Annals of Oncology 3:771-774, 1992.

Letters to the editor Local treatment of malignant pleural mesothelioma with intracavitary cytosine-arabinoside and cisplatin In experimental systems cytosine arabinoside (Ara-C) has exhibited synergistic cytotoxicity with cisplatin [1]. In a phase I clinical evaluation of Ara-C and cisplatin Schilsky et al. [2] observed a 42% response rate in patients with non-small-cell lung cancer. Some studies showed a high response rate in patients with malignant pleural effusions using a combination of Ara-C and cisplatin administered intrapleurally [3—5]. When administered into the pleural cavity, these drugs produce peak intracavitary levels that are many times greater than plasma levels [5], and perhaps this offers an opportunity to take advantage of long-term exposure of tumor cells to these drugs with minor systemic toxicity. Five patients (four males and one female), median age 52 (range 37-68), with malignant mesothelioma were studied. All had cytologically and histologicaJly confirmed tumors (Table 1). None had a documented history of asbestos exposure. Informed consent was obtained from all of the patients before they were included in the study. Entry requirements included Karnofsky performance status 0-2 (ECOG criteria), serum creatinine < 1.8 mg/100 ml, creatinine clearance >6() ml/minute, a WBC count >4000/mm 3 and a platelet count > 120,000/mm\ Prior to beginning loco-regional chemotherapy, evaluation included a complete history, a physical examination, chest x-ray, EKG, a complete blood count and a serum biochemical screening profile. Serum WBC count, platelet count, serum creatinine and electrolytes were determined weekly before each intracavitary administration. Patients were hydrated with 0.5 L of 0.9% sodium chloride i.v. The cavity was drained as completely as possible. The drugs were instilled in the pleura! cavity at the dose of 100 mg for Ara-C and 100 mg/mq for cisplatin diluted in 0.4 L of 0.9% sodium chloride over 20 minutes. The cavity was drained again 4 hours later. Concurrent with the instillation of Ara-C and cisplatin, all patients began a 3-hour hydration with 1.5-2 L of 0.9% sodium chloride including electrolyte supply. Diuresis was established by rapid i.v. injection of 20 mg of furosemide. Response and toxicity criteria were those recommended by WHO. Survival was determined from the time of diagnosis. Responses are summarized in Table 1. The five patients received a total of 27 locoregional treatment courses (range 3-8). The overall toxicity was acceptable. The main side effect of the treatment, myelosuppression, was generally modest. The median WBC count nadir was 2100/mm1 (range, 900-3400) and median platelet count nadir was 170,000/mm' (range, 110,000-320,000). Neither fever nor sepsis occurred. Only two patients experienced mild nausea and vomiting.

Discussion The approximate median survival rate of pleural mesothelioma ranges between 8 and 25 months. Metastatic dis-

ease is rarely seen at diagnosis, but in about 40% of patients it becomes generalized during the clinical course [6]. To date, systemic chemotherapy has achieved only very low complete remission rates in both limited and metastatic disease. Since intracavitary administration of Ara-C and cisplatin is safe, we used these drugs in the treatment of malignant mesothelioma. Although we treated only five patients with non-metastatic disease, by this schedule we achieved very important results with an absence of local, neurological and nephrological toxicity and only mild myelosuppression. Although intrapleural chemotherapy could be an important treatment in limited disease, in long-term survivors it does no seem able to prevent metastatic progression, but perhaps it can delay it: in fact our patients, nos 1 and 2 showed, respectively, a peritoneal and hepatic involvement a long time after diagnosis (50 and 23 months, respectively). The small number of cases reported does not allow definitive conclusions to be drawn about the real efficacy of local treatment with this schedule, but it suggests that this kind of therapy in non-metastatic pleural mesothelioma could play an important role in the local control of the disease, with minimal systemic toxicity. Perhaps new programs with integration of locoregional and systemic treatment could achieve better results.

Acknowledgments We thank Mrs Milena Benedini for preparation of the

manuscript. E. Aitini,1' E. Pasquini,2 G. Cavazzini,1 P. P. Fattori2 & F. Smerieri' 1 Department of Medical Oncology, Ospedale C. Poma, Mantova; 2Department of Medical Oncology, Ospedale degli Infermi, Rimini, Italy; ('address for correspondence). References 1. Bergerat JP, Drewinko B, Corry P et al. Synergistic lethal effect of cis-dichlorodiammineplatinum and 1-beta-D-arabinofuranosylcytosine. Cancer Res 1981; 41: 25-30. 2. Schilsky RL, Muscato JJ, Muscato MS et al. Phase I clinical evaluation of cytarabine and cisplatin in patients with advanced cancer. Cancer Treat Rep 1984; 68: 1097-102. 3. Markman M, Cleary S, King ME. Cisplatin and cytarabine administered intrapleurally as treatment of malignant pleural effusions. Med Pediatr Oncol 1985; 13: 191-3. 4. Aitini E, Cavazzini G, Cantore M et al: Local treatment of primary or metastatic pleural effusions with intracavitary cytosine arabinoside and cisplatin: A phase-II study. Reg Cancer Treat 1991:3:320-2. 5. Markman M, Howell SB. The intracavitary administration of cytarabine to patient.s with non-hematopoietic malignancies: An update. Semin Oncol 1987: 14(suppl 1)116-120. 6. Hillcrdal G. MaJignant mesothelioma 1982: Review of 4710 published cases. BrJ Dis Chest 1983; 77: 321-43.

772 Table 1. Patient characteristics. Patient

Age

Sex

Histology

Prior therapy

Courses

Response

Duration of response (months)

Survival (months)

epithelial subtype not defined mixed mixed epithelial

doxorubicin none

8 6

CR CR

15 23

51 26

none epirubicin doxorubicin Rx therapy

3 4 6

PR PD CR

9 16

16 6 25+

(years) 1 2

44 59

F M

3 4 5

53 68 37

M M M

Secondary lymphoblastic leukemia following treatment of a malignant germ cell tumour Therapy-related secondary leukemia represents a major concern in patients with curable malignant tumours. PedersenBjergaard et al. [1] have reported five cases of AML/myelodysplasia (MDS) in a cohort of 212 patients with germ cell tumours treated by cisplatinum, etoposide, and bleomycin (PEB). These cases appeared to be closely linked to the use of etoposide and the issue of topoisomerase II inhibitors and the risk of secondary leukemia has been excellently reviewed by Ratain and Rowley |2] in Annals of Oncology. While mostly cases involving the myeloid cell lineage (secondary AML or MDS) have been published so far |3], we have observed a case with secondary lymphoblastic leukemia after treatment for malignant germ cell tumour. In October 1989 a metastatic testicular germ cell tumour of mixed histology (embryonal carcinoma, chorioncarcinoma and teratoma) was diagnosed in a 42-year-old male. The patient was classified as Lugano stage IHR (abdominal lymph nodes and pulmonary metastases) and received four cycles of the PEB-regimen with a total cumulative dose of 2000 mg/ m2 of etoposide. A complete ongoing remission was achieved after the second cycle. Sixteen months later, in January 1991, the patient suffered from a pulmonary infection and thrombocytopenia. A bone marrow biopsy revealed the diagnosis of acute lymphoblastic leukemia (ALL) with 90% infiltration of blasts. The blasts were PAS-positive and POX-negative. The diagnosis of a pre-B-ALL was confirmed by positive staining for CD 19, CD 24, cytoplasmatic IgM and TDT, while CD 7, CD 33, CD 34 and CD 10 had been negative. The patient was treated according to the protocol of the German cooperative ALL study group, containing prednisone, asparaginase, vincristine, cytosinarabinoside, cyclophosphamide, and intrathecal therapy as induction treatment and entered complete remission after four weeks. However, early relapse occurred after 7 months. The patient died during a granulocytopenic infection throughout the further treatment. Cytogenetic analysis at the time of initial diagnosis of ALL revealed a translocation t (4; 11) (q21; q23) in 19 of 23 metaphases of the bone marrow and the peripheral blood. No isochromosome i (12p) was detected, indicating that this was not a case of germ-cell tumour-associated hematologic neoplasia as described by Nichols et al. [4] in 16 patients with mediastinal germ cell cancer. The t (4; 11) translocation

found in this patient, may not only be typical for a pre-pre-Bsubtype of lymphoblastic leukemia but also for secondary leukemia, particularly after prior treatment with epipodophyllotoxins [5, 6]. The interval of only 16 months between exposure and secondary leukemia was short, but is within the range of published data (15-68 months [1|; 15-37 months [5]). The involvement of Ilq23 after treatment with drugs targeting at topoisomerase Ii has been reported in several cases, particularly for AML M4 or M5a without prior myelodysplasia and with a short latency [3, 6J. The development of secondary leukemia after etoposide seems not to be restricted to the myeloid cell lineage alone.

C. Bokemeyer,1 M. Freund,1 H.-J. Schmoll,1 H. Rieder2 & C. Fonatsch2 1 Dep. Hematology/Oncology, Hannover Medical School, Konstanty-Gutschow Str. 8, 3000 Hannover 61, FRG; 2 Dep. Human Genetics, - Tumourcytogenetics Liibeck Medical School, Liibeck, FRG

References 1. Pedersen-Bjergaard J, Hansen SW, Larsen SO et al. Increased risk of myelodysplasia and leukemia after etoposide, cisplatin, and bleomycin for germ-cell tumours. Lancet 1991; 338: 35963. 2. Ratain MJ, Rowley JD. Therapy-related acute myeloid leukemia secondary to inhibitors of topoisomerase II: From the bedside to the target genes. Ann Oncol 1992; 3: 107-11. 3. Pedersen-Bjergaard J, Philip P, Larsen SO et al. Chromosome aberrations and prognostic factors in therapy-related myelodysplasia and acute nonlymphocytic leukemia. Blood 1990; 76: 1083-91. 4. Nichols CR, Roth BJ, Heerema N et al. Hematologic neoplasia associated with primary mediastinal germ-cell tumours. N Engl J Med 1990; 322: 1425-9. 5. Pedersen-Bjergaard J, Philip P. Balanced translocations involving chromosome bands 11q23 and 21q22 are highly characteristic of myelodysplasia and leukemia following therapy with cytostatic agents targeting at DNA-topoisomerase II. Blood 1991; 78: 1147-8. 6. Pui C-H, Ribeiro RC, Hancock ML et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphobla-stic leukemia. N Engl J Mcd 1991; 325: 1682-7. 7. Pedersen-Bjergaard J, Philip P, Ravn V et al. Therapy-related acute nonlymphocytic leukemia of FAB type M4 or Y15 with early onset and t (9; 11) (p21; q23) or a normal karyotype: a separate entity? J Clin Oncol 1988; 6: 395-7.

Local treatment of malignant pleural mesothelioma with intracavitary cytosine-arabinoside and cisplatin.

Annals of Oncology 3:771-774, 1992. Letters to the editor Local treatment of malignant pleural mesothelioma with intracavitary cytosine-arabinoside a...
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