197

CDDP and MTX but not in cells resistant to anthracyclines or VP16. CDDP-resistant ceils with lower SOMI antiwn became MTX-resistant although the cells were ne;er expo& to MTX. Cells that reverted to CDDP-sensitivity showed increased SQMI antigen and also reverted to MTX sensitivity. SQMl protein formed complexes with the membrane folate receptor in solution and in reconstituted membrane vesicles. Aoti-SQMl antibody inhibited transport of MTX in carcinoma cells, suggesting that SQMl protein participates in regalation of drug transport. Cloningofthegenecodingfor SQMl pmteinrevealsanewcDNA sequence with motifs similar to dihydmfolate reductase, epi- dermal growth factor receptor and cellular adhesion proteins. No significant similarities were found with GP170 protein or DNA sequence. SQMl is a differentiation-related membrane protein that may he associated with a new multi-drug resistance (mdr) phenotype.

REVERSAL OF PRENEOPLASTIC CHANGES IN UPPER RESPIRATORY EPITHELIUH. Scott H. Liooman and Waun K. Hong The University of Texas M. 0. Anderson Cancer Center, Houston, Texas, USA

Pharmacologic inhibition or reversal of carcinogenesis in premalignant stages (chemoprevention) with retinoids [natural derivatives and synthetic analogues of vitamin A) has recently come to the forefront of cancer research. Retinoids can suppress multistep carcinogenesis in its promotion/progression phases in various epithelial tissues. Recent work suggests that this occurs at the gene transcription level, possibly mediated by nuclear retinoic acid receptors, the most recent members of the steroid/thyroid hormone receptor family. Our early phase III placebo-controlled trial, which established the ability of high dose (l-2 mg/kg/d) 13-cis-retinoic acid (13&A) to reverse precancerous oral lesions, led to our recently completed phase III placebo-controlled high-dose adjuvant study, which indicated suppression of second primary tumors (SPTs) in head and neck cancer patients (p = ,005). SPTs, the major cause of death in early-stage patients, appear to evolve from progression of multifocal premalignant lesions in the carcinogen-exposed field at risk (head-and-neck, lung, esophagus). The significant mucocutaneous toxicities and need for long-term treatment led to our current study of low-dose 13-W (O.Wg/kg/d). This nearly completed NCI-sponsored trial with over 60 patients indicates that low-dose 13-cRA is well tolerated and is highly effective (more effective than r-carotene, p = .Ol) as short-term (q-month) maintenance therapy after a 3-month induction oeriod with hiah-dose 13-&A. Ue now plan a large-scale iow-dose trial-in early-stage head and neck squamous cell carcinoma. Study of bio- markers as intermediate endpoints will complement the clinical work and will allow us to identify high risk sites and to assess chemopreventive efficacy. Marker classes under study include genetic, differentiation, proliferation and regulatory factor alterations. This work bridges basic research and broad clinical appli- cation and is at the interface between early cancer detection and chemoprevention.

ROLE OF SURGERY IN LOCALLY ADVANCED NON-SMALL CELL LA$Gy;~uFkA~: MEMORIAL SLQAN.RETlERlNG:

Lung - Is largely a w’gical disease mince most reporkd cures have acawed In @knts rho baw been bwkd by sur~wy. However. surgial treatment Is potentially cuntive only il complete reswtion is possible. Factors that Umil mecbbilily in locally advanced stageIll carcinoma ioclnde atension d lbe (urnor to &at wall or mediastinum (T3 dkasc) and metastasis to medbstld lymph wdes (NZ disease). Combined mod&y tbenpy become9 wc%smy la lhb mp dpalkob. In those wilb tumor involving tbc chest wall, raectiom of the tumor ritb all involved tlssues is stlli tbe most effective form of bwabnd protided tbe rwecUoa can encompass ail disease. lbe prqwsls of these pnlknts is Influenced pr 'wipaliy by 3 factawl) mectabUily, 2) mediasUnai lymph node status and 3) exlenl of chest wail involvement. Survival folicmi~ resecticw in the abs .noc ol iympbatk metestases is 56% at 5 )cars. Despite the presence of nodal metastases and cbesl wall invasion, 33 patients nre bvated by complete rcwctioo and bad a Spar survival of 21%. We recommend surgical resection

rbencver possible for ail patients with tumors extending to tic chest nil. We do not rsommeod postoperative radiation therapy nor cbemotbeRpy if the fwectioo is complete. For ru~erior suicus tumors. mosl centers currentiv favor preopw& radiation ihe~py folimnd by &cai rrsection. Fro& 196&1982.129 patients were treated sugiuiiy at our center. Tbc overall sunivsi was 25% at 5 yar with median survival or 20 months. Survival r0iiOting p~pt?ItiVC ~diation aad s”rg~v ‘*16 30% for patients titb TJNO disease, 20% for Uwse with Homer% and ipsiiater~i neck node melastasrs and 10% for those with N2 disease. From 1974 to 1981,151 patients with N2 disease had completely rwectabie tumors. ‘Ibe 5 yaw survival folimvlog resection was 30%. Age, sex, bislology and lymph node size or locallou did not influence sunivai. Factors influencing survival werr tumor size, clinical nodal status and resectabiiity. Paticots who benefited from sur@ai trtatmenl bad generally peripheral tumors titb a nommi mediastioum on chest r-rays. Patients with bulky N2 disease evident on plain chest x.ppys did poorly. Only 14% of tbest rnrr rrsstPble and only 9% did well loiimving resecUon. We now treat this latter group of potienb with prtopcntive cbemolberapy using eisplatin, viadesine or vinbinstine and mitomycin C.

CONTROVERSIES IN THE TREATMENT OF NON SMALL CELL LUNG CANCER WITH RADIOTHERAPk Andrew~T. Turrisi. 111. University of Michigan hlcdical Center. Ann Arbor. Ml. USA.

For years. the patients. found to he unresectahlr OI inoperable. have heen cor&leretl apprqwiate radiotherapy candidates. Few prospective trialc have clearly established this practice. Today. a new staging system has promoted more patients to wgical cbdidacv. whether taking more patients ICI ~!gcl! will im&ove endooints of survival 01 of local (.on~!c;l may yet he de&mined. At the Fame time. I!,, 1111nt or neoadjuvant chemotherapy also hat gained (I IrIot hold. Recent trials will he reviewed atldrcwn~g lhc choices currently ayailahle. the experimental qruti~w and the current strategies and rotionaler for ~t.q!c (II A and III-B lung cancer. Pre-operative ratliothclap! (‘?Paleo-adjuvant) therapy will also he reviewed. I II< role of radiotherapy. as reported in trial7 :md theoreticallv. in neoaduvant treatment. aill bc discussed. 1

The strategy for pancoast tumors and thtz Ilata IOI pre-operative v. definitive radiotherapy will Ihc discussed.

Recent repons of early-stage NSCLC and the role ()I thoracic Iradiotherapy in patients either medically. inoperable or refusing surgery will he prewntcd Factors influencing control such as staging. tumw Gx. continuous v. split course therapu. will he diwwcd

Post-operative therap\: indi<ators. endpoints and toxicity will he revietied.

Proohvlactic Cranical irradiation trial? anal rati<lnnlr will ie ‘detailed.

LeSS controversial is the pallalive I(~l( 01 radiotherapy. The use in hl-ain mctacta~~~. IVIW metastasis. svc and atelectasis. and the I.&, 1111 endohronchial XRT will he evaluated.

MULTIMODALITY THERAPY FOR STAGE III NON-SMALL CELL LUNG CANCER. J.D. BITRAN, UNIVERSITY OF CHICAGO MEDICAL CENTER, CHICAGO, IL, USA.

testmg m patlents with Stage III non-small ccl cancer (NSCLC). In some trials the chemotherapy (almost exclusively cisplatin based) has been administered either above or with simultaneous radiotherapy. The results of these phase II will he reviewed. The performed to date demonstrate the feasibility of these combined modality approaches; however, the outcome of many of these studies stems a wide range of variability with median survrvals ranging from 8 months to 18 to 24 months. The variable results are explained by patient selection and exclusion criteria. Based on the demonstrated feasibility of combined modality treatment, randomized phase III trials should be initiated in Stage IIIA patients with NSCLC with stratification based on clinical model involvement No versus N2.