Transcriptional CCND1 expression as a predictor of poor response to neoadjuvant chemotherapy with trastuzumab in HER2-positive/ER-positive breast cancer.

Several trials have confirmed that the pathological complete response (pCR) rates after neoadjuvant chemotherapy (NAC) are significantly lower in HER2-positive/ER-positive patients than in HER2-positive/ER-negative patients. To understand this phenomenon, we investigated the association between NAC resistance and CCND1, which is frequently overexpressed in ER-positive tumors. Pretreatment formalin-fixed tumor tissues were collected from 75 HER2-positive patients receiving NAC comprised anthracyclines, taxanes, and trastuzumab. Seventeen gene transcripts along with PIK3CA mutations were detected using MassARRAY (Sequenom, San Diego, CA). The gene expression levels were dichotomized according to the median values. The immunohistochemical expression of ER, PTEN, BCL-2, and cyclin D1 was scored. The relationship between the variables was assessed using the Spearman correlation. A logistic regression analysis was performed to detect predictors of pCR, which was defined as no invasive tumor in the breast or axilla. Forty-seven percent of the cases were ER-positive and 52 % (40/63 % in ER-positive/ER-negative) achieved a pCR. Among the ER-positive patients, the CCND1 gene expression level was 2.1 times higher than that in ER-negative patients and was significantly correlated with the expression of cyclin D1 protein. In a univariate analysis, a pCR was associated with high mRNA levels of ESR1, PGR, LMTK3, HER2, IGF1R, INPP4B, PDL-1, BCL-2, and CCND1 (P ≤ 0.05). In contrast, none of these genes were significantly correlated with a pCR among the ER-negative tumors and only EGFR was significantly correlated with a pCR. PIK3CA mutations or PTEN loss were not associated with a pCR in either group. After excluding ESR1 (r = 0.58), PGR (r = 0.64), and IGF1R (r = 0.59), the expressions of which were correlated with CCND1, a multivariate analysis revealed that CCND1 [P = 0.043; OR, 0.16] and HER2 [P = 0.012; OR, 11.2] retained its predictive value for pCR among ER-positive patients, but not among ER-negative patients. A High Level of CCND1 gene expression is a poor predictor of a pCR and provides a rationale for evaluating CDK4/6 inhibitors in HER2-positive/ER-positive breast cancer patients.

A randomised, placebo-controlled, double-blind study of aprepitant in nondrinking women younger than 70 years receiving moderately emetogenic chemotherapy.

BACKGROUND: We evaluated the efficacy of aprepitant plus granisetron and an increased dose of dexamethasone in selected patients undergoing moderately emetogenic chemotherapy (MEC). METHODS: Nondrinking women <70 years undergoing MEC were randomly assigned to aprepitant (day 1, 125 mg; days 2 and 3, 80 mg) or placebo. Dexamethasone on days 1-3 was 12, 4, and 4 mg with aprepitant and 20, 8, and 8 mg with placebo. The primary end point was complete response (CR; no emesis or rescue therapy) during 120 h of the first cycle. Logistic regression analysis was performed to identify predictors of overall CR. RESULTS: Of the 94 patients enrolled, 91 were assessable. Most received carboplatin-based chemotherapy. In the aprepitant (n=45) and placebo (n=46) groups, the overall, acute (day 1), and delayed (days 2-5) CR rates were 62% and 52%, 98% and 96%, and 62% and 52%, respectively. Although not statistically significant, the overall CR rate was 10% higher in the aprepitant group. Both regimens were well tolerated. On multivariate analysis, advanced ovarian cancer (OR, 0.26 (0.10-0.72)) was independently associated with a lower CR. CONCLUSION: Even with an increased dose of dexamethasone, aprepitant seemed more effective than placebo in these selected patients undergoing MEC; however, delayed phase management remains a significant problem.

Phase III trial of docetaxel plus gemcitabine versus docetaxel in second-line treatment for non-small-cell lung cancer: results of a Japan Clinical Oncology Group trial (JCOG0104).

BACKGROUND: This trial evaluated whether a combination of docetaxel and gemcitabine provides better survival than docetaxel alone in patients with previously treated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligibility included pathologically or cytologically proven NSCLC, failure of one platinum-based regimen, performance status of zero or one, 20-75 years old, and adequate organ function. Patients received docetaxel 60 mg/m(2) (day 1) or docetaxel 60 mg/m(2) (day 8) and gemcitabine 800 mg/m(2) (days 1 and 8), both administered every 21 days until disease progression. RESULTS: Sixty-five patients participated in each arm. This trial was terminated early due to an unexpected high incidence of interstitial lung disease (ILD) and three treatment-related deaths due to ILD in the combination arm. Docetaxel plus gemcitabine compared with docetaxel-alone patients experienced similar grade and incidence of toxicity, except for ILD. No baseline factor was identified for predicting ILD. Median survival times were 10.3 and 10.1 months (one-sided P = 0.36) for docetaxel plus gemcitabine and docetaxel arms, respectively. CONCLUSION: Docetaxel alone is still the standard second-line treatment for NSCLC. The incidence of ILD is higher for docetaxel combined with gemcitabine than for docetaxel alone in patients with previously treated NSCLC.

Quality of life and disease-related symptoms in previously treated Japanese patients with non-small-cell lung cancer: results of a randomized phase III study (V-15-32) of gefitinib versus docetaxel.

BACKGROUND: This report describes quality of life (QoL) findings of a randomized study comparing gefitinib with docetaxel in patients with advanced/metastatic pretreated non-small-cell lung cancer. PATIENTS AND METHODS: This open-label, phase III study randomized 490 Japanese patients to gefitinib (250 mg/day) or docetaxel (60 mg/m(2)/3 weeks), with survival as the primary outcome. Preplanned QoL analyses included Functional Assessment of Cancer Therapy-Lung (FACT-L), Trial Outcome Index (TOI) and Lung Cancer Subscale (LCS) improvement rates, and mean change from baseline. RESULTS: Gefitinib showed statistically significant benefits over docetaxel in QoL improvement rates (FACT-L 23% versus 14%, P = 0.023; TOI 21% versus 9%, P = 0.002) and mean change from baseline score [mean treatment difference: FACT-L 3.72 points, 95% confidence interval (CI) 0.55-6.89, P = 0.022; TOI 4.31 points, 95% CI 2.13-6.49, P < 0.001], although differences did not meet the clinically relevant six-point change. There were no significant differences between treatments in LCS improvement rates (23% versus 20%, P = 0.562) or mean change from baseline score (0.63 points, 95% CI -0.07 to 1.34, P = 0.077). CONCLUSIONS: Gefitinib improved aspects of QoL over docetaxel, with superior objective response rate and a more favorable tolerability profile and no statistically significant difference in overall survival (although noninferiority was not statistically proven).

Expression of novel interleukin 2 binding molecules and their functional roles in human B cell differentiation.

Expressions and functional roles of novel IL-2 binding molecules (p70, 75) in the differentiation of B cells into Ig secreting cells were explored by using human several B cell lines and tonsillar B cells. Affinity-crosslinking studies revealed that five of nine B cell lines expressed p70 and p75 without detectable Tac antigen (p55) expression and the expression was associated with B cell maturation. In tonsillar B cells, small high-density B cells did not express p70 and p75, whereas large low-density B cells, which were thought to be activated in vivo, expressed them. Binding assays of radiolabeled IL-2 showed that the affinity of these molecules was intermediate (kD = 1-3 nM, 700-3,000 sites/cell). Furthermore, high concentrations of IL-2 (greater than 100 U/ml) induced Ig productions in large B cells and two of five cell lines. These results taken together suggest that B cells may express novel IL-2 binding molecules, associated with B cell differentiation and differentiate into Ig secreting cells by IL-2 through novel IL-2 binding molecules.

Establishment of tumor cell lines as an independent prognostic factor for survival time in patients with small-cell lung cancer.

We studied tumor samples from 39 patients, who entered our study from January 1989 to May 1990, to assess whether the ability to establish a continually growing tumor cell line from fresh tumor specimens can be associated with decreased survival times in patients with small-cell lung cancer. The tumor samples were used to establish cell lines in culture using a serum-free medium supplemented with hydrocortisone, insulin, transferrin, estrogen, and selenium (HITES). Thirty-three of these specimens were obtained by fiberoptic bronchoscopy from primary sites during routine diagnostic procedures. A total of 11 (28%) cell lines were established: seven (21%) from 33 primary tumors and four (80%) from five peripheral lymph nodes. Survival times of the 11 patients whose tumor cell specimens continually grew in culture at any time during their clinical course were significantly shorter than those of the 28 patients whose tumor cell specimens did not grow in vitro (median survival time of 26 weeks versus 73 weeks; P = .0068). Cox's proportional hazards model, including sex, age, Eastern Cooperative Oncology Group performance status, stage, source of specimen, treatment, and in vitro tumor cell growth in the overall patient group, showed that cell line establishment (P = .0017) and no therapy (P = .0015) were the most important factors indicating poor survival time. For the subgroup of 23 primary tumor patients, the important factors (in decreasing order) that indicated decreased survival times were the establishment of a cell line (P = .0112) and with cyclophosphamide-doxorubicin-vincristine alternating with cisplatin-etoposide, versus cisplatin-vincristine-doxorubicin-etoposide therapy (P = .0463). Our study demonstrates that in vitro tumor cell growth is an adverse predominant prognostic factor in patients with small-cell lung cancer.

Phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer.

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) is a novel camptothecin derivative that has been selected for clinical evaluation because of its broad spectrum of antitumor activity in animal models and its unique inhibitory effects on mammalian DNA topoisomerase I. Seventeen patients with advanced non-small-cell lung cancer were treated with CPT-11 at weekly dose levels ranging from 50 to 150 mg/m2. At least three weekly doses were given to all patients except four, and a total of 74 weekly doses were given to the 17 patients. The dose-limiting toxic effects were myelosuppression (predominantly leukopenia) and unpredictable diarrhea. Gastrointestinal toxic effects were severe and not well controlled by standard therapy in some patients. Interpatient variability of toxic effects was substantial (including two deaths) and did not correlate with the pharmacokinetic parameters of CPT-11 and 7-ethyl-10-hydroxycamptothecin, its major metabolite. Two previously untreated patients, who received doses of 100 and 125 mg/m2, had partial responses lasting 3.2 and 4.0 months, respectively. The maximum tolerated dose on this schedule was 100 mg/m2, which we also recommend as a starting dose for phase II studies. This schedule appears to allow a CPT-11 dose intensity which is double the dose intensity possible on a once-a-month schedule. However, careful supervision to assess gastrointestinal toxic effects and myelosuppression is indispensable because of wide individual differences in drug tolerance.

Several new monoclonal antibodies directed to human T-cell leukemia antigens.

Murine monoclonal hybridoma antibodies were generated efficiently by using a human leukemia antigen preparation which was isolated from the cell membranes of MOLT-4 (a T-leukemia cell line) by means of a novel system. The generated monoclonal hybridoma antibodies were screened and characterized by a radioimmunoassay using a variety of cell specimens as targets. The results showed that the antigen(s) defined by several of these monoclonal hybridoma antibodies is associated with human T-cell leukemia and further suggest that this antigen(s) is a new type of human leukemia-associated cell surface antigen.

Strong, specific anti-human leukemia antisera prepared with the use of purified cell membrane antigen.

Two rabbits immunized with 15 micrograms of a purified human thymus leukemia-associated antigen preparation and boosted once with the same amount of the antigen preparation yielded antisera that showed strong specificity for human leukemic T-cells without any prior absorptions. These antisera from the two rabbits showed a 50% killing of cells at antiserum dilutions of 5700- and 1600-fold, respectively, against JM, a leukemic T-cell line, and slightly weaker activity against MOLT-4, another leukemia T-cell line. These antisera, without any absorption, showed no or minimal reaction against two nonmalignant B-cell lines (RPMI 1788 and RPMI 8057), a leukemic non-T, non-B-cell line (NALM-16), a leukemic pre-B-cell line (NALM-1), normal peripheral blood lymphocytes, and T-cells isolated from peripheral blood lymphocytes. Antiserum 7557, which showed the higher antibody activity, was further studied by an absorption test using various human cell lines. The antiserum showed strong activity against all three leukemic T-cell lines tested, i.e., CCRF-CEM, RPMI 8402, and CCRF-HSB-2, whereas it showed no significant activity against other cell lines which included two leukemic non-T, non-B-cell lines (KM-3 and NALM-6), NALM-1 and RPMI 1788. These are the first anti-human leukemia antisera, except for monoclonal hybridoma antibodies, that showed good specificity for leukemia cells without prior absorption. The present procedure of immunizing animals with a small amount of human thymus leukemia-associated antigen preparation isolated from cell membrane will also be useful for obtaining strong, specific antisera of other cell membrane antigens.

Cell surface membrane antigen present on neuroblastoma cells but not fetal neuroblasts recognized by a monoclonal antibody (KP-NAC8).

Neuroblastoma (NB) arises from primitive sympathetic neuroblasts in the adrenal gland or the sympathetic ganglion. NB in situ, sometimes observed in the adrenal glands of autopsied infants, is considered to be a premalignant lesion that may develop into NB. Little is understood about the morphological and biochemical changes that accompany this malignant progression. In this study, a unique monoclonal antibody, KP-NAC8, raised against a human NB cell line is described. This binds to NB cells but not to fetal neuroblasts. The antibody recognizes a Mr 200,000 surface protein on NB cells. KP-NAC8 binds to 15 of 17 human NB cell lines and all 26 fresh NB samples either from tumor tissues or from marrow aspirates involved with tumor. The antibody was found to cross-react with some other tumor cell lines, namely, Ewing's sarcoma (1 of 2), melanoma (1 of 4), lung cancer (3 of 3), and leukemia (2 of 14) cell lines. However, KP-NAC8 did not bind to any rhabdomyosarcoma (0 of 4), Wilms' tumor (0 of 4), retinoblastoma (0 of 2), glioma (0 of 4), and gastric cancer (0 of 2) cell lines examined. Among fetal tissues, KP-NAC8 did not react with normal neuroblasts in the adrenal glands of 5 fetuses. In a further study, the membrane phenotype of fetal adrenal neuroblasts was analyzed by a panel of 12 monoclonal antibodies including KP-NAC8. A comparison of the binding of the same panel of antibodies to fresh NB revealed that antibodies UJ13A, UJ127:11, PI153/3, anti-Thy-1, A2B5, BA-1, BA-2, HSAN1.2, and Leu-7 bound to both fetal adrenal neuroblasts and NB cells. Monoclonal antibodies OKIa-1 and J5 did not bind to either tissues. The only antibody that could distinguish fetal adrenal neuroblasts from NB cells was KP-NAC8. KP-NAC8 may, therefore, define a differentiation-related antigen that may prove helpful in understanding the biological nature of NB and NB in situ.

Altered expression of cell surface membrane antigens in a common acute lymphoblastic leukemia-associated antigen-expressing neuroblastoma cell line (SJ-N-CG) with morphological differentiation.

The expression of common acute lymphoblastic leukemia antigen (CALLA) on a human neuroblastoma cell line, SJ-N-CG, was demonstrated by indirect membrane immunofluorescence, complement-dependent cytotoxicity, and quantitative absorption, using two monoclonal antibodies (J-5 and BA-3) directed against CALLA. Immunoprecipitation of solubilized 125I-labeled membrane proteins from SJ-N-CG cells with J-5 antibody revealed a protein with a molecular weight of 100,000 as determined on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Morphological differentiation of SJ-N-CG cells could be induced in the presence of 2.0 mM dibutyryl adenosine 3'-5'-cyclic monophosphoric acid for 10 days of culture. Changes in cell surface membrane antigens associated with morphological differentiation were studied by indirect immunofluorescence and complement-dependent cytotoxicity using a panel of seven monoclonal antibodies. Increases in the antigens recognized by BA-2 (detecting leukemia-associated antigen), anti-Thy-1, and antibody 390 (Thy-1 antigen) were found in "differentiated cells," while those detected by BA-1 (B-cell-associated antigen) and J-5 (CALLA) were unchanged. In contrast, the antitransferrin receptor defined by B3/25 was inhibited, and expression of B7/21-defined la-like antigen was not induced. Kinetic studies on antigenic alterations showed that the expression of BA-2-defined antigen rose on Day 2 and remained at the same level until Day 10. The expression of CALLA was not changed from Days 2 to 10. The augmentation of Thy-1 antigen was noted on Day 4 and reached the maximum on Day 10. These results show that dibutyryl adenosine 3'-5'-cyclic monophosphoric acid is capable of inducing phenotypic changes in SJ-N-CG cells. The changes of expression of some antigens on exposure of cells to dibutyryl adenosine 3'-5'-cyclic monophosphoric acid may enable us to have a greater understanding of the differentiation of neuroblastoma to a more mature ganglioneuroblastoma phenotype.

Glycoprotein 130 regulates cardiac myocyte survival in doxorubicin-induced apoptosis through phosphatidylinositol 3-kinase/Akt phosphorylation and Bcl-xL/caspase-3 interaction.

BACKGROUND: We recently reported that the activation of glycoprotein (gp) 130 by leukemia inhibitory factor (LIF) upregulates Bcl-xL and exerts antiapoptotic effects in cardiac myocytes. In addition, LIF induces activation of phosphatidylinositol (PI) 3-kinase and Akt, which are known to be required for cell survival. However, their regulatory roles in cell death remain unknown. METHODS AND RESULTS: We investigated the fate of these proteins and the cytoprotective effects of LIF on doxorubicin (DOX)-induced apoptosis in cultured neonatal rat cardiac myocytes. Myocyte apoptosis increased significantly in DOX-treated cells but was significantly reduced by LIF pretreatment. The kinase activities of PI 3-kinase and Akt declined below basal levels but were partially recovered with LIF. Moreover, DOX-induced caspase-3 activation and decrease in Bcl-xL abundance are completely inhibited by LIF and caspase inhibitor. LIF phosphorylates Bad through PI 3-kinase and reduces the heterodimerization of Bad with Bcl-xL. Adenovirus transfer of the constitutively active form of Akt to cardiac myocytes restored cardiac myocyte survival after DOX treatment. Conversely, the dominant-negative form of Akt inhibited LIF-induced increase in cell viability and suppression of caspase-9 activation. CONCLUSIONS: Activation of gp130 inhibits DOX-induced cell death in cardiac myocytes, resulting in the restoration of PI 3-kinase/Akt activities and in the inactivation of caspase-3, leading to facilitation of the protective function of Bcl-xL.

Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutase.

BACKGROUND: Mice with cardiac-specific overexpression of signal transducer and activator of transcription 3 (STAT3) are resistant to doxorubicin-induced damage. The STAT3 signal may be involved in the detoxification of reactive oxygen species (ROS). METHODS AND RESULTS: The effects of leukemia inhibitory factor (LIF) or adenovirus-mediated transfection of constitutively activated STAT3 (caSTAT3) on the intracellular ROS formation induced by hypoxia/reoxygenation (H/R) were examined using rat neonatal cardiomyocytes. Either LIF treatment or caSTAT3 significantly suppressed the increase of H/R-induced ROS evaluated by 2',7'-dichlorofluorescin diacetate fluorescence. To assess whether ROS are really involved in H/R-induced cardiomyocyte injury, the amount of creatine phosphokinase in cultured medium was examined. Both LIF treatment and caSTAT3 significantly decreased H/R-induced creatine phosphokinase release. These results indicate that the gp130/STAT3 signal protects H/R-induced cardiomyocyte injury by scavenging ROS generation. To investigate the mechanism of scavenging ROS, the effects of LIF on the induction of antioxidant enzymes were examined. LIF treatment significantly increased the expression of manganese superoxide dismutase (MnSOD) mRNA, whereas the expression of the catalase and glutathione peroxidase genes were unaffected. This induction of MnSOD mRNA expression was completely blocked by adenovirus-mediated transfection of dominant-negative STAT3. Moreover, caSTAT3 augmented MnSOD mRNA and its enzyme activity. In addition, the antisense oligodeoxyribonucleotide to MnSOD significantly inhibited both LIF and caSTAT3-mediated protective effects. CONCLUSIONS: The activation of STAT3 induces a protective effect on H/R-induced cardiomyocyte damage, mainly by inducting MnSOD. The STAT3-mediated signal is proposed as a therapeutical target of ROS-induced cardiomyocyte injury.

Phase I and pharmacologic study of docetaxel and irinotecan in advanced non-small-cell lung cancer.

PURPOSE: We conducted a phase I trial of docetaxel, a new antimicrotubule agent, combined with irinotecan (CPT-11), a topoisomerase I inhibitor. The aim was to determine the maximum-tolerated dose (MTD) of docetaxel combined with CPT-11, as well as the dose-limiting toxicities (DLTs) of this combination in advanced non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Thirty-two patients with stage IIIB or IV NSCLC were treated at 4-week intervals with docetaxel (60 minutes, day 2) plus CPT-11 (90 minutes, days 1, 8, and 15). The starting doses of docetaxel/CPT-11 were 30/40 mg/m(2), and doses were escalated in 10-mg/m(2) increments until the MTD was reached. RESULTS: The MTD of docetaxel/CPT-11 was 50/60 mg/m(2) (level 5A), or 60/50 mg/m(2) (level 5B). Neutropenia and diarrhea were the DLTs. CPT-11 did not affect the pharmacokinetics of docetaxel. There were 11 (37%) partial responses among 30 patients. The median survival time was 48 weeks, and the 1-year survival rate was 44.9%. CONCLUSION: The combination of docetaxel and CPT-11 seems to be active against NSCLC, with acceptable toxicity. The recommended dose for phase II studies is 50 mg/m(2) of CPT-11 (days 1, 8, and 15) and 50 mg/m(2) of docetaxel (day 2) administered every 28 days.

Phase II study of concurrent radiotherapy and chemotherapy for unresectable stage III non-small-cell lung cancer. Southern Osaka Lung Cancer Study Group.

PURPOSE: To evaluate the response rate, toxicity, and 2-year survival rate of concurrent radiotherapy and chemotherapy for unresectable stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between July 1989 and October 1990, 65 patients with histologically or cytologically proven unresectable stage III NSCLC without T3N0-1M0 disease were entered onto this study. Sixty-one patients were eligible for response, survival, and toxicity analysis. Chemotherapy consisted of vindesine (3 mg/m2 on days 1, 8, 29, and 36), cisplatin (100 mg/m2 on days 1 and 29), and mitomycin (8 mg/m2 on days 1 and 29). Radiotherapy was administered for 3 weeks (2 Gy given 13 times, five fractions per week), followed by 10-day rest periods and then the previous schedule of radiotherapy repeated for 3 weeks. RESULTS: Of 61 eligible patients, 53 (86.9%) had a partial response (PR). The median response duration was 39.1 weeks (range, 8.4 to 163+). The median survival time was 16 months and the 2-year survival rate was 36.7%. Of 53 responding patients, 10 (16.4%) are alive and disease-free after 2 years. The major toxicity was leukopenia (> or = grade 3, 95%). Other toxicities of > or = grade 3 included thrombocytopenia (45%), anemia (28%), nausea/vomiting (16%), fever (11%), and esophagitis (6%). Treatment-related death occurred in two patients. One patient died of pulmonary toxicity (interstitial pneumonitis) and the other of esophagobronchial fistula with pulmonary infection. CONCLUSION: Concurrent radiotherapy plus chemotherapy with mitomycin, vindesine, and cisplatin (MVP) can be safely administered to patients with stage III NSCLC, with excellent response rates and 2-year survival rates.

Role of radiotherapy in combined modality treatment of locally advanced non-small-cell lung cancer.

PURPOSE: For patients with locally advanced (stage III) non-small-cell lung cancer (NSCLC), radiotherapy (RT) has been used conventionally for many years. Few prospective trials have determined the role of RT. Recently, chemotherapy (CT) has been shown to produce excellent responses in regionally advanced disease. We therefore conducted a randomized trial using cisplatin (P)-based CT regimens with or without thoracic irradiation. PATIENTS AND METHODS: We randomly assigned 92 patients with locally advanced NSCLC to receive one of three arms of P-based combination chemotherapy: vindesine (V) plus P, mitomycin (M) plus V plus P, or etoposide (E) plus P alternating with V plus M. After two cycles of CT, patients were reevaluated and those with stage III were again randomized to receive RT or not. RT consisted of 50 to 60 Gy in 5 to 6 weeks; 2 Gy was delivered once daily in conventional fractions. RESULTS: Sixty-three patients were included in the second randomization. The patients in the CT/RT group (n = 32) and CT-alone group (n = 31) were comparable in terms of age, sex, performance status, histologic features, stage of disease, and induction CT regimen. The median durations of survival were similar for the two groups (461 days in CT/RT group and 447 days in CT-alone group). The survival rate in the CT/RT group was 58% at 1 year, 36% at 2 years, and 29% at 3 years, as compared with 66%, 9%, and 3% at 1, 2, and 3 years, respectively, in the CT-alone group. One patient in the CT/RT group died of pneumonitis, but there were no CT-related deaths. CONCLUSION: In locally advanced NSCLC, P-based combination CT followed by chest irradiation significantly increases the number of long-term survivors as compared with CT alone. RT to bulky disease in the thorax is thus an important part of combined modality therapy, and a necessary part of further studies in locally advanced disease.

A phase II study of CPT-11, a new derivative of camptothecin, for previously untreated non-small-cell lung cancer.

PURPOSE: Camptothecin-11 (CPT-11) is a new semisynthetic derivative of CPT, and has been shown to inhibit DNA topoisomerase I and to have a strong antitumor activity with low toxicity in murine tumors. To evaluate the effectiveness of CPT-11 in patients with non-small-cell lung cancer (NSCLC), a phase II study was conducted between April 1989 and February 1990. PATIENTS AND METHODS: Seventy-three patients were entered onto the study. All patients had had no previous therapy and had measurable disease. Their median age was 67 years (range, 34 to 75 years). Fifty-four patients had a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale, and 19 had a PS of 2. CPT-11 was given at a dose of 100 mg/m2 by intravenous 90-minute infusion once a week. The dose of CPT-11 was modified based on the WBC count obtained on the day of drug administration. RESULTS: Of 72 assessable patients, 23 (31.9%) showed a partial response (95% confidence interval, 20.2% to 43.6%). Of 40 patients with a stage IV disease, 13 (32.5%) responded. Response rates for patients with PS 0 or 1 and those with PS 2 did not differ (34.0% and 26.3%, respectively). The median duration of response in patients showing a PR was 15 weeks. The median survival time for all patients was 42 weeks. The major toxicities were leukopenia and diarrhea. Grade 3 or 4 leukopenia and diarrhea occurred in 18 patients (25%) and 15 patients (21%), respectively. These toxicities were unpredictable. Other toxicities of greater than or equal to grade 3 included nausea/vomiting (22%), anemia (15%), alopecia (4%) and pneumonitis (3%). One patient died of pulmonary toxicity (interstitial pneumonitis). CONCLUSIONS: CPT-11 is a very active agent for NSCLC with acceptable toxicities. Further trials in combination with other agents for this disease are warranted.

CPT-11 in combination with cisplatin for advanced non-small-cell lung cancer.

PURPOSE: The purpose of this study was to determine the maximum-tolerated dose and the dose-limiting toxicities of CPT-11, a new derivative of camptothecin, in combination with a fixed dose of cisplatin in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-seven previously untreated patients with stage IIIB or IV NSCLC were assessable for toxicity, and 26 were assessable for response. The initial dose of CPT-11 was 30 mg/m2 given as a 90-minute intravenous (IV) infusion on days 1, 8, and 15 in combination with cisplatin (80 mg/m2 IV on day 1) given every 4 weeks. The dose of CPT-11 was escalated in increments of 10 mg/m2 until severe or life-threatening toxic effects were observed. RESULTS: Significant toxicity was infrequent up to 60 mg/m2 of CPT-11. The maximum-tolerated toxicity was reached at a dose of 70 mg/m2. Three of six patients either had leukocyte count nadirs of less than 2,000/microL or experienced grade 4 diarrhea during the first cycle of therapy at 70 mg/m2. The major toxic effects were leukopenia and diarrhea. There were 14 partial responses (54%) among the 26 patients. CONCLUSIONS: A combination of CPT-11 and cisplatin seems to be effective against NSCLC with acceptable toxicities. The recommended dose for phase II studies is 60 mg/m2 of CPT-11 on days 1, 8, and 15, and 80 mg/m2 of cisplatin on day 1 every 4 weeks.

CPT-11: a new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer.

PURPOSE: To evaluate the activity of CPT-11, which is a new derivative of camptothecin, against refractory or relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS: Sixteen patients with refractory or relapsed SCLC were entered onto a prospective, non-randomized, single-institution phase II trial. All 16 patients had been pretreated heavily with some form of cisplatin-based combination chemotherapy. Five patients had received previous chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide (CODE) as an induction therapy. Six patients had been treated with concurrent cisplatin and etoposide plus chest x-ray. The median time off chemotherapy was 7.3 months (range, 1.9 to 15.1 months). Patients were treated with a CPT-11 starting dose of 100 mg/m2 body surface given as a 90-minute intravenous (IV) infusion every week with subsequent doses based on toxicity. Fifteen patients were assessable for toxicity, response, and survival. RESULTS: Seven patients (47%; 95% confidence limits for an overall response rate, 21.4% to 71.9%) responded to CPT-11 with a median duration of response of 58 days. The major toxicities were myelosuppression (predominantly leukopenia), diarrhea, and pulmonary toxicity. CONCLUSION: CPT-11 is an active agent against refractory or relapsed SCLC and deserves to be studied more closely as both a single agent and in combination with other drugs to treat patients with SCLC.

A randomized trial in inoperable non-small-cell lung cancer: vindesine and cisplatin versus mitomycin, vindesine, and cisplatin versus etoposide and cisplatin alternating with vindesine and mitomycin.

Patients with inoperable non-small-cell lung cancer (NSCLC) were randomly assigned to receive one of three dosage regimens: (1) vindesine and cisplatin (VP); (2) mitomycin, vindesine, and cisplatin (MVP); or (3) etoposide and cisplatin alternating with vindesine and mitomycin (EP/VM). In 199 assessable patients, the response rates were VP, 33%; MVP, 43%; and EP/VM, 19%. The addition of mitomycin to the VP regimen did not significantly improve the response rate. The response rate was significantly lower with the EP/VM regimen than with the MVP regimen (P less than .01). The median survival times were VP, 50 weeks; MVP, 42 weeks; and EP/VM, 40 weeks. These differences were not significant. Grade III or IV thrombocytopenia was significantly greater (P less than .01) in MVP patients (22%) than in the VP (5%). Other toxicities were similar in the three groups. Analyses of prognostic factors showed that treatment with MVP, sex, and histologic classification (squamous cell carcinoma) were predictive of improved response. Important factors for improved survival, according to the Cox regression analysis, were the stage of disease, performance status, sex, weight loss before diagnosis, and hemoglobin concentration.