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 often, collagenrich 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.^6,7,8 Several cases of PVOD associated with chemotherapy have been described.^9,10,11,12 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 al.¹¹ 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 al.¹² 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 disease. PVOD has also been reported in a patient with untreated Hodgkin disease¹³ and after preparative regimens for bone marrow transplantation (BMT).^14,15 In children with malignant infantile osteoporosis who undergo stem cell transplant 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 (not related to chemotherapy) case of PVOD.¹⁸ In addition, decreased pulmonary artery pressure after hydralazine therapy was helpful in one patient.¹³

HVOD, now formally referred to as sinusoidal obliteration syndrome,¹⁹ 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 thickening,^20,21,22 hence the new name. By comparison, thrombotic occlusion of the large hepatic veins has been used to define the Budd-Chiari syndrome.^20,23 However, the clinical and pathologic findings may overlap in these syndromes, and distinctions may therefore be superfluous. Major causes of HVOD are irradiation²⁴ and toxic pyrolizidine alkaloids.²¹ Several chemotherapeutic agents, including urethane,²⁵ 6-thioguanine,^26,27,28 cytosine arabinoside,^29,30 BCNU,³¹ busulfan,³² dimethyl busulfan,³³ mitomycin-C,^34,35 cyclophosphamide,³³ dacarbazine,³⁶ azathioprine,^37,38 dactinomycin,^{39,40,41,42,43,44} and gemcitabine,^45,46 gemtuzumab,^47,48,49 and oxaplatin⁵⁰ have been implicated in HVOD. Regarding dactinomycin, there is a higher incidence of hepatic toxicity with the higher single-dose schedule than with divided doses.⁴⁰ Isolated thrombocytopenia after dactinomycin administration maybe a risk factor for subsequent development of full-blown HVOD.⁴¹ The Intergroup Rhabdomyosarcoma Study Group reported an overall incidence of 1.2% of HVOD.⁴² Notably, this complication only developed in patients treated with vincristine, actinomycin D, and cyclophosphamide. No patient who was treated with vincristine and actinomycin D experienced this problem. HVOD was strongly associated with escalated doses of cyclophosphamide. The Children’s Oncology Group reported the greatest risk factor for development of HVOD after vincristine, adriamycin,

cyclophosphamide (VAC) chemotherapy was age.⁵¹ For patients younger than 36 months, the risk of hepatopathy was 15%, whereas for children 3 years or older, the risk was 4%. In several cases, combination chemotherapy has been administered as preparatory regimens for BMT.^{15,28,29,31,34,36} Indeed, essentially all preparative regimens have been implicated in HVOD, and HVOD is now a major early complication of BMT.⁵²

In an early study at the University of Washington, in 255 consecutive patients who underwent BMT, the incidence of HVOD was 21%.⁵³ However, HVOD subsequently developed in 109 of 355 consecutive patients (31%) undergoing BMT at their institution.⁵⁴ 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 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.⁵⁴ The use of methotrexate for graft-versus-host disease prophylaxis,⁵⁵ increased plasma levels of busulfan,⁵⁶ low protein C levels before transplantation,⁵⁷ and hepatitis C virus infection⁵⁸ have also been implicated as risk factors for HVOD. Despite these observations, no clinical factor is definitely predictive of HVOD in an individual patient.

Johns Hopkins investigators also reported HVOD in approximately 20% of their BMT patients.⁵⁹ 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 BMT.⁶⁰ 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, an immunotoxic monoclonal antibody utilized in the treatment of acute myeloid leukemia (withdrawn from the U.S. market), has also been associated with the development of HVOD.^47,48,49 Moreover, it was also shown to be associated with the development of potentially fatal HVOD in patients with leukemia who had not received stem cell transplant and who also had not received any prior chemotherapeutic agent.⁴⁹ This is concerning because many of the acute leukemic patients 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 gemtuzumab, 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 cell populations of the liver are the potential mechanisms of liver toxicity.⁵¹ In patients using sirolimus for graft-versus-host disease prophylaxis after allogeneic transplantation, busulfan-based conditioning was associated with a higher rate of HVOD.⁶¹

Clinically, as noted in the preceding text, 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.⁶² The diagnosis can be established by percutaneous or transvenous liver biopsy.²⁰ 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-occlusive disease. The change in blood flow can be detected 5 to 6 days before the clinical 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 stem cell transplant patients. Stoneham et al. reported HVOD in 12% of acute lymphoblastic leukemic patients who were on maintenance
6-thioguanine.⁶⁶ Maintenance with 6-mercaptopurine has also resulted in similar pathology.⁶⁷ HVOD may vary from mild and reversible to life threatening and lethal.^58,68,69 Bearman et al.⁶⁹ developed a mathematic model for predicting fatal outcome after BMT, based on serum bilirubin 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 BMT might be the serum concentration of an aminopeptide of type III procollagen.^70,71 Elevated serum concentrations 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 al. 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 BMT in patients with breast cancer.⁷² 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 two standard deviations 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.⁷² 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 α⁷³ and plasminogen activators⁷⁴ as a predictive test for HVOD need confirmation. Plasminogen activator inhibitor-1 (PAI-1) was reported to diagnose as well as predict the severity of the disease after allogeneic transplantation following cyclophosphamide and busulfan conditioning.⁷⁵ PAI-1 also has a role in pediatric HVOD and may facilitate an early diagnosis.⁷⁶

Because severe HVOD is lethal in most patients, interventions would be most welcome. In this regard, continuous low-dose heparin,^77,78 pentoxifylline,^79,80,81 and prostaglandin E^82,83 have 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 BMT. Ursodeoxycholic acid prophylaxis against hepatic complications warrants additional investigation.^84,85 However, Ruutu et al.⁸⁶ reported a survival advantage in patients pretreated with ursodeoxycholic acid despite no difference in the incidence of HVOD following allogeneic stem cell transplantation. They suggest a role for ursodeoxycholic acid in the prevention of transplant-related HVOD. Chalandon et al.⁸⁷ treated 52 patients with defibrotide as a prophylactic agent. No cases of HVOD were noted, but this was not a randomized trial.⁸⁷

Except for supportive care, there is no standard effective therapy for HVOD. Treatment for severe HVOD with recombinant human tissue plasminogen activator (tPA) has produced conflicting results.^88,89,90,91 Further studies of tPA and similar agents are necessary before any definitive conclusions can be drawn. Endothelial injury following chemotherapy can lead to the activation of coagulation cascade in the hepatic sinusoids and veins with increased consumption of antithrombin III, protein C, and protein S.⁹² Peres et al.⁹² in their retrospective study noticed benefit from the use of antithrombin III in patients with

HVOD. Once fibrosis occurs, there is no treatment that can reverse the pathology and liver transplantation has resulted in some success.⁹³ Defibrotide is a novel agent, which, by reactivating tPA and tissue factor pathway inhibitor, decreases thrombin generation, inhibits fibrin generation, and modulates fibronectin release.^94,95,96,97 In a series of studies, defibrotide has resulted in complete resolution in 42%, 52%, and 36%, respectively.^64,98,99 Defibrotide is the most active agent for treatment of severely affected patients.^100,101 Defibrotide has also been used as prophylaxis in pediatric thalassaemic hematopoietic stem cell recipients.¹⁰² Future trials are to determine the effective dose and role of defibrotide in HVOD.

Occlusion of the large hepatic veins, manifested clinically as the Budd-Chiari syndrome, has been reported in association with several chemotherapeutic agents.¹⁰³ Dacarbazine, alone^104,105 and in combination with other cytotoxic drugs,^106,107 and 6-thioguanine plus cytosine arabinoside¹⁰⁸ or methotrexate¹⁰⁹ 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.¹¹⁰

Fatal hepatic necrosis with widespread thrombotic occlusion of the small hepatic veins has been observed in patients who are treated with dacarbazine.^{111,112,113,114,115} 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.^{112,113,114,115}

Raynaud 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 phenomenon has been documented after the administration of bleomycin, either alone^116,117,118 or in combination with a vinca alkaloid^{119,120,121,122,123,124,125}; cisplatin, and a vinca alkaloid^{119,120,124,126,127}; etoposide, and cisplatin^{128,129,130,131,132,133,134,135,136,137}; and doxorubicin, and vincristine.^125,138,139 It is also reported in a 14-year-old receiving vincristine.¹⁴⁰ In addition, Raynaud phenomenon and digital vasculitis have been reported with interferon therapy^{141,142,143,144} and tamoxifen.¹⁴⁵ Vogelzang et al. initially noted Raynaud 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.¹²⁰ Raynaud phenomenon was usually chronic, persisting for 5 or more years. Although 50% of the patients had clinical improvement over time, 12 had lifestyle changes because of intractable digital ischemia. Arteriograms in two of the patients revealed diffuse arterial narrowing that was consistent with vasculitis or arteritis.¹²⁰ Subsequent reports by others noted Raynaud phenomenon or persistent digital cold sensitivity after cisplatin, bleomycin, and vinblastine sulfate in 2.6% to 49.0% of patients.^{124,129,146,147}
Every reported patient with Raynaud phenomenon has been treated with bleomycin, either alone or in combination regimens. This strongly suggests that bleomycin is the primary drug responsible for this disorder. In some patients, Raynaud phenomenon is of minor or no clinical concern; in others, it is a severe debilitating chronic problem. Rarely, it progresses to digital gangrene^125,138,139 that may require amputation.^{125,148,149,150}

A few data are available regarding the management of therapy-related Raynaud phenomenon. Topical nitroglycerin and oral tolazoline hydrochloride were of no value in two patients.¹²⁰ Nifedipine or other calcium channel blockers might be of benefit in some individuals.^151,152,153 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.¹⁵⁴

Acute myocardial infarction has been reported to occur in association with vinca alkaloids^155,156; etoposide^157,158; cisplatin¹⁵⁹; gemcitabine⁴⁶; vinblastine and bleomycin¹⁶⁰; vinblastine, bleomycin, and cisplatin^{161,162,163,164}; cisplatin, cyclophosphamide, and adriamycin¹⁶⁵; cisplatin, etoposide, and bleomycin¹⁶⁶; and combination chemotherapy for Hodgkin disease¹⁶⁷ and metastatic colorectal cancer.¹⁶⁸ Mediastinal irradiation,^157,164,169 preexisting coronary artery disease,¹⁵⁸ smoking,¹⁶⁰ and age older than 40 years¹⁶¹ were coexisting factors in some patients. Several patients had no known risk factors for heart disease and had normal coronary angiograms.^{162,163,164,167} Three patients had a prior history of Raynaud phenomenon,^160,164 and in one patient, ergonovine maleate precipitated diffuse coronary spasm and chest pain.¹⁶⁴ In another case, coronary artery occlusion by fibrous intimal proliferation was demonstrated at autopsy.¹⁶² These results should be tempered by the data of the Testicular Cancer Intergroup Study.¹⁷⁰ They found no greater risk of major cardiovascular complications in patients treated with cisplatin-based chemotherapy for testicular cancer than in an untreated control group.

Cardiac ischemia has been reported in association with vinca alkaloids,^171,172,173 cisplatin,¹⁷⁴ cyclophosphamide,¹⁷⁵ bleomycin infusions,¹⁷⁶ carboplatin and etoposide,¹⁷⁷ and cisplatin, etoposide, and bleomycin.¹⁷⁸ Of note is the increasing number of reports of cardiac toxicity associated with 5-FU.^{179,180,181,182,183,184,185,186,187,188,189} 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 infusion of 5-FU, the incidence of cardiac toxicity was 7.6%.¹⁸⁴ Although the mechanism is unknown, these events appear to be more likely to occur when 5-FU is administered at a high dose by continuous infusion in the presence of preexisting coronary artery disease.^184,185,186 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.¹⁸⁷ Angina occurred in 48%, myocardial infarction in 23%, arrhythmias in 16%, acute pulmonary edema in 7%, cardiac arrest and pericarditis in 7%.¹⁸⁷ Symptoms were reproducible when patients were rechallenged with 5-FU or capecitabine. Nineteen percent of these rechallenged patients had died. In some cases, prophylaxis with calcium channel blockers was effective in preventing angina.^188,189 Physicians should be aware of the potential cardiotoxic properties of 5-FU and capecitabine,¹⁹⁰ and treatment should be discontinued immediately if coronary symptoms develop. Rechallenging should not be done. Prophylactic telemetry monitoring during 5-FU administration does not detect vasospasm and is therefore not recommended.¹⁹¹ Plasma N-terminal probrain natriuretic peptide and lactic acid levels increased in patients treated with fluorouracil and oxaliplatin (FOLFOX4), but the left ventricular ejection fraction remain unchanged during therapy and at 6-month follow-up.¹⁹²

Cardiovascular disease as a long-term complication of treatment in survivors of testicular cancer is now a well-known phenomenon.^193,194,195 Huddart et al. reported data on 992 patients. After a median follow-up of 10.2 years, there was a 2-fold or greater risk of developing cardiovascular disease. The risk was approximately 10% for patients after radiation and 6.7% after chemotherapy.¹⁹⁴ Investigators at the Netherlands Cancer Institute compared cardiovascular disease incidence in 2,512 testicular cancer survivors with general population rates.¹⁹⁵ Cisplatin, vinblastine, bleomycin chemotherapy was associated with a 1.9-fold increased myocardial infarction risk and bleomycin, etoposide, platinum was associated with a 1.5-fold increased cardiovascular risk.¹⁹⁵

QTc interval should be monitored in patients receiving arsenic trioxide. QTc <500 milliseconds, serum potassium >4 mEq/L and magnesium >1.8 mg/dl is the recommended approach for patients receiving arsenic trioxide.¹⁹⁶