Pilot study with cisplatin, ifosfamide, and etoposide in advanced non-small-cell lung carcinoma

275

4’-Epi-doxorubicin

in advanced

lung cancer.

A phase II trial

Giaccone G. Donadto M, Bonardi G, Iberti V, Calciati A. Division of Medical Oncology. Ospedale S. Giovanni. A.S., Torino. Invesl New Dregs 1990;8:393-6. Fifty evaluable patients with advanced lung cancer (28 small cell and 22 non-small cell carcinomas), mainly preueated by chemotherapy, received 4’-epi-doxorubicin 90 mg/m’ every 3 weeks. Two partial responses were obtamed in small cell lung cancer patients, which lasted 153 and 168 days, Leukopenia, emesis and alopecia were the most frequent side effects. Two patients who previously received anthracyclines died suddenly of cardiac failure, another patient had severe congestive heart failure, and four others had minor cardiac dysfunctions. 4’-Epi-doxornbicin has a modest activity in advanced lung cancer, mainly preueated by chemotherapy and is not devoid of significant cardiotoxicity in this patient population.

for advanced lung carcinoma Focan C, Bastens B, Driesschaert P et al. CIinrque St-Josph-SteElisaberh. Liege. Anna Rev Chronopharmacol 1990;7:219-22. The authors reported on the clinical toxicity of a randomized chemotherapy uial admimstering etoposide (100 mg/m2,days 1 + 2 + 3) given eitheratham (A)orat6pm (B)andcisplatin lOOmg/m2at6pmon day 4. Thts chemotherapy protocol was administered to previously unueated patients suffering from an advanced lung cancer. Despite some differences among both groups (less severe nausea-vomiting, less otoloxicity and less dose reductions in group B. but more severe alopecta in this group - p < 0.006-0.045). no difference in overall dose intensities could be detected wtth regard to the time scheduled chemotherapy. Relationshipsamongtumorresponsiveness,cellsensitivity,doxorobicin cellular

pharmacokinetics

and drug-induced

DNA

alterations

lung cancer xenografls Pratesi G, Capranico G, Binaschi M et al. Division of Expermenra/ Oncology B. lsritulo Nazionale per lo Studio e la Cura dei Tumori, Via Venerian I, 20133 Milan. Int J Cancer 1990:46:669-74. In an altempl lo understand the underlymg cellular/biochemical factors of sensitivity/resistance m human small-cell lung cancer (SCLC), 2 SCLC tumor lines were compared with respect to tumor responsiveness lo drug treatment, cell sensitivity, cellulardoxorubicin accumulation, and DNA topoisomerase-B-mediated DNA cleavage. The tumor lmes growing in nude mice with similar growth characteristics (doubling time around IO days) were selected since one (POCI tumor) was found to be hypersensitive and the other (FOSG tumor) resistant to doxorubicin treatment. The pattern of anti-tumor drug response of the doxotubtcm-resistant mmorwasatypical (i.e.,non-adherent to the wellcharacterized multi-drug-resistant phenotype), since it responded to vincristine. The markedly different in vtvo tumor response reflected the Intrinsic cellular sensitivity to doxorubicin. No correlation was found belweencellulardrugaccumulation anddoxorubicinsensitivtty following in viuo exposure to thedrug. In agreement with this observation, the expression of mdr-I gene was undetectable in dtese tumors. Thus, in the PGSG tumor. resistance to doxorubtcm occurred without expression of the P-glycoprotein and reduction of cellular drug accumulation. In conuast. the extent of DNA cleavage produced by doxorubicin was markedly higher in the doxorubicin-hypcrsensittve than in the doxortbicin-resistant lumor. These results, taken together with previousobservalions in SCLC cell lines, support the important role of DNA topoisomerase-mediated effects in the sensitivity of SCLC to doxornbicm. in two human

small-cell

Cyclophosphamide chemotherapy meta-analytic

for

and locally

ifosfamide advanced

combination

as neoadjuvaot

nonsmall-cell

lung cancer:

A

review

Rose11R, Moreno I, Maesue J et al. Deparrmenr of Oncology. Hospital de Badalona. Germans Trios i Pujol. Box 72.08916 Badalona. Barcelona. J Surg Gncol 1990;45: 124-30. Twenty-three patients with margmally resectable and unresectable non-small-cell lung cancer (stages IIIA and IIIB) were treated by neoadjuvant chemotherapy. All patients received three cyclesofpreopcrativc chemotherapy with two alkylating agents, cyclophosphamide 2.5 g/m2 muavenously (I.v.) and ifosfamide 3.5 p/m’ iv., mesna 12 9/

mz was given addittonally to prevent drug hcmaturia. Six of 23 patients (26%) had partial response. Of the seven patients who underwent thoracotomy, lwo were completely resected, but with macroscopic residual disease. Mean time to progression for the whole group was 7 months. Fifteen patients had progression of disease, with local metastams only in SIX,and distant metasmses in eight. After administering 52 chemotherapy cycles, cyclophosphamide-ifosfamide doses were cut down. as eight of 16 patients required hospitalizstion for fever durmg neutropenia nadirs. This two-alkylating (non-cisplatm) regimen, unltke cisplatin-based regimens, was ineffective, and further trials are not recommended Carboplatin small-cell

in combination lung cancer

with

etoposide

in inoperable

non-

(NSCLC)

Weynants P, Humblet Y, Bosly A et al. UCL CIlnrcal Oncology Group. Cliniques UniversitairesSr. Luc, IOAvenueHippocrale, IZOOBrussels. Med Oncol Tumor Pharmacother 1990:7:219-22. Carboplatin, a second generation platinum complex, is less nephrotoxic and emetogenic than its parent compound. We have tested the objective response to and the toxicity of the combination carboplatm 330 mg m 2 on day 1 with etoposide 120 mg m-z on days I,3 and 5, administered every 3 weeks in histologically proven inoperable nonsmall-cell lung cancer (NSCLC) patients with a good performance status. Thirty-one patients entered the study; 29 were evalttable for response, 24 after 3 courses and 5 after 2 courses of chemodterapy. An overall response rate of 21% was found including zero complete response and 6 partial responses, In addition, 3 minor responses (IO%), 12 stable diseases (38%). and 9 progressive diseases (39%) were observed. The median survival was 48 weeks, including 68 weeks for non-metastatic (MO) patients and 27 weeks for metastatic (M+) patients. This regimen was well tolerated. Gasuointestinal toxicity never exceeded WHO grade II and renal function remained in the normal range for all cases. Haematological toxicity was low m the majority of the cases; nevertheless it proved to be the dose limiting toxicity as illustrated by two grade III anemia, one grade III leucopenia, one grade 111and one grade IV duombocytopcnia. Carboplatm-etoposide combination is not more active, but clearly much less toxic than cisplatinetoposide in NSCLC. Phaselstadyofacivicinandcisplatin A National

Cancer

Institute

innon-small-celllungcancer: of Canada

study

Maroun JA, Stewart DJ, Verma S, Evans WK. Eisenhauer E. Orlawa Regional Cancer Cenfre General Hospilal Division, SO1 Smyrh Road. Omva. Onr.,KlHRL6. Am JClin GncolCanccrClin Trials 1990;13:4014. Seventeen previously unueated patients with metastalic non-smallcell lung cancer were entered in this phase I uial. Treatment consisted of acombinatton ofacivicin andcisplatinata starting dose of I2 and 15 mg/m’, respectively, given iv. during 5 days and repeated every 28 days. A lotalof46cycles wasgiven. Renal functionabnormality wasthe dose-limiting toxicity of cisplaun with a maximum tolerated dose of 12 mg/m’. This toxicity occurred at a dose lower than expected, indicating a possible potentiation of platinum renal toxicity by acivicin. Myelosuppression was thedoselimiting toxicity of acrvicin. with a maximum tolerated dose of 12 mgfm’. Other side effects included generalized weakness and gasuointeslinal and neurological symptoms. In I5 patients evaluable for response seven progressed, six were stable for a median duration of 13 weeks, and two patients achieved a partral remission lasting 8 and 24 weeks, respectively. The overall response rate was 13%. The recommended phase II dose of both agents in this schedule was 12 mg/m2. The possible enhancement of cisplatm toxicity might have compromised the overall response rate of the combination and further studies using these drugs m this schedule are not recommended. Pilot

study

non-small-cell

with

cisplatia,

ifosfamide,

and etoposide

in advanced

lung carcinoma

Bidoli P, Spinazze S, Santoro A, Casali P, Bedini AV, Guzzon A. Division of Medical Oncology. Isrituto Nazionale Tumori. Via Venezian. J 20133 Milan. Am J Clm Oncol Cancer Clin Trials 1990: 13:424-6. Twenty-five patients with advanced non-small-cell lung carcmoma

216

(NSCLC) were treated with a multidrug regimen (CIV) consistingof ifosfamide (IFX), cisplatin (CDDP), and etoposide(VP-16). Twentyfour patients were evaluable for response. An objective responsewas detected in eight cases(33%). including one case with complete tumor response. Median duralion of response.was 31 weeks, and median overall survival 46 weeks, with no signtficartl difference between respondersand nonresponders.Myelosuppressionand gastrointestinal side effects represented themain toxic manifestations;a toxic death and an ischemiccardiac episode were also observed. CIV seemsa moderately effective regimen in NSCLC, but unlikely to providean advantage over the widely employed two-drug combinationof CDDP and VP-16. Establishment of a camptothecin analogue (CPT-II)-resistant cell line of human non-small cell lung cancer: Characterization and mechanism of resistance Kanrawa F, Sugimoto Y, Minato K et al. Pharmacology Division. Nofional Cancer Center Research Insfitute, S-Chom, Tsukiji, Chuoku. Tokyo 104. Cancer Res 1990;50:5919-24. Camptothecin-1 1 (CPT-I 1) is a new derivative of camptothecin, a plant alkaloid antitumor agent, and a good candidate for clinical trials because of higher antitumor activity, less toxicity, and high aqueous solubility.CPT-11 is knowntobealtered intoanactiveform, SN-38, by esterasein vivo. CPT-1 l-resistant cells (PC-7/CpT) establishedfrom a human non-small cell lung cancer cell (PC-7) by stepwise.continuous treatmentwithCPT-I 1 exhibit about a IO-fold increasein resistanceto the drug. CPT-1 l-resistant cells show a moderate cross-resistanceto camptothecin(x 8.6) and SN-38 (x 8.6). and weak cross-resistanceto adriamycin (x 2.2) and 5-fluorouracil (x 2.4). The comparative studies between tlte parent (PC-7) and resistant (PC-7/CPT) cell lines with respect to their growth characterization show a longer cell doubling time (45.8 versus35.5 h), a lower cloning efficiency (3.2 versus7.1%), and a lower population of S-phasecells (26.4 versus36.0%) in the CPT11-resistantcells. This observationmay partly explain the resistanceLO CPT-1 I, a drug whose activity is cell cycle specific. Accumulation of CPT-11 is nearly the same in both cell lines. However, the intracellular concentrationof SN-38 formed in the parent cells was 2-fold greater than in the CPT- 1l-resistant cells. This alteration may affect to some extent to the resistance.As assayedby relaxattonof supercoiledplasmid DNA, the total activity of DNA topoisomerascI from the CPT-1 lresistant cells was shown to be reduced to onc-fourth its level in sensitive cells. The reduced activity was caused by a reduction of amount of DNA topoisomeraseI. Furthermore, the enzyme from the resistantcells was shown to be 5-fold more resistanttoCPT-11 than the enzyme from the parent cells. Thus, decreased total activity of topoisomeraseI may play an importantrole in cellular resistanceIOCPT-11, and it appears that this decreased activity is due to a resistantform of topoisomeraseI in CPT- 11reststan cells. Drug delivery strategies in malignant disease of the lung Royal College, Universiry of Willmott N. Deparrmenr ofPharmacy, Stmhclyde, Glasgow Gl IXW. Adv Drug Deliv Rev 1990;5:133-48. There is an unmet need for innovative approachesto the treatment of solid lung tumours (both primary and memstatic). Strategies are reviewed that have attempted to address this problem by optimising the localisation and activity of active agents in soluble, liposomal and microspherical form in the lung. Attention is drawn to the biological constraintsthat mustbe faced before rational strategiescan be devised. Microspherical systems suitable for emboltsation (diameter greater than 10 pm) offer most efficient localisation and retention in the lung vasculature:subsequentevents relevant to relocation of active agents incorporatedin microspheresfrom vasculatureto tumour tissueare also considered. Phase II study of 5day continuous infusion Of CiSdiamminedicbloroplatinum(11) in the treatment of non-small-cell lung cancer Saito Y. Mori K, Tominaga K, Yokoi K, Miyazawa N. Division of Thoraric Disease, Tochigi Cancer Cenrer, d-9-13. Yohnm. lilsummiyaciry 320. Cancer Chemother Pharmacol 1990;26:389-92.

Cis-diamminedichloroplatinum(Il) (CDDP) was given as a single agent at a dose of 25 mg/m* daily for 5 days by continuousinfusion; treatment was repeated every 4 weeks in 30 previously untreated patients with advanced non-small-cell lung cancer (NSCLC). The median age of the patientswas 61 years; 13 patientshad limited disease and 17. extensive disease. The overall responserate was 40% (l2/3O; 95% conlidence limits, 23-58%). with a median survival of 8 months. Vomiting was observed in 37% of patients;elevated serum creatinine levels (> I.5 mg/dl), in 7%; leukopenia (< 3,000/mm3), in 39%; thrombocytopenia(< 70,OOO/mm’),in 26%; and anemia (hemoglobin< 9.5 g/dl), in 60% of patients.In all cases, these toxicities were mild and transient, requiring no dose modification. The exposure to filterable platinum, determinedfrom the area under the concentration-timecurve, was 9.08 f 3.21 pg h ml-‘. We conclude that CDDP given by 5-&y continuousi.v. infusion is safe and effective for treatment of NSCLC. Phase II study of (glycolate-0.0’) diammineplatinum(II), a novel platinum complex, in the treatment of non-small-cell lung cancer F&da M, Shinkai T, Eguchi K et al. Deparmenr ofInferno Medicine. National Cancer Center Hospifal. l-l. Tsukij 5-chome. Chuo-ku, Tokyo 104. Cancer Chemother Pharmacol 1990;26:393-6. A total of 68 patientswith non-small-cell lung cancer who either had not previously been treated (38) or had undergone prior therapy (30) were treatedin a phaseII studyof (glycolate-0,O’) diammineplatinumt.lI) (NSC 375 lOID; 254-S). a new platinum complex. The drug was given as a single intravenousinfusion at a dose of 100 mglmlevery 4 weeks. All 68 patients could be evaluated for responseand 62, for toxicity. Objective responseswere seen in 10 of 68 cases (14.7%; 95% conftdence interval, 7.3%-25.4%). and the median durationof responsewas 15 weeks (range, 8-23 weeks). The response rates were similar for previously untreatedand treated patients(13% and 17%. respectively), including three previously treated wtth cisplatin. Myelosuppression wasthedose-limitingtoxicity.Thrombocytopenia(~ 100,OOOplate1ets/ mm’) and leukocytopenia (< 3,ooO WBC/mmr) were observed in 22 (35%)and 18(29%)patients,respectively. Mildtomoderatenauseaand vomiting occurred in 45 cases(73%). No significant renal or neuroloxicily was observed. We conclude that as a single agent, 254-S is well tolerated but appears to have marginal acttvity against non-small-cell lung cancer. Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer: A phase II trial JohnsonDH, Greco FA, Strupp J, Hande KR, Hainsworth JD. Vanderbilt Clinic. Nashville, TN 37232-5536. J Clin Oncol 1990;8:1613-17. Twenty-two patients with recurrent small-cell lung cancer (SCLC) were trealed with single-agentetoposide 50 mg/m’/d by mouth for 21 consecutivedays. Eleven patientshad received previouschemotherapy with cyclophosphamide,doxorubicin. and vincristine (CAV) or etoposide (CAE) or both (CAVE). Four of the latter patientsalso received salvage treatment with cisplatin and etoposide(EP). Nine patients had been treated with EP as induction therapy, while two patients had receivedhigh-dosecyclophosphamide. etoposideand cisplatin(HDCPP). Altogether, I8 patients had received previous intravenousetoposide. The median time off chemotherapy was 4.5 months (range, 1 to 28.9 months). Ten patients (45.5%; 95% confidence Interval [CII, 27% to 65%) achieved a complete or partial response.Responseswere most common in patientswho had respondedto previous chemotherapyand who had not received any treatment in the 90 days before initiation of oral etoposide.Median responseduration was 4 months(range. 1.5 10 9.5 months) and median survival was 3.5+ months (range, 1.0 to 15+ months).Leukocyte and platelet nadirs were 1,8OO/uLand l6O,OOO/pL, respectively.duringcycle 1 of treatment and occurred between days 21 and 28. Overall, total leukocyte count decreasedto less than 1.OOO/pL during lOof56cycles(18%). Fivepatientsrequiredsix hospitalizations for neutropeniaand fever. There were two toxic deaths due to sepsis. Platelet counts less than 5O,ooO/pL occurred in 14 cycles (25%). Alopecia developedin all patients:gastrointestinaltoxicity was uncommon. This scheduleof etoposideadministrationwarrants further study in combinationwith other active agentsin previously untreatedpatients with SCLC.