be associated with abnormalities of vWF, and increased vWF activity has been reported in patients with drug-associated vascular complications.411 Although a deficiency of vWF-cleaving protease has been described in classic TTP,412 this abnormality has not been reported in chemotherapy-associated microangiopathy.413 Moreover, increases in serum angiotensin-converting enzyme activity414,415 and endothelin416,417 may be secondary to endothelial cell injury and have been reported in animals that were treated with nitrosoureas414 and bleomycin.415 Drug-induced perturbation of the clotting cascade or platelet activation is another possible mechanism. Bleomycin,418 cisplatin,419 and high-dose chemotherapy420 may in-

Vascular toxicity of antineoplastic agents duce platelet activation and aggregation. Cisplatin may produce such an effect via monocyte procoagulant activity.419 Antineoplastic agents may reduce fibrinolytic activity,421 increase fibrinopeptide A levels,422,423 decrease thrombin time and partial thromboplastin time,424 and reduce levels of proteins C and S.425-433 Furthermore, tamoxifen may decrease antithrombin III levels,423,433 although this may not be clinically significant.432,433 Not all studies have documented a decrease in coagulation factors in patients who are undergoing chemotherapy.434,435 Nonetheless, such alterations in the coagulation system could induce a hypercoagulable state and initiate thrombosis. An abnormality in the cytokine network is another possible factor. Tumor necrosis factor alpha is known to down regulate thrombomodulin, Prostaglandins El and E2, and protein S and to upregulate cellular adhesion molecules and platelet-derived growth factor, producing a procoagulant effect.436,437 Overexpression of tumor necrosis factor alpha messenger RNA has been reported in peripheral monuclear cells in the post-transplantation state.438 An abnormality of this cytokine or others may be a causative factor in HVOD. Hypomagnesaemia may be involved in the development of vasospastic disorders. Hypomagnesemia, a common toxicity of cisplatin, occurs in 75% to 87% of patients receiving this drug.439 Magnesium has a major role in the maintenance of vascular smooth muscle tone,440,441 and magnesium deficiency has been observed to produce coronary artery spasm in dogs.440 However, Raynaud’s phenomenon has also been documented in patients who did not receive cisplatin.83,92 Finally, the idea of an abnormality in the sympathetic nervous system should be entertained. Autonomic neuropathy has been reported after treatment with cisplatin alone,442 cisplatin, vinblastine, and bleomycin,443 and vinca alkaloids.444-447 Autonomic dysfunction, in particular enhanced alpha-adrenergic tone, may potentiate arterial vasospasm. These observations suggest that multiple pathogenic mechanisms may be acting in concert, and that the response of the host to the cancer and to its treatment may be central to our understanding of these heterogeneous vascular events.125,126,280,293,296,298-300,302,303

References 1. Bastounis EA, Karayiannakis AJ, Makri GG, et al: The incidence of occult cancer in patients with deep vein thrombosis: A prospective study. J Intern Med 239:153-156, 1996 2. Monreal M, Fernandez-Liamazares J, Perandreu J: Occult cancer in patients with venous thromboembolism: Which patients, which cancer? Throm Haemost 78:1316-1318, 1997 3. Prandorti P, Lensing AWA, Buller HR, et al: Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 327:1128-1133, 1992 4. Doll DC, Yarbro JW: Vascular toxicity associated with antineoplastic agents. Semin Oncol 19:580-596, 1992 5. Doll DC, Yarbro JW: Vascular toxicity associated with chemotherapy and hormonotherapy Curr Opin Oncol 6:345-350, 1994 6. Wagevoort CA: Pulmonary veno-occlusive disease. Entity or syndrome? Chest 69:82-86, 1997 7. Thadany V, Burrow C, Whitaker W, et al: Pulmonary veno-occlusive disease. Q J Med 44:133-156, 1975 8. Corrin G, Spencer H, Turner-Warwich M, et al: Pulmonary veno-occlusion: An immune complex disease? Virchows Arch 364:81-91, 1974

129 9. Rose AG: Pulmonary veno-occlusive disease due to bleomycin therapy for lymphoma. South Afr Med J 64:636-638, 1983 10. Joselson R, Warnock M: Pulmonary veno-occlusive disease after chemotherapy. Hum Pathol 13:88-91, 1983 11. Waldhorn RE, Tsou E, Smith FP, et al: Pulmonary veno-occlusive disease associated with niicroangiopathic hemolytic anemia and chemotherapy of gastric adenocarcinoma. Med Pediatr Oncol 12:394-396, 1984 12. Lombard CM, Churg A, Winokur S: Pulmonary veno-occlusive disease following therapy for malignant neoplasms. Chest 92:871-876, 1987 13. Capewell Sj, Wright Aj, Ellis DA: Pulmonary veno-occlusive disease in association with Hodgkin’s disease. Thorax 39:554-555, 1984 14. Troussard X, Bemaudin JF, Cordonnier C, et al: Pulmonary venoocclusive disease after bone marrow transplantation. Thorax 39:956957, 1984 15. Giralt SA, LeMaistre CF, Vriesendorp HM, et al: Etoposide, cyclophosphamide, total body irradiation, and allogenic bone marrow transplantation for hematologic malignancies. J Clin Oncol 12:1923-1930, 1990 16. Steward GC, Pellier I, Mahajan A, et al: Severe pulmonary hypertension: a frequent complication of stem cell transplantation for malignant infantile osteoporosis. Br J Haematol 124:63-71, 2004 17. Bruckman C, Linder W, Roos R, et al: Severe pulmonary vascular occlusive disease following bone marrow transplantation. Eur J Transplant 150:242-245, 1991 18. Sanderson JE, Spiro SG, Hendry AT, et al: A case of pulmonary venoocclusive disease responding to treatment with azathioprine. Thorax 32:140-148, 1977 19. Zafrani S, Pinaudeau Y, Dhumeaux D: Drug-induced vascular lesions of the liver. Arch Intern Med 143:495-502, 1983 20. Bras G, Jelliffe DB, Stuart KL: Veno-occlusive disease of liver with non-portal type of cirrhosis occuring in Jamaica. Arch Pathol Lab Med 57:285-300, 1954 21. Rollins BJ: Hepatic veno-occlusive disease. Am J Med 81:297-306, 1986 22. Ledwig L Hashimoto E, McGill DB: Classification of hepatic venous outflow obstruction: ambiguous terminology of the Budd-Chiari syndrome. Mayo Clin Proc 65:51-55, 1996 23. Reed GB Jr, Cox AJ: The human liver after radiation injury: A form of veno-occlusive disease. Am J Pathol 48:597-611, 1966 24. Brodsky 1, Johnson H, KiUmann SA, et al: Fibrosis of central and hepatic veins, and perisinusoidal spaces of the liver following prolonged administration of urethane. Am J Med 30:976-980, 1961 25. Griner PF, Elbadawi A, Packman CH: Veno-occlusive disease of the liver after chemotherapy of acute leukemia: Report of two cases. Ann Intern Med 85:578-582, 1976 26. Gill RA, Onstad GR, Cardamone JM, et al: Hepatic veno-occlusive disease caused by 6-thiioguanine. Ann Intern Med 96:58-60, 1982 27. Sloane JP, Farthing NUG, Powles PL: Histopathological changes in the liver after allogeneic bone marrow transplantation. J Clin Pathol 33: 344-348, 1980 28. Woods WG, Dehner LP, Nesbit ME, et al: Fatal veno-occlusive disease of the liver following high dose chemotherapy, irradiation and bone marrow transplantation. Am J Med 68:285-290, 1980 29. Burkhardt A, Kloppet G: Unusual obliterative disease of the hepatic veins in an infant. Virchows Arch 375:225-232, 1977 30. McIntyre RE, Magidson JG, Austin GE, et al: Fatal veno-occlusive disease of the liver following high-dose 1,3-bis (2-chloroethyl)l-nitrosourea (BCNU) and autologous bone marrow transplantation. Am J Clin Pathol 75:614-617, 1981 31. Vassal G, Hartmann 0, Benhamon E: Busulfan and veno-occlusive disease of the liver. Ann Intern Med 112:881, 1991 (letter) 32. Shuhnan HM, McDonald GB, Matthews D, et al: An analysis of hepatic veno-occlusive disease and centrilobular hepatic degeneration following bone marrow transplantation. Cancer 79:1178-1191, 1982 33. Lazarus HM, Gottfried MR, Herzig RH, et al: Veno-occlusive disease of the liver after high-dose mitomycin C therapy and autologous bone marrow transplantation. Cancer 49:1789-1795, 1982 34. Gottfried MR, Sudilovsky O: Hepatic veno-occlusive disease after high-dose mitomycin C and autologous bone marrow transplantation therapy. Hum Pathol 13:646-650, 1982

130 35. Erichsen C, Jonsson PE: Veno-occlusive liver disease after dacarbazine therapy (DTIC) for melanoma. J Surg Oncol 27:268-270, 1984 36. Marubbio AT, Danielson B: Hepatic veno-occlusive disease in a renal transplant patient receiving azathioprine. Gastroenterology 69:739743, 1975 37. Read AE, Wiesner RH, LaBrecque DR, et al: Hepatic veno-occlusive disease associated with renal transplantation and azathioprine therapy. Ann Intern Med 104:651-655, 1986 38. Green DM, Finkelstein JZ, Norkool P, et al: Severe hepatic toxicity after treatment with single-dose dactinomycin and vincristine. Cancer 62:270-273, 1988 39. Green DM, Norkool P, Breslow NE, et al: Severe hepatic toxicity after treatment with vincristine and dactinomycin using single-dose or divided-dose schedules: A report from the National Wilms’ Tumor Study. J Clin Oncol 8:1525-1530, 1990 40. Raine J, Bownian A, Wallendszus K, et al: Hepatopathy-thrombocytopenia syndromes complication of dactinomycin therapy for Wilms’ tumor. A report from the United Kingdom Children’s Cancer Study Group. J Clin Oncol 9:268-273, 1991 41. Ortega JA, Donaldson SA, Ivy SP, et al: Venoocclusive disease of the liver after chemotherapy with vincristine, actinomycin D, and cyclophosphamide for the treatment of rhabdomyosarcoma. Cancer 79: 2435-2439, 1997 42. Hazar V, Kutluk T, Akyuz C, et al: Veno-occlusive disease-like hepatotoxicity in two children receiving chemotherapy for Wilms’ tumor and clear cell sarcoma of kidney. Pediatr Hematol Oncol 15:85-89, 1998 43. Cubc S, Kraker J, Kuljis D, et al: Fatal hepatic veno-occlusive disease with fibrinolysis as the cause of death during preoperative chemotherapy for nephroblastoma. Med Pediatr Oncol 31:175-176, 1998 44. Dobbie M, Hofer S, Oberholzer R, et al: Veno-occlusive disease of the liver induced by gemcitabine. Ann Oncol 9:681, 1998 (letter) 45. Dumontet C., Morschauser F, Solal-Gelginy P, et al: Gemcitabine as a single agent in the treatment of replased or refractory low grade nonHodgkin’s lymphoma. Br J Haematol 113:772-778, 2001 46. Giles FJ, Kantarjian HM, Kornblau SM, et al: Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation. Cancer 92:406-413, 2001 47. Kell WJ, Burnett AK, Chopra R, et al: A feasibility study of simultaneous administration of gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in younger patients with acute leukemia. Blood 102:4277-4283, 2003 48. Rajvanshi P, Shulman HM, Sievers EL, et al: Hepatic sinusoidal obstruction after gemtuzumab ozogamicin therapy. Blood 99:23102314, 2002 49. Bearman SI: The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 85:3005-3020, 1995 50. McDonald GB, Sharma P, Matthews DE, et al: Veno-occlusive disease of the liver after bone marrow transplantation: Diagnosis, incidence, and predisposing factors. Hepatology 4:116-122, 1984 51. McDonald GB, Hinds MS, Fisher LD, et al: Veno-occlusive disease of the liver and multi-organ failure after bone marrow transplantation: A cohort study of 355 patients. Ann Intern Med 118:255-267, 1993 52. Essel JH, Thompson JM, Harman GS, et al: Increase in veno-occlusive disease of the liver associated with methotrexate use for graft-versushost disease prophylaxis in patients receiving busulfan/cyclophosphamide. Blood 79:2782-2788, 1992 53. Grochow LB, Jones RJ, Brundett RB, et al: Pharmacokinetics of busulfan: Correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. Cancer Chemother Pharmacol 25:5561, 1989 54. Faioni E, Krachmalnicoff A, Bearman SI, et al: Naturally occurring anticoagulants and bone marrow transplantation: plasma protein C predicts the development of venoocclusive disease of the liver. Blood 81:3458-3462, 1993 55. Frickhofen N, Wiesneth M, Jainta C, et al: Hepatitis C virus infection is a risk factor for liver failure from veno-occlusive disease after bone marrow transplantation. Blood 83:1998-2004, 1994

N. Shahab, S. Haider, and D.C. Doll 56. Beschomer WE, Pino J, Boitnott JK, et al: Pathology of the liver with bone marrow transplantation: Effects of busulfan, carmustine, acute graft-versus- host disease, and cytomegalovirus infection. Am J Pathol 99:369-386, 1980 57. Ayash LJ Hunt M, Antman K, et al: Thrombocytopenia in veno-occlusive disease in autologous bone marrow transplantation of solid tumors and lymphomas. J Clin Oncol 8:1699-1706, 1990 58. Anscher MS, Peters WP, Reisenbid-der H, et al: Transforming growth factor P as a predictor of liver and lung fibrosis after autologous bone marrow transplantation for advanced breast cancer. N Engl J Med 328:1592-1598, 1993 59. Murase T, Jirtle RL, McDonald GB: Transforming growth factor plasma concentrations in patients with leukemia and lymphoma receiving chemo radiotherapy and marrow transplantation. Blood 83: 2383-2384, 1994 (letter) 60. Gugliotta L, Catani L, Vianelli N, et al: High plasma levels of tumor necrosis factor-alpha may be predictive of veno-occlusive disease in bone marrow transplantation. Blood 83:2385-2386, 1994 (letter) 61. Salat C, Holler E, Kolb HJ, et al: Plasminogen activator inhibitory confirms the diagnosis of hepatic veno-occlusive disease in patients with hyperbilirubinemia after bone marrow transplantation. Blood 89:2184-2188, 1997 62. Rio B, Andreu G, Nicod A, et al: Thrombocytopenia in veno-occlusive disease after bone marrow transplantation or chemotherapy. Blood 67:1773-1776, 1986 63. Yoshimoto K, Yahushiji K, Ijuin H et al: Colour doppler ultrasonography of a segmental branch of the portal vein is useful for early diagnosis and monitoring of the therapeutic course of venoocclusive disease after allogenic haematopoietic stem cell transplantation. Br J Haematol 115:945-948, 2001 64. Richardson P, Guinan E: The pathology, diagnosis and treatment of hepatic veno-occlusive disease: Current status and novel approaches. Br J Haematol 107:485-493, 1999 65. Saviola A, Luppi M, Potenza L, et al: Late occurrence of hepatic venoocclusive disease following gemtuzumab ozogomicin: Successful treatment with defibrotide. Br J Haematol 123:752-753, 2003 (letter) 66. Stoneham S, Lennard L, Coen P, et al: Veno-occlusive disease in patients in patients receiving thiopurines during maintenance therapy for childhood acute lymphoblastic leukemia. Br J Haematol 123:100102, 2003 67. Piel B, Vaidya S, Lancaster D et al: Chronic hepatotoxicity following 6-thioguanine therapy for childhood acute lymphoblastic leukemia. Br J Haematol 125:410-411, 2004 68. Blostein MD, Paltiel OB, Thibault A, et al: A comparison of clinical criteria for the diagnosis of veno-occlusive disease of the liver after bone marrow transplantation. Bone Marrow Transplant 10:439-443, 1992 69. Bearman SI, Anderson GL, Mori M, et al: Veno-occlusive disease of the liver: Development of a model for predicting fatal outcome after marrow transplantation. J Clin Oncol 11:1729-1736, 1993 70. Eltani M, Trivedi P, Hobbs JR, et al: Monitoring of veno-occlusive disease after bone marrow transplantation by serum aminopropeptide of type III procollagen. Lancet 342:518-521, 1993 71. Attal M, Huguet F, Rubie H, et al: Prevention of hepatic veno-occlusive disease after bone marrow transplantation by continuous infusion of low-dose heparin: A prospective, randomized trial. Blood 79:28342840, 1992 72. Lee JH, Lee KH, Lee JH, et al: Plasminogen activator inhibitor-1 is an independent diagnostic marker as well as severity predictor of hepatic veno-occlusive disease after allogenic bone marrow transplantation in adults conditioned with busulfan and cyclophosphamide. Br J Haematol 118:1087-1094, 2002 73. Heikinheimo M, Halila R, Fasth A: Serum procollagen type III is an early and sensitive marker for veno-occlusive disease of the liver in children undergoing bone marrow transplantation. Blood 83:30363040, 1994 74. Cahn JY, Flesch M, Brion A, et al: Prevention of veno-occlusive disease of the liver after bone marrow transplantation: Heparin or no heparin? Blood 80:2149-2150, 1992

Vascular toxicity of antineoplastic agents 75. Bianco JA, Appelbaum FR, Nemunaitis J, et al: Phase I-II trial of pentoxifyline for the prevention of transplant-related toxicities following bone marrow transplantation. Blood 78:1205-1211, 1991 76. Clift RA, Bianco JA, Appelbaum FR, et al: A randomized controlled trial of pentoxifyline for the prevention of regimen-related toxicities in patients undergoing allogeneic marrow transplantation. Blood 82: 2025-2030, 1993 77. Attal M, Huguet F, Rubie H, et al: Prevention of regime-related toxicities after bone marrow transplantation by pentoxifyline: A prospective, randomized trial. Blood 82:732-736, 1993 78. Bearman 51, Shen DD, Hinds MS, et al: A phase I/II study of prostaglandin El for the prevention of hepatic veno-occlusive disease after bone marrow transplantation. Br J Haematol 94:727-730, 1993 79. Gluckman E, Jolivet L, Scrobohaci ML, et al: Use of prostaglandin El for prevention of liver veno-occlusive disease in leukemic patients treated by allogeneic bone marrow transplantation. Br J Haematol 74:277-281, 1990 80. Essell JH, Schroeder MT, Harrnan GS, et al: Ursodial prophylaxis against hepatic complications of allogeneic bone marrow transplantation. Ann Intern Med 128:975-981, 1998 81. Ruutu T, Eriksson B, Remes K, et al: Urideoxycholic acid for the prevention of hepatic complications in allogenic stem cell transplantation. Blood 100:1977-1983, 2002 82. Bearman SI, Shuhart MC, Hinds MS, et al: Recombinant human tissue plasminogen activator for the treatment of established severe venoocclusive disease of the liver after bone marrow transplantation. Blood 80:2458-2462, 1992 83. Rostic G, Bandini G, Belardinelli A, et al: Alteptase for hepatic venoocclusive disease after bone-marrow transplantation. Lancet 339: 1481-1482, 1992 84. Ringden O, Wennberg L, Ericzon BG, et al: Alteplase for hepatic veno-occlusive disease after bone marrow transplantation. Lancet 340:546-547, 1992 85. Bearman SI, Lee JL, Baron AE, et al: Treatment of hepatic venoocclusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients. Blood 89:1501-1506, 1997 86. Harie WD, Stephens LC, Ruby EI, et al: Antithrombin III treatment of organ dysfunction during bone marrow transplantation: Results of a pilot study. Blood 88:458a, 1996 (abstr) 87. Stasser S, McDonald G: Gastrointestinal and hepatic complications, in Forman S, Blune K, Thomas E (eds): Haematopoietic Cell Transplantation., Oxford, UK, Blackwell Science, 1999, pp 1-127 88. Schitt HJ, Tischler HJ, Ringe B et al: Allogenic liver transplantation for hepatic veno-occlusive disease after bone marrow transplantation: Clinical and immunological considerations. Bone Marrow Transplant 16:473-478, 1995 89. Coccheri S, Biago G: Defibrotide. Cardiovasc Drug Rev 9:172-196, 1991 90. Ulutin ON: Antithrombotic effect and clinical potential of defibrotide. Semin Thromb Hemost 19:186-191, 1993 91. Chopra R, Eaton JD, Grassi A, et al: Defibrotide for the treatment of hepatic veno-occlusive disease: Results of European compassionateuse study. Br J Haematol 111:1122-1129, 2000 92. Richardson PG, Murakami C, Jin Z et al: Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: Response without significant toxicity in a high risk population and factors predictive of outcome. Blood 100:4337-4343, 2002 93. Greenstone MA, Dowd PM, Nfikhailidis DP, et al: Hepatic vascular lesions associated with dacarbazine treatment. Br Med J 282:17441745, 1981 94. Asbury RF, Rosenthal SN, Descalzi ME, et al: Hepatic veno-occlusive disease due to DTIC. Cancer 45:2670-2674, 1980 95. Houghton AN, Shafi N, Rickles FR: Acute hepatic vein thrombosis occurring during therapy for Hodgkin’s disease. A case report. Cancer 44:2324-2329, 1979 96. Lehrner IM, Enck RE: Hepatic vein thrombosis after chemotherapy for histiocytoma. Ann Intern Med 88:575-576, 1977 (letter)

131 97. Wasser JS, Coleman M: Leukemia chemotherapy and centrilobular hepatic necrosis. Ann Intern Med 86:508-509, 1977 (letter) 98. Krivoy N, Raz R, Carter A, et al: Reversible hepatic veno-occlusive disease and 6-thioguanine. Ann Intern Med 96:788, 1982 (letter) 99. Meindok H, Langer B: Liver scan in Budd-Chiari syndrome. J Nucl Med 17:365-368, 1976 100. Frosch PJ, Czametzki BM, Macher E, et al: Hepatic failure in a patient treated with dacarbazine (DTIC) for malignant melanoma. J Cancer Res Clin Oncol 95:281-286, 1979 101. Feaux de Lacroix W, Runne U, Hauk H, et al: Acute liver dystrophy with thrombosis of hepatic veins: A fatal complication of dacarbazine treatment. Cancer Treat Rep 67:779-784, 1983 102. Joensuu H, Soderstrom K-0, Mikkanen V: Fatal necrosis of the liver during ABVD chemotherapy for Hodgkin’s disease. A case report. Cancer 58:1437-1440, 1986 103. McClay E, Lusch CJ, Mastrangelo MJ: Allergy-induced hepatic toxicity associated with dacarbazine. Cancer Treat Rep 71:219-220, 1987 (letter) 104. Ceci G, Bella M, Melissani M, et al: Fatal hepatic vascular toxicity of DTIC: Is it really a rare event? Cancer 61:1988-1991, 1988 105. Sundstrup B: Raynaud’s phenomenon after bleomycin treatment. Med J Aust 2:266, 1978 (letter) 106. Adoue D, Arlet P: Bleomycin and Raynaud’s phenomenon. Ann Intern Med 100:770, 1984 (letter) 107. Malcolm D: Bleomycin-induced injury to the hands. J Med Soc N J 75:314-316, 1978 108. Vogelzang NJ, Bosl GJ, Johnson K, et al: Raynaud’s phenomenon: A common toxicity after combination chemotherapy for testicular cancer. Ann Intern Med 95:288-292, 1981 109. Teutsch C, Lipton A, Harvey HA: Raynaud’s phenomenon as a side effect of chemotherapy with vinblastine and bleomycin for testicular cancer. Cancer Treat Rep 61:925-926, 1977 110. Rothberg H: Raynaud’s phenomenon after vinblastine-bleomycin chemotherapy. Cancer Treat Rep 62:569-570, 1978 (letter) 111. Soble AR: Chronic bleomycin-associated Raynaud’s phenomenon. Cancer Treat Rep 62:570, 1978 (letter) 112. Chemicoff DP, Buiowski RM, Young JR: Raynaud’s phenomenon after bleomycin treatment. Cancer Treat Rep 62:570-571, 1978 (letter) 113. Schuten ME, Schmidt CG: Raynaud’s phenomenon and cancer chemotherapy. Ann Intern Med 96:256, 1982 (letter) 114. Paty JG Jr, Ruffner BW: Bleomycin-vinblastine associated Raynaud’s phenomenon. J Rheumatol 7:927-928, 1980 (letter) 115. Vogelzang NJ: Raynaud’s phenomenon and cancer chemotherapy. Ann Intern Med 96:256, 1982(letter) 116. Grau JJ, Grau M, Nfilla A, et al: Cancer chemotherapy and Raynaud’s phenomenon. Ann Intern Med 98:258, 1983 (letter) 117. Dunlop PR, Handy PM: Raynaud’s phenomenon and cryoglobulinemia during chemotherapy for testicular cancer. Cancer Treat Rep 67:317-318, 1983 (letter) 118. Garnick MB, Canellos GP, Richie JP: Treatment and surgical staging of testicular and primary extragonadal germ cell cancer. JAMA 250: 1733-1741, 1983 119. Kukla Lj, Burrows D, Bressler L, et al: Bleomycin-induced Raynaud’s phenomenon. Arch Dermatol 117:604, 1981 (letter) 120. Bostrom B, Woods WG, Ramsay NKL, et al: Cisplatin, vinblastine, and bleomycin (CVP) therapy for relapsed disseminated neuroblastoma. Cancer Treat Rep 68:1157-1158, 1984 121. Fossa SD, Aass N, Kaalhus O, et al: Long term survival and morbidity in patients with metastatic malignant germ cell tumors treated with cisplatin-based combination chemotherapy. Cancer 58:2600-2605, 1986 122. Stefenelli T, Kuzmits R, Ulrich W, et al: Acute vascular toxicity after combination chemotherapy with cisplatin, vinblastine, and bleomycin for testicular cancer. Eur Heart J 9:552-556, 1988 123. Hansen SW, Olsen N: Raynaud’s phenomenon in patients treated with cisplatin, vinblastine, and bleomycin for germ cell cancer: Measurement of vasoconstrictor response to cold. J Clin Oncol 7:940-942, 1989 124. Boyer M, Raghaven D: Intensive late toxicity assessment program for patients treated for metastatic germ cell tumors with cisplatin-containing combination chemotherapy. Proc Am Soc Clin Oncol 8:142, 1989 (abstr 552)

132 125. Roth BJ, Greist A, Kubilis PS, et al: Cisplatin-based combination chemotherapy for disseminated germ cell tumors: Long-term follow-up. J Clin Oncol 6:1239-1247, 1988 126. Stoter G, Koopman A, Vendrick CPJ, et al: Ten-year survival and later sequelae in testicular cancer patients treated with cisplatin, vinblastine, and bleomycin. J Clin Oncol 7:1099-1104, 1989 127. Brada M, Horwich A, Peckham MJ: Treatment of favorable-prognosis non- seminomatous testicular germ cell tumors with etoposide, cisplatin, and reduced dose of bleomycin. Cancer Treat Rep 71:655-656, 1987 128. Cohen IS, Mosher MB, O’Keefe EJ, et al: Cutaneous toxicity of bleomycin therapy. Arch Dermatol 107:553-555, 1973 129. Von Gunten CF, Roth EL, Von Roenn JHV: Raynaud’s phenomenon in three patients with acquired immune deficiency syndrome-related Kaposi sarcoma treated with bleomycin. Cancer 72:2004-2006, 1993 130. Flomaa L, Pajunen M, Virkkunen P: Raynaud’s phenomenon progressing to gangrene after vincristine and bleomycin therapy. Acta Med Scand 216:323-326, 1984 131. Fertakos RJ, Mintzer DM: Digital gangrene following chemotherapy for AIDS-related Kaposi’s sarcoma. Am J Med 93:581-582, 1992 132. Reid TJ HI, Lombardo FA, Redmond J III, et al: Digital vasculitis associated with interferon therapy. Am J Med 92:702-703, 1992 133. Creutzig A, Caspary L, Freund M: The Raynaud’s phenomenon and interferon therapy. Ann Intern Med 125:423, 1996 (letter) 134. Bachrneyer C, Farge D, Gluckman E, et al: Raynaud’s phenomenon and digital necrosis induced by interferon-alpha. Br J Dermatol 135: 481-483, 1996 135. Linden D: Severe Raynaud’s phenomenon associated with interferonbeta treatment for multiple sclerosis. Lancet 352:878-879, 1998 (letter) 136. Goffin E, Angangio R, Shapiro LM, et al: Digital gangrene following chemotherapy. Am J Med 96:571, 1994 (letter) 137. van Basten JPA, Hoekstra HJ, van Driel MF, et al: Sexual dysfunction in non-seminoma testicular cancer patients is related to chemotherapy-induced angiopathy. J Clin Oncol 15:2442-2448, 1997 138. Bokemeyer C, Berger CC, Kuczyk M, et al: Evaluation of long-term toxicity after chemotherapy for testicular cancer. J Clin Oncol 14: 2923-2932, 1996 139. Raiser M, Burns C, Hartmann P, et al: Raynaud’s phenomenon and acral necrosis after chemotherapy for AIDS-related Kaposi’s sarcoma. Eur J Clin Microbiol Infect Dis 117:58-60, 1998 140. Hladunewich M, Sawka C, Fam A, et al: Raynaud’s phenomenon and digital gangrene as a consequence of treatment for Kaposi’s sarcoma. J Rheumatol 12:2371-2375, 1997 141. Malamet R, Wise RA, Ettinger WH, et al: Nifedipine in the treatment of Raynaud’s phenomenon: Evidence for inhibition of platelet activation. Am J Med 78:602-608, 1985 142. Rodenheffer RJ, Runner JA, Wigley F, et al: Controlled double-blind trial of nifedipine in the treatment of Raynaud’s phenomenon. N Eng J Med 308:880-883, 1983 143. Hantel A, Rowinsky EK, Donehower RC: Nifedipine and oncologic Raynaud’s phenomenon. Ann Intern Med 108:767, 1988 (letter) 144. Mandel EM, Lewinski U, Djaidetti M: Vincristine-induced myocardial infarction. Cancer 30:1979-1982, 1975 145. Somers G, Abram M, Witter M, et al: Myocardial infarction: A complication of vincristine treatment? Lancet 2:690, 1976 (letter) 146. Lejonc JL, Vernant JP, Macquin I, et al: Myocardial infarction following vinblastine treatment. Lancet 2:692, 1980 (letter) 147. Schuster JP, Jones SE: Myocardial infarction in a 27 year old woman: Possible complication of treatment with VP-16-213 (NSC-141540), mediastinal irradiation, or both. Cancer Chemother Rep 59:887-888, 1975 (letter) 148. Aisner J, Van Echo DA, Whitaker M, et al: A phase I trial of continuous infusion VP-16-213 (etoposide). Cancer Chemother Pharmacol 7:157-160, 1982 149. Mortimer JE, Crowley L, Eyre H, et al: A phase II randomized study comparing sequential and combined intra-arterial cisplatin and radiation therapy for primary brain tumors. Cancer 69:1220-1793, 1992 150. Ricci JA, Goldstein L: Coronary artery disease in the presence of bleomycin therapy. Cancer Treat Rep 66:410, 1982 (letter)

N. Shahab, S. Haider, and D.C. Doll 151. Vogelzang NJ, Frenning DH, Kennedy BJ: Coronary artery disease after treatment with bleomycin and vinblastine. Cancer Treat Rep 53:1159-1160, 1980 (letter) 152. Vogelzang NJ, Torkelson JL, Kennedy BJ: Hypomagnesemia, renal dysfunction, and Raynaud’s phenomenon in patients treated with cisplatin, vinblastine and bleomycin. Cancer 56:2765-2770, 1985 153. Samuels BL, Vogelzang NJ, Kennedy BJ: Severe vascular toxicity associated with vinblastine, bleomycin and cisplatin chemotherapy. Cancer Chemother Pharmacol 19:253-256, 1987 154. Bodensteiner DC: Fatal coronary artery fibrosis after treatment with bleomycin, vinblastine, and cisplatin. South Med J 74:898-899, 1981 155. Doll DC, List AF, Greco FA, et al: Acute arterial ischemic events following cisplatin-based combination chemotherapy for germ cell tumors of the testis. Ann Intern Med 105:48-51, 1986 156. Talcott JA, Herman TS: Acute ischemic vascular events and cisplatin. Ann Intern Med 107:121-197, 1987 (letter) 157. Icli F, Karaoguz H, Dincol D, et al: Severe vascular toxicity associated with cisplatin-based chemotherapy. Cancer 72:587-593, 1993 158. House KW, Simon SR, Pugh RP: Chemotherapy-induced myocardial infarction in a young man with Hodgkin’s disease. Clin Cardiol 15: 122-125, 1992 159. Rothenberg ML, Meropol NJ, Poplin EA, et al: Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: Summary findings of an independent panel. J Clin Oncol 19:3801-3807, 2001 160. Boiven JF, Hutchinson GB, Lubin JH, et al: Coronary artery disease mortality in patients treated for Hodgkin’s disease. Cancer 69:12411247, 1992 161. Nichols CR, Roth BJ, Williams SD, et al: No evidence of acute cardiovascular complications of chemotherapy for testicular cancer: An analysis of the Testicular Cancer Intergroup Study. J Clin Oncol 10: 760-765, 1992 162. Yancey RS, Talpaz M: Vindesine-associated angina and ECG changes. Cancer Treat Rep 66:587-588, 1982 (letter) 163. Dexeus F, Logothetis CJ, Samuels ML, et al: Continuous infusion of vinblastine for advanced hormone refractory prostate cancer. Cancer Treat Rep 69:885-886, 1985 164. Subar M, Muggia FM: Apparent myocardial ischemia associated with vinblastine administration. Cancer Treat Rep 70:690-691, 1986 (letter) 165. Tomirotti M, Riundi R, Pulici S, et al: Ischemic cardiopathy from cis-diamminedichloroplatinum (CDDP). Tumori 70:235-236, 1984 166. Shachor L Beker B, Geffen Y, et al: Acute ECG change during cyclophosphamide infusion in a patient with bronchogenic carcinoma. Cancer Treat Rep 69:734-735, 1985 (letter) 167. White DA, Schwartzberg LS, Kris MG, et al: Acute chest pain syndrome during bleomycin infusions. Cancer 59:1582-1585, 1987 168. Yano S, Shimada K: Vasospastic angina after chemotherapy by with carboplatin and etoposide in a patient with lung cancer. Jpn Circ J 60:185-188, 1996 169. Rodriguez L, Collazos J, Gallardo M, et al: Angina pectoris following cisplatin, etoposide, and bleomycin in a patient with advanced testicular cancer. Ann Pharmacother 29:138-139, 1995 170. Leone B, Rabinovitch M, Ferrari CR, et al: Cardiotoxicity as a result of 5-fluorouracil therapy. Tumori 71:55-57, 1985 171. Sanani S, Spaulding M, Masud AR, et al: 5-FU cardiotoxicity. Cancer Treat Rep 65:1123-1125, 1981 172. Labianca R, Beretta G, Clerici M, et al: Cardiotoxicity of 5-fluorouracil: A study of 1083 patients. Tumori 68:505-510, 1982 173. Pottage A, Holt S, Ludgate S, Langlands AO: Fluorouracil cardiotoxicity. Br Med J 1:547, 1978 174. Freeman N, Costanza M: 5-Fluorouracil associated cardiotoxicity. Cancer 61:36-45, 1988 175. Gradishar W, Vokes E, Schilsky R, et al: Vascular events in patients receiving high-dose infusional 5-fluorouracil based chemotherapy: The University of Chicago experience. Med Pediatr Oncol 19:8-15, 1991 176. Vorbiof DA: Cardiotoxicity of 5-fluorouracil. South Afr Med J 61:635637, 1982

Vascular toxicity of antineoplastic agents 177. Dent RG, McColl L: 5-Fluorouracil and angina. Lancet 1:347-348, 1975 (letter) 178. Stevenson DL, Mikhaikidis DP, Gillet DS: Cardiotoxicity of 5-fluorouracil. Lancet 2:406-407, 1977 (letter) 179. Soukop M, MeVie JG, Cahnan KC: 5-Fluorouracil cardiotoxicity. Br Med J 1:14-22, 1978 180. Kleiman NA, Lehane DE, Geyer E, et al: Prinzmetal’s angina during 5-fluorouracil chemotherapy. Am J Med 82:566-568, 1987 181. Gauci T, Zampa G: Cardiotoxicity of 5-FU. Tumori 65:487-495, 1979 182. Umsawasdi T, Sawamkatata P: Cardiotoxicity of 5-fluorouracil. Cancer Chemother Rep 59:1051-1053, 1975 183. Oleksowicz L, Bruckner HW: Prophylaxis of 5-fluorouracil-induced coronary vasospasm with calcium channel blockers. Am J Med 85: 750-751, 1988 184. Chaudary S, Song SYK, Jaski BE: Profound, yet reversible, heart failure secondary to 5-fluorouracil. Am J Med 85:454-456, 1988 185. Collins C, Weiden PL: Cardiotoxicity of 5-fluorouracil. Cancer Treat Rep 71:733-736, 1987 186. Rezkalla S, Kloner RA, Ensley J, et al: Continuous ambulatory ECG monitoring during fluorouracil therapy: A prospective study. J Clin Oncol 7:509-514, 1989 187. Patel B, Kloner RA, Ensley J, et al: 5-Fluorouracil cardiotoxicity: Left ventricular dysfunction and effects of coronary dilators. Am J Med Sci 294:238-243, 1987 188. Jakubowski AA, Kemeny N: Hypotension as a manifestation of cardiotoxicity in three patients receiving cisplatin and 5-fluorouracil. Cancer 62:266-269, 1988 189. Robben NC, Pippas AW, Moore JO: The syndrome of 5-fluorouracil cardiotoxicity: an elusive cardiomyopathy. Cancer 71:493-509, 1993 190. Schooben C, Papageorgiou E, Harstick A, et al: Cardiotoxicity of 5-fluorouracil in combination with foiling acid in patients with gastrointestinal cancer. Cancer 72:2242-2247, 1993 191. De Fond M, Makt-Martino MC, Jaillais P, et al: Cardiotoxicity of high dose continuous infusion fluorouracil: A prospective clinical study. J Clin Oncol 10:1795-1801, 1992 192. Anderson NM, Lokich JJ, Moore C: The syndrome of 5-fluorouracil cardiotoxicity: an elusive cardiomyopathy. Cancer 72:9787-2288, 1993 193. Forastiere AA, Metch B, Schuller DE, et al: Comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous cell carcinoma of the head and neck: A Southwest Oncology Group Study. J Clin Oncol 10:1245-1251, 1992 194. Saif MW, Szabo E, Grem J, et al: The clinical syndrome of 5-fluorouracil cardiotoxicity. Proc Am Soc Clin Oncol 20;404a, 2001 (abstr 1613) 195. Pizzolato JF, Baum M, Steingart RM, et al: Cardiac toxicity of 5FU: does prophylactic telemetry monitoring of patients at increased risk for cardiac toxicity improve safety? A 10-year experience. Proc Am Soc Clin Oncol 22:755s, 2004 (abstr) 196. Meinardi MT, Gietema JA, van der Graaf WTA, et al: Cardiovascular morbidity in long term survivors of metastatic testicular cancer. J Clin Oncol 18:1725-1732, 2000 197. Huddart RA, Norman A, Shahidi M, et al: Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 21:1513-1523, 2003 198. Murgo AJ: Thrombotic microangiopathy in the cancer patient including those induced by chemotherapeutic agents. Semin Hematol 24: 161-177, 1987 199. Gulati SC, Sordiu P, Kernpin S, et al: Microangiopathic hemolytic anemia observed after treatment of epidermoid carcinoma with mitomycin C and 5-fluorouraril. Cancer 45:2252-2257, 1980 200. Hanna WT, Krauss S, Regester RF, et al: Renal disease after mitomycin C therapy. Cancer 48:2583-2588, 1981 201. Harden E, Lucas VS, Proia A, et al: Hemolytic uremic syndrome during therapy with mitomycin C (MMC) plus 5-fluorouracil (5-FU). Proc Am Soc Clin Oncol 1:93, 1982 (abstr C-360) 202. Home MK III, Cooper B: Microangiopathic hemolytic anemia with metastatic adenocarcinonia: Response to chemotherapy. South Med J 75:503-504, 1982 203. Jones BG, Newman CE, Fielding JW, et al: Intravascular hemolysis

133

204.

205.

206.

207.

208. 209. 210.

211. 212.

213.

214. 215.

216.

217.

218.

219.

220.

221.

222. 223. 224.

225. 226. 227.

and renal impairment after blood transfusion in two patients on long-term 5-fluorouracil and mitomycin C. Lancet 1:1275-1277, 1980 Karlin DA, Stroehlein JR: Rash, nephritis, hypertension, and hemolysis in patients on 5-fluorouracil, doxorubicin, and mitomycin C. Lancet 2:534-535, 1980 (letter) Krauss S, Sonoda T, Solomon A: Treatment of advanced gastrointestinal cancer with 5-fluorouracil and mitomycin C. Cancer 1598-1603, 1974 Kressel BR, Ryan KP, Kuong AT, et al: Microangiopathic hemolytic anemia, thrombocytopenia, and renal failure in patients treated for adenocarcinoma. Cancer 48:1734-1745, 1981 Laffay DL, Tubbs RR, Valenzuela R, et al: Chronic glomerular microangiopathy and metastatic carcinoma. Hum Pathol 10:433-438, 1979 Lempert KD: Hemolysis and renal impairment syndrome in patients on 5- fluorouracil and mitomycin C. Lancet 2:369-370, 1980 (letter) Pavy ME, Wiley EL, Abeloff MD: Hemolytic uremic syndrome associated with mitomycin therapy. Cancer Treat Rep 66:457-461, 1982 Rabadi SJ, Khandekar JD, Miller HJ: Mitomycin-induced hemolytic uremic syndrome: Case presentation and review of the literature. Cancer Treat Rep 66:1244-1247, 1982 Rump KW, Rieger J, Landkisch PG, et al: Mitomycin-induced hemolysis and renal failure. Lancet 2:1037-1038, 1980 (letter) Bruntsch U, Froos G, Tigges F, et al: Microangiopathic hemolytic anemia, a frequent complication of mitomycin therapy in cancer patients. Eur J Clin Oncol 20:905-909, 1984 Zimmerman S, Smith FF, Phillips TM, et al: Gastric carcinoma and thrombotic thrombocytopenic purpura: Association with plasma immune complex concentration. Br Med J 284:1432-1434, 1982 Perry DJ: Reversible microangiopathic hemolytic anemia after mitomycin C. Cancer Chemother Pharmacol 10:223, 1983 Lyman NW, Michaelson R, Viscuso RL, et al: Mitomycin-induced hemolytic uremic syndrome. Successful treatment with corticosteroids and intense plasma exchange. Arch Intern Med 143:1617-1618, 1983 Grocker J, Jones EL: Hemolytic-uremic syndrome complicating longterm mitomycin C and 5-fluorouracfl therapy for gastric carcinoma. J Clin Pathol 36:24-29, 1983 Cantrell JE Jr, Phillips TM, Schein PS: Carcinoma-associated hemolytic-uremic syndrome: A complication of mitomycin C chemotherapy. J Clin Oncol 3:723-734, 1985 Jolivet J, Giroux L, Laurin S: et al: Microangiopathic hemolytic anemia, renal failure, and noncardiogenic pulmonary edema: A chemotherapy induced syndrome. Cancer Treat Rep 67:429-434, 1983 Tanriock IF: Methotrexate and mitomycin for patients with metastatic transitional cell carcinoma of the urinary tract. Cancer Treat Rep 61: 503-504, 1983 Fielding JWL, Fagg SL, Jones BG, et al: An interim report of a prospective, randomized, controlled study of adjuvant chemotherapy in operable gastric cancer: British Stomach Cancer Group. World J Surg 7:390-399, 1983 Laufnian L, Courter S, Iritchard J: Fatal mitomycin C (MMC) syndrome heralded by pulmonary symptoms. Proc Am Soc Clin Oncol 2:197, 1983 (abstr 768) RavikurnarFS , Sibley R, Reed K, et al: Renal toxicity of mitomycin C. Am J Clin Oncol 7:279-285, 1984 Loprinzi CL: Mitomycin C-induced pulmonary and renal toxicities. Wis Med J 83:16-17, 1984 Ito S, Hirono S: Two cases of microangiopathic hemolytic anemia caused by anticancer drugs which showed rapid improvement after administration of aspirin and dipyridamole. Rinsho Ketsueki 23:730735, 1982 Jao W, Manaligod JR: Renal disease associated with mitomycin therapy. Ultrastruct Pathol 5:83-88, 1983 Boven E, Findeo IM: Mitomycin C. Interstitial pneumonitis and hemolytic uraemic syndrome. Neth J Med 26:153-156, 1983 Khojasteh A, Reynolds RD, Garcia AR, et al: Hemolytic uremic-like syn-

N. Shahab, S. Haider, and D.C. Doll

134

228. 229. 230.

231.

232. 233.

234.

235.

236.

237.

238.

239.

240.

241.

242.

243.

244. 245. 246. 247. 248.

249.

250.

251.

252.

drome following a single dose of mitomycin C. Proc Am Soc Clin Oncol 3:4, 1984 (abstr 16) Van Speeuwel JP, Hemrika MH, Dammaat CEM, et al: Letter to the editor. Neth J Med 26:287-288, 1983 (letter) Peterson KB, Smith WE: Mitomycin induced hemolytic uremic syndrome. Samaritan Med 2:17-20, 1984 Simon P, Herve JP, Ramee MP, et al: La nephrotoxicite de la mitomycin C. Trois nouvelles observations et revue de la litterature. Nephrologie 3:152-157, 1982 Willie GR, Levy SM, Michaels RE, et al: Hemolytic uremic syndrome in a patient receiving mitomycin C and 5-fluorouracil. Henry Ford Hosp Med J 31:104-109, 1983 Valavaara R, Nordman E: Renal complications of mitomycin C therapy with special references to the total dose. Cancer 55:47-50, 1985 Hug V, Burgess A, Blumenschein G, et al: Effect of cyclophosphamide on the mitomycin-based syndrome of thrombotic thrombocytopenic purpura. Cancer Treat Rep 69:565-566, 1985 (letter) Price TM, Murge AJ, Keveney JJ, et al: Renal failure and hemolytic anemia associated with mitomycin C: A case report. Cancer 55:51-56, 1985 Verwey J, Boven E, Van Der Muelen J, et al: Recovery from mitomycin C induced hemolytic uremic syndrome: A case report. Cancer 54: 2878-2881, 1984 Garibotto G, Acquarone N, Saffloti S, et al: Successful treatment of mitomycin-C associated hemolytic uremic syndrome by plasmapheresis. Nephron 51:409-412, 1989 Fields SM, Lindley CM: Thrombotic n-microangiopathy associated with chemotherapy: A case report and review of the literature. DICP 23:582-588, 1989 Sheldon R, Slaughter D: A syndrome of microangiopathic hemolytic anemia, renal impairment, and pulmonary edema in chemotherapytreated patients with adenocarcinoma. Cancer 58:1428-1436, 1986 Hostetter AL, Tubbs RR, Ziegler T, et al: Chronic glomerular microangiopathy complicating metastatic carcinoma. Hum Pathol 18:342348, 1987 Verwey J, Vries JD, Pinedo HM: Mitomycin C induced renal toxicity, a dose dependent side effect? Eur J Cancer Clin Oncol 23:195-199, 1987 Mergenthaler HG, Binsack T, Wilmanns W: Carcinoma associated hemolytic-uremic syndrome in a patient receiving 5-fluorouracilAdriamycin-mitomycin C combination chemotherapy. Oncology 45: 11-14, 1988 McCarthy JT, Staats BA: Pulmonary hypertension, hemolytic anemia, and renal failure: A mitomycin associated syndrome. Chest 89:608611, 1986 Lessesne JB, Rothschild N, Erickson B, et al: Cancer associated hemolytic uremic syndrome: Analysis of 85 cases from a national registry. J Clin Oncol 7:781-789, 1989 Liu KM, Mittelman A, Sproul EE, et al: Renal toxicity in man treated with mitomycin C. Cancer 28:1314-1320, 1971 Weiss RB, Poster DS: The renal toxicity of cancer chemotherapeutic agents. Cancer Treat Rev 9:37-56, 1982 Haur RW, Verani R, Weirunan EJ: Mitomycin associated renal failure. Case report and review. Arch Intern Med 143:803-807, 1983 Morel-Maroger L: Nephrology forum: Adult hemolytic uremic syndrome. Kidney Int 18:125-134, 1980 Agnelli G, Gresele P, Nenci GG: Clotting activation after blood transfusion in patients receiving 5-fluorouracil and mitomycin C treatment. Cancer Chemother Pharmacol 5:205-206, 1981 (letter) Chow S, Roscoe J, Cattran DC: Plasmapheresis and antiplatelet agents in the treatment of the hemolytic uremic syndrome to mitomycin. Am J Kidney Dis 7:407-412, 1986 Grem JL, Merritt JA, Carbone PP: Treatment of mitomycin associated microangiopathic hemolytic anemia with vincristine. Arch Intern Med 46:566-568, 1986 Zimmerman SE, Smith FF, Phillips TM, et al: Gastric carcinoma and thrombotic thrombocytopenic purpura: Association with plasma immune complex concentrations. Br Med J 284:1432-1434, 1982 Korec 5, Schein PS, Smith FP, et al: Treatment of cancer associated

253.

254.

255.

256.

257.

258.

259.

260.

261.

262.

263. 264. 265.

266.

267.

268.

269.

270.

271.

272. 273.

274.

275.

hemolytic uremic syndrome with staphylococcal protein A immunoperfusion. J Clin Oncol 4:210-215, 1986 Snyder HW Jr, Mittleman A, Oral A, et al: Treatment of cancer chemotherapy associated thrombocytopenia purpura/hemolytic uremic syndrome by protein A immunoadsorption of plasma. Cancer 71: 1882-1892, 1993 Licciardello J, Moake J, Rudy C, et al: Elevated plasma von Willebrand factor levels and arterial occlusive complications associated with cisplatin-based chemotherapy. Oncology 42:296-300 1985 Jackson AM, Rose BD, Graff LG, et al: Thrombotic microangiopathy and renal failure associated with antineoplastic chemotherapy. Ann Intern Med 101:41-44, 1984 Desablens B, Fievet P, Pruna A, et al: Hemolytic-uremic syndrome after cancer chemotherapy without mitomycin C. Nephron 42:340344, 1986 Van De Meer J, De Vries EGE, Vriesendorp R, et al: Hemolytic uremic syndrome in a patient on cisplatin, vinblastine, and bleomycin. J Cancer Res Clin Oncol 110:119-122, 1985 Gradishar WJ, Vokes EE, Mi K, et al: Chemotherapy related hemolytic-uremic syndrome after the treatment of head and neck cancer. A case report. Cancer 66:1914-1918, 1990 Watson PR, Guthrie TH Jr, Caruana RJ: Cisplatin-associated hemolytic uremic syndrome: Successful treatment with staphylococcal protein A column. Cancer 64:1400-1403, 1989 Coates AS, Childs A, Cox K, et al: Severe vascular adverse effects with thrombocytopenia and renal failure following emetogenic chemotherapy and ondansetron. Ann Oncol 3:773-774, 1992 van der Heijden M, Ackland SP, Deveridge S: Haemolytic uraemic syndrome associated with bleomycin, epirubicin and cisplatin chemotherapy: A case report and review of the literature. Acta Oncol 37:107-109, 1998 Walker RW, Rosenblum MK, Kempin SJ, et al: Carboplatin-associated thrombotic microangiopathic hemolytic anemia. Cancer 64:10171020, 1989 Case records MGH. Case 16-1988. N Engl J Med 318:1047-1057, 1988 Carey RW, Harris N: Thrombotic microangiopathy in three patients with cured lymphoma. Cancer 63:1393-1397, 1989 Byrnes JJ, Baquerizo H, Gonzalez M, et al: Thrombotic thrombocytopenic purpura subsequent to acute myelogenous chemotherapy. Am J Hematol 21:299-304, 1986 Leach JW, Pham T, Diamandidis D et al: Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following treatment with deoxyforcomycin in a patient with cutaneous T-cell lymphoma: A case report. Am J Hem 61:268-270, 1999 Fung MC, Storniolo AM, Nguyen B et al: A review of hemolytic uremic syndrome in patients with gemcitabine therapy. Cancer 85:20232032, 1999 Harris DCH, Lawrence S, Bradstock KF, et al: Intraglomerular thrombosis with deoxycoformycin-reversible acute renal failure. Clin Nephrol 21:194-196, 1984 Sakai C, Takagi T, Wakatsuki S, et al: Hemolytic uremic syndrome due to deoxycoformycin: A report of the second case. Intern Med 34:593-596, 1995 Honda K, Ando A, Endo M, et al: Thrombotic microangiopathy associated with alpha-interferon therapy for chronic myelocytic leukemia. Am J Kidney Dis 30:123-130, 1997 Fisher DC, Sherrill GB, Hussein A, et al: Thrombotic microangiopathy as a complication of high-dose chemotherapy for breast cancer. Bone Marrow Transplant 18:193-198, 1996 Pettitt AR, Clark RE: Thrombotic microangiopathy following bone marrow transplantation. Bone Marrow Transplant 14:495-504, 1994 Moake JL, Byrnes JJ: Thrombotic microangiopathies associated with drugs and bone marrow transplantation. Hematol Oncol Clin North Am 10:485-497, 1996 Rabinowe SN, Soiffer RJ, Tarbell NJ, et al: Hemolytic uremic syndrome following bone marrow transplantation in adults for hematologic malignancies. Blood 77:1837-1844, 1991 Fuge R, Bird JM, Fraser A et al: The Clinical features, risk factors and

Vascular toxicity of antineoplastic agents

276.

277.

278.

279.

280. 281.

282.

283. 284.

285. 286.

287.

288. 289.

290.

291.

292.

293. 294.

295.

296.

297.

298.

outcome of thrombotic thrombocytopenia purpura occurring after bone marrow transplantation. Br J Haematol 113:59-64, 2001 Ojik HV, Biesma DH, Fijhnheer R, et al: Cyclosporin for thrombotic thrombocytopenic purpura after autologous bone marrow transplantation. Br J Haematol 96:641-643, 1997 Sack GH, Levin J, Bell WRrousseau’s syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: Clinical, pathophysiologic and therapeutic features. Medicine 56:1-37, 1997 Kukla LJ, McGuire WP, Lad T, et al: Acute vascular episode associated with therapy for carcinoma of the upper aerodigestive tract with bleomycin, vincristine, and cisplatin. Cancer Treat Rep 66:369-370, 1982 Fallon B, Clark J, Frei E: Vascular complications during cisplatin-bleomycin-methotrexate and cisplatin 5-FU in induction chemotherapy for advanced stage III and IV squamous cell carcinoma of the head and neck. Proc Am Soc Clin Oncol 5:134, 1986 (abstr 521) Allerton R: Acute mesenteric ischemia associated with 5-FU, cisplatin and vincristine chemotherapy. Clin Oncol 8:116-117, 1996 Cantwell BMJ, Manniz KA, Roberts JT, et al: Thromboembolic events during combination chemotherapy for germ cell malignancy. Lancet 2:1086-1087, 1988 (letter) Hall MR, Richards MA, Harper PG: Thromboembolic events during combination chemotherapy for germ cell malignancy. Lancet 2:1259, 1986 (letter) Lederman GS, Garnick MB: Pulmonary emboli as a complication of germ cell cancer treatment. J Urol 137:1236-1237, 1987 Czaykowski PM, Moore M, Tannock IF: High risk of vascular events in patients with urothelial transitional cell carcinoma treated with cisplatin based chemotherapy. J Urol 160:2021-2024, 1998 Garsft IWH, Cooper GG, Hood JM: Arterial thrombosis after treatment with bleomycin and cisplatin. Br Med J 300:10-18, 1990 (letter) Molloy RG, Welch GC, Drury JK, et al: Arterial thrombosis after chemotherapy with cisplatin, vinblastine and methotrexate. Br J Clin Pract 49:50-51, 1995 Lepidini G, Biancari F, D’Andma V: Severe thrombosis after chemotherapy for metastatic adenocarcinorna of the testis maintaining complete remission for a long period. Scand J Urol Nephrol 31:221-299, 1996 Seiffer EJ, Young RC, Longo DL: Deep venous thrombosis during therapy for Hodgkin’s disease. Cancer Treat Rep 69:1011-1013, 1985 Clarke CS, Otridge BW, Carney DN: Thromboembolism. A complication of weekly chemotherapy in the treatment of non-Hodgkin’s lymphoma. Cancer 66:2027-2030, 1990 Cantwell BMJ, Carmichael J, Ghani SE, et al: Thromboses and thrombolic in patients with lymphoma during cytotoxic chemotherapy. Br Med J 2:179-180, 1988 Miller TP, Dahlberg S, Weich JK, et al: Unfavorable histologies of non-Hodgkin’s lymphoma treated with ProMACE-CytaBOM: A groupwide Southwest Oncology Group Study. J Clin Oncol 8:19511958, 1990 Weiss RB, Tormey DC, Holland JF, et al: Venous thrombosis during multimodality treatment of primary breast carcinoma. Cancer Treat Rep 65:677-679, 1981 Booth BW, Weiss RB: Venous thrombosis during adjuvant chemotherapy. N Engl J Med 305:168, 1981 (letter) Manni A, Trujillo JE, Pearson OH: Sequential use of endocrine therapy and chemotherapy for metastatic breast cancer: Effects on survival. Cancer Treat Rep 64:111-116, 1980 Goodnough LT, Saito H, Manni A, et al: Increased incidence of thromboembolism in stage IV breast cancer patients treated with a five-drug chemotherapy regimen. A study of 159 patients. Cancer 54:1264-1268, 1984 Levine MN, Gent M, Hirsh J, et al: The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Eng J Med 318:404-407, 1988 Saphner T, Toriney DC, Gray R: Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol 9:286-294, 1991 Fisher B, Redmond C, Wickerham DL, et al: Doxorubicin-containing regimens for the treatment of stage II breast cancer: The National

135

299.

300.

301.

302.

303.

304.

305.

306.

307. 308. 309.

310.

311.

312.

313.

314.

315. 316.

317. 318.

319.

Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol 7:572-582, 1989 Pritchard KI, Pater L Paul N: et al: Thromboembolic complications related to chemotherapy in a National Institute of Canada randomized trial for tamoxifen versus tamoxifen plus chemotherapy in postmenopausal women with axillary node positive receptor positive breast cancer. Proc Am Soc Clin Oncol 8:25, 1989 (abstr 92) Wall JG, Weiss RB, Norton L, et al: Arterial thrombosis associated with adjuvant chemotherapy for breast carcinoma: A Cancer and Leukemia Group B study. Am J Med 87:1455-1466, 1989 Rivkin SE, Green S, Metch B, et al: Adjuvant CMFVP versus tamoxifen versus concurrent CMFVP and tamoxifen for postmenopausal, nodepositive, and estrogen receptor-positive breast cancer patients: A Southwest Oncology Group Study. J Clin Oncol 12:2078-2085, 1994 Theodossiou C, Kroog G, Ettinghausen S, et al: Acute arterial thrombosis in a patient with breast cancer after chemotherapy with 5-fluorouracil, doxorubicin, leucovorin, cyclophosphamide, and interleukin-3. Cancer 74:2808-2810, 1994 Clahsen PC, van De Velde CJH, Julien JP, et al: Thromboembolic complications after perioperative chemotherapy in women with early breast cancer: A European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group study. J Clin Oncol 12: 1266-1271, 1994 Levine M, Hirsh J, Gent M, et al: Double-blind randomized trial of very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 343:886-889, 1994 Pritchard KI, Paterson AHG, Paul NA, et al: Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant chemotherapy for women with breast cancer. J Clin Oncol 14:2731-2737, 1996 Shlebak AA, Smith DB: Incidence of objectively diagnosed thromboembolic disease in cancer patients undergoing cytotoxic chemotherapy and or hormonal therapy. Cancer Chemother Pharmacol 39:462466, 1997 Chan ATC, Yeo W, Leung WT, et al: Thrombolic events with paclitaxel. Clin Oncol 8:133, 1996 (letter) Deshmukh N, Tripathi SP: Thrombosis of tibial arteries in a patient receiving tamoxifen therapy. Cancer 76:1006-1008, 1995 Weitz IC, Israel VK, Liebman HA: Tamoxifen-associated venous thrombosis and activated protein C resistance due to factor V Leiden. Cancer 79:2024-2027, 1997 Hall MR, Richards MA, Harper PG: Thromboembolic events during combination chemotherapy for germ cell malignancy. Lancet 2:1259, 1988 (letter) Weijl NI, Rutten MFJ, Zwinderman AH, et al: Thromboembolic events during chemotherapy for germ cell cancer: A cohort study and review of the literature. J Clin Oncol 18:2169-2178, 2000 Lynch TJ Jr, Kass F, Kalish LA, et al: Cisplatin, 5-fluorouracil, and etoposide for advanced non-small lung cancer. Cancer 71:29532957, 1993 Mathews J, Goel R, Evans WK, et al: Arterial occlusion in patients with peripheral vascular disease treated with platinum-based regimens for lung cancer. Cancer Chemother Pharmacol 40:19-22, 1997 Kasimis BS, Spiers ASD: Thrombotic complications in patients with advanced prostatic cancer treated with chemotherapy. Lancet 1:159, 1979 (letter) Del Prado PF, Meana JA, Carrion JR: Acute cerebrovascular accident after treatment with cisplatin. Acta Oncol 31:593-595, 1992 Gandia D, Spielman M, Kac J, et al: Cerebrovascular accident associated with chemotherapy for oesophageal carcinoma. Eur J Cancer 28:245, 1992 Sevelda P, Mayerhofer K, Obermain A, et al: Thrombosis with paclitaxel. Lancet 343:727, 1994 (letter) Becker JC, Winkler B, Klingert S, et al: Antiphospholipid syndrome associated with immunotherapy for patients with melanoma. Cancer 73:1621-1624, 1994 Conti JA, Scher M: Acute arterial thrombosis after escalated-dose methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy

N. Shahab, S. Haider, and D.C. Doll

136

320.

321.

322.

323.

324.

325. 326.

327.

328.

329.

330.

331. 332. 333.

334. 335.

336. 337. 338.

339. 340. 341.

342.

with recombinant granulocyte colony-stimulating factor. Cancer 70:2699-2702, 1992 Antman KS, Griffin JD, Elias A, et al: Effect of recombinant human granulocyte-macrophage colony-stimulating factor on chemotherapy-induced myelosuppression. N Engl J Med 319:593-598, 1988 Stephens LC, Haire WD, Pokorny KS, et al: Granulocyte macrophage colony stimulating factor: High incidence of apheresis catheter thrombosis during stem cell collection. Bone Marrow Transplant 11:57-59, 1993 Kawachi Y, Watanabe A, Uchida T, et al: Acute arterial thrombosis due to platelet aggregation in a patient receiving granulocyte colony stimulating factor. Br J Haematol 94:413-416, 1996 Stadler WM, Vogelzang NJ, Amato R, et al: Flavopiridol, a novel cyclin-dependent kinase inhibitor, in metastatic renal cell cancer: A University of Chicago phase II consortium study. J Clin Oncol 18: 371-375, 2000 Zangari M, Siegel E, Barlogie B, et al: Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: Implications of therapy. Blood 100:1168-1171, 2002 Zangari M: Thalidomide and thromboembolism. Blood 99:4249, 2002 (letter) Steurer M, Sudmeier I, Stauder R, et al: Thromboembolic events in patients with myelodysplastic syndrome receiving thalidomide in combination with Darbepoietin-alpha. Br J Haematol 121:101-103, 2003 Desai AA, Vogelzang NJ, Rini BI, et al: A high rate of venous thromboembolism in a multi-institutional phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil and daily thalidomide in patients with metastatic renal cell carcinoma. Cancer 95:1629-1636, 2002 Fisher B, Costantino J, Redmond C, et al: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor positive tumors. N Engl J Med 320:479-484, 1989 Cushman M, Costantino JP, Bovill EG, et al: Effect of tamoxifen on venous thrombosis risk factors in women without cancer: The Breast Cancer Prevention Trial. Br J Haematol 120:109-116, 2003 Rutqvist LE, Mattsson A: Cardiac and thromboembolic morbidity among postmenopausal women with early stage breast cancer in a randomized trial of adjuvant tamoxifen. The Stockhohn Breast Cancer Study Group. J Natl Cancer Inst 85:1398-1406, 1993 Issell BF, Crooke ST: Etoposide (VP-16-213). Cancer Treat Rev 6:107-124, 1979 O’Dwyer PJ, Alonso MT, Leyland-Jones B, et al: Teniposide: A review of 12 years of experience. Cancer Treat Rep 68:1455-1466, 1984 Antman KH, Mayer RJ, Frei E, et al: Vascular, hormonal, teratogenic and miscellaneous toxicities of chemotherapeutic agents, in Perry MC, Yarbro TW (eds): Toxicity of Chemotherapy. Philadelphia, PA, Grune & Stratton, 1984, pp 521-538 Buesa JM, Garcia M, Vaile M, et al: Phase I trial of intermittent highdose dacarbazine. Cancer Treat Rep 68:499-504, 1984 Henner WD, Peters WP, Eder JP, et al: Pharmacokinetics and immediate effects of high-dose carmustine in man. Cancer Treat Rep 70: 877-880, 1986 Legha SS, Keating M, Picket S, et al: Phase I clinical investigation of homoharringtonine. Cancer Treat Rep 68:1085-1091, 1984 Neidhart JA, Young DC, Derocher D, et al: Phase I trial of homoharringtonine. Cancer Treat Rep 67:801-804, 1983 Warnell RP Jr, Coonley CJ, Gee TS: Homoharringtonine: An effective new drug for remission induction in refractory non-lymphoblastic leukemia. J Clin Oncol 3:617-621, 1985 Carndchael SM, Eagieton L, Ayers CR, et al: Orthostatic hypotension during vincristine therapy. Arch Intern Med 126:290-293, 1970 DiBella NJ: Vincristine-induced orthostatic hypotension: A prospective clinical study. Cancer Treat Rep 64:359-360, 1980 (letter) Kletzel M, Jaffe N: Systemic hypertension: A complication of intraarterial cis-diammine dichloroplatinum (II) infusion. Cancer 47:245247, 1981 Harrell RM, Sibley R, Vogelzang NJ: Renal vascular lesion after che-

343.

344. 345. 346.

347.

348.

349.

350. 351. 352. 353. 354. 355. 356.

357.

358.

359.

360. 361.

362. 363.

364.

365.

366. 367.

368.

motherapy with vinblastine, bleomycin, and cisplatin. Am J Med 73:429-433, 1982 Hansen SW, Growth S, Augured G, et al: Long-term effects on renal function and blood pressure of treatment with cisplatin, vinblastine, and bleomycin in patients with germ cell cancer. J Clin Oncol 6:17281731, 1988 Spinach SD: Procarbazine. Ann Intern Med 81:795-800, 1974 O’Dwyer PI, Weiss RB: Hypersensitivity reactions induced by etoposide. Cancer Treat Rep 68:959-961, 1984 Weiss RB: Hypersensitivity reactions to cancer chemotherapy, in Perry MC, Yarbro JW (eds): Toxicity of Chemotherapy. Philadelphia, PA, Grune & Stratton, 1984, pp 101-123 Kuenen BC, Egdbert LR, Smit EF, et al: Dose finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors. J Clin Oncol 20:1657-1667, 2002 Kampmann KK, Graves T, Rogers SD: Acral erythema secondary to high-dose cytosine arabinoside with pain worsened by cyclosporine infusions. Cancer 63:2482-2485, 1989 Burgdorf WC, Gilmore WA, Canick RG: Peculiar acral erythema secondary to high-dose chemotherapy for acute myelogenous leukemia. Ann Intern Med 97:61-62, 1982 Baer MR, King LE, Wolff SN: Palmer-plantar erythrodysesthesia and cytarabine. Ann Intern Med 102:556, 1985 (letter) Comonnier C, Roujeau JC, Vernant JP, et al: Cancer chemotherapy and acral erythema. Ann Intern Med 97:785, 1982 (letter) Silver FS, Espinoza LR, Hartmann RC: Acral erythema and hydroxyurea. Ann Intern Med 98:675, 1983 (letter) Lokich JJ, Moore C: Chemotherapy-associated palmer-plantar erythrodysesthesia syndrome. Ann Intern Med 101:798-799, 1984 Feldman LD, Ajani JA: Fluorouracil-associated dermatitis of the hands and feet. JAMA 254:34-79, 1985 Curtan CF, Luce JF: Fluorouracil and palmar-plantar erythrodysesthesia. Ann Intern Med 111:858, 1989 (letter) Vukelja SJ, Lanbando FA, James WD, et al: Pyridoxine for the palmarplantar erythrodysesthesia syndrome. Ann Intern Med 111:688-689, 1989 (letter) Bellmunt J, Mavarno M, Hidalgo R, et al: Palmar-plantar erythrodysesthesia syndrome associated with short-term continuous infusion (5 days) of 5-fluorouracil. Tumori 74:329-331, 1988 Chiara S, Nobile MT, Barzacchi C, et al: Hand-foot syndrome induced by high dose, short-term, continuous 5-tluorouracil infusion. Eur J Cancer 33:967-969, 1997 Lurlo A, Fornier M, Caldiera S, et al: Palmar-plantar erythrodysaesthesia syndrome due to 5-fluorouracil therapy—An underestimated toxic event? Acta Oncol 36:653-654, 1997 Doyle LA, Berg C, Bottino G, et al: Erythema and desquamation after high-dose methotrexate. Ann Intern Med 98:611-612, 1983 Cox GJ, Robertson DB: Toxic erythema of palms and soles associated with high dose mercaptopurine chemotherapy. Arch Dermatol 199: 1413-1414, 1986 Murphy CP, Harden EA, Herzig RH: Dose related cutaneous toxicities with etoposide. Cancer 71:153-155, 1993 Twelves C, Harper P, Cutsem CV, et al: A phase III trial of Xeloda (capecitabine) in previously untreated advanced metastatic colorectal cancer. Proc Am Soc Clin Oncol 18:263a, 1999 (abstr 1010) Conti JA, Kemeny NE, Saltz LB, et al: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14:709-715, 1996 Hoff PM, Valero V, Ibrahim N, et al: Hand-foot syndrome following prolonged infusion of high doses of vinorelbine. Cancer 82:965-969, 1998 Argila D, Dominguez JD, Iglesias L: Taxol-induced acral erythema. Dermatology 192:377-37, 1996 Zimmerman GC, Keeling JH: Prevention of docetaxel-induced erythrodysesthesia with local hypothermia. J Natl Cancer Inst 86:557-558, 1994 Vukelia S, Baker WJ, Burris HA: Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with taxotere. J Natl Cancer Inst 1432-1433, 1993

Vascular toxicity of antineoplastic agents 369. Bastida J, Diaz-Cascajo C, Borghi S: Chemotherapy induced acral erythema due to tegafur. Acta Dermatol Venereol 77:72-73, 1997 (letter) 370. Buceta LR, Buezo GF, Penas PF, et al: Paimar plantar erythrodysaesthesia syndrome and other cutaneous side effects after treatment with tegafur. Acta Dermatol Venereol 77:80-81, 1997 (letter) 371. Muggia FM, Hainsworth JD, Jeffers S, et al: Phase II study of liposomal doxorubicin in refractory ovarian cancer: Antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 15:987993, 1997 372. Burke MC, Bernhard JD, Michelson AD: Chemotherapy induced painful acral erythema in childhood: Burgdorf’s reaction. Am J Pediatr Hematol 11:44-45, 1989 373. Demircay Z, Gurbuz O, Alpdogan TB, et al: Chemotherapy induced acral erythema in leukemic patients: A report of 15 cases. Int J Dermatol 36: 593-598, 1997 374. Ogawa H, Sugiyama H, Tani Y, et al: High incidence of chemotherapy induced acral erythema in female patients with non-Hodgkin lymphoma treated with the VACOP-B regimen. Leuk Lymphoma 29:171177 1997 375. Patel JS: Pyridoxine for hand-foot syndrome. Pharmacy 34:604-609, 1999 376. Lauman M, Mortimer J: Effect of pyridoxine on the incidence of palmar plantar erythroderma in patients receiving capecitabine. Proc Am Soc Clin Oncol 20:392a, 2001 (abstr 1565) 377. Pendharkar D, Goyal H: Novel management of capecitabine induced hand foot syndrome. Proc Am Soc Clin Oncol 22:755s, 2004 (abstr 8105) 378. Kingsley EC: 5-Fluorouracil dermatitis prophylaxis with a nicotine patch. Ann Intern Med 120:8135, 1994 (letter) 379. Gibson LE: Cutaneous vasculitis: Approach to diagnosis and systemic associations. Mayo Clin Proc 65:791-229, 1990 380. Paydays S, Zorludemir S, Sahin B: Vasculitis and leukemia. Leuk Lymphoma 40:105-112, 2000 381. Fonderila CG, Milone GA, Parlovsky S: Cutaneous vasculitis after intermediate dose of methotrexate. Br J Haematol 72:591-592, 1989 382. Navarro M, Pedragosa R, Lafuerza A, et al: Leukocytoclastic vasculitis after high dose methotrexate. Ann Intern Med 105:471-472, 1986 (letter) 383. Marks CR, Willkins RF, Wilske KR, et al: Small-vessel vasculitis and methotrexate. Ann Intern Med 100:916, 1984 (letter) 384. Rowinsky EK, McGuire WO, Anhalt GJ, et al: Hexamethylene bisacetamide induced cutaneous vasculitis. Cancer Treat Rep 71:471-474, 1987 385. Ahmed I, Chen KR, Nakayama H, et al: Cytosine arabinoside induced vasculitis. Mayo Clin Proc 73:239-242, 1998 386. Denefrio JM, Kaplan RS, Eisenberger MA, et al: Phase II study of cyclophosphamide and cytarabine in the treatment of metastatic adenocarcinoma of the colon and rectum. Cancer Treat Rep 65:163-164, 1981 387. Bucaloiu ID, Dubagunta S, Pachipala KK et al: Fluorouracil related small bowel vasculitis. J Clin Oncol 21:2441-2442, 2003 388. Voorburg AA, van Beek FT, Slee PH et al: Vasculitis due to gemcitabine. Lung Cancer 37:22, 2003 (letter) 389. Suzuki Y, Tokuda Y, Saitu Y, et al: Combination of trastuzumab and vinorelbine in metastatic breast cancer. Jpn J Clin Oncol 33:524-517, 2003 390. Paydas S, Yavuz S, Disel U, et al: Vasculitis associated with all trans retinoic acid in a case with acute promyelocytic leukemia. Leuk Lymphoma 44:547-548, 2003 391. Steinmetz JC, DeConti R, Ginsburg R: Hypersensivity vasculitis associated with 2-deoxycoformycin and allopurinol therapy. Am J Med 86:499, 1989 (letter) 392. Greenberg HS, Ensminer WE, Seeger JF, et al: Intraarterial BCNU chemotherapy for the treatment of malignant gliomas of the central nervous system: A preliminary report. Cancer Treat Rep 65:803-810, 1981 393. DeWys WD, Fowler ED: Report of vasculitis and blindness after intra

137

394.

395. 396.

397. 398.

399. 400.

401. 402.

403. 404.

405. 406.

407. 408. 409.

410. 411.

412.

413.

414.

415.

416.

417. 418.

carotid injection of 1,3-bis (2-chloroethyl)-l-nitrosourea (BCNU: NSC-409962) in dogs. Cancer Chemother Rep 57:33-40, 1973 Bernauer W, Gratwohl A, Keller A, et al: Microvasculopathy in the ocular fundus after bone marrow transplantation. Ann Intern Med 116:956-957, 1991 Wilding G, Caruso R, Lawrence TS, et al: Retinal toxicity after highdose cisplatin therapy. J Clin Oncol 3:1683-1685, 1985 Feun LG, Wallace S, Stewart DJ, et al: Intracarotid infusion of cisdiamminedichloro-platinum in the treatment of recurrent malignant brain tumors. Cancer 54:794-799, 1984 Rankin EM, Pitts JF: Ophthalmic toxicity during carboplatin therapy. Ann Oncol 4:337-338, 1993 Semb KA, Aamdal S, Oan P: Capillary protein leak syndrome appears to explain fluid retention in cancer patients who receive docetaxel treatment. J Clin Oncol 16:3426-3432, 1998 Schwartz RN, Stover L, Dutcher J: Managing toxicities of high-dose interleukin-2. Oncology 16:11-20, 2002 Pulkkanen K, Kataja V, Johansson R: Systemic capillary syndrome resulting from gemcitabine treatment in renal cell carcinoma: A case report. J Chemo 15:287-289, 2003 DePas T, Curigliano G, Franceschelli L, et al: Gemcitabine induced capillary leak syndrome. Ann Oncol 12:1651-1652, 2001 Naubec E, Oberlin O, Belhadj K, et al: Subcutaneous inflammatory edema induced by MINE chemotherapy. Ann Dermatol 128:534-537, 2001 Lazo JS: Endothelial injury caused by antineoplastic agents. Biochem Pharmacol 35:1912-1923, 1986 Nicholson GL, Custead S: Effects of chemotherapeutic drugs on platelet and metastatic tumor cell-endothelial cell interactions as a model for assessing vascular endothelial integrity. Cancer Res 45:331-336, 1985 Adamson IYR, Bowden DH: The pathogenesis of bleomycin-induced pulmonary fibrosis in mice. Am J Pathol 77:185-198, 1974 Otsuka K, Murota SL Mori Y: Stimulatory effect of bleomycin on the hyaluronic acid synthetase in cultured fibroblasts. Biochem Pharmacol 27:1551-1554, 1978 Finch WF, Rodan GP, Buckingham RB, et al: Bleomycin-induced scleroderma. J Rheumatol 7:651-659, 1980 Mosekey PL, Heniken C, Hunninghake GW: Augmentation of fibroblast proliferation by bleomycin. J Clin Invest 78:1150-1154, 1986 Gould VE, Miller J: Sclerosing alveolitis induced by cyclophosphamide: Ultrastructural observations on alveolar injury and repair. Am J Pathol 81:513-530, 1975 Cattell V: Mitomycin induced hemolytic uremic kidney: An experimental model in the rat. Am J Pathol 121:88-95, 1985 Charba D, Moake JL, Harris NIA, et al: Abnormalities of von Willebrand factor multimers in drug-associated thrombotic microangiopathies. Am J Hematol 42:268-277, 1993 Furlan M, Robles R, Solenthaler M, et al: Deficient activity of von Willebrand factor-cleaving protease in chrome relapsing thrombotic thrombocytopenic purpura. Blood 89:3097-4003, 1997 van der Plas RM, Sdiiphorst ME, Huizinga EG, et al: von Willebrand factor proteolysis is deficient in classic, but not in bone marrow transplantation-associated, thrombotic thromocytopenic purpura. Blood 93:3798-3802, 1999 Smith AC, Boyd MR: Effects of BCNU on pulmonary and serum angiotensin converting enzyme activity in rats. Biodiem Pharmacol 32: 3719-3722, 1983 Lazo JS: Angiotensin converting enzyme activity in mice after subacute bleomycin administration. Toxicol Appl Pharmacol 59:395-404, 1981 Lerinan A, Hildebrand FL Jr, Margulies KB, et al: Endothelin. A new cardiovascular regulatory peptide. Mayo Clin Proc 65:1441-1455, 1990 Kanno K, Hirata Y, Emori T, et al: Endothelin and Raynaud’s phenomenon. Am J Med 90:130-132, 1991 Gobble U, Ebel W, Jurgens H, et al: Coagulation changes following bleomycin treatment in animals. Proc Am Soc Clin Oncol 2:39, 1983 (abstr 155)

N. Shahab, S. Haider, and D.C. Doll

138 419. Yen T, Walsh JD, Pejler G, et al: Cisplatin-induced platelet activation requires mononuclear cells: Role of GMP-140 and modulation of procoagulant activity. Br J Haematol 83:259-269, 1993 420. Panella TJ, Peters W, White JG, et al: Platelets acquire a secretion defect after high dose chemotherapy. Cancer 65:1711-1716, 1990 421. Ruiz MA, Marugan I, Estelles P, et al: The influence of chemotherapy on the plasmatic coagulation and fibrinolytic system in lung cancer patients. Thromb Haemost 158:110, 1987 (abstr) 422. Edwards RL, Klaus M, Matthews E, et al: Heparin abolishes the chemotherapy induced increase in plasma fibrinopeptide A levels. Am J Med 89:25-28, 1990 423. Kuzel T, Exparaz B, Green D, et al: Thrombogenity of intravenous 5-fluorouracil alone or in combination with cisplatin. Cancer 65:885889, 1990 424. Canobbio L, Passio T, Ardizzoni A, et al: Hypercoagulable state induced by cytostatic drugs in stage II breast cancer patients. Cancer 54:1032-1036, 1986 425. Conard L Horellou MH, Van Dreden P, et al: Decrease in protein C in L-asparaginase-treated patients. Br J Haematol 59:725-727, 1985 (letter) 426. Rogers JS II, Murgo AF, Fantana JA, et al: Chemotherapy for breast cancer decreases plasma protein C and protein S. J Clin Oncol 6:276281, 1988 427. Feffer SE, Carinosino LS, Fox RL: Acquired protein C deficiency in patients with breast cancer receiving cyclophosphamide, methotrexate, and 5-fluorouracil. Cancer 63:1303-1307, 1989 428. Gordon BG, Haire WD, Patton DF, et al: Thrombotic complications of BMT: association with protein C deficiency. Bone Marrow Transplant 11:61-65, 1993 429. Rella C, Coviello M, Giotta F, et al: A prothrombotic state in breast cancer patients treated with adjuvant chemotherapy. Breast Cancer Treat Res 40:151-159, 1996 430. Enck RE, Rios CN: Tamoxifen treatment of metastatic breast cancer and antithrombin III levels. Cancer 53:2607-2609, 1984 431. Jordan VC, Fritz NF, Tormey DC: Long term adjuvant therapy with tamoxifen and effects on sex hormone binding globulin and antithrombin III. Cancer Res 45:4517-4519, 1987 432. Jones AL, Fowles TJ, Trelearen JG, et al: Haemostatic changes and thromboembolic risk during tamoxifen therapy in normal women. Br J Cancer 66:744-747, 1992 433. Love RR, Surawicz TS, Williams EL: Antithrombin III level, fibrinogen

434.

435.

436. 437.

438.

439.

440.

441.

442. 443.

444. 445. 446. 447.

level, and platelet count changes with adjuvant tamoxifen therapy. Arch Intern Med 152:317-320, 1992 Tempelhoff GFV, Dietrich M, Hommel G, et al: Blood coagulation during adjuvant epirubicin cyclophosphamide chemotherapy in patients with primary operable breast cancer. J Clin Oncol 14:25602568, 1996 Bairy O, Cabbay U, Blickstein D, et al: Levels of protein C and S do not decline subsequent to first line chemotherapy in lymphoma patients. Hematol Oncol 15:121-127, 1997 Jaattela M: Biologic activities and mechanisms of action of tumor necrosis factor-alpha/cachexin. Lab Invest 64:724-742, 1991 Bevilacqua ND, Pober JS, Majeau GR, et al: Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: Characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci USA 83:4533-4537, 1986 Tanaka L Imamura M, Kasai M, et al: Rapid analysis of tumor necrosis factor-alpha MRNA expression during veno-occlusive disease of the liver after allogeneic bone marrow transplantation. Transplantation 55:430-433, 1993 Schilsky RL, Anderson T: Hypomagnesemia and renal magnesium wasting in patients receiving cisplatin. Ann Intern Med 90:929-931, 1979 Turiapaty PDNW, Altur BM: Magnesium deficiency produces spasms of coronary arteries: Relationship to etiology of sudden death ischemic heart disease. Science 280:198-200, 1980 Altura BM, Altura BT, Gebrewold A: Magnesium deficiency and hypertension: Correlation between magnesium-deficient diets and microcirculatory changes in situ. Science 223:1315-1317, 1984 Rosenfield CS, Broder LE: Cisplatin-induced autonomic neuropathy. Cancer Treat Rep 68:659-660, 1984 Hansen SW: Autonomic neuropathy after treatment with cisplatin, vinblastine, and bleomycin for germ cell cancer. Br Med J 300:511512, 1990 Carmichael SM, Eagieton L, Ayers CR, et al: Orthostatic hypotension during vincristine therapy. Arch Intern Med 126:290-293, 1970 Dibella NJ: Vincristine-induced orthostatic hypotension: A prospective clinical study. Cancer Treat Rep 64:359-360, 1980 Roca E, Bruera E, Politi PM, et al: Vinca alkaloid-induced cardiovascular autonomic neuropathy. Cancer Treat Rep 69:149-151, 1985 Hivomen HE, Sahni TT, Heinonen E, et al: Vincristine treatment of acute lymphoblastic leukemia induces transient autonomic cardioneuropathy. Cancer 64:801-805, 1989