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Journal of Clinical Oncology, Vol 26, No 6 (February 20), 2008: pp. 1008-1010 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.8486
Recombinant Factor VIIa in the Management of Pulmonary Hemorrhage Associated With Metastatic ChoriocarcinomaDepartment of Medical Oncology, Southampton General Hospital, Southampton, United Kingdom
Department of Haematology, Southampton General Hospital, Southampton, United Kingdom
Department of Critical Care, Southampton General Hospital, Southampton, United Kingdom A 25-year-old man presented in September 2005 with relapsed metastatic germ cell tumor and a rapidly rising serum human beta chorionic gonadotropin (HCG; from 10,000 to 40,000 U/L over the preceding 10 days). He had been diagnosed 18 months earlier with International Germ Cell Cancer Collaborative Group (IGCCCG) poor prognosis extragonadal retroperitoneal metastatic germ cell cancer. He had presented then with lower back pain, hemoptysis, and weight loss. A computed tomography (CT) scan of the brain, chest, abdomen, and pelvis had shown a large retroperitoneal mass with a left hydronephrosis, multiple pulmonary deposits, and multiple brain metastases. Blood markers showed HCG 522,442 U/L, alpha-fetoprotein 5 KU/L, and lactate dehydrogenase 1,500 U/L. Testicular examination and ultrasound were unremarkable. Following placement of a nephrostomy, he was treated with four cycles of bleomycin, etoposide, and cisplatin chemotherapy. His HCG level fell to normal, but unresectable residual masses were present on CT chest and abdomen. Seven months later, he developed a rising HCG and progressive disease on CT, and second-line chemotherapy was commenced with paclitaxel, ifosfamide, and cisplatin. Following four cycles of treatment, the serum HCG once again fell to normal with a further, though unresectable, improvement at all sites on CT. During the current presentation, repeat imaging with CT once again showed modest volume disease progression with an increase in size and number of pulmonary deposits and enlarging right-sided retroperitoneal adenopathy. There was rapid elevation of HCG to 40,500 U/L. He was admitted to commence cisplatin and epirubicin chemotherapy, which was started the day of admission. Twenty-four hours after beginning chemotherapy, the patient developed overt hemoptysis associated with chest tightness and breathlessness. Clinical examination revealed widespread crepitations throughout both lung fields. Pulse oximetry showed oxygen saturation of 80%, and arterial blood gas analysis with FiO2 of 21% showed a pO2 of 50.5 mmHg, pCO2 of 34.2 mmHg, and pH of 7.33. Coagulation and platelets were normal; international normalized ratio was 1.1, activated partial thromboplastin time ratio was 0.9, fibrinogen of 4.7 g/L, and platelets were 270 x 109/L. A chest radiograph was performed and showed bilateral alveolar shadowing consistent with pulmonary hemorrhage (Fig 1).
He was treated with high-flow oxygen, intravenous furosemide, and intravenous tranexamic acid, though his hemoptysis continued. He became increasingly tired with repeat arterial blood gas analysis showing a rising pCO2 (FiO2, 100%; pO2, 76.5 mmHg; pCO2, 76.5 mmHg; pH, 7.3). Following review by the intensive care team, he was administered intravenous recombinant activated factor VII (NovoSeven; Novo Nordisk Pharmaceuticals, Bagsvaerd, Denmark) 100 µg/kg. Repeat blood gas analysis 5 hours later showed improved oxygenation (FiO2, 100%; pO2, 110.3 mmHg; pCO2, 41.1 mmHg; pH, 7.34). His hemoptysis rapidly resolved, and his oxygen was weaned; by the following morning, he was ambulatory without oxygen. He was discharged 4 days later with normalization of his chest radiograph (Fig 2).
A further five cycles of carboplatin and epirubicin were given with once again marker normalization and further response on CT imaging. Following harvesting of peripheral stem cells, he received CarboPEC high-dose chemotherapy (high-dose carboplatin, etoposide, cyclophosphamide) with stem-cell support in March 2006. He remains well with normal markers 3 years from his initial diagnosis. The choriocarcinoma syndrome occurs in a subgroup of nonseminomatous germ cell tumors with greatly elevated serum HCG.1 Pulmonary metastases are frequently present at diagnosis with pulmonary hemorrhage, a recognized complication. Tracheal intubation and positive pressure ventilation may be necessary if respiratory failure occurs, often with a poor outcome.2 In a recently published series, 87% of patients with choriocarcinoma syndrome and respiratory compromise developed acute respiratory distress syndrome following full dose chemotherapy. Even with reduced intensity induction chemotherapy, 30% of patients developed acute respiratory distress syndrome of whom two thirds died.3 Despite these high rates of early complications, patients with nonseminomatous germ cell tumors poor prognosis disease may achieve long-term remission with platinum-based chemotherapy. Five-year survival may be as high as 48%4 with several lines of effective salvage therapy. The combination of paclitaxel, ifosfamide, and cisplatin has shown high complete response rates (70%) in patients with relapsed testicular germ cell tumors with a progression-free survival of 65% at 2 years.5 A trial of cisplatin and epirubicin in patients with relapsed disease and at least one prior line of platinum-based chemotherapy also showed activity with a 57% response rate, which was durable at more than 1 year in 23% of patients.6 Both single and consecutive high-dose therapy with autologous stem-cell rescue have been investigated. In a recent review of 184 patients with germ cell tumors treated at a single institution with either a single or two consecutive courses of high-dose carboplatin based chemotherapy, 63% remained disease free at a median follow-up of 2 years. In those receiving high-dose therapy as third or subsequent line therapy, 45% remained disease free at 2 years.7 The subgroup of patients with choriocarcinoma (either pure choriocarcinoma of the testis or the choriocarcinoma syndrome) may also be successfully managed with salvage high-dose chemotherapy. Forty-six percent of patients with choriocarcinoma treated with two cycles of high-dose carboplatin and etoposide remained alive and disease free with a median survival of 37 months.8 Recombinant factor VII has been used to treat pulmonary hemorrhage in variety of settings, including complications of pneumonia9 and during allogeneic hematopoeitic stem-cell transplantation.10
Recombinant VIIa (rVIIa) is licensed in the United Kingdom for treatment of hemophilia patients with inhibitors to factor VIII or IX. The suspected mode of action is through an enhanced burst of thrombin generation, localized at sites of tissue factor (TF) expression and activated platelet (phospholipid) surfaces.11,12 The TF-VIIa complex mediates both factors Xa and IXa generation. Small amounts of thrombin, generated by TF-VIIa and activated factor ten in the vicinity of platelets, induce platelet activation, which in turn provide an ideal surface for the activated factor nine to be fully active, generating large amounts of thrombin. Thrombin causes the cleavage of fibrinogen to produce fibrin and the subsequent stabilization of clot by the actions of activated factor XIII, which render it more resistant to both mechanical stress and fibrinolysis. At relatively high levels of FVIIa ( This is the first reported case of the use of rVIIa in the setting of pulmonary hemorrhage secondary to chemotherapy for choriocarcinoma. The rapid clinical deterioration of our patient appeared to be immediately arrested, allowing subsequent effective salvage therapy. Thus recombinant factor VIIa should be considered as a treatment option for this group of patients who may not otherwise survive. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. McKendrick JJ, Theaker J, Mead GM: Nonseminomatous germ cell tumor with very high serum human chorionic gonadotropin. Cancer 67:684-689, 1991[Medline] 2. Benditt JO, Farber HW, Wright J, et al: Pulmonary hemorrhage with diffuse alveolar infiltrates in men with high-volume choriocarcinoma. Ann Intern Med 109:674-675, 1988 3. Fizazi K, Massard C, Postel-Vinay S, et al: Chemotherapy for poor prognosis non seminomatous germ cell tumors (NSGCT): Should doses be reduced at first cycle to prevent acute respiratory distress syndrome (ARDS) in patients with multiple lung metastases? J Clin Oncol 25:18S, 2007 (suppl; abstr 5087) 4. International Germ Cell Consensus Classification: A prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 15:594-603, 1997 5. Kondagunta GV, Bacik J, Donadio A, et al: Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol 23:6549-6555, 2005 6. Bedano PM, Brames MJ, Williams SD, et al: Phase II study of cisplatin plus epirubicin salvage chemotherapy in refractory germ cell tumors. J Clin Oncol 24:5403-5407, 2006 7. Einhorn L WS, Chamness, Brames MJ, et al: High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumours. N Engl J Med 357:340-348, 2007 8. Brames M, Papiani G,, Einhorn L: Results with salvage chemotherapy with high dose carboplatin + etoposide and peripheral blood stem cell transplant in male choriocarcinoma. J Clin Oncol 25:18S, 2007 (suppl; abstr 5091) 9. Macdonald JA, Fraser JF, Foot CL, et al: Successful use of recombinant factor VII in massive hemoptysis due to community-acquired pneumonia. Chest 130:577-579, 2006[CrossRef][Medline] 10. Pastores SM, Papadopoulos E, Voigt L, et al: Diffuse alveolar hemorrhage after allogeneic hematopoietic stem-cell transplantation: Treatment with recombinant factor VIIa. Chest 124:2400-2403, 2003[CrossRef][Medline] 11. Monroe DM, Hoffman M, Oliver JA, et al: A possible mechanism of action of activated factor VII independent of tissue factor. Blood Coagul Fibrinolysis 9:S15-20, 1998 (suppl 1)[Medline] 12. Hoffman M, Monroe DM 3rd, Roberts HR: Activated factor VII activates factors IX and X on the surface of activated platelets: Thoughts on the mechanism of action of high-dose activated factor VII. Blood Coagul Fibrinolysis 9:S61-5, 1998 (suppl 1)[Medline] 13. Hedner U: NovoSeven as a universal haemostatic agent. Blood Coagul Fibrinolysis 11:S107-11, 2000 (suppl 1)[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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90 µg/kg) it may be possible to achieve phospholipid-dependent activated factor ten generation in the absence of TF and activated factor nine.
