Leyvraz, S.

Perey, L.

Rollier, P.

Wasserfallen, J.-B

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Annals of Oncology 10: 243-245, 1999.Letters to the editorHepatocellular carcinoma in apatient with Gaucher disease onenzyme supplementation therapyGaucher disease is an autosomal recessive disorder character-ized by the deficiency of the lysosomal enzyme glucocerebrosi-dase. Accumulation of glucocerebroside occurs in macrophagesleading to hepatosplenomegaly and bone marrow infiltrationwith consequently cytopenia and bone disease (type I Gauch-er). Neurological disturbances are rare and have a rapidly fatal(infantile, type II) or chronic progressive (juvenile, type III)course [1]. In 1991 the first series appeared about enzymesupplementation therapy [2], followed by the experience fromother centers [3]. Over the last years more than 1500 patientsreceived or are receiving enzyme replacement therapy. Thistherapy consists of alglucerase or imiglucerase injections.Alglucerase is purified from a pool of placental tissue collectedfrom several donors and therefore human chorionic gonado-trophin (hCG) is present in this product. The recently developedimiglucerase is produced using recombinant DNA technology.Increased risk of malignancy in patients with Gaucher dis-ease has been observed [4]. It has been hypothesized that thismight be due to a defective immune surveillance due to chronicstimulation as consequence of accumulation of glucocerebro-side in macrophages, T-cell dysfunction resulting from highlevels of ferritin or from a factor released from monocytes.Hematological malignancies are predominant (myeloma, lym-phatic leukemia, lymphoma), solid tumors are rare. Hepato-cellular carcinoma (HCC) was reported once in a type IGaucher disease patient with cirrhosis and hepatitis B, inwhich both diseases were suggested as possible causativefactors for the malignancy [5]. We report a case of HCC in a62-year-old Caucasian male, known with Gaucher diseasetype I. His disease was characterized by hepatosplenomegalyand bone and joint.destructions. In 1988 severe leuco- andthrombopenia developed due to hypersplenism which resolvedafter splenectomy. Because of progressive bone destructionresulting in a serious mobility impairment, he was offeredtherapy with alglucerase. He has received weekly 15 U/kgfrom April 1995 till November 1996. No side-effects occurredand he responded well, as judged by a decrease in liver volume.In December 1996, ultrasound and computed tomography ofupper abdomen, performed because of persistent pain in theright upper abdomen, revealed an echodense lesion in the leftliver lobe. Diagnostic laparotomy revealed metastatic lesionsin peritoneum, omentum and tumor in the left liver lobe.Histological examination showed HCC cells in all specimens.At the moment of HCC diagnosis, laboratory test showednormal liver synthesis (ATIII 92%, cholinesterase 2100 IU,albumin 41 g/l), negative hepatitis B serology, normal immu-noglobulin electrophoresis and elevated a-foetoprotein (AFP)of 89.000 ug/1.There were no known predisposing factors for HCC. Retro-spective analysis of blood samples, taken every six months,revealed that the AFP level prior to the start of alglucerasetherapy was normal (3 ug/1). Six months later it was slightlyelevated (11 ug/1) and showed further rise (101, 36500, 83628ug/1) in following samples. The increase in AFP during thesupplementation therapy suggests a possible relation with thealglucerase treatment and thus simultaneous long-term expo-sure to hCG. In alglucerase, hCG is partially deglycosylatedduring the production process and cleared at a higher rate thannative hCG. However, its in vivo biological activity is yetunclear. HCC's often express hCG. Occurrence of HCC dur-ing pregnancy has been reported and oral contraceptives are arisk factor for its development. It could be speculated thatexogenous administered hCG might serve directly as growthfactor in inducing HCC or play an indirect role by modifica-tion of other hormones. Imiglucerase as a recombinant DNAproduct does not contain hCG. Another option is that occur-rence of HCC in this patient is merely due to prolongedcompromized immune surveillance secondary to macrophagedysfunction. The fact that HCC has never been reported inGaucher disease patients without risk factors and that enzymesupplementation therapy is new, justifies attention for thepotential carcinogenic effect of hCG alglucerase therapy. Itmight be relevant to check AFP levels during this therapy inorder to evaluate whether other patients also develop a HCCand, if so, to reveal this at an early stage.Z. Erjavec,1 C. E. M. Hollak2 & E. G. E. de Vries3Departments of iHematology, z Medical Oncology, Uni-versity Hospital Groningen; 2Department of Hematology,Academic Medical Center, Amsterdam, The NetherlandsReferences1. Beutler E, Grabowski G. Gaucher disease. In: Scriver CRBA, SlyWS, Valle D (eds): The Metabolic Basis of Inherited Disease. NewYork: McGraw-Hill 1995; 2641.2. Barton NW, Brady RO, Dambrosia JM et al. Replacement therapyfor inherited enzyme deficiency-macrophage-targeted glucoccrc-bridase for Gaucher's disease. N Engl J Med 1991; 324: 1464.3. Hollak CE, Aerts JM, Goudsmit R ct al. Individualised low-dosealglucerase therapy for type I Gaucher's disease. Lancet 1995; 345:1474.4. Shiran A, Brenner B, Laor A.Tatarsky I. Increased risk of cancerin patients with Gaucher disease. Cancer 1993; 72: 219.5. Breidem-Langen CM, Buchsel K, Brambs HJ et al. Koinzidenzeines Morbus Gaucher mit primarem hepatocellularem Karzinom.Laben-Magen-Darm 1991; 21: 126, 129.Cost comparison between PAV andICE treatment with peripheral bloodprogenitor cells (PBPC) reinfusion insmall-cell lung cancer (SCLC)High-dose chemotherapy with reinfusion of autologous hemato-poietic progenitors has improved the prognosis of patients withlymphomas [1]. For patients with small cell lung cancer (SCLC),early intensification with ICE (ifosfamide, carboplatinum, eto-poside) resulted in a median survival of 19 months for patientswith limited disease (LD) and 10 months for patients withextensive disease (ED) [2]. The standard PAV regimen (cispla-244tinum, adriamycine and etoposide = VP16) results in a mediansurvival of 12 months (15 for LD and 10 for ED patients) [3].The costs of the two regimens were compared in fourpatients treated with PAV (two men and two women, one LDand three ED, median age: 60 years, range 48-70) and fourpatients treated with ICE and PBPC reinfusion (three men andone woman, two LD and two ED, median age: 61 years, range41-63).The chemotherapy regimens were as follows: PAV (plati-num: 30 mg/m2, days 1-3; adriamycin: 40 mg/m2, day 1 andVP16: 100 mg/m2, days 1-3) was administered every 28 daysfor six cycles. The ICE regimen included two phases: PBPCmobilization with epirubicine (150 mg/m2 over two days)followed by filgrastim (5 jig/kg/day) until leucaphereses com-pletion. ICE consisted in ifosphamide (2.5 g/m2/day, con-tinuous infusion for four days), carboplatin (300 mg/m2/day)and etoposide (300 mg/m2/day) days 1-4, followed by reinfusionof PBPC and filgrastim (5 ug/kg/day) until leucocyte recovery.Three cycles were administered at monthly intervals.Cost identification was carried out as follows: physician,nurse, secretarial and administrative times were estimated foreach patient specifically according to the data provided bymultiple sources. Blood, platelets transfusions and drugs werevalued at cost price; laboratory tests, paramedical services andexternal consultations at price charged. Overhead was extractedfrom the cost accounting system.The hospital stay was 36 ± 5 days in the PAV group and59 ± 2 days in the ICE group. The break down of costs pertreatment phase, per nature of expenses and the comparisonbetween treatments is shown in Table 1. Intensification chemo-therapy with PBPC reinfusion for treatment of SCLC was 2.4times more expensive than traditional PAV treatment, due tolonger hospital stay, more febrile neutropenia, higher drugacquisition costs, and greater platelets and red cells trans-fusion needs.This cost comparison study was based on too few patientsto analyze their survival. The recent multicentric phase II trialwith sequential ICE and other recently published results usinggrowth factors [4] suggest that intensifying chemotherapy inSCLC patients may increase the number of long survivors.Table 1. Break down of costs by treatment phase and type of resources.PAV group(71=4)Cost per phase (mean ± SEM)Pre-treatmentChemotherapyFebrile neutropeniaOutpatient visits (onemonth)Cost per type of resources(mean ± SEM)Physician timeNursing timeAdministrative timeLaboratory testsOther paraclinic testsDrugsBlood productsOther direct chargesIndirect chargesTotal cost (CHF)034,883 ± 5,6019,341 + 7,6455,498 ± 7484,478 ± 38914,779 ± 1,7181,076 ±994,801 ±8185,880 ± 1,1637,496 ± 373330 ± 2702,018 ±2378,865 ± 1,31949,721 ±4,617ICE group(«=4)641 ± 085,138 + 3,43831,667 ±4.1363,353 ± 7525,978 ± 5534,986 ± 5051,124 ±5017,490 ± 1,6077,844 ± 42626,150 ±3,4389,358 ± 6873,654 ± 11914,216 ±437120,798 +4,401ICE/PAVratio_2.43.40.61.32.41.03.61.33.528.41.81.62.4However, in order to remain within the cost-benefit ratio usuallyaccepted for medical interventions, the difference in cost be-tween the two treatments should not exceed $50,000/life-yearsaved or quality-adjusted life-year saved (QALY) [5]. In oursetting, this implies that survival would have to increase by afull year.High-dose chemotherapy followed by PBPC in SCLC pa-tients is presently evaluated in a randomized phase III studysupported by the EBMT. Cost analysis and cost/benefit ratioswill undoubtly help delineating the clinical role of this approach.J.-B.Wasserfallen,1 P. Rollier,2 S. Leyvraz2 & L. Perey2^Medical Direction and 2Centre Pluridisciplinaired'Oncologie, University Hospital, Lausanne, SwitzerlandReferences1. Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone mar-row transplantation as compared with salvage chemotherapy inrelapses of chemotherapy-sensitive non-Hodgkin's lymphoma. NEngl J Med 1995; 33: 1540-5.2. Perey L, Leyvraz S, Rosti G et al. Sequential high-dose chemo-therapy for small-cell lung cancer: Final results of the EBMT phaseII study. Proc ASCO 1998; 17: 474a.3. Joss RA, Bacchi M, Hurny C et al. Early versus late alternatingchemotherapy in small cell lung cancer. Ann Oncol 1995; 6:157-66.4. Stewart WP, von Pawel J, Gatzemeier U et al. Effects of granulo-cyte-macrophage colony-stimulating factor and dose intensificationof V-ICE chemotherapy in small-cell lung cancer: A prospectiverandomized study of 300 patients. J Clin Oncol 1998; 16: 642-50.5. Goldman L, Gordon DJ, Rifkind BM et al. Cost and healthimplications of cholesterol lowering. Circulation 1992; 85: 1960-8.A specific approval procedure forprescribing albumin: Impact onconsumption in a cancer treatmentinstitutionAlbumin solution is a natural colloid solution which is mainlyindicated for hypovolemia and osmotic pressure disorders.Alternative, equally effective treatments, such as crystalloid orsynthetic colloid solutions are available at a lower cost [1].Until 1994, our 500-bed cancer treatment institution wasdevoid of a system for channeling albumin consumption. InJanuary 1995, the hospital's executive committee entrusted theTransfusion and Hemosurveillance Safety Committee (THSC)with the responsibility of rationalizing albumin consumption.The hospital hemobiologist, a THSC member in charge oftransfusion, proposed institute-specific guidelines definingvery limited indications for albumin based on current knowl-edge [2, 3]. These guidelines were validated by three otherphysicians in the institute and by an outside expert and werethen approved by all THSC members and the institute MedicalAffairs Manager. A letter was sent to all physicians informingthem of these recommendations in March 1995. Subsequently,albumin prescriptions were systematically vetted, accordingto these recommendations, by the hemobiologist who thencontacted the prescriber to check and validate each prescrip-tion before delivery of albumin.Results of the rationalization procedure are presented inTable 1. Between 1994, the baseline year before implementation

Cost comparison between PAV and ICE treatment with peripheral blood progenitor cells (PBPC) reinfusion in small-cell lung cancer (SCLC)

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