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A new trial in the treatment of brain metastasis from small cell lung cancer: is PC1 neccessary?.

Miyamoto,T. Nomoto,Y. Yasukawa.T. and 0ka.K. National Institute of Radiological Sciences, Japan.

It has been reported that prophyraxic cranial irradiation (PCI) can successfully suppress the appearance of brain metastasis from small cell lung Cancer(SCLC), but frequently results in severe mental deterioration especially for the elder and/or long- term survivors. Nowadav, brain metastasis from SCLC can be detected in the tumor size more than 2 mm in diameter by using Ga- ennanced MRI. Eighteen brain metastases in various tumor size from 7 patients with SCLC receiving whole brain and/or local radiation were analysed under this study. To determine the control dose, metastatic tumors were moritored in recurrence with time after irradiation by using Gd-enhanced MRI and/or examined in response histologically at autopsy. As a result, it was found that the control dose was clearly dependent to tumor size: the metastases smaller than 10 mm in diameter could be controlled by giving 4OGy while the tumor in size ranging from 10 to 30 mm were required to be more than 55Gy. The tumors larger than 30 mm could not controlled even at over 60Gy. If brain metastasis is found in the controllable size by irradiation, PC1 would be of no use in the treatment of the brain metastasis and the patients without potentially brain metastasis can be relieased from unnecessary brain damage by whole brain irradiation.

555

TM ,WFl.“E”CE OF PRoPH”LlCTlC CRAYllL lRRAol*T*Ow 0” SlTES OF RELAPSE ANO

sw!VlWL I” PATlEWTS “IT” SIULL CELL Lwi UWCER I” ecuPETE REMSSICN

W. Ydf. Y. Warts. *. Schroeder, E. Sruska, R. Coerg, W. Pritsch, P. Drings, K. nswmam Dept. of Int. Med., Philipps-Univ., Ilarkurg, Ce-

Frm 1981 to 1968 a total of 1179 patients with SCLC entered for German aulticnter trials. The study protocols included the awlicatim of a PC1 in a dose of 30 Gy in the case of cnplete rmissim. Of the 1179 patients 252 (21.4%) achiwed a CR. However, only 160 of thm received PCI, in 92 cases PC1 was not given due to refusal or local physicians decision. Know prognostic factors like extent of disease, performance status, sex, LDH and WE were nearly identical in both groups. Of the patients receiving PCI, 69 wre irradiated within 4 lnonths after diagnoses and 81 after 4 months. In 10 patients the tire of PCI was not dowvented. The fr-ies of isolated brain retapes, combined sites of relapse with the occurrence of brain lnetastases and other sites within 4 weeks, and no brain rrtastases in relation to the prfornwce of PC1 are shorn on the following table.

M mn, & brain rel - brain rel - brain rel.

within 4 ma 3 ( 4%) 5 ( 7x1 59(88x) 2 pcI

after 4 m 13 <18X) 2 ( 3%) 59@0%) 7

pcI 16 (20%) 9 (11%) 56 (69%) (1

The mdian survival ws I8 -ths end identical in both groups. Hwever, the 4 year survival rate wss significantly higher (17% vs 28%) in the patients Yithwt PC!. Yithin the population receiving PCI, patients with early treatmnt had a shorter r&inn survival (14 rn VI 21 mo> than patients with late PCI, but the 4 year survival rate did not differ between both grcq% (li%). This analyses d-trates a reduction of brain lnetastases as relapse site by PCI, but, however, the cnparism of survival favared the patient pcpulatim without this treatrent procedure.

Contralateral Expression of Alveolar Macrophage Produc- tion of Fibroblast Growth Mediators in Ipsilateral Radlation- Induced Pulmonary Fibrosis. P. Rubin, S. McDonald, J. Williams, C.Reed, J.Finkelstein. Radiation Oncology, University of Rochester, Rochester NY.

There is increasing evidence that pulmonary fibrosis is a consequence of multiple cell systems interacting in response to radiation injury. Earlier work from this laboratory had shown that alveolar macrophages (AM’s) respond during the so-called “latent period” through the production of growth factors which affect fibroblast proliferation (Int.J.Rad.Oncol.Biol.Phys.24;1992). Using our rabbit mode!, male New Zealand White rabbits were exposed to unilung radtation at varying doses (5, 10, 17.5 Gy); the animals were sacrificed between 1 to 24 weeks post-irradiation. Alveolar macrophages were obtained by bronchoalveolar lavage (BAL) and were cultured in vim in serum-&e media. After 24 hrs, the AM conditioned media was evaluated for its effects on a fibroblast cell line through the measurement of [3I-Il thymidine incorporation.

In these extended studies, we have shown that not only is there an early persistent response, but at those doses which result in pneumonitis and fibrosis, there is a biphasic response: following a slight reduction at 8 weeks, there is a dramatic increase in growth factor production which is persistent to 24 weeks post-irradiation.

Irradiation of only one lung made it possible for us to examine the response of the unirradiated lung. Response by the tibroblasts to conditioned media from those AM’s recovered from the contralateraI.lung showed no early proliferation; however, by 16 weeks post-irradiation, there was a dramatic increase in growth factor production which persisted to 24 weeks. Although the full nature of the factors is unknown, antibodies to PDGF block this response.

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m4sE 1 TRIAL OF RECOMBINANT B-INTERFERON (R- IFNB, R-FRONE,) AND RADIATION THERAPY (RT) FOR NON-SMALL CELL LUNG CANCER (NSCLC) R Byhardt, JF Wilson, C Lawton, P Win, E Borden, L Vaickus#, J. Breitmeyer# and AY Chang* Med. Coil. of Wisconsin, Milwaukee, WI 53226, #Serono Labs Inc., Norwell, MA 02061 and *U. of Rochester, Rochester, NY 14642.

Fourteen patients with Stage IIIA and IIIB NSCLC received subcutaneous r-IFNE on each day of conventionally fractionated RT (2 Gy fractions to 60 Gy in 6 wks). r-IFNB is virtuaIly identical to natural IFNB and is expected to be non- antigenic with chronic use. Cohorts of 3 patients each were treated with escalating doses of r-IFNS as follows: 1.5, 3, 6, 12, and 24 MIU/m2. Acute RT toxicity was assessed according to Radiation Therapy Oncology Group (RTOG) criteria; toxicity was graded on a WHO scale. The r-IFN8 maximum tolerated dose (MTD) was defmed as that at which one patients developed 2 Gr. 4 toxicity. Biologic and antigenic effects of r-lFN8 were assessed by: 2’S oligoadenylate synthetase, 02 microglobulin, neopterin, p78-Mx, cellular MHC Class II surface antigen expression, and measurement of antibodies to r-IFNB. There were no acute toxicities 2 Gr. 4, however, the majority have had one or more Gr. 1 to 3 gastrointestinal (GI) toxicities; dysphagia/esophagitis (14/14); nausea/vomiting (12/14); anorexia (7/14); liver transaminasemia (5/14). Most GI toxicities have been only Gr. 1 or 2, but when combined with the acute RT effects, may lead to the MTD of r-IFNE being defined as dose below the classically defined MTD. Biologic markers of IFN action, further accrual at the 24 MIU/m2 level, and late toxicity data will be included in the final abstract presentation and may allow a more precise determination of a r-IFNB Phase II dose.