Long-term results of neoadjuvant ifosfamide, cisplatin, and etoposide combination in locally advanced non-small-cell lung cancer

Abstracts/Lung

Cancer

~IIItrinlofrreombimnatintelfemagrmmnia~~Fespoaden with small-cell hmgcaocer Jett JR, Maksymiuk AW, Su JQ, Mailliard JA, Krook JE, Tschetter LK et al. NCCTWO. 200 First Sr SrC: Rochesm: MN 55905. J Clin Oncal 1994; 12:23216. Purpose: We evaluated the effect of recombinant interferon gamma (rIFNgamma) on survival and toxicity in small-cell lung cancer (SCLC) patients in complete remission (CR). Patients and Mefhodr: One hundred patients in CR following treatment with six cycles of combination chemotherapy, thoracic radiotherapy (TRT), and prophylactic cranial irradiation (PCI) were studied. All patients had ban enrolled onto a cooperative group trial (North Central Cancer Treatment Group [NCCTG] 86-20-S I). Patients rcccivcd observation only or rIFN-gamma at a dose of 4 x lb U subcutaneously per day for 6 months. Rem&s: Six patients (12%) did not comply with rIFN-gamma treatment. Substantial nonhcmatologic toxicities consisting of chills, myalgia, lethargy, and alteration of mood-personality wcrc observed. No patient experienced lifcthreatening or fatal toxicity. The median times to progression for rIFN-gamma trcabnent or observation wcrc 6.9 and 8.1 months (P = .54). The median survival times were 13.3 and 18.8 months, rc.spcctively (P = .43). Approximately 70% of all patients relapsed within 2 years. Conclusion: Time to progression and survival were inferior in patients treated with rlFN- gamma compared with randomized control subjects, although this difference was not strdistically significant. Thcsc data indicate that rlFN-gamma treatment is not ass&&d with a 33% improvement in survival (F’ = .04). -use of the high rate of relapse, SCLC paticnts in CR arc an ideal 8rwp in which to cvalustc novel and minimally toxic agents.

-g-term combllation

resulta ofneoadjuvant in locally advanced

ifohmide,ciaplatin, sod etoposide naa-sm~ ltmg wnccr

Pujol J-L, Hayot M. Rouanct P, Lc Chevalier T. Michel F-B. Maladies Respirafoires, CHU Montpellier, Ifopital Arnoud de Villeneuve. 34059 Monrpellier Cedex. Chest 1994;lo6:1451-5. Thirty-three patients with T3,NZ,MO or T4,N2,MO, non-small-cell lung cancer (NSCLC) took part in a phase 2 study in an attempt to evaluate the feasibility of ncoadjuvant chemotherapy followed by surgery and thoracic radiotherapy. Chemotherapy consisted of daily administration of the following treatment: etoposide, 100 mg/m’; cisplatin, 25 mg/m’; ifosfamidc, 1.5 8/m’; and mnna, I.8 g/m’ for 4 days. Thea cycles were planned starting every 21 days. Responding patients underwent a thoracotomy in order to attempt a resection and then rcccived a 45 Gy of thorn&c radiotherapy. The results of response and nscction rates have been published and the prcscnt final report deals with the long-term results. Chcmothcmpy induced B 55 percent partial response rate and a I5 percent complete response rate allowing a complete resection in 55 percent of the patients. Complete remission was histologically contirmcd for the five complete responders. Although the median survival was short (IO months), six patients were long- term survivors (3-year survival rate; I9 percent). Survival was significantly influenced by the type of resection: patients for whom a complete resection was possible survived the longest with a median survival three times that of the other patients. Modalities of relapses differed according to the results of surgery: 8 of the I5 patients who did not undergo a complete surgical resection experienced a local relapse during the first I8 months of follow- up whetas in the complete resection group, central nervous system metastasis was the main site of relapse. We conclude that the ncoadjuvants ifosfamidc, cisplatin, and ctoposide in patients with locally advanced NSCLC arc feasible to use and allow a 19 percent 3-year survival rete. These results arc the rationale of an ongoing randomized study comparing ncoadjuvant chcmothcrapy followed by surgery and surgery alone. This study is designed to test whether neoadjuvant chemotherapy improves survival of patienta with locally advanced NSCLC.

Dauaorubicin glycoprotein

efflur against multidtu~resiatant

a concentration lung-cancer

gradient cells

in non-P-

Mulder HS. Lankclma J, Dekker H, Broxtcrrnan HJ, Pincdo HM. Deparbmnf of Chxdogy Free Universiy Hospital, De BoeIelaon 1117,1081 HVAmsterdmm. Int J Cancer 1994;59:275-81, Multidrug-resistant, human non-small-cell lung carcinoma SW-1573/2Rl20 (ZRIZO) culls, not oontining the drug cfflux pump P-glycopmtcin (Pgp), have reduced initial daunorubicin (DN) accumulation rates and decreased cellular

12 (1995)

265-329

steady-state drug concentmtions. Previously we found indications of the presence of a plasma membrane ‘vacuum cleaner’, pumping DN directly from the membrane, and rcpmicd evidence of active DN pumping using digitonin. Further evidence of active DN pumping is now provided via a differcnt methodology and the active drug pump flux is cstimatcd. Cells were exposed to a flowing medium containing the cytotoxic agent DN. After rarching a steady state, in which net DN uptake equals net DN cfflux, high concentration pulses of vincristinc (VCR) were injected into the flowing medium. A rapid increase in cellular DN content was observed, while only a minimal effect was seen in SW-1573 wild-typz cells. Af?cr passage of the VCR pulse, the cxtm accumulated DN was etlluxed against .a concentration gradient. Upon increasing the VCR concentration, a maximum pump inhibition was reachcd which was similar to the effect of cellular cncrgy depletion. Similar effects were observed for Pgp containing SW-1573RR160 (2R160) cells as well as non-Pgp MDR human smallall lung carcinoma GLC4/ADR cells. With increasing extracellular DN ~~n~~ntrations, .sahtration of the VCR-induced DN influx was observed (DN medium conccntmtion 2.5 iM at % V(max). At an extmccllular DN con~tration of 5 iM, higher concentrations of VCR wcrc needed to reach the maximum effect in 2Rl20 cells than at 0.5 iM DN. This is an indication of corn@& interaction behvecn DN and VCR for the putative DN efflux system In summary, WC found indications of inhibition of active DN efflux by VCR and DN cfllux against a concentration gradient in non-Pgp MDR 2Rl20 and GLCX/ADR cells. These features are consistent with the presence of a multidrug transporter, different from Pgp, in the plasma mcmbmnc of these cells.

DT-diapborase as a determinaot of sensitivity to adriamycin in nonsmall-cell lung-cancer cell lines Kasshara K, Shibata K, Bsndo T, Numata Y, Fujimura M, Matsuda T. 3rd Deporbnmt ofInkmolMedicine, Konawwa Univ School ofMedicine, Tahwramachi 13-1, Kamumva 920. Int J Cancer 1994,59:204-7. WC have reported the establishment of a mitomycinC @4MC)resistant nonsmallccll lung-cancer cell line. PC-9h4C4. As dctermincd by an MTT assay, this resistant cell line was found to be 4 times more scnsitivc to adrismycin (ADM) than was the parental PC-9. There were no significant differences in sensitivity to ctoposidc, mitoxantronc, daunomycin, epirubicin, pirarubicin, 9aminoanthracyclinc or 3’-dcamino-3’-morpholino-l3-dcoxo-IO-hydroxy carminomycin. Thcsc data suggest that neither qualitative or quantitative changes in DNA topoisomcrase 11 nor the enhanced repair of DNA can explain the differing sensitivity to ADM obscrvcd. No significant differences were found in the accumulation of ADM and glut&one (GSH) in these ccl1 lines. Although total glutathione-S-transfcrasc (GST) activity in PC-9iMC4 cells was lower than that observed in PC-9 cells and treatment with cthacrynic acid (EA) reduced sensitivity to ADM in both cell lines, rclativc resistance was unaffcctcd. NADHcytochmmc b5 reductasc (B5R) activity in PG9h4C4 cells showed a 3-fold grcatcr decrease than that in PC-9 cells, and DTdiaphomsc (DTD) activity in PC-9M24 CCUSshowed an approximately 200-fold greater dccrcnse than that in PC-9 cells. Addition of dicumarol, an inhibitor of DTD, decreased the sensitivity of ADM of PC-9 but not of PC-9/MC4. DTD activity in the PC-9 ccl1 lim was inhibitcd by trabnent with dicumarol whii in PC-9MC4 it rcrnainxl unchanged. Thcac data suggest that DTdiiphorase is a dctcrminant of sensitivity to ADM in the 2 ccl1 lines.

Syocrgk

Cmcer:

actioo wltb octreotidc

A pht

and chemotherapy

in Small-Cell

Lung

r8udy

Soresi E, Invcrnizi G, B&i R, Liti A, Borghini U, Mantcllini PV Pncumology Deparbnen~, Niguardo Hqital. Milan. Internists 1994;2:183-5. Among the immunochcmical markers currently used to characterize ncumcndocrinc (NE) tumors ncumnc spccitic enolasc @SE) was shown to be useful for evaluating chemoscnsitivity of the hlmor and for monitoring the followup in patients with Small-Cell Lung Cancer (SCLC), a tumor expressing NE activation. Octrcotide (OCT), a long-acting somatostatin analoguc. showed promising results in the treatment of NE tumors. Accordingly, we have carried out a pilot shrdy for the trcatmcnt of SCTC combining OCT 500 mcg thrice daily for 7 days followed by CEVE chemotherapy on the 8th day. After completing twatment OCT 200 mcg thrice a day was continued until rccurrencc. At present the 24 patients recruited show II good tolerance to the therapy; responses obtained on the 20 cvrduablc patients have bum: 4 CR, 8 PR, 5 S, 3 P, totally similar to those obtained by conventional chemotherapy. The free-