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Randomized study with the pineal hormone melatonin versus supportive care alone in advanced nonsmall cell lung cancer resistant to a first-line chemotherapy containing cisplatin
Abstracts/Lung
147
Cancer 10 (1993) 123-150
lines, NCI-H69/P (small cell). COR-L23/P (large cell). pad MORlP (adeaocarcinoma), were grown in increasing wnceatrations of cisplatio over a period of 6-9 months. This resulted in the development of sublines. H69/CPR, L23/CPR, and MOR/CPR which were 3- to E-fold resistnnt to cisplatin as determined by P 6day 3-(4,5- dimethylthiazolZ-yl)-2,5diphenyltetrs?olium bromide zway. None of the resistam sublines showed P significant change in cellulu glutathione content or sensitivity tocadmiumcblori&(~indi~~rof~Uothi~eincoo~t), although changes in glutathiooe-S-transferwe activity were seen. The sublines each showed cross-resistance to melphalan. Cisplatin accumulation was unchaoged in H69/CPR. I.&fold reduced in L23/ CPR,snd2.0-foldrsducedioMOR/CPRcomptedwitbtheirnspective parent lines. In P pale1 of 10 small cell lung cancer cell lies. there was B 16-fold range of sensitivities to cisplatin. ‘Ilte panels have been used to examine cross- resistance between cisplatin, carboplatin. iproplatin, tetraplatin, sod P series of 10 novel ammine/amine dicarboxylate platinum(IV) compounds. Whereas H69/CPR pod MORlCPR showed little or no cross-resistance to my of the other compounds, L23lCPR was generally cross-resistant to all of them. In the panel of small cell lines, whereas the ranking of sensitivity to carboplatin and cisplatio were similar, each of the other compounds provided individual patterns ofsensitivity. Therealwaysa widenngeofsensitivities among the panel, ranging from S- toll-fold. Among thedicarboxylatecompounds, there was a great range of potencies, with two compounds (JM273 and JM274) being approximately 100-fold more pot& thao cisplatin. Study of NCC-m-439 in patiwts with lung cancer Shiota T, Matsukam Y, Ikeda S, Hetakenaka R, Fooittso T. Kyoro Kmura Hospital, Chest Dimme Centw, 17 Yawdahirao, Kyofo 615. Long Cancer (The Netherlands) 1992;8:203-12 NCC-ST-439 is a glycoprotein recognized by P moooclonal antibody (ST439) which is obtained by using P human gastric cancer xenograph, ST+ as ao immuoogen. Using P Law Enzyme Kit from Nippon Kay&u, we measwed the serum level of NCC-ST-439 in 223 patients with long cancer, 344 patientswith benign lung diseaseaand 97 healthy adults. When weadopted acut-off level of4.5 U/ml forwomeo aged 50 years or more sod for mea of any age, nod 7.0 U/ml for women aged less than 50, the ovendl positive rates were 22.0% for the lung cancer patients, 7.0% for p&i&s with benign long diseases sod 3.1% for the healthy adults. ‘Ibe positive rate of the lung cancer patients was significantly higher than for patients with benign hmg diseases (P < 0.05). Accordiig to the histological type of lung cancer, the positive rates were 34.3% for 105 patients with adenoarcinoma, 9.8% for 68 patients with squmow cell carcinoma, sod 16.7% for 6 patients with large fell carcinoma. Clpssificotion of the lung cancer patients revealed positive rates for swum NCC-ST-439 of 0% for 40 Stage I patients, 8.3% in 12 Stage II patients, 12.5% io 48 Stage IIIA patients, 37.0% in 46 Stage IIIB patients. and 33.3% in 45 Stage IV patients. After we performed immunostaining for NCC-ST-439 using ST-439, positive immunoactivity was demonstrated mainly in the membrane of adamcarcinoma cells. NCC-ST439 thus seems to be a tomor associated marker in patients with lung adenowcinoma. Randomized study with the pineal hormone melatonin versus supportivecarealoneinndvaneedno~leellllmg-re~istant to a fit-line chenotherppy containing cisplatin Lissoni P, Bami S, Ardizzoia A, Paolorossi F, Crispino S, Taocini G et al. Divisionedi Radiofempia, Ospedale S Germdo, I-2WS2 Monza. Gncology (Switzerland) 1992;49:3369. At present. there is no effective medical therapy io metestatic nonsmall cell (NSC) lung cancer patients who progressed under a firstline chemotherapy containing cisplatio. Since recent data have demonstratedtheantineoplpsticpropertiesandthelackoftoxicityofthe pineal hormone melatonin (MLT), a randomized study was designed to evaluate the influence of an MLT treatment (10 mg/day orally at 7.00 p.m.) on the survival time at 1 year from the progression under chemotherapy in respect to supportive care alone in a group of m&static NSClungcancerpatient~~ whodidnotrespoodtoafirst-linechemotherapy containing cisplatin. The study includes 63 consecutive metestatic NSC lung cancer patients, who were randomized to receive MLT (n = 3 I) or
supportive care alone (n = 32). The percentage of both stabilizations of disease and survival at 1 yearwas significantly higher in patients treated with MLT than in those treated only with supportive care. No dmgrelated toxicity was seen in patients treated with MLT, who, on tbe contrary, showed P significant improvement in performance status. This randomiredshdyshowsthstthepineslbormooeMLTmaybesuccessfully administered to prolong the survival time in mete&tic NSC long caocer patients who progressed under P first-line chemotherapy with cisplatin, for whom no other effective therapy is available up to now. Random&d
phase U triaI of High-Dose 4’-Etd-Doxorubicin +
K&tzE, Kc&c K, J&mJ. M&l Z, Pawlicki M, Ringwal~G et al. National Irwtitute of Oncology, Rath Gyorgy u 7-9, H 1122 B&pm. Oncology (Switzerland) 1992;49:32732. One hundred and eleven previously untreated patients with ex(ensivesmpllcdlIungcpocerwaeinciudedinapmspectiverPndomitad study with the aim to asseas tbe efficacy and tolerance of bigbdose epirubicin (120 mgln?) in combiiation with either cyclophosphamide (800 mgld; arm 1) or cisplptin (60 mg/ m’: arm 2). Ninety-six patients were evahmble for response and toxicity and edditiooal 12 patients for toxicity only. Theoverall resporwrate (CR + PR) inann 1 and Zwere 61.4 (27144) and 67.3% (35152). respectively. The own duration of remission was 4.4 months (arm I) and 4.9 months (arm 2). The survival time was 6.6 months in ano 1 and 7.7 months in arm 2. WHO grade 4 toxicity was encountered in 25.5 and 15.8% of patients in arm 1 and 2, respectively. One case of cardiotoxicity resulting in the patient’s death was observed io arm 1. Both combinations showed considerable antitumor activity. Toxicity was acceptable. Fhase II study of &h-dme epirubicia and etoposide in advanced noll-slmu cell IuqJ Smit EF, Piers DA, Postmos PE. Drpamnenr of Puhtmmy Direare, University Hospiral. Free Univemify, De B&e&an 1117, 1007 MB Amteti. Eur J Cancer Part A Gee Top 1992;28: 1965-7. 25 coosecutive patients with advanced non-small cell lung c~ncer(NSCLC)wcretreotcdwithbighd~epirubicia(HDE) 135mg/ mZ nod etoposide 60 tug/m2 (days l-3) every 3 we&s. 121 courses, (median 6, range l-7). were administered and evaluable for toxicity: WHO grades III/IV leukocytopenin in 60136 (80%) courses, thmmbocytopenin in 1816 (20%) and gradea Ill111 anaemia in 31/6 (31%). Median (moge) left ventricular ejection fraction (LVEF) fell from 63% (53-73, n = 25) to 60% (48-73, n = 16) after 5 courses (P < 0.02). 2 patients had P drop of more thao 15 56 in LVEF with an epimbicin doseof mglm’. Apartfmm 1 patient who had tachycardia 6 months after the last course, no patient had congestive heart failure. Therewere2completesnd7partisl~spoases[totpI9/25(36%,95% confidence interval: 18-57.5%)]. Mediao survival is 31.8 (4.3-75) weeks. Combiiion HDE and etoposide in NSCLC offers no advantage over HDE alone sad is more toxic.
Radiotherapy
GmhamMV,GeitzLM,ByhardtR,AsbeUS,RoschMIII,UrtasunRC et al. Radiation Oncology Center, Washington Univ. Sdwolofbfcdicine. 4939Audubon.St.Louis, M063110. JNatICancerInst 1992;84:17315. Backgmund: Many stodies have sported differences in caocer incidence and survival between populations of Blacks end Whites. A 45 % higher death rate fmm loog cancer for BIack men sod a survival duration for Black p&ads with lung cancer that is generally shelter than that for White @as have also beat report& Purpose: Tile purpose of this study was to evallute whether race affects known prognostic factors for aoa-smrdIsslI lung cancer in Black versus White patients. This analysis attempts to de&mine which prognostic factors
147
Cancer 10 (1993) 123-150
lines, NCI-H69/P (small cell). COR-L23/P (large cell). pad MORlP (adeaocarcinoma), were grown in increasing wnceatrations of cisplatio over a period of 6-9 months. This resulted in the development of sublines. H69/CPR, L23/CPR, and MOR/CPR which were 3- to E-fold resistnnt to cisplatin as determined by P 6day 3-(4,5- dimethylthiazolZ-yl)-2,5diphenyltetrs?olium bromide zway. None of the resistam sublines showed P significant change in cellulu glutathione content or sensitivity tocadmiumcblori&(~indi~~rof~Uothi~eincoo~t), although changes in glutathiooe-S-transferwe activity were seen. The sublines each showed cross-resistance to melphalan. Cisplatin accumulation was unchaoged in H69/CPR. I.&fold reduced in L23/ CPR,snd2.0-foldrsducedioMOR/CPRcomptedwitbtheirnspective parent lines. In P pale1 of 10 small cell lung cancer cell lies. there was B 16-fold range of sensitivities to cisplatin. ‘Ilte panels have been used to examine cross- resistance between cisplatin, carboplatin. iproplatin, tetraplatin, sod P series of 10 novel ammine/amine dicarboxylate platinum(IV) compounds. Whereas H69/CPR pod MORlCPR showed little or no cross-resistance to my of the other compounds, L23lCPR was generally cross-resistant to all of them. In the panel of small cell lines, whereas the ranking of sensitivity to carboplatin and cisplatio were similar, each of the other compounds provided individual patterns ofsensitivity. Therealwaysa widenngeofsensitivities among the panel, ranging from S- toll-fold. Among thedicarboxylatecompounds, there was a great range of potencies, with two compounds (JM273 and JM274) being approximately 100-fold more pot& thao cisplatin. Study of NCC-m-439 in patiwts with lung cancer Shiota T, Matsukam Y, Ikeda S, Hetakenaka R, Fooittso T. Kyoro Kmura Hospital, Chest Dimme Centw, 17 Yawdahirao, Kyofo 615. Long Cancer (The Netherlands) 1992;8:203-12 NCC-ST-439 is a glycoprotein recognized by P moooclonal antibody (ST439) which is obtained by using P human gastric cancer xenograph, ST+ as ao immuoogen. Using P Law Enzyme Kit from Nippon Kay&u, we measwed the serum level of NCC-ST-439 in 223 patients with long cancer, 344 patientswith benign lung diseaseaand 97 healthy adults. When weadopted acut-off level of4.5 U/ml forwomeo aged 50 years or more sod for mea of any age, nod 7.0 U/ml for women aged less than 50, the ovendl positive rates were 22.0% for the lung cancer patients, 7.0% for p&i&s with benign long diseases sod 3.1% for the healthy adults. ‘Ibe positive rate of the lung cancer patients was significantly higher than for patients with benign hmg diseases (P < 0.05). Accordiig to the histological type of lung cancer, the positive rates were 34.3% for 105 patients with adenoarcinoma, 9.8% for 68 patients with squmow cell carcinoma, sod 16.7% for 6 patients with large fell carcinoma. Clpssificotion of the lung cancer patients revealed positive rates for swum NCC-ST-439 of 0% for 40 Stage I patients, 8.3% in 12 Stage II patients, 12.5% io 48 Stage IIIA patients, 37.0% in 46 Stage IIIB patients. and 33.3% in 45 Stage IV patients. After we performed immunostaining for NCC-ST-439 using ST-439, positive immunoactivity was demonstrated mainly in the membrane of adamcarcinoma cells. NCC-ST439 thus seems to be a tomor associated marker in patients with lung adenowcinoma. Randomized study with the pineal hormone melatonin versus supportivecarealoneinndvaneedno~leellllmg-re~istant to a fit-line chenotherppy containing cisplatin Lissoni P, Bami S, Ardizzoia A, Paolorossi F, Crispino S, Taocini G et al. Divisionedi Radiofempia, Ospedale S Germdo, I-2WS2 Monza. Gncology (Switzerland) 1992;49:3369. At present. there is no effective medical therapy io metestatic nonsmall cell (NSC) lung cancer patients who progressed under a firstline chemotherapy containing cisplatio. Since recent data have demonstratedtheantineoplpsticpropertiesandthelackoftoxicityofthe pineal hormone melatonin (MLT), a randomized study was designed to evaluate the influence of an MLT treatment (10 mg/day orally at 7.00 p.m.) on the survival time at 1 year from the progression under chemotherapy in respect to supportive care alone in a group of m&static NSClungcancerpatient~~ whodidnotrespoodtoafirst-linechemotherapy containing cisplatin. The study includes 63 consecutive metestatic NSC lung cancer patients, who were randomized to receive MLT (n = 3 I) or
supportive care alone (n = 32). The percentage of both stabilizations of disease and survival at 1 yearwas significantly higher in patients treated with MLT than in those treated only with supportive care. No dmgrelated toxicity was seen in patients treated with MLT, who, on tbe contrary, showed P significant improvement in performance status. This randomiredshdyshowsthstthepineslbormooeMLTmaybesuccessfully administered to prolong the survival time in mete&tic NSC long caocer patients who progressed under P first-line chemotherapy with cisplatin, for whom no other effective therapy is available up to now. Random&d
phase U triaI of High-Dose 4’-Etd-Doxorubicin +
K&tzE, Kc&c K, J&mJ. M&l Z, Pawlicki M, Ringwal~G et al. National Irwtitute of Oncology, Rath Gyorgy u 7-9, H 1122 B&pm. Oncology (Switzerland) 1992;49:32732. One hundred and eleven previously untreated patients with ex(ensivesmpllcdlIungcpocerwaeinciudedinapmspectiverPndomitad study with the aim to asseas tbe efficacy and tolerance of bigbdose epirubicin (120 mgln?) in combiiation with either cyclophosphamide (800 mgld; arm 1) or cisplptin (60 mg/ m’: arm 2). Ninety-six patients were evahmble for response and toxicity and edditiooal 12 patients for toxicity only. Theoverall resporwrate (CR + PR) inann 1 and Zwere 61.4 (27144) and 67.3% (35152). respectively. The own duration of remission was 4.4 months (arm I) and 4.9 months (arm 2). The survival time was 6.6 months in ano 1 and 7.7 months in arm 2. WHO grade 4 toxicity was encountered in 25.5 and 15.8% of patients in arm 1 and 2, respectively. One case of cardiotoxicity resulting in the patient’s death was observed io arm 1. Both combinations showed considerable antitumor activity. Toxicity was acceptable. Fhase II study of &h-dme epirubicia and etoposide in advanced noll-slmu cell IuqJ Smit EF, Piers DA, Postmos PE. Drpamnenr of Puhtmmy Direare, University Hospiral. Free Univemify, De B&e&an 1117, 1007 MB Amteti. Eur J Cancer Part A Gee Top 1992;28: 1965-7. 25 coosecutive patients with advanced non-small cell lung c~ncer(NSCLC)wcretreotcdwithbighd~epirubicia(HDE) 135mg/ mZ nod etoposide 60 tug/m2 (days l-3) every 3 we&s. 121 courses, (median 6, range l-7). were administered and evaluable for toxicity: WHO grades III/IV leukocytopenin in 60136 (80%) courses, thmmbocytopenin in 1816 (20%) and gradea Ill111 anaemia in 31/6 (31%). Median (moge) left ventricular ejection fraction (LVEF) fell from 63% (53-73, n = 25) to 60% (48-73, n = 16) after 5 courses (P < 0.02). 2 patients had P drop of more thao 15 56 in LVEF with an epimbicin doseof mglm’. Apartfmm 1 patient who had tachycardia 6 months after the last course, no patient had congestive heart failure. Therewere2completesnd7partisl~spoases[totpI9/25(36%,95% confidence interval: 18-57.5%)]. Mediao survival is 31.8 (4.3-75) weeks. Combiiion HDE and etoposide in NSCLC offers no advantage over HDE alone sad is more toxic.
Radiotherapy
GmhamMV,GeitzLM,ByhardtR,AsbeUS,RoschMIII,UrtasunRC et al. Radiation Oncology Center, Washington Univ. Sdwolofbfcdicine. 4939Audubon.St.Louis, M063110. JNatICancerInst 1992;84:17315. Backgmund: Many stodies have sported differences in caocer incidence and survival between populations of Blacks end Whites. A 45 % higher death rate fmm loog cancer for BIack men sod a survival duration for Black p&ads with lung cancer that is generally shelter than that for White @as have also beat report& Purpose: Tile purpose of this study was to evallute whether race affects known prognostic factors for aoa-smrdIsslI lung cancer in Black versus White patients. This analysis attempts to de&mine which prognostic factors