National Cancer Institute®
Last Modified: June 1, 2002
UI - 12025223
AU - Bernardo G; Cuzzoni Q; Strada MR; Bernardo A; Brunetti G; Jedrychowska
TI - I; Pozzi U; Palumbo R First-line chemotherapy with vinorelbine, gemcitabine, and carboplatin in the treatment of brain metastases from non-small-cell lung cancer: a phase II study.
SO - Cancer Invest 2002;20(3):293-302
AD - Service of Preventive Oncology, Fondazione S. Maugeri I.R.C.C.S., Via Ferrata 8, 27100 Pavia, Italy. firstname.lastname@example.org
On the basis of the hypothesis that responsiveness of brain metastases (BM) to chemotherapy is primarily determined by the chemosensitivity of primary tumor, rather than the ability of cytotoxic agents to penetrate the blood-brain barrier, we addressed the role of a new combination regimen with Vinorelbine (VNR), Gemcitabine (GEM), and Carboplatin (CBDCA) as a primary treatment modality in non-small-cell lung cancer (NSCLC) patients with BM. Twenty-two consecutive chemotherapy-naive patients with documented BM from NSCLC and at least 1 evaluable extracerebral lesion were enrolled in this phase II study. Vinorelbine (25 mg/m2) and GEM (1000 mg/m2) were given on day 1, combined with a fixed daily dose of CBDCA at AUC = 5.0 for three consecutive days. The cycle was repeated every three weeks in an outpatient setting. A total of 116 cycles was given (median 4, range 3-9 per patient). Specific evaluation of BM by contrast-enhanced computed tomography (CT) scan showed an overall response rate of 45% in 20 evaluable patients (95% confidence interval, 26-66%), with 3 (15%) complete and 6 (30%) partial remissions; in addition, three minor regressions, five disease stabilizations, and three progressions were found. Patients who responded for the brain also had a response at the extracerebral sites, and a benefit by a remission of symptoms and improvement of performance index was observed in 77% of the whole group. Median time to response was 10 weeks (range 6-12 weeks) and median response duration was 25 weeks (range 12-32 weeks). Median survival time was 33 weeks (range 18-62 + weeks) in the whole group and 48 weeks in responders (range 26-62 + weeks). The adopted schedule was well tolerated and easy to use in the outpatient setting, with good patient compliance. Our results, which are consistent with the study hypothesis, suggest that BM respond to chemotherapy in the same way as systemic disease and primary tumor, and further support the need for reconsideration of the role of chemotherapy in such a clinical setting. Controlled trials comparing chemotherapy with radiotherapy or concomitant sequential chemo-radiotherapy would be appropriate.
UI - 12011140
AU - De Pas T; Pastorino U; Spaggiari L; Curigliano G; de Braud F; Robertson
TI - C Preoperative chemotherapy in non-small-cell lung cancer: nothing new in N2 disease.
SO - J Clin Oncol 2002 May 15;20(10):2603-4; discussion 2605
UI - 11986597
AU - Ichinose Y; Tsuchiya R; Koike T; Yasumitsu T; Nakamura K; Tada H;
TI - Yoshimura H; Mitsudomi T; Nakagawa K; Yokoi K; Kato H A prematurely terminated phase III trial of intraoperative intrapleural hypotonic cisplatin treatment in patients with resected non-small cell lung cancer with positive pleural lavage cytology: the incidence of carcinomatous pleuritis after surgical intervention.
SO - J Thorac Cardiovasc Surg 2002 Apr;123(4):695-9
AD - National Kyushu Cancer Center, Fukuoka; National Cancer Center Hospital, Tokyo, Japan. email@example.com
BACKGROUND: The prognosis of patients with resected non-small cell lung cancer without carcinomatous pleuritis whose intrapleural cancer cells were detected by means of a cytologic examination of pleural lavage fluid obtained immediately after a thoracotomy has been reported to be poor. METHODS: The Japan Clinical Oncology Group conducted a phase III whether intraoperative intrapleural hypotonic cisplatin treatment could effectively control pleural disease and thereby prolong the survival of these patients. The patients were randomized to receive either intraoperative intrapleural hypotonic cisplatin treatment or no treatment before closure of the open thorax. The intraoperative intrapleural hypotonic cisplatin treatment consisted of exposing the entire thorax to cisplatin (50 microg/mL) in distilled water for 15 minutes. RESULTS: Because of the slow registration pace, the study was the start of the registration, 49 patients were entered into the study, and all were eligible. Twenty-five and 24 patients were randomly assigned to the treatment and control groups, respectively. No statistically significant difference in the overall survival and disease-free survival between the 2 groups was observed. However, the appearance of carcinomatous pleuritis was suppressed by the hypotonic cisplatin treatment (42% of the control group vs 8% of the treatment group, P =.008). CONCLUSIONS: Although the randomized trial was prematurely terminated, the intraoperative intrapleural hypotonic cisplatin treatment was found to effectively suppress the appearance of carcinomatous pleuritis in resected patients who demonstrated a positive pleural lavage cytology finding.
UI - 11844605
AU - Tsurutani J; Nitta T; Hirashima T; Komiya T; Uejima H; Tada H; Syunichi
TI - N; Tohda A; Fukuoka M; Nakagawa K Point mutations in the topoisomerase I gene in patients with non-small cell lung cancer treated with irinotecan.
SO - Lung Cancer 2002 Mar;35(3):299-304
AD - Fourth Department of Internal Medicine, Kinki University School of Medicine, Ohonohigashi 377-2, Osakasayama, Osaka 589-8511, Japan.
Reverse transcription polymerase chain reaction (RT-PCR) single-strand conformation polymorphism analysis was used to detect topoisomerase I (top1) mutations in total RNA from 16 specimens that were excised during surgery from eight patients with non-small cell lung cancer (NSCLC) who had received preoperative chemotherapy consisting of irinotecan (CPT-11) and cisplatin. PCR single-strand conformation polymorphism and subsequent DNA sequencing analysis showed two nucleotide substitutions resulting in Trp736stop (TGG to TGA) and Gly737Ser (GGT to AGT) in one tumor specimen. The mutations were located near a site in top1 that was previously reported to harbor a mutation in the human lung cancer cell line PC7/CPT, which was selected for CPT resistance. These results demonstrate that mutations in top1 occur after chemotherapy with CPT-11 in NSCLC patients and suggest that development of resistance to CPT-11 in some patients may involve mutation of top1. However, the significance of top1 mutations to CPT resistance needs to be further investigated.
UI - 11844607
AU - Koumakis G; Demiri M; Barbounis V; Vassilomanolakis M; Gontikakis E;
TI - Pamouksoglou P; Dahabre J; Efremidis AP Is weekly paclitaxel superior to paclitaxel given every 3 weeks? Results of a phase II trial.
SO - Lung Cancer 2002 Mar;35(3):315-7
AD - B' Medical Oncology Department, Saint Savas Oncology Hospital, Hellenic Cancer Institute, 171 Alexandras Avenue, 115 22 Athens, Greece.
Twenty-four patients previously treated with platinum containing regimens with stage IIIB-IV non-small-cell lung cancer (NSCLC) participated in the study. Sequential cohorts of patients were treated with 60 and 90 mg/m(2) of Paclitaxel per week. Paclitaxel was administered weekly over 1 h infusion for 6 consecutive weeks followed by 2 weeks without treatment (8-week cycle). A total of 252 treatments were administered to the 24 patients. In 29 (12%) of 252 treatments grade 2 granulocytopenia was observed while four patients (17%) developed grade 2 neuropathy. Seven patients (29%) achieved a partial response and five (21%) had stable disease. Paclitaxel 90 mg/m(2) per week as salvage treatment is well tolerated and has shown promising activity in patients with NSCLC who progress after platinum treatment.
UI - 11844608
AU - Migliorino MR; De Marinis F; Nelli F; Facciolo F; Ammaturo MV; Cipri A;
TI - Belli R; Ariganello O; Diana F; Di Molfetta M; Martelli O A 3-week schedule of gemcitabine plus cisplatin as induction chemotherapy for Stage III non-small cell lung cancer.
SO - Lung Cancer 2002 Mar;35(3):319-27
AD - 5th Pneumoncology Unit, Department of Lung Diseases, San Camillo-Forlanini Hospital, v. Portuense 332, 00149 Rome, Italy.
BACKGROUND: Our aim was to explore the activity and feasibility of gemcitabine plus cisplatin as induction chemotherapy in patients with Stage IIIA N(2) and selected IIIB non-small cell lung cancer (NSCLC). patients with Stage III NSCLC, median age of 64 years, World Health Organization performance status 0, 1, or 2, and the ability to tolerate a pneumonectomy entered the study and received gemcitabine 1250 mg/m(2) on days 1 and 8 and cisplatin 70 mg/m(2) on day 2 every 3 weeks. After three cycles of induction chemotherapy, patients underwent resection or radiotherapy. RESULTS: Responses were seen in 40 of the 69 assessable patients, for an intent-to treat overall response rate of 57.1% (95% confidence interval, 45-62%), with 4.2% complete response. Response rates were 68 and 35% in patients with Stage IIIA and IIIB disease, respectively. The overall pathological CR rate after induction chemotherapy was 3%, with an overall pathological downstaging rate of 20%. Median survival for all patients was 14.5 months, with an estimated 1-year survival rate of 67% (95% CI, 54.3-79.5%). The estimated time to treatment failure was 12.6 months. Grade 3/4 thrombocytopenia was the main hematologic toxicity, occurring in 26% of patients, but was not associated with life-threatening bleeding. Febrile neutropenia was rare and other severe non-hematologic toxicities were uncommon. CONCLUSIONS: The 3-week schedule of gemcitabine plus cisplatin is highly active as induction chemotherapy in Stage IIIA N(2) unresectable NSCLC. This suggests a need for a multimodality approach upfront, such as concurrent chemoradiation therapy, particularly in patients with Stage IIIB disease.
UI - 12040671
AU - Tsuboi M; Kato H
TI - [Current status of the chemotherapy for lung cancer]
SO - Gan To Kagaku Ryoho 2002 May;29(5):684-94
AD - Dept. of Surgery, Tokyo Medical University.
In the treatment of limited-stage small cell lung cancer (LD-SCLC) and unresectable locally-advanced non-small cell lung cancer, several phase III trials and meta-analysis have demonstrated the following: 1) combining chemotherapy and thoracic irradiation is better than chemotherapy alone or radiotherapy alone, 2) the concurrent use of chemoradiotherapy has been expected a better survival than the sequential use, 3) the improvement in outcome seen with a concurrent chemoradiotherapy approach may be because of spatial cooperation, enhanced radiosensitization, and/or enhanced cytotoxicity, and 4) the chemoradiotherapy is tolerable without significant morbidities, such as pneumonitis and esophagitis. However, the chemoradiotherapy is still an investigational strategy because of the absence of a definite schedule and dose on radiotherapy. Newer, more tolerable chemotherapeutic agents, molecular biologic novel approaches and newer irradiated procedures are now being investigated.
UI - 12040679
AU - Tada A; Ueoka H; Kiura K; Tabata M; Takemoto M; Yamane H; Hiyama J; Aoe
TI - K; Shibayama T; Kamei H; Kawahara S; Harita S; Sato T; Kobayashi M; Eguchi K; Hiraki S; Hiraki Y; Tanimoto M [Combination chemotherapy with carboplatin and etoposide for elderly patients aged 76 years or older with small cell lung cancer]
SO - Gan To Kagaku Ryoho 2002 May;29(5):751-6
AD - Dept. of Internal Medicine, National Minami-Okayama Hospital.
Eighteen elderly patients aged 76 years or older with small cell lung cancer were treated with carboplatin (AUC = 4 mg/ml.min, i.v. day 1) and etoposide (70 mg/m2 i.v. day 1-3) and 17 patients were evaluable. The median age of the study population was 77 years (range: 76-81). Eight patients had limited disease (LD) and nine did extensive disease (ED). The overall response rate was 88% for LD patients and 67% for ED patients. Median survival time was 219 days for LD patients and 158 days for ED patients. Grade 3 and 4 leukopenia, neutropenia, thrombocytopenia and anemia occurred in 41%, 76%, 24% and 6% of patients, respectively. There was one treatment-related death due to pneumonitis.
UI - 12001113
AU - Vincent-Salomon A; Jouve M; Genin P; Freneaux P; Sigal-Zafrani B; Caly
TI - M; Beuzeboc P; Pouillart P; Sastre-Garau X HER2 status in patients with breast carcinoma is not modified selectively by preoperative chemotherapy and is stable during the metastatic process.
SO - Cancer 2002 Apr 15;94(8):2169-73
AD - Department of Pathology, Institut Curie, Paris, France.
BACKGROUND: The objective of this study was to determine whether HER2 expression levels in breast carcinomas were modified by chemotherapy or during the metastatic process. METHODS: HER2 expression was analyzed on sequential tissue specimens taken from the primary tumor before patients received preoperative chemotherapy (CT) and from post-CT residual breast tumor or at a metastatic site. The first group of patients included 59 women who presented with T2-T4,N1-N2 breast carcinoma and were treated by preoperative anthracycline-based CT and then underwent surgery. The second group included 44 patients with metastatic breast carcinoma localized to the lung (27 patients) or to the liver (17 patients). HER2 status was determined by immunohistochemistry using an anti-p185(HER/neu) monoclonal antibody and was classified as overexpressed or not overexpressed. RESULTS: Among the patients who received preoperative CT, HER2 overexpression was observed in 15 of 59 patients (25%). A complete pathologic response was observed in 2 of these 15 patients. HER2 still was overexpressed in 11 of 13 remaining residual tumors and was no longer detectable in 2 tumors. In addition, the 29 tumors with no HER2 overexpression before CT remained negative after treatment. In patients with metastatic breast carcinoma, HER2 was overexpressed in 11 of 44 primary tumors (25%). In 9 of these 11 tumors, HER2 overexpression was maintained in the metastases (9 pulmonary metastases and 4 hepatic metastases). In two patients who had low levels of HER2 overexpression in their primary tumors, no staining was observed in the secondary tumor (one pulmonary tumor and one liver tumor). There were no tumors in which the overexpression of HER2 was found only in the metastasis. CONCLUSIONS: The current study showed that, in most patients, HER2 overexpression was unchanged after CT and in metastatic sites. No HER2 negative primary tumors became HER2 positive after patients received CT or during the metastatic process. In a few patients, a diminution in the level of HER2 expression was observed after CT or in secondary tumors. This may have been due to a transitory state of altered tumor cells or to the selection of HER2 negative tumor cells clones. Copyright 2002 American Cancer Society.
UI - 12018735
AU - Moinpour CM; Lyons B; Grevstad PK; Lovato LC; Crowley J; Czaplicki K;
TI - Buckner ZM; Ganz PA; Kelly K; Gandara DR Quality of life in advanced non-small-cell lung cancer: results of a Southwest Oncology Group randomized trial.
SO - Qual Life Res 2002 Mar;11(2):115-26
AD - Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA. firstname.lastname@example.org
PURPOSE: The main purpose of this paper is to present the results of a randomized trial comparing the effects of two chemotherapy regimens on the Quality of life (QOL) of patients with advanced non-small-cell lung cancer (NSCLC). Trials in advanced stage disease represent an important treatment context for QOL assessment. A second purpose of this paper is to examine methods for handling the level of missing data commonly observed in the advanced stage disease context. METHODS: Patients were randomized to receive cisplatin plus vinorelbine or carboplatin plus paclitaxel. The QOL of 222 patients was assessed with the Functional Assessment of Cancer Therapy-Lung (FACT-L) prior to randomization; follow-up assessments occurred at 13 and 25 weeks. Three methods were used to analyze the QOL data: (1) cross-sectional analysis of four patient categories (improved, stable, missing, and declined) based on changes in the FACT-L score, (2) a mixed linear model, and (3) a pattern mixture model. The longitudinal analyses addressed two potential data biases. RESULTS: Questionnaire submission rates were 91% at baseline, 68% at 13 weeks, and 47% at 25 weeks. The cross-sectional and mixed linear model analyses did not show significant differences by treatment arm in patient-reported QOL. The pattern mixture model analysis, more appropriate given non-ignorable missing data, also found no statistically significant effect of treatment on patient QOL. CONCLUSION: We present a sensitivity analysis approach with multiple methods for analyzing treatment effects on patient QOL in the presence of substantial, non-ignorable missing data in an advanced stage disease clinical trial. We conclude that the two treatment arms did not differ statistically in their effects on patient QOL over a 25-week treatment period.
UI - 11911315
AU - Gridelli C; Curcio C; Iaffaioli RV; Brancaccio L; D'Aprile M; Gebbia V;
TI - Rossi A; Tortoriello A; Veltri E; Maione P; Barbarisi A; Gallo C; Guida C; Perrone F Carboplatin + epirubicin +VP-16 + lenograstim followed by radiotherapy + carboplatin as radiosensitizer in limited small cell lung cancer. A multicenter phase II study.
SO - Anticancer Res 2001 Nov-Dec;21(6A):4179-83
AD - Oncologia Medica B, Istituto Nazionale Tumori, Napoli, Italy. email@example.com
A phase II trial was undertaken to test the activity and toxicity of carboplatin (300 mg/m2, i.v. day 1) + epirubicin (75 mg/m2, i.v. day 1) + VP-16 (100 mg/m2, i.v. days 1 to 3) + lenograstim (5 mcg/kg, s.c. days 6 to 15) administered every 3 weeks for 4 cycles and subsequent chest irradiation (50 Gy) + daily carboplatin (25 mg/m2) in the first-line treatment of adults affected by limited small cell lung cancer (SCLC). PATIENTS AND METHODS: A single-stage phase II design was used; the complete response (CR) rate after chest radiotherapy was the primary end-point. Twenty-three CRs were required out of 38 patients to consider the treatment worthy of further study. Prophylactic cranial irradiation (PCI) was planned in case of CR. Patients aged < or = 70 were eligible if they had limited SCLC, a performance status not worse than 2 by the ECOG scale and no prior chemotherapy or radiotherapy. RESULTS: From was 60 years. All the patients started chemotherapy; 23 patients received chest irradiation and concurrent daily carboplatin; 11 patients also received PCI. Toxicity was generally mild. Sixteen CRs (48.5%, 95% CI: 30.8-66.5) were recorded; the objective response rate was 72.7% (95% CI: 54.5-86.7). The median time-to-progression was 7.9 months (95% CI: 6.5-10.4). The median-survival was 10.7 months (95% CI: 9.2-16.1). CONCLUSION: Induction chemotherapy with carboplatin + epirubicin + VP-16 followed by chest irradiation plus concurrent daily carboplatin is well-tolerated but not sufficiently active to warrant further study in the treatment of patients with limited SCLC.
UI - 12033195
AU - Hainsworth JD; Morrissey LH; Scullin DC Jr; Houston GA; Prasthofer EF;
TI - Gray JR; Burris HA 3rd; Greco FA Paclitaxel, carboplatin, and topotecan in the treatment of patients with small cell lung cancer: a phase II trial of the Minnie Pearl Cancer Research Network.
SO - Cancer 2002 May 1;94(9):2426-33
AD - The Sarah Cannon Cancer Center, Nashville, Tennessee 37203, USA. firstname.lastname@example.org
BACKGROUND: The objective of this study was to evaluate the feasibility, toxicity, and efficacy of a novel three-drug regimen containing paclitaxel, carboplatin, and topotecan followed by oral etoposide in the first-line treatment of patients with small cell lung carcinoma. METHODS: One hundred five patients with previously untreated, limited stage or extensive stage small cell lung carcinoma were treated in this multicenter, community-based, Phase II trial. All patients received paclitaxel 135 mg/m(2) by 1-hour intravenous (i.v.) infusion on Day 1, carboplatin at an area under the serum concentration-time curve of 5.0 i.v. on Day 1, and topotecan 0.75 mg/ m(2) i.v. on Days 1-3. The treatment regimen was repeated at 21-day intervals for 4 courses. Patients with limited stage disease also received radiation therapy (45 grays [Gy]; in single daily fractions of 1.8 Gy) beginning concurrently with the third course of chemotherapy. Patients who had an objective response or stable disease after 4 courses of combined paclitaxel, carboplatin, and topotecan then received 3 courses of oral etoposide (50 mg alternating with 100 mg for 10 consecutive days) repeated at 21-day intervals. RESULTS: Treatment with paclitaxel, carboplatin, and topotecan produced response rates of 88% and 93% in patients with extensive stage disease and limited stage disease, respectively. The median survival for patients with extensive stage and limited stage disease was 8.3 months and 17.2 months, respectively. The addition of oral etoposide was feasible, but there was no suggestion that it prolonged remission. This three- drug regimen was associated with acceptable toxicity in patients with a good performance status, although it was tolerated very poorly by patients with an Eastern Cooperative Oncology Group performance status of 2; 5 of 12 patients (42%) had treatment-related deaths. CONCLUSIONS: Although this three-drug regimen was active in the treatment of patients with small cell lung carcinoma, it was more toxic than standard platinum and etoposide regimens and provided no apparent improvement in efficacy. Further investigation of topotecan as a component of first-line therapy should focus on two-drug combination regimens in which the topotecan dose can be optimized. Routine use of three-drug regimens in patients with small cell lung carcinoma should await demonstration of superiority in randomized trials.
UI - 12023159
AU - Jeremic B
TI - In regard to Sim et al., IJROBP 2001;51:660-665.
SO - Int J Radiat Oncol Biol Phys 2002 Jun 1;53(2):512-3; discussion 513
UI - 11776757
AU - Franzke A; Buer J; Probst-Kepper M; Lindig C; Framzle M; Schrader AJ;
TI - Ganser A; Atzpodien J HLA phenotype and cytokine-induced tumor control in advanced renal cell cancer.
SO - Cancer Biother Radiopharm 2001 Oct;16(5):401-9
AD - Department of Hematology and Oncology, Medizinische Hochschule Hannover, Germany. email@example.com
BACKGROUND: The natural history of malignancies, the response to cytokine-based therapy and survival of patients may be partly determined by the human leukocyte antigen (HLA) phenotype. Here, we investigated in a retrospective analysis the correlation of the HLA phenotype of 73 prognostic favored patients with advanced renal cell carcinoma to (a) the expected HLA distribution in Caucasians, (b) the susceptibility or resistance to metastatic sites, (c) response to cytokine-based therapy and (d) sustained cytokine-induced effective tumor control. METHODS: We retrospectively determined the MHC class I and II antigens in patients with metastatic renal cell carcinoma selected by survival. Antigens were serologically typed by standard lymphocytotoxicity techniques. For statistical analysis, we calculated the probability of the presented HLA antigens in correlation to the expected Caucasian HLA phenotypes. An independent confirmation was performed by using the chi-square and two-tailed Fisher's exact test. RESULTS: Various HLA antigens deviated significantly from the normal distribution in the Caucasian population. HLA.B44 was the only antigen associated (p < 0.01) with the absence of lung and presence of bone metastases, while it did not impact on overall survival or response to therapy. A1 (p < 0.0001, p < 0.002) and B8 (p < 0.009, p < 0.04) alleles were more frequently expressed in responding patients than expected from the normal distribution in Caucasians and that observed in non-responding patients, respectively. The HLA analysis of patients achieving a durable complete remission showed a significantly higher frequency of expression of the A1 and B8 antigens and furthermore of the B14 antigen (p < 0.05). CONCLUSIONS: Our data underline the pivotal role of the MHC complex in controlling and regulating the cellular immune response in renal cell cancer. We could identify HLA antigens, which correlate with response to cytokine-treatment, with a long-lasting effective tumor control and prolonged overall survival.
UI - 12023788
AU - Postmus PE; Bunn PA Jr
TI - Pemetrexed as a single agent in the therapy of advanced lung cancer.
SO - Semin Oncol 2002 Apr;29(2 Suppl 5):17-22
AD - Department of Pulmonary Diseases, Vrije Universiteit, University Hospital Vrije Universiteit, Amsterdam, The Netherlands..
Pemetrexed is a multitargeted antifolate with activity as a single agent against non-small cell lung cancer at a recommended dose of 500 mg/m(2) as a 10-minute infusion every 21 days. The response rate in untreated patients with stage IIIB/IV disease is from 18% to 23%. It is also active in the second-line setting in patients progressing after pretreatment with a number of drugs or after a very short treatment-free interval. The response rate in these difficult-to-treat patients is approximately 9%. Toxicity in both situations is mild; myelotoxicity is primarily seen. This review describes phase I and II studies performed before folic acid and vitamin B(12) supplementation. Copyright 2002, Elsevier Science (USA). All rights reserved.
UI - 12023789
AU - Rosell R; Crino L
TI - Pemetrexed combination therapy in the treatment of non-small cell lung cancer.
SO - Semin Oncol 2002 Apr;29(2 Suppl 5):23-9
AD - Medical Oncology Service, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
Until recently, the treatment of non-small cell lung cancer (NSCLC) was limited to the cisplatin combinations, including a small number of cytotoxic drugs. More recently, combinations with taxanes and gemcitabine have slightly improved outcome. However, when the literature is revisited, it can be realized that older drugs such as nitrogen mustard have some degree of activity in NSCLC, traditionally considered a chemoresistant tumor. However, drugs that are mostly ineffective when used as single agents, such as 5-fluorouracil (5-FU), have significant activity when combined with cisplatin in the treatment of patients with NSCLC. 5-FU constitutes the backbone of chemotherapy for colorectal cancer patients. 5-FU is equally interesting because it permits investigation of thymidylate synthase (TS) levels as a genetic target for predicting response and survival. The assessment of TS levels and ERCC1 as a marker of cisplatin resistance is leading to customized chemotherapy. The possibility of discriminating cisplatin resistance is particularly attractive in choosing between cisplatin and non-cisplatin combinations in the treatment of NSCLC. We have reviewed phase I and II studies of pemetrexed in NSCLC. The response rate is approximately 20% with single-agent pemetrexed and approximately 40% in combination with cisplatin. This combination has mild to moderate toxicity. Other synergistic combinations that should be explored include pemetrexed with gemcitabine, CPT-11, docetaxel, carboplatin, or oxaliplatin. In the future, pharmacogenomically oriented chemotherapy trials should be undertaken based on the accumulated evidence that several genetic markers, such as ERCC1, beta-tubulin mutations, and loss of heterozygosity in the region of the enzyme ribonucleotide reductase, can predict resistance to cisplatin, taxanes, or gemcitabine, respectively. Mechanisms of resistance to pemetrexed need to be investigated, including the potential role of TS messenger RNA. In summary, pemetrexed has emerged as a promising new cytotoxic drug in the arsenal of chemotherapy treatments for NSCLC. Copyright 2002, Elsevier Science (USA). All rights reserved.
UI - 11911799
AU - Ruotsalainen TM; Mattson K
TI - Interferon trials in small cell lung cancer at one institution: a comparison of results obtained before and after initiation of systematic treatment trials using IFN-alpha in combination with other modalities.
SO - J Interferon Cytokine Res 2002 Feb;22(2):165-71
AD - Department of Oncology, Division of Respiratory Diseases, Helsinki University Central Hospital, Finland. Tarja.Routsalainen@hus.fi
Chemotherapy became the primary treatment for small cell lung cancer (SCLC) in the early 1970s. The standard drug combinations were first vincristine, adriamycin, and cyclophosphamide (VAC) and then, from the early 1980s, etoposide-platinum combinations. Despite a good initial objective response, however, patients usually suffer a rapid relapse. Treatment development has, therefore, focused on ways to overcome drug resistance, and on the addition of cytokines to the chemotherapeutic arsenal. Interferon (IFN) was one of the first cytokines found to have anticancer effects, and it was introduced into the combined modality regimens used to treat SCLC in the early 1980s in an attempt to overcome the problem of early relapse. The role of IFN was investigated with the aim of establishing how best to combine it with other treatments for SCLC. In this paper, we review the impact of IFN on the outcome for 714 SCLC patients who were treated in randomized IFN trials at one institution over a period of 20 years and IFN trials conducted at other institutions during the same period. The parameters we used at our institution to measure outcome tended to improve during the period when patients were being treated in our three randomized IFN trials, compared with the period when patients received only standard treatment in a nonclinical trial setting. However, the differences were not statistically significant. During this period, IFN was used as maintenance therapy, concomitantly with chemotherapy, and combined with other treatment modalities. Our experience is that IFN-alpha is most effective when administered as low-dose maintenance treatment. Other IFN trials published during the same period were small and heterogeneous. Results were inconsistent and added little new information, although it has been shown that high pretreatment levels of serum vascular endothelial growth factor (VEGF) predict a poor response to treatment and consequently a poor outcome. The recently confirmed antiangiogenic properties of IFN deserve to be investigated in studies of maintenance treatment, in combination with other biologic agents. Patient should be selected according to criteria based on pretreatment assessment of biologic markers, such as VEGF and basic fibroblast growth factor (bFGF). Our studies, all at one institution, pioneered the biologic treatment of solid tumors and developed a solid basis of knowledge for future studies of biologic agents in cancer treatment.
UI - 12014670
AU - Gauvin A; Bressolle F; Martineau P; Astre C; Pinguet F
TI - In vitro schedule-dependent interaction between irinotecan and vinorelbine in NCI H460 non-small cell lung cancer cell line.
SO - Anticancer Res 2002 Mar-Apr;22(2A):905-12
AD - Laboratoire d'Onco-Pharmacologie, Centre Regional de Lutte contre le Cancer, Montpellier, France.
Despite recent developments, treatment outcome in advanced non-small cell lung cancer (NSCLC) remains far from satisfactory. Vinorelbine and irinotecan have shown good single-agent activity against NSCLC. These two anticancer agents target different phases of the cell cycle: the cytotoxicity of camptothecin occurs mainly in the S-phase while the cytotoxicity of vinca alkaloids occurs mainly in the M-phase. Thus, it seemed interesting to study the combined activity of these two drugs against human NSCLC cell lines in vitro. In this study, the cytotoxic interaction between vinorelbine and SN 38 (the active metabolite of irinotecan), administered at various schedules, was assessed against a human NSCLC cell line, NCI H460. Cell growth inhibition was determined by the MTT assay. The effects of drug combinations were analysed by the isobologram method. The mean IC50 was 2.06 x 10(-6) mg/ml or vinorelbine, 2.72 x x 10(-3) mg/ml for irinotecan and 2.76 x 10(-6) for SN 38. On simultaneous exposure to these two drugs, additive effects were observed, while antagonistic effects were observed on sequential exposure to vinorelbine followed by SN 38. On sequential exposure to SN 38 first followed by vinorelbine, a slight antagonistic effect was observed at the isoeffect 50%; at the isoeffect 70%, additive effects were observed. These findings suggested that simultaneous exposure to vinorelbine and SN 38 may be the optimum schedule for this combination, while sequential administrations may be less cytotoxic and inadequate. Further preclinical and clinical studies are required to elucidate the relationship between vinorelbine and SN 38 with regard to both anti-tumor activity and toxicity.
UI - 12040278
AU - Itoh Y; Fuwa N; Matumoto A; Asano A; Morita K
TI - Continuous infusion low-dose CDDP/5-FU plus radiation in inoperable or recurrent non-small-cell lung cancer: preliminary experience.
SO - Am J Clin Oncol 2002 Jun;25(3):230-4
AD - Department of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
The combination therapy of continuous infusion low-dose cisplatin plus 5-fluorouracil (5-FU) with radiation for non-small-cell lung cancer (NSCLC) was performed to assess its effectiveness and any adverse patients with inoperable or recurrent NSCLC at Aichi Cancer Center Hospital had been treated by chemoradiation with continuous infusion of low-dose cisplatin/5-FU. The median total radiation dose was 66 Gy (range: 60-74.4 Gy). The daily doses of cisplatin and 5-FU ranged from 3 to 6 mg/m2, and from 170 to 250 mg/m2, respectively. In 18 total patients, a complete response was achieved in 4 patients (22%), and a partial response was observed in 12 patients (67%). Grade III toxicity was limited to leukopenia (14.3%). The 1-year and 2-year survival rate in 14 previously untreated patients were 77.4% and 53.1%, respectively. This combination therapy is a well-tolerated regimen. In the future, a study protocol should be designed with a dose-escalation component to further define the optimal doses and schedule for this regimen.
UI - 12040280
AU - Kim TY; Yang SH; Lee SH; Park YS; Im YH; Kang WK; Ha SH; Park CI; Heo
TI - DS; Bang YJ; Kim NK A phase III randomized trial of combined chemoradiotherapy versus radiotherapy alone in locally advanced non-small-cell lung cancer.
SO - Am J Clin Oncol 2002 Jun;25(3):238-43
AD - Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine, Korea.
A phase III randomized trial was conducted to investigate whether induction chemotherapy followed by radiation can influence survival as compared with radiation alone in unresectable, locally advanced non-small-cell lung cancer (LADNSCLC). A total of 101 patients with unresectable stage IIIA or IIIB NSCLC were enrolled. Patients were stratified by performance status, weight loss, histology and stage, and then randomized to receive combined chemoradiotherapy or radiotherapy alone. Radiotherapy was administered in 1.8 Gy to 2.0 Gy standard fractions daily 5 times weekly for a total dose of 60 Gy to 65 Gy. The combined group received induction of cisplatin, etoposide, and vinblastine (PEV) chemotherapy with cisplatin 20 mg/m2 on days 1 to 5, etoposide 100 mg/m2 on days 2 to 4, and vinblastine 6 mg/m2 on day 1, which wasrepeated every 3 weeks for 3 courses, after which time the patients underwent radiotherapy. Of 101 patients registered, 89 patients (43 combined, 46 radiotherapy alone) were eligible for analysis. The response rates for the combined and radiotherapy groups were 65% (28/43) and 70% (32/46), respectively. The median survival time (MST) showed a tendency to be more prolonged in the combined group than in the group receiving radiotherapy alone (13.8 vs. 8.5 months). The MST in patients with nonsquamous histology was strikingly prolonged in the combined group as compared with the radiotherapy group (14 vs. 3.6 months, p 0.027). Likewise, the MST in patients with stage IIIB was significantly prolonged in the combined group as compared with the radiotherapy group (11.1 vs. 7.2 months, p 0.045). Together, the MST of the high-risk group with nonsquamous or stage IIIB was significantly higher in the combined group than that seen in the radiotherapy group (11.6 vs. 8 months, p 0.046), whereas the MST of the low-risk group, defined as having both squamous histology and stage IIIA, was similar in the two treatment groups (18.3 vs. 20.8 months, p = 0.293). In conclusion, induction PEV chemotherapy plus radiotherapy is superior to radiotherapy alone in high-risk subsets of unresectable LAD-NSCLC and therapeutic strategy should be based on the identification of prognostic factors.
UI - 12040286
AU - Breathnach OS; Kasturi V; Kaye F; Herscher L; Georgiadis MS; Edison M;
TI - Schuler BS; Pizzella P; Steinberg SM; O'Neil K; Johnson BE Phase II neoadjuvant trial of paclitaxel by 96-hour continuous infusion (CIVI) in combination with cisplatin followed by chest radiotherapy for patients with stage III non-small-cell lung cancer.
SO - Am J Clin Oncol 2002 Jun;25(3):269-73
AD - Medicine Branch, Division of Clinical Sciences, National Cancer Institute (NCI)/National Naval Medical Center, NNMC, Bethesda, Maryland, USA.
Sixteen patients with untreated locally advanced (n = 15) or recurrent (n = 1) non-small-cell lung cancer (NSCLC) were enrolled in this study seven had stage IIIB disease, and one had recurrent disease after prior resection of stage I disease. Patients were treated with paclitaxel 30 mg/m2/d for 4 days by continuous intravenous infusion followed by cisplatin 80 mg/m2 on day 5. Therapy was administered every 3 weeks until disease progression or a maximum of four cycles. Thoracic radiation was started within 3 to 4 weeks of day 1 of the last cycle of paclitaxel and cisplatin. Fourteen patients (87.5%) received all four cycles of chemotherapy and subsequent radiation therapy. Forty-four percent of patients achieved a partial response, and 1 patient complete response (overall response rate, 50%). The median progression-free survival was 8.8 months. At a median potential follow-up of 3.7 years, the median survival for all 16 enrolled patients was 13.2 months, and the actuarial 1-, 2-, and 3-year survivals were 62.5%, 43.8%, and 21.9%. In contrast to predictions from in vitro cytotoxicity models, the sequential use of prolonged infusional paclitaxel and bolus cisplatin followed by thoracic radiation does not appear to have a greater impact over shorter chemotherapy
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