Chemotherapy For Small Cell Lung Cancer Research Articles

P1-218: Evaluation of the Recommended Dose and Efficacy of Amrubicin as 2nd and 3rd-line Chemotherapy for Small-Cell Lung Cancer

P1-218: Evaluation of the Recommended Dose and Efficacy of Amrubicin as 2nd and 3rd-line Chemotherapy for Small-Cell Lung Cancer

Increasing Chemotherapy in Small-Cell Lung Cancer: From Dose Intensity and Density to Megadoses

The hypothesis that increasing cytotoxic dose intensity will improve cancer cure rates is compelling. Although supporting evidence for this hypothesis has accrued for several tumor types, including lymphomas, breast cancer, and testicular cancers, it remains unproven. Small-cell lung cancer is extremely chemo- and radiosensitive, with a response rate of 80% achieved routinely, but few patients are cured by chemoradiotherapy. In this setting, increased cytotoxic dose intensity might improve cure rates. The finding that response rates in small-cell lung cancer correlate with received cytotoxic dose intensity merely confirms that "less is worse" and "more is better." Within conventional ranges, dose intensity can be increased with the support of hematopoietic growth factors and/or by shortening treatments intervals; however, dose intensity could be increased by only 20%-30%, and a survival advantage has not been clearly demonstrated. Given its high chemosensitivity, small-cell lung cancer was one of the first malignancies deemed suitable for increasing dose intensity and even for the use of a megadose with the support of autologous bone marrow transplantation. Some interest is emerging again due to improvements in supportive care, such as the availability of hematopoietic growth factors and peripheral blood progenitor cells.

Tumor Lysis Associated with Sudden Onset of Syndrome of Inappropriate Antidiuretic Hormone Secretion

Syndrome of inappropriate antidiuretic hormone secretion is frequent in small-cell lung carcinomas. We report on a case of syndrome of inappropriate antidiuretic hormone secretion after each of the first 2 cycles of chemotherapy for small-cell lung cancer. The association with chemotherapy-induced tumor lysis is proposed, particularly based on the course of antidiuretic hormone levels, and a review of the literature is presented. Syndrome of inappropriate antidiuretic hormone secretion can occur during tumor lysis syndrome.

The association of chemotherapy induced neutropenia on treatment outcomes in small cell lung cancer

Chemotherapy induced neutropenia has been shown to be associated with improved treatment outcomes in selected solid tumours. We studied the association of chemotherapy induced neutropenia with treatment related outcomes in small cell lung cancer (SCLC). This is a retrospective analysis of patients receiving chemotherapy for SCLC at the Royal Marsden Hospital, UK over an 8 year period. The chemotherapy included Carboplatin AUC 5, IV and Etoposide 100mg/m(2) IV on day 1 and 100mg/m(2) PO, B.I.D. on day 2 and 3 every 21 days. Patients were stratified into two groups (A) those experiencing grades 0-2 neutropenia and group (B) those experiencing grades 3-4 neutropenia. The outcomes studied were response rate, time to progression (TTP) and overall survival (OS). 173 patients were studied. The median age 64 (range 39-83) and M/F ratio was 112:61. The response rates in groups A and B was 90% versus 90%, p=1.0. The median TTP in groups A and B was 30 and 38 weeks, p=0.05. The median OS in groups A and B was 47 weeks versus 60 weeks, p=0.008. The differences in TTP and OS were not significant in patients with extensive stage disease. Occurrence of chemotherapy induced grade 3 or 4 neutropenia correlated with OS in patients with SCLC receiving carboplatin and etoposide chemotherapy. Trials exploring controlled, safe intra-patient dose escalation with the intent of achieving grade 3 or 4 neutropenia in patients with SCLC are warranted.

Early Compared With Late Radiotherapy in Combined Modality Treatment for Limited Disease Small-Cell Lung Cancer: A London Lung Cancer Group Multicenter Randomized Clinical Trial and Meta-Analysis

To replicate an earlier National Cancer Institute of Canada (NCIC) trial that examined the effect on survival of the timing of thoracic radiotherapy (TRT) in patients with limited disease small-cell lung cancer (SCLC). Patients received three cycles of cyclophosphamide, doxorubicin, and vincristine alternating with three cycles of etoposide and cisplatin. Three hundred twenty five chemotherapy- and radiotherapy-naïve patients were randomly assigned to either early TRT administered concurrently in the second cycle or late TRT administered concurrently with the sixth cycle; the dose was 40 Gy in 15 fractions over 3 weeks. TRT was received by 92% and 82% of patients in the early and late arms, respectively (P = .01). Sixty-nine percent of patients in the early arm received all six courses of chemotherapy compared with 80% in the late arm (P = .003). There was no evidence of a survival difference; median overall survival time was 13.7 and 15.1 months in the early and late arms, respectively (P = .23). In a meta-analysis of all eight trials that compared early and late TRT, there were three in which the proportion of patients who completed their planned chemotherapy was similar between the TRT arms (hazard ratio [HR] = 0.73; 95% CI, 0.62 to 0.86) and five in which proportionally fewer patients in the early TRT arm completed their chemotherapy (HR = 1.06; 95% CI, 0.97 to 1.17). This study failed to show a survival advantage for early TRT with chemotherapy in limited-stage SCLC, unlike the NCIC trial. However, the results of a meta-analysis suggest that it is essential to ensure that the delivery of chemotherapy is optimal when administered with early TRT.

Randomized phase III study of high-dose sequential chemotherapy (CT) supported by peripheral blood progenitor cells (PBPC) for the treatment of small cell lung cancer (SCLC): Results of the EBMT Random-ICE trial

7064 Background: EBMT has defined in a phase II trial (JCO 1999, 3531) feasibility and activity of high-dose sequential CT for SCLC increasing 3 fold the dose-intensity and significantly the peak-dose and the total dose of CT. Methods: Randomized prospective study aiming to improve the 3-year survival from 12% in the standard (S) to 24% in the high-dose (H) arm, for a total accrual of 340 patients. Limited or extensive ≤ 2 metastatic sites, age ≤ 65 y.o., PS 0–1. Arm S/Arm H: ifosfamide 5 g/m2 d1/2.5 g/m2/d × 4; carboplatin 300 mg/m2 d1/AUC = 5/d × 4; etoposide 180 mg/m2/d. × 2/300 mg/m2/d × 4, every 28 days, for 6 cycles in Arm S. Three cycles were given in Arm H supported by PBPC collected after 2 courses of epirubicin 150 mg/m2/paclitaxel 175 mg/m2. Due to low accrual, a formal stopping rule was introduced with boundaries for early stopping in favour of a difference (O’Brien-Fleming) or of lack thereof (Pocock). The present analysis has been done with 110 deaths. Results: Since June 1997, 145 patients have been accrued (evaluable =140, S = 71, H = 69), median age 53, prognostic factors balanced. Mobilization toxicity ≥ 3: neutropenia 61%, thrombopenia 11%, anemia 7%, infection 6%, mucositis 9% and 2 toxic deaths. Toxicity ≥ 3 among 353 cycles of S and 152 of H respectively: neutropenia 26%/100%, thrombopenia 12%/100%, anemia 8%/69%, infection 1%/15%, fever 11%/72%, toxic death 1/8. Response rate of S and H: 67% (CR 32%)/77% (CR 37%) (p = 0.188). Median follow-up 4.9 years. Progression free survival 8.8 and 12 months (p = 0.737, unadjusted) and median overall survival 15 and 19.1 months (p = 0.659, unadjusted) for S and H respectively. At 3 years, 19% of the patients were alive in both arms. Conclusions: Random-ICE was designed with strong statistical power and shows no evidence that the treatment of SCLC can be improved by increasing the dose-intensity, the peak-dose or the total dose of ICE and that such intensification strategy should probably be abandoned. No significant financial relationships to disclose.

Prognostic Factors for Patients With Spinal Metastases From Lung Cancer

We conducted a retrospective study to identify prognostic factors of patients with spinal metastases from lung cancer. To provide clinical data with strong association to the prognosis and to propose criteria determining indication of operation for spinal metastases. To make a proper selection of patients for whom surgery is indicated, forecasting short-time survival after spinal metastases is very important. In the past, there has been no report of prognostic factors of patients with such metastases from this cancer. This study included 114 patients with spinal metastases of lung cancer. Tumors were histologically categorized as non-small cell lung cancer (NSCLC) in 94 patients and small cell lung cancer (SCLC) in 20 patients. We investigated prognostic factors after spinal metastases using Cox comparative hazard model and a preoperative prognostic score proposed by Tokuhashi. We also investigated the patients who underwent operation for spinal metastases from lung cancer in our hospital. Multivariate analysis showed that the significant prognostic factors for survival after spinal metastases from NSCLC were performance status (PS), Ca, Alb. Among SCLC patients, Ca, Alb, and a history of chemotherapy were significant (P < 0.05) in univariate analysis. The score of Tokuhashi was not correlative to the survival period. Among the operated patients, postoperative PS was significant for the period of postoperative survival. PS, Ca, and Alb in NSCLC and Ca, Alb, and a history of chemotherapy in SCLC are useful for determining an indication of operation for spinal metastases from lung cancer.

Antibiotics plus granulocyte colony-stimulating factor reduces febrile neutropenia in the first cycle of chemotherapy in people with small-cell lung cancer

Febrile neutropenia, a complication of chemotherapy, results in loss of quality of life and sometimes death. Prophylactic antibiotics and granulocyte colony-stimulating factor have individually been reported to be effective in reducing chemotherapy-induced febrile neutropenia (FN). However, the safety and efficacy of prophylactic treatment with antibiotic combined with granulocyte colony-stimulating factor after chemotherapy for small-cell lung cancer is unclear.

Third-line chemotherapy for small cell lung cancer

Efficacy of third-line chemotherapy treatment for small cell lung cancer (SCLC) is unknown. We present our experience with third-line chemotherapy for recurrent SCLC. Between January 1996 and July 2004 all consecutive patients treated for SCLC were retrospectively studied. We recorded patient characteristics, treatment details for each subsequent regimen, response to chemotherapy and survival. From 191 patients treated with chemotherapy 35 patients (18%) received third-line chemotherapy. At the start of third-line therapy, median age was 58 years (range 36-77), male/female 54%/46%, and ECOG performance score was 0/1/2/3 in 15%/64%/12%/9% of patients. Median time from diagnosis till start of third-line treatment was 15 months (range 5-34). Tumor response to first-line, second-line, and third-line therapy was 91%, 51%, and 26%, respectively. Median survival time estimated from the start of third-line treatment was 5 months (range 1-15). No toxic deaths were observed. Comparison of characteristics of patients who were treated with third-line chemotherapy with patients treated with maximally two lines of chemotherapy revealed that those who received third-line therapy were younger (p<0.001), had a better performance score (p<0.001), and had a better response to first-line treatment (p=0.004). In conclusion, third-line chemotherapy is still active in one in four SCLC patients.

Cost Effectiveness of Increasing the Dose Intensity of Chemotherapy with Granulocyte Colony-Stimulating Factor in Small-Cell Lung Cancer

The use of granulocyte colony-stimulating factor (G-CSF) can enable dose intensification of chemotherapy in small-cell lung cancer (SCLC). However, given its acquisition cost, it is important to assess its cost effectiveness within a resource-constrained health service. To assess the cost effectiveness, from the UK NHS perspective, of G-CSF given in addition to doxorubicin, cyclophosphamide and etoposide (ACE) versus ACE alone in the management of SCLC. Using data from a UK Medical Research Council trial (LU19) to assess chemotherapy dose intensification in patients with previously untreated SCLC of any disease extent, a retrospective cost-effectiveness analysis was undertaken. Resource use data, including hospitalisations and non-protocol cancer treatments, were collected during the first 6-month treatment phase of the trial. Mean costs ( pound, 2003 values) of managing patients in the two arms of the trial were calculated. Mean survival duration was calculated for the two groups using patient-specific follow-up data collected in the trial. Incremental cost-effectiveness analysis was undertaken, and uncertainty in cost effectiveness was expressed using cost-effectiveness acceptability curves. The use of G-CSF in addition to ACE chemotherapy is more costly ( 4647 pounds) but results in longer mean survival duration (0.20 years; 0.18 years when discounted). This generates an incremental cost per additional life-year of 25,816 pounds for ACE + G-CSF therapy. The probability of the addition of G-CSF being cost effective, if decision makers are willing to pay 30,000 pounds for an additional life-year, is 0.57. Secondary analysis suggests that cost effectiveness is likely to be sensitive to assumptions about the health-related quality of life (HR-QOL) experienced by patients. Based on data collected in the LU19 trial, chemotherapy dose intensification using G-CSF in SCLC adds to health service costs but increases survival duration. Its overall cost effectiveness is likely to be finely balanced.

Time and chemotherapy treatment trends in the treatment of elderly patients (age ⩾70 years) with small cell lung cancer

Platinum-based treatment for small cell lung cancer (SCLC) has been established since 1995. This study investigates treatment outcome of elderly patients (age ⩾70 years) with SCLC over the past 20 years in a large UK cancer centre. Comparison of all-cause survival was assessed in patients presenting between two predefined time periods: 1982–1994 and 1995–2003. All the survival analysis were adjusted for stage and performance status and age if appropriate. Survival between different chemotherapy treatment regimens was compared. A total of 322 elderly patients (31% of all) registered between 1982–2003 received chemotherapy for SCLC. Patients presenting in 1995–2003 had an overall better median survival (43 vs 25 weeks) and a 1-year survival (37 vs 14%) than patients presenting in 1982–1994 (P<0.001). This applied to patients with both limited and extensive stage disease and all age groups. There was a trend towards the use of more platinum-based treatments in the later cohort but the use of radiotherapy remained constant. Patients who received platinum combinations (Carboplatin or Cisplatin) had significantly improved survival over those who received single agents or other combinations (P<0.001) and there was no significant difference between carboplatin and cisplatin (P=0.7). The analysis demonstrates that there has been a significant improvement in survival for elderly patients with lung cancer treated by chemotherapy in the past 20 years despite more very elderly patients being treated with a poorer performance status. This change is probably multifactorial and may be due to the increased use of platinum-based treatment and improved supportive care.

P-763 Lack of efficacy of weekly topotecan as 2nd line chemotherapyfor small cell lung cancer

P-763 Lack of efficacy of weekly topotecan as 2nd line chemotherapyfor small cell lung cancer

Second-line chemotherapy with cyclophosphamide, doxorubicin and vincristine (CAV) in patients with small cell lung cancer (SCLC) initially treated with platinum and etoposide

7325 Background: SCLC is usually highly sensitive to chemotherapy but, despite a frequent dramatic initial response, most patients relapse. The purpose of this study was to evaluate the efficacy and toxicity of a second-line chemotherapy with CAV in patients with SCLC previously treated with platinum and etoposide. Methods: Eligibility criteria were: progressive disease after first-line chemotherapy with platinum and etoposide for SCLC, ECOG PS less than or equal to 2, adequate haematological, hepatic and renal function. Patients were treated with CAV every four week (cyclophosphamide: 1.5 mg/msup2, adriamycine: 70 mg/msup2, vincristine: 1.4 mg/msup2). Results: Among 58 patients who were treated with platinum and etoposide as first-line chemotherapy for SCLC in our institution between 1997 and 2002, 20 patients received a second-line chemotherapy; 17 patients fulfilled the eligibility criteria and were included in this study. Patients characteristics were: male/female: 15/2; median age: 59 years (range 47–75); limited disease/extensive disease: 6/11; chemotherapy-free interval was less than or equal to 4 months in 14 patients (82%) and > 4 months in 3 patients (7, 17 and 20 months). Efficacy: complete response was observed in 1 patient (6%), partial response in 5 patients (29%), stable disease in 0 patient and progression in 11 patients (65%). Toxicity profile: neutropenia G3–4 occurred in 7 patients (41%), anemia G3–4 in 2 patients (12%); thrombocytopenia G3–4 in 1 patient (6%), neuropathy G1–2 in 1 patient (6%). There were 3 therapy-related deaths. Median survival time was 13 months. Conclusions: CAV is effective as second-line chemotherapy in patients with SCLC initially treated with platinum and etoposide. However, its toxicity rate is high. No significant financial relationships to disclose.

Randomized Phase III Trial of Dose-Dense Chemotherapy Supported by Whole-Blood Hematopoietic Progenitors in Better-Prognosis Small-Cell Lung Cancer

Recent dose-intensity studies of small-cell lung cancer (SCLC) have yielded conflicting results. We carried out a phase III randomized trial in patients with better-prognosis SCLC (i.e., prognostic score of 0-1) to investigate whether doubling the dose density of ifosfamide, carboplatin, and etoposide (ICE) chemotherapy with filgrastim and blood-progenitor-cell support improves survival, compared with standard ICE chemotherapy. We studied 318 patients with pathologically proven SCLC who were randomly assigned to receive six cycles of ICE chemotherapy with a 4-week (standard arm) or 2-week (dose-dense arm) interval between cycles. Patients in the dose-dense arm received filgrastim subcutaneously daily on days 4 through 14 and had autologous blood collected before cycles 2 through 6, which was returned 24 hours after treatment. Toxicities, including hematologic toxicity and incidence of neutropenic sepsis, were monitored. Survival was calculated by the Kaplan-Meier method. All statistical tests were two-sided. The delivered median dose intensity was 99% (interquartile range = 96%-100%) for the standard arm and 182% (interquartile range = 163%-196%) for the dose-dense arm. After a median follow-up of 14 months, overall response to treatment was observed in 118 (80%) of the 148 evaluable patients in the standard arm and in 129 (88%) of the 147 evaluable patients in the dose-dense arm, a statistically non-significant difference. Median overall survival was 13.9 months (95% confidence interval [CI] = 12.9 to 15.8 months) in the standard arm and 14.4 months (95% CI = 12.7 to 16.0) in the dose-dense arm, and the 2-year survival was 22% (95% CI = 16% to 29%) and 19% (95% CI = 14% to 27%), respectively--neither difference being statistically significant. The median treatment free time was 286 days (95% CI = 229 to 343 days) for the standard arm and 367 days (95% CI = 321 to 413 days) for the dose-dense arm (difference = 81 days; P = .109). Statistically significantly more hematologic toxicity was reported in the dose-dense arm than in the standard arm, but the number of cycles complicated by neutropenic sepsis was statistically significantly higher in the standard arm than in the dose-dense arm (15.3% versus 11.6%, respectively; difference = 3.7%, 95% CI = -4.1% to 11.5%; P = .03). Dose-dense ICE chemotherapy for SCLC led to shorter treatment duration and less neutropenic sepsis than did standard ICE but did not improve overall survival.

Second-line chemotherapy with weekly paclitaxel and gemcitabine in platinum-etoposide pretreated patients with small cell lung cancer (SCLC): A single institution phase II trial

7209 Background: Paclitaxel and gemcitabine are active drugs in SCLC. Preliminary analysis suggest that weekly paclitaxel yields in non-small-cell lung cancer patients equivalent efficacy results, maintains dose intensity. Methods: We tested the activity of their combination with a weekly schedule of paclitaxel in a phase II trial as second-line chemotherapy. In this trial progressing patients after first-line treatment with platinum-etoposide were treated with paclitaxel 80 mg/m2 days 1,8,15 and gemcitabine 1000 mg/m2 days 1 and 8 every three weeks. Eligibility criteria were: progressive disease after first-line chemotherapy, age < 75 years, adequate haematological, hepatic and renal function. Results: Between 7/1999 and 2/2003 we enrolled 31 patients. Pts characteristics: male/female: 24/7; ECOG PS 0/1/2: 3/20/8; median age: 64 years (range 48–68); LD/ED: 5/26; prior thoracic/brain radiotherapy was administered in 17 and 5 pts, respectively; chemotherapy-free interval was ≤3 months in 10 pts (32%) and >3 months in 21 pts (68%). A total of 106 cycles were given with a median number of 3 cycles per patient. Median dose intensity for paclitaxel was 58 mg/m2/week (72% of planned dose) and for gemcitabine 553 mg/m2/week (83% of planned dose). Partial responses were observed in 8 pts (26%), stable disease in 5 (16%) and progression in 18 (58%). In refractory and sensitive pts RR was 20 and 29%, respectively. Toxicity: neutropenia G3–4 in 26% and 0% of pts, thrombocytopenia G3–4 in 22% and 3%; G3–4 asthenia in 13%; G1–2 neurophaty in 32%. Median time to progression was 9.6 weeks. Median survival time was 7.4 months. Conclusions: This weekly schedule of paclitaxel and gemcitabine is an active second-line chemotherapy in SCLC and is very well tolerated. The low dose intensity of paclitaxel could be related to previous radiation therapy in 70% of pts. It seems non-cross resistant with cisplatin or carboplatin and etoposide combination and warrant further evaluation in the

Therapeutic efficacy of chemotherapy with VIP for small cell lung cancer

To evaluate the effect of combination chemotherapy with etoposide plus ifosfamide and cisplatin (VIP) for small cell lung cancer (SCLC). One-hundred and twenty patients with localized SCLC who never received chemotherapy were randomly divided into VIP regimen group and EP regimen group. The response and toxicity were evaluated after 3 cycle chemotherapy with VIP or EP respectively. In addition, salvage chemotherapy by VIP was given to 25 patients, who had progression or recurrence of the cancer after treatment with EP regimen, and the response was assessed after 3 cycles of the treatment. In 118 evaluable patients, response rate was 89.6% for VIP regimen group and 78.3% for EP regimen group. There was no remarkable difference of response rates between the two groups. Toxicity of the two regimens was similar. However, complete response rate for VIP regimen group (43.1%) was significantly higher than that for EP regimen group (25.0%) (P < 0.05). In 23 patients who were progressive or relapsed after treatment with EP regimen, the complete response, partial response, progression and total response were 13.0%, 39.1%, 47.8% and 52.2% respectively. VIP regimen may be used as the first-line chemotherapy for localized SCLC, its efficacy is superior to that of EP regimen. VIP can also be used as salvage chemotherapy regimen for patients with SCLC who failed to EP regimen chemotherapy.

Present trends in the treatment of advanced non small-cell lung cancer.

Lung cancer is the leading cause of cancer deaths all over the world. As most patients present with advanced disease, major efforts have been made in the treatment of such disease with systemic chemotherapy. Several new agents and new combinations of chemotherapy have been developed recently. This article reviews the randomized clinical trials investigating chemotherapy for advanced non small-cell lung cancer (NSCLC) in relapse or progressive disease while being treated and in elderly patients. Therapies that incorporate new biological agents to target specific defects in lung cancer are also discussed. Several clinical trials have demonstrated improvement in overall survival as well as quality of life with presently available chemotherapy treatment of advanced NSCLC. Better options are available for the elderly as well as those having relapse after first-line chemotherapy. Despite all this progress the 5-year survival rate still remains at a dismal 14%. New therapies with good results are still desired.

Phase I/II trial of gemcitabine plus cisplatin and etoposide in patients with small-cell lung cancer

Objective: The objectives of this phase I/II study were to define the maximum tolerated dose (MTD), safety, and activity of cisplatin, etoposide, and gemcitabine (PEG) in the treatment of previously untreated patients with small-cell lung cancer (SCLC). Patients and Methods: Chemonaive patients received fixed doses of gemcitabine (1000 mg/m 2 on days 1 and 8) and cisplatin (70 mg/m 2 on day 2) and escalating doses of etoposide (starting dose of 50 mg/m 2 on days 3, 4, and 5) every 3 weeks. No prophylactic granulocyte colony-stimulating factors were used. Results: From September 1998 to April 2000, 56 patients with limited- or extensive-stage SCLC were enrolled and received a total of 235 cycles. Two different etoposide doses were tested in eight patients. At the second level (75 mg/m 2), two out of two patients experienced dose-limiting toxicities (neutropenia and thrombocytopenia) and no further dose-escalation was attempted, thus an etoposide dose of 50 mg/m 2 was defined as the MTD. In the subsequent phase II evaluation, 48 additional patients were enrolled, for a total of 54 patients treated at the MTD. Grade 3/4 neutropenia and thrombocytopenia occurred in 66.7 and 53.7% of patients, respectively. Non-hematologic toxicity was mild, with grade 3 diarrhea and fatigue as the main side effects. Two patients died of neutropenic sepsis (one at 75 mg/m 2 and the other at 50 mg/m 2 etoposide). Ten complete and 29 partial responses were reported, for an overall response rate of 72.2% (95% confidence interval, 56.6–85.0%). The median duration of response and median survival were 8.0 and 10 months, respectively, with a 1-year survival probability of 37.5%. Conclusions: The combination of PEG is feasible and well tolerated as front-line chemotherapy in SCLC. A randomized comparison of this triplet is underway.

Detection of occult tumor cells in peripheral blood from patients with small cell lung cancer by promoter methylation and silencing of the retinoic acid receptor-β

In order to investigate the possibility of detecting occult tumor cells of small cell lung cancer (SCLC), we used the methylation-specific PCR assay to detect methylation of retinoic acid receptor-beta (RARbeta) in peripheral mononuclear cells (PMNC). The methylation-specific PCR assay can detect one tumor cell per 10(3) normal cells. Seventy-two patients participated in this study. They received an initial full-dose of combination chemotherapy for SCLC between October 1995 and June 2000. The patients were classified according to the clinical stage of their tumors as limited disease (LD) in 31 patients and extensive disease (ED) in 41. PMNC were obtained before each patient underwent chemotherapy. We detected RARbeta methylation in PMNC from 42 of the 72 SCLC patients (58.3%). Nineteen of 31 patients with LD-SCLC (61.3%) and 23 of 41 patients with ED-SCLC (56.1%) were positive for RARbeta methylation. The overall survival for patients who were positive and negative for RARbeta methylation was not significantly different in both the LD- and ED-SCLC groups (log-rank test, p=0.13 and p=0.38, respectively); however, 2-year survival was significantly greater in the RARbeta methylation-positive LD-SCLC patients (chi(2) test, p=0.044). In conclusion, occult tumor cells can be detected in the peripheral blood of patients with SCLC using methylation of RARbeta, and long-term survival appears to be better in LD-SCLC patients with occult tumor cells in their blood.

Phase II Study of Topotecan and Etoposide as Second-line Treatment in Chemotherapy-refractory Small-cell Lung Cancer.

Refractory small-cell lung cancer (SCLC) has a poor prognosis, and current salvage chemotherapy for refractory SCLC, such as CAV (cyclophosphamide, adriamycin, vincristine) or topotecan, has an unsatisfactory outcome, with a response rate and overall survival of less than 10% and 6 months, respectively. This phase II study evaluated the role of topotecan combined with etoposide in SCLC patients that have progressed, or relapsed, within 3 months following completion of the initial chemotherapy. Twenty-seven patients were entered into this study. Eligible patients had an ECOG performance status of less than, or equal to, 2, at least one bidimensionally measurable lesion and adequate end organ function. IV topotecan, 1.0 mg/m2/d for 5 consecutive days, and etoposide, 100 mg/m2/d through days 1 to 3, were administered every 3 weeks until disease progression or undue toxicity. The major toxicity was myelosuppression. Grade 3/4 anemia, granulocytopenia, and thrombocy-topenia occurred in 14.2, 34.8, and 27.3% of cycles, respectively. There was no treatment-related death, and other non-hematologic toxicities were generally mild. Four patients achieved partial responses, with a response rate RR of 14.8%. The progression-free survival PFS ranged from 1 to 7 months, with a median of 2.0 months (95% confidence interval 1.22~2.78 months). Twenty-five patients died, with a median overall survival of 5.5 months (ranging from 1 to 21 months, 95% CI 4.32~6.68 months), and the 6-month survival rate was 32.1% (95% confidence interval 14.4~49.8%). The combination of topotecan and etoposide chemotherapy showed a modest response rate, but failed to prolong survival of refractory SCLC patients compared to topotecan monotherapy.