Pulmonary Emboli in Patients Receiving Chemotherapy for Non-Hodgkin's Lymphoma

Pulmonary Emboli in Patients Receiving Chemotherapy for Non-Hodgkin's Lymphoma* Luther D. Glenn, M.D.;t James Q Armitage, M.D.;t Jonathan C. Goldsmith, M.D.;t Scot Sorensen, M.D.;+ David Howe, M.D.;§ and Dennis D. Weisenberger, M.D. t

Combination chemotherapy has dramatically improved the prognosis of patients with intermediate and high grade histologic subtypes of non-Hodgkin's lymphomas. Treatment-related complications, however, are considerable, and a common problem encountered is respiratory distress or respiratory insufficiency; Usually these difficulties have been attributed to infectious etiologies or to chemotherapyinduced interstitial fibrosis, most often involving bleomycin. We describe five patients presenting with respiratory problems several weeks after the initiation of chemotherapy These patients, who represent 3 percent of all patients treated with a single bleomycin-containing regimen for intermediate or high grade non-Hodgkins lymphoma, were

all initially thought to have chemotherapy-induced interstitial fibrosis but were found on subsequent evaluation to have pulmonary emboli. Of the three patients in whom pulmonary emboli were diagnosed antemortem, two had symptoms suggestive of pulmonary emboli and all were successfully treated and remained well and free of lymphoma for over 24 months. Two additional patients were diagnosed at autopsy; We suggest that pulmonary emboli may contribute significantly to the morbidity and mortality of patients undergoing chemotherapy for non-Hodgkins lymphoma and recommend that patients presenting with respiratory difficulties be evaluated for pulmonary emboli. (Chest 1988; 94:589-94)

pulmonary problems in patients who are receiving or have received chemotherapy for any type of malignancy are a major source of morbidity and mortality: The differential diagnosis of the pulmonary infiltrate is quite extensive and includes infection, involvement of the lung by the underlying disease, injury from radiation or contrast agents used during lymphangiography and toxicities of chemotherapy: 1 The importance of this was recognized early in the history of combination chemotherapy for non-Hodgkins lymphoma, as Skarin et al2 noted almost 30 percent of their patients developed pulmonary infiltrates during therapy with a wide variety of etiologies documented. Bleomycin was found in early clinical trials to have significant activity against all types of lymphomas and has been incorporated into many frontline chemotherapeutic regimens for non-Hodgkins lymphomas. Bleomycin causes an interstitial fibrosis, the incidence of which has been reported from 3 to 18 percent. 3-5 The risk of developing pulmonary fibrosis is increased with cumulative doses greater than 450 units, with age , greater than 70 years, with previous radiation to the lung and with inhalation of high concentrations of oxygen. 6,7 Schein et al" observed a significant incidence

of pulmonary toxicity with BACOP when bleomycin was administered at a dose of 15 IJ./m 2 which did not occur at a dose of 5 U/m 2 • Pleuropneumonitis" and an acute fulminant reaction characterized by profound hyperpyrexia, hypotension, and cardiopulmonary decompensation following a single high dose of bleomycin'? have also been described. Cyclophosphamide, methotrexate, and procarbazine have also been associated with the development of interstitial pneumonitis. 11 Patients with cancer have long been associated with thrombotic tendencies. Armand Trousseau" initially reported a high incidence of venous thrombosis in patients with gastric carcinoma in 1865, and since that time, the incidence in cancer patients has been reported as 1 to 11 percent.Pi'" In certain neoplasms, the incidence of venous thrombosis has been striking, with a 16.1 percent incidence of thrombosis in patients in carcinoma of the head of the pancreas, and a 56.2 percent incidence in carcinoma of the body or tail of the pancreas." Virtually every type of neoplasm has been associated with venous thrombosis.P-" although historically thrombosis associated with lymphoma been reported infrequently: 20-22 We describe five patients with non-Hodgkins lymphoma and no underlying pulmonary disease prior to treatment who developed respiratory difficulties while receiving chemotherapy and were found to have pulmonary emboli subsequently: These patients are compared to those patients who did not sustain pulmonary

*From the University of Nebraska Medical Center, Omaha]', Lincolnj, and Hastings§, NE. Manuscript received November 13; revision accepted February 10. Reprint requests: Dr: Armitage, University of Nebraska Medical Center, 42nd andDeuieu, Omaha 68105

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589

embolism and the impact of the development of pulmonary emboli on ultimate survival is discussed. PATIENTS AND METHODS

Between July 1982 and January 1986, 187 cases of non-Hodgkins lymphoma with intermediate or high grade histologic type were identified by the Lymphoma Study Group, composed of oncologists and hematologists in Nebraska and western Iowa with its headquarters at the University of Nebraska Medical Center. These patients had histologically proven non-Hodgkins lymphomas of intermediate or high grade histologic type according to the Working Formulation of the Non-Hodgkins Lymphomas for Clinical Usage.v These types represent all non-Hodgkins lymphomas except for diffuse small cleaved lymphoma, follicular small cleaved lymphoma, and follicular mixed lymphoma. Patients also underwent staging procedures prior to treatment as described by Armitage et al. 24 All patients were treated with CAP-BO~ which consists of cyclophosphamide, 650 mg/m- IV on day 1; doxorubicin, 50 mg/m- IV on day 1; procarbazine, 100 mg/m- PO on days 1 to 7; bleomycin, 10 units1m2 SQ on day 15; vincristine, 1.4 mg/ms IV on day 15; and prednisone, 100 mg PO days 15 to 21. The cycle was repeated every 28 days, and treatment was continued for two cycles after documented complete response or up to a maximum of seven cycles. 24 The records of these 187 patients were reviewed and from these, five patients were found to have unequivocal evidence of pulmonary embolism. Patients were felt to have pulmonary emboli if they had a ventilation-perfusion scan which showed multiple ventilationperfusion mismatches with a chest x-ray film showing minimal abnormalities, a positive pulmonary arteriogram or autopsy proof of .pulmonary embolism. Ventilation scans were obtained utilizing 30 mCi of 133Xe from a closed circuit radionuclide gas spirometer, while perfusion scans were performed following the intravenous administration of 4 mCi of WTc macroaggregated albumin. Patients were not included if diagnostic tests were insufficient, in spite of improvement clinically following treatment for pulmonary embolism. Patients undergoing treatment of their pulmonary emboli received heparin by continuous infusion for at least seven days, followed by oral anticoagulation therapy. RESULTS

A summary of the clinical characteristics of our patients who experienced pulmonary emboli while receiving combination chemotherapy of non-Hodgkin's lymphoma is presented in Table 1. In our patients who were found to have pulmonary emboli, all presented with progressive dyspnea over the preceding week to one month. All had reported low grade fevers, although none had sweats or chills. Weakness and fatigue were reported by three patients and syncopal episodes by two patients. Pleuritic chest pain was described by only two patients. Only two patients had a smoking history and none was smoking during the period of chemotherapy for lymphoma. No patient had a.prior history of thrombotic events. All patients were over 60 years of age, but only two had widespread disease at the time of initial diagnosis of the lymphoma. Other than the chemotherapeutic agents for treatment of their aggressive lymphoma, no common group of medication was apparent. Four patients had a documented low grade fever at presentation. Only two patients were tachycardiac and 590

three patients presented with tachypnea. In three patients, the lung examination was entirely normal upon admission to the hospital. Two patients had physical findings of deep venous thrombosis, while a third had mottling and cyanosis of the extremities. Two patients presented with leukopenia, and one other patient presented with thrombocytopenia. No patient had an elevated platelet count. Prothrombin times and partial thromboplastin times were all within normal limits. In the four patients in whom arterial blood gases were obtained, all were hypoxic, although only one patient exhibited a classic respiratory alkalosis. Four of five chest x-ray films showed pulmonary opacities, and two patients h-ad atelectasis present. The ECG showed S-T wave abnormalities in three of our patients in whom they were obtained, and two patients had sinus tachycardia. Although diffusing capacity has been reported to be of great utility in the diagnosis of bleomycin-induced lung injury;" it was clearly misleading in the two patients in whom it was performed. Improvement in the diffusing capacity was noted in both patients following anticoagulation without the use of steroids. Only three patients had diagnostic tests to assess for pulmonary emboli. Two patients underwent ventilation-perfusion scanning which showed high probability of pulmonary emboli in both cases. The patient who underwent pulmonary angiography had a clot in the left lower lobe. Two patients were diagnosed at autopsy All patients diagnosed with pulmonary emboli had no tumor documented at autopsy or are in unmaintained remission 20 to 41 months after completing five cycles ofCAP-BOE A comparison of our five patients who were identified as having pulmonary emboli with the remaining 182 patients treated with the same regimen reveals no pretreatment feature to identify the patients with pulmonary emboli. The Karnofsky performance status of our patients who developed pulmonary emboli was 80 to 90 percent; several of the patients who did not develop pulmonary emboli had Karnofsky scores of60 percent or less. Only one of our patients had extensive disease (stage III or IV disease), while over one half of the patients not sustaining pulmonary emboli had stage IV disease. Bulky intra-abdominal tumor was not predominant in patients who developed pulmonary emboli. The pulmonary complications encountered by patients receiving CAP-BOP are shown in Table 2. As can be seen, approximately one-third of patients developed some pulmonary problems in temporal relation to receiving chemotherapy In all patients suffering acute respiratory insufficiency pulmonary fibrosis or decreased diffusing capacity with a normal chest x-ray film during the course of chemotherapy bleomycin was deleted from the regimen. Most of the Pulmonary Emboli after Chemotherapy for Lymphoma (Glenn et al)

Table I-Clinical Course ofPatients Receiving Treatment for Non-Hodgkins Lymphoma Upon Presentation With Pulmonary Emboli Histologic type of Patient Age/Sex lymphoma* Stage 1

63/M

G

2

72/F

E

3

70/M

E

4

65/F

G

5

61/M

I

Clinical Symptoms

Physical Examination

37.0°C-92-20IIA Increasing 114/70 shortness of Rare inspiratory breath for crackles with 1 week Left calf tenderness. decreased breath Low grade fever sounds in L base Tender L calf with (100°F) positive Homan's sign on left lIB Increasing dyspnea 37.3°C-120-30-114/ 62 on exertion over Few crackles in lung the previous bases bilaterally month Swelling in left leg Low grade fever with bilateral Increasing pedal edema weakness, Diffuse tenderness fatigue and left leg tremor Increasing peripheral edema Weight loss-13Y2 lbs over previous month 99°F-88-16-105/65 IVB Fever, vomiting, Lungs clear chills Heart regular Coughing on rhythm exertion No calf tenderness

Chest X-Ray Film

Diagnostic Procedures

Bibasilar atelectasis Pulmonary angiogram and volume loss Bilateral pleural Clot in left lower effusions lobe

Outcome Intravenous heparin, followed by oral anticoagulants Alive and well currently

Indistinct opacity in VentilationIntravenous heparin, basilar segment perfusion scan followed by oral of left lower lobe Multiple anticoagulants mismatched perfusion defects in right posterior basilar segment of the right lower lobe Additional subsegmental defects in both lungs. Normal ventilation scan Patchy areas of consolidation in right upper lung and both bases

Bronchoscopy Normal bronchoscopy Transbronchial biopsy showed acute inflammatory cells only IIA Increasing dyspnea 99.6°F-116-28-116/ Density in the left Ventilationlower lobe perfusion scan on exertion and 76 Mildly tachypneic Accentuated lung Large segmental generalized and dyspneic markings in the perfusion weakness Upper extremities lingula. Increased abnormalities Excruciating left slightly mottled density in R lung involving the chest wall pain over the 7th rib Low grade fever and cyanotic right upper lobe Lungs clear posterolaterally and middle lobe Large perfusion abnormality involving all but the superior segment of the left lower lobe 98°F-88-16-168/78 Small density near None lIB Dyspnea on 0.75 X 0.75 em the apex of the exertion and heart fatigue over the nodule on scalp Lung clear Increased size of previous 7 days the right hilum Pleuritic right-sided Heart regular No cyanosis of chest pain 4-6 syncopal extremities episodes Nonproductive cough Low grade fever

Died-Autopsy revealed subacute pulmonary embolism

Intravenous heparin, followed by oral anticoagulants

Died-Autopsy revealed massive pulmonary embolus with focal infarction of the lower lobe of the right lung

*Classified according to the Working Formulation. 23

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Table 2-Pulmonary Complication in Patients Undergoing Therapy with CAP-BOPfor Intermediate and Aggressive Lymphomas CXR, No pulmonary complications Pulmonary complications Fever and pulmonary infiltrate (organism not identified) Fever and pulmonary infiltrate (organism identified) Pulmonary fibrosis Acute respiratory insufficiency Pulmonary embolism Decreasing diffusing capacity with normal chest x-ray Bronchitis Died-insufficient data Not evaluable

132 (70.6%) 48 (25.7%) 18 (37.5%) 7 (14.6%) 7 6 5 4

(14.6%) (12.5%) (10.4%) ( 8.3%)

1 ( 2.1%) 4 ( 2.1%) 3 ( 1.6%)

patients who developed problems which resulted in deletion of bleomycin did so by the completion of the fourth cycle of therapy; thus, most patients had received less than 50 units/m" of bleomycin at the onset of respiratory difficulty In up to 40 percent of patients with pulmonary problems, the exact nature of the process is not elucidated. Patients presenting with fever and/or pulmonary infiltrates were usually had blood cultures and promptly were started on broad-spectrum antibiotic treatment. Bronchoalveolar lavage was performed in patients who failed to respond to antibiotics or had other clinical indications for further evaluation; open lung biopsies were not performed. With the relatively nonspecific nature of the presenting signs and symptoms of pulmonary embolism, it is conceivable that several of these patients listed with fever and pulmonary infiltrate could have had undiagnosed pulmonary emboli. As our patients were not routinely evaluated specifically for pulmonary embolism, it is possible that several of the patients in other categories could have had unrecognized pulmonary emboli superimposed upon acute or chronic pulmonary problems. Also of interest is the fact that no deep venous thromboses have been diagnosed among the patients in whom pulmonary emboli were also found. DISCUSSION

Several recent reports have summarized the increased frequency of venous thrombosis in patients with Hodgkin's disease;" breast cancer, 27,28 and ovarian cancer." However, thrombotic tendencies in patients with non-Hodgkins lymphomas rarely have been reported in the literature. A case of interstitial pneumonitis in a patient with diffuse histiocytic lymphoma who died during her second cycle of CHOP and at autopsy was found to have multiple pulmonary emboli has been reported. 21 Pulmonary venoocclusive disease has also been described in two patients with lymphocytic lymphoma.P'' Patients undergoing splenectomy 592

for Hodgkin's disease were recently found to be at no higher risk for deep venous thrombosis and pulmonary embolism than control subjects undergoing cholecystectorny However, patients undergoing splenectomy for non-Hodgkins lymphoma were at much higher risk for thromboembolic phenomena than either of the previously described groups. These patients did have massively enlarged spleens; the risk of thromboembolism was significantly increased even when spleen size was corrected. 31 Tumor emboli have been reported in a wide variety of tumors,20,32-35 and can be distinguished from thromboemboli by the response to anticoagulant therapy by lung biopsy or at autopsy Patients with cancer and hematologic malignancies have been shown for several decades to be at increased risk for thrornboembolism.P'-" Armand Trousseau" reported a high incidence of venous thrombosis in patients with gastric carcinoma in 1865. Since then, a number of clinical and autopsy studies have demonstrated an increased incidence of thrombotic events in patients with a variety of neoplasms, especially those with mucin-secreting carcinomas of the gastrointestinal tract. Conspicuously absent, however, is the increased incidence of thrombotic events associated with the non-Hodgkins lymphomas. Sack et a120 were able to identify only two patients with non-Hodgkin's lymphoma in their review of 373 patients with tumors who had symptoms of thrombophlebitis. Although the cause(s) have not been elucidated, factors identified which may contribute to or resulted from this tendency include elevation of factor VIII activity38 qualitative abnormalities of von Willebrand factor;" thrombocytosis.t- qualitative platelet abnormalities.s" and elevated fibrinopeptide A levels. 41-46 No abnormalities were identified in our patient which could have predicted a hypercoagulable state. In patients receiving chemotherapy for lymphomas or other malignancies who present with respiratory difficulties, we recommend a careful history and physical examination, arterial blood gas values, and a chest x-ray film be obtained. If there is any evidence of venous thrombosis on examination, a venogram of that extremity should be performed. A diffusing capacity should be obtained, although caution should be used in the interpretation of low values. Those patients who have negative work-ups or inconclusive evaluations to this point should be strongly considered for pulmonary angiography Bronchoalveolar lavage may be useful in the diagnosis of opportunistic infections or recurrent tumor. Should these efforts fail to yield a conclusive answer, open lung biopsy may be required. The recognition of life-threatening pulmonary emboli as the cause of respiratory problems in patients undergoing therapy for non-Hodgkins lymphoma with subsequent anticoagulation is of utmost importance. In our patients treated with CAP-BOJ?, approximately Pulmonary Emboli after Chemotherapy for Lymphoma (Glenn et al)

70 percent of patients attain complete remission. 24 Since all five patients with pulmonary emboli attained a complete remission with therapy the failure to consider this diagnosis and treat accordingly will reduce the long-term cure rate and thus, the effectiveness of this mode of therapy Due to the retrospective nature of these results, we suspect that the actual incidence of pulmonary emboli in patients receiving chemotherapy for non-Hodgkin's lymphomas to be higher than the 3 percent reported here. Not every patient who presented with abnormal respiratory findings while receiving therapy underwent evaluation to search for pulmonary emboli, and not every patient who died underwent postmortem examination. In addition, there was no patient identified who had a pulmonary embolism while not receiving chemotherapy In summary we have presented five patients who developed pulmonary emboli while receiving chemotherapy for non-Hodgkins lymphoma. In each instance, the patient presented with a picture consistent with an interstitial fibrosis; three of these patients had little evidence to support pulmonary embolism as the cause of their respiratory insufficiency We are unable to demonstrate any risk factors in these patients; four of our five patients had limited stage disease and all had a good performance status. All of our patients either had a complete response to therapy for nonHodgkin's lymphoma at the time of autopsy or were in unmaintained complete remission for over 24 months after completing chemotherapy with CAP-BOP; two of these patients remain in unmaintained complete remission 24 + and 25 + months after completion of CAP-BOE In patients who develop respiratory difficulties while receiving chemotherapy for non-Hodgkins lymphoma, pulmonary emboli result in significant morbidity and mortality and should be ruled out as the underlying problem. REFERENCES 1 Sostman HD, Putman CE, Gamsu G. Diagnosis of chemotherapy lung. AJR 1981; 136:33- 40 2 Skarin AJ: Rosenthal DS, Moloney We, Frei III E. Combination chemotherapy of advanced non-Hodgkin lymphoma with bleomycin, adriamycin, cyclophosphamide, vincristine, and prednisone (BACOP). Blood 1977; 49:759-70 3 Bauer KA, Skarin AJ: Balikian JP, Garnick MB, Rosenthal DS, Canellos GE Pulmonary complications associated with combination chemotherapy programs containing bleomycin. Am J Med 1983; 74:557-63 4 Blum RH, Carter SK, Agre K. A clinical review of bleomycin: a new antineoplastic agent. Cancer 1973; 31:903-14 5 White DA, Stover DE. Severe bleomycin-induced pneumonitis: clinical features and response to corticosteroids. Chest 1984; 86:723-28 6 Weiss RB, Muggia FM. Cytotoxic drug-induced pulmonary disease: update 1980. Am J Med 1980; 68:259-66 7 Einhorn L, Krause M, Hornback N, Furnas B. Enhanced pulmonary toxicity with bleomycin and radiotherapy in oat cell lung cancer. Cancer 1976; 37:2414-16

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Pulmonary Emboliafter Chemotherapy for Lymphoma (Glennet al)