The newborn screening tests in Brazil: regional and socioeconomic prevalence and inequalities in 2013 and 2019

Abstract Objective: To analyze the prevalence evolution of Guthrie, hearing, and eye screening testing among newborns in Brazil, between 2013 and 2019, according to demographic and socioeconomic characteristics. Methods: This is a cross-sectional study with data from 5231 infants from the Pesquisa Nacional de Saude (PNS), in 2013, and 6637 infants, in 2019, for the Guthrie test, hearing, and red reflex tests. The authors analyzed the outcomes according to the region of residence, self-reported color/race, having health insurance, and per capita household income. By using bivariate and multivariate Poisson regression models, the prevalence ratios and their respective 95 % Confidence Intervals (CI95%) were calculated for each year. Results: In 2013, Guthrie test, hearing, and red reflex tests were performed in 96.5 % (95%CI 95,8;97,0), 65.8 % (95%CI 63,9;67,7), and 60.4 % (95%CI 58,5;62,3) of infants, respectively. In 2019, the prevalence was 97.8 % (95%CI 97,3;98,2) in the Guthrie test, 81.6 % (95%CI 80,3;82,9) in the hearing test, and 78.6 % (95%CI 77,1;79,9) in the red reflex test. The testing frequency was higher among residents of the Southeast and South regions of Brazil, among infants whose mother or guardian was white, had health insurance, and was in the higher income strata; and the most evident differences were in the eye and hearing testing. Conclusions: The coverage inequalities according to the region of residence, income, and having health insurance highlight the need to use strategies that enable exams to be carried out, with more information about their importance, encompassing actions from primary care, prenatal care to the puerperium, aiming at universal access and equity.

The newborn screening tests in Brazil: regional and socioeconomic prevalence and inequalities in 2013 and 2019.

OBJECTIVE: To analyze the prevalence evolution of Guthrie, hearing, and eye screening testing among newborns in Brazil, between 2013 and 2019, according to demographic and socioeconomic characteristics. METHODS: This is a cross-sectional study with data from 5231 infants from the Pesquisa Nacional de Saúde (PNS), in 2013, and 6637 infants, in 2019, for the Guthrie test, hearing, and red reflex tests. The authors analyzed the outcomes according to the region of residence, self-reported color/race, having health insurance, and per capita household income. By using bivariate and multivariate Poisson regression models, the prevalence ratios and their respective 95 % Confidence Intervals (CI95%) were calculated for each year. RESULTS: In 2013, Guthrie test, hearing, and red reflex tests were performed in 96.5 % (95%CI 95,8;97,0), 65.8 % (95%CI 63,9;67,7), and 60.4 % (95%CI 58,5;62,3) of infants, respectively. In 2019, the prevalence was 97.8 % (95%CI 97,3;98,2) in the Guthrie test, 81.6 % (95%CI 80,3;82,9) in the hearing test, and 78.6 % (95%CI 77,1;79,9) in the red reflex test. The testing frequency was higher among residents of the Southeast and South regions of Brazil, among infants whose mother or guardian was white, had health insurance, and was in the higher income strata; and the most evident differences were in the eye and hearing testing. CONCLUSIONS: The coverage inequalities according to the region of residence, income, and having health insurance highlight the need to use strategies that enable exams to be carried out, with more information about their importance, encompassing actions from primary care, prenatal care to the puerperium, aiming at universal access and equity.

Neonatal screening tests in Brazil: prevalence rates and regional and socioeconomic inequalities / Realização dos testes de triagem neonatal no Brasil: prevalências e desigualdades regionais e socioeconômicas

Abstract Objective: To identify the prevalence and associated factors with the performance of the Guthrie test, hearing, and red reflex screening tests in Brazil. Methods: This was a population-based, cross-sectional study that analyzed data on 5,231 children under 2 years of age participating in the National Health Survey of 2013. The study described the prevalence and Confidence Intervals (95% CI) of the three neonatal screening tests performed, in any period, and their association with the country's regions, skin color/ethnicity, private health insurance, and per capita household income. Logistic regression models were used, and odds ratios were calculated by incorporating sample weights. Results: The prevalence of Guthrie test screening in Brazil at any time of life was 96.5%, that of the newborn hearing screening was 65.8% and that of the red reflex screening test was 60.4%. The performance of the three screening tests was significantly higher among children whose mothers/guardians reported higher per capita household income, who lived in the South and Southeast regions, and who had private health insurance (p < 0.001). There was no statistically significant difference regarding the performance of the tests according to skin color/ethnicity (p > 0.05). The same inequalities were verified when the tests were performed during the recommended periods, with a strong socioeconomic gradient. Conclusions: There are inequalities in the performance of neonatal screening tests in the country, and also in the performance of these tests during the periods established in the governmental guidelines. The guarantee of the performance of these tests in a universal and public health system, as in Brazil, should promote equity and access to the entire population.

Resumo Objetivo: Identificar prevalência e fatores associados à realização dos testes do pezinho, da orelhinha e do olhinho no Brasil. Método: Estudo transversal analítico de base populacional que analisou os dados de 5.231 crianças menores de dois anos participantes da Pesquisa Nacional de Saúde (2013). Foram descritas prevalências e intervalos de confiança (95% IC) da realização dos três testes de triagem neonatal, em qualquer período, e sua associação com as regiões do país, cor/etnia, posse de plano de saúde e renda domiciliar per capita. Empregaram-se modelos de regressão logística e calcularam-se as odds ratio e incorporaram-se os pesos amostrais. Resultados: A prevalência de realização do teste do pezinho no Brasil em qualquer momento de vida foi de 96,5%; do teste da orelhinha de 65,8% e do teste do olhinho de 60,4%. A realização dos três testes de triagem foi significativamente maior entre as crianças cujas mães/responsáveis reportaram maior renda domiciliar per capita, residiam nas regiões Sul e Sudeste e tinham plano de saúde (p < 0,001). Não houve diferença estatisticamente significativa na realização dos testes segundo cor/etnia (p > 0,05). As mesmas desigualdades foram verificadas para a realização dos testes no período preconizado, com forte gradiente socioeconômica. Conclusões: Existem desigualdades na realização dos testes de triagem neonatal no país e, também, na realização desses dentro dos prazos previstos nas diretrizes governamentais. A garantia desses testes em um sistema universal e público como no Brasil deveria promover a equidade e o acesso a toda a população.

Neonatal screening tests in Brazil: prevalence rates and regional and socioeconomic inequalities.

OBJECTIVE: To identify the prevalence and associated factors with the performance of the Guthrie test, hearing, and red reflex screening tests in Brazil. METHODS: This was a population-based, cross-sectional study that analyzed data on 5,231 children under 2 years of age participating in the National Health Survey of 2013. The study described the prevalence and Confidence Intervals (95% CI) of the three neonatal screening tests performed, in any period, and their association with the country's regions, skin color/ethnicity, private health insurance, and per capita household income. Logistic regression models were used, and odds ratios were calculated by incorporating sample weights. RESULTS: The prevalence of Guthrie test screening in Brazil at any time of life was 96.5%, that of the newborn hearing screening was 65.8% and that of the red reflex screening test was 60.4%. The performance of the three screening tests was significantly higher among children whose mothers/guardians reported higher per capita household income, who lived in the South and Southeast regions, and who had private health insurance (p<0.001). There was no statistically significant difference regarding the performance of the tests according to skin color/ethnicity (p>0.05). The same inequalities were verified when the tests were performed during the recommended periods, with a strong socioeconomic gradient. CONCLUSIONS: There are inequalities in the performance of neonatal screening tests in the country, and also in the performance of these tests during the periods established in the governmental guidelines. The guarantee of the performance of these tests in a universal and public health system, as in Brazil, should promote equity and access to the entire population.

Carboplatin calculated with Chatelut's formula plus etoposide for elderly patients with small-cell lung cancer.

OBJECTIVE: This dose escalation was conducted to evaluate the applicability of Chatelut's dosing, and to determine the efficacy and toxicity of carboplatin with etoposide in previously untreated elderly patients (>70 years) with small cell lung cancer. PATIENTS AND METHODS: Seventeen patients were treated with etoposide for 3 days and carboplatin calculated dose using Chatelut's formula on day 1 intravenously. The starting doses of etoposide on days 1 to 3, and carboplatin using the area under the concentration versus time curve (AUC) were 90 mg/m2 and 4 mg/ml x min, respectively. RESULTS: The median age was 77 years (range 71 to 87). Dose-limiting toxicity (DLT) was seen at level 4 (AUC 5 mg/ml x min of carboplatin and etoposide 100 mg/m2). Hematologic toxicity was the primary DLT. Grade 4 thrombocytopenia and Grade 4 leukopenia were observed at level 4. Non-hematologic toxicity was insignificant. The overall response rate was 94%. CONCLUSION: Etoposide at 100 mg/m2 and AUC of carboplatin of 4.5 mg/ml x min as calculated using Chatelut's formula every four weeks is the recommended dose for further phase II trials for elderly patients with small cell lung cancer.

Intrapleural administration of cisplatin and etoposide to treat malignant pleural effusions in patients with non-small cell lung cancer.

BACKGROUND: To determine the efficacy, toxicity and pharmacokinetics of intrapleural cisplatin (CDDP) and etoposide as a treatment for malignant pleural effusions (MPE) in patients with non-small cell lung cancer (NSCLC). METHODS: Seventy patients with MPE associated with NSCLC were enrolled in this study. In 68 patients, a catheter was inserted into the pleural cavity, within 24 h after complete drainage of the pleural effusion, CDDP (80 mg/m2) and etoposide (80 mg/m2) were simultaneously administered successfully via the catheter and the catheter was clamped. Seventy-two hours later, the catheter was unclamped to allow drainage. The catheter was removed when the accumulated intrapleural fluid decreased to 20 ml or less per day. RESULTS: The pharmacokinetic profiles showed high maximum concentrations of CDDP (free form, 88 microg/ml) and etoposide (182. 4 microg/ml) in intrapleural fluids. CDDP did not remain for a long period (free form, beta-phase half-life = 10.51 h) in the fluids, while etoposide persisted for a long period (beta-phase half-life = 62.53 h). The overall response rate was 46.2%, the median survival time 32.3 weeks, the 1-year survival rate 28.7% and the 2-year survival rate 12.8%. The most serious adverse reactions were WHO grade 3 anemia (3 patients), grade 3 nausea and vomiting (17 patients), grade 3 constipation (1 patient), grade 3 pulmonary toxicity (1 patient), grade 4 fever (1 patient), grade 3 infection (1 patient) and grade 3 mental disorder (1 patient). CONCLUSION: Intrapleural administration of CDDP and etoposide was an effective and acceptable regimen for patients with MPE due to NSCLC.

Combination of irinotecan and etoposide for treatment of refractory or relapsed small-cell lung cancer.

PURPOSE: To determine the response rate, survival, and toxicity of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with etoposide, a topoisomerase II inhibitor, in refractory or relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS: Twenty-five patients with refractory or relapsed SCLC were entered onto the trial. All 25 patients had been pretreated with some form of cisplatin-based combination chemotherapy and had also received previous etoposide- or anthracyclinecontaining chemotherapy. The median time off chemotherapy was 6.7 months (range, 0.9 to 23.5). Patients were treated at 4-week intervals using CPT-11 (a starting dose of 70 mg/m2 intravenously on days 1, 8, and 15) plus etoposide (80 mg/m2 intravenously on days 1 to 3), with a subsequent dose based on toxicity. In addition, recombinant human granulocyte colony-stimulating factor (rhG-CSF; 2 microg/kg/d) was given from day 4 to day 21, except on the days of CPT-11 administration. RESULTS: All patients were assessable for toxicity and survival. Twenty-four patients were assessable for response. There were 14 partial responses (PRs) and three complete responses (CRs), for an overall response rate of 71% (95% confidence interval, 53% to 89%). The median response duration was 4.6 months. Median survival was 271 days. Major toxicities were myelosuppression (predominantly leukopenia) and diarrhea. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 56% and 20% of patients, respectively. Grade 3 to 4 diarrhea was observed in 4%. There was one treatment-related death due to severe myelosuppression. CONCLUSION: A combination of CPT-11 and etoposide with rhG-CSF support is an active therapy against refractory or relapsed SCLC and deserves to be studied more extensively in a phase III trial.

Phase II trial of carboplatin plus oral etoposide for elderly patients with small-cell lung cancer.

A phase II trial was conducted to evaluate the efficacy and toxicity of the Egorin's carboplatin dosing formula with 14-day oral etoposide in 38 elderly patients with small-cell lung cancer (SCLC). The overall response rate was 81%. Median survival times were 15.1 months for 16 limited-disease (LD) and 8.6 months for 22 extensive-disease (ED) patients. Myelosuppression was the principal side-effect. This regimen is an active regimen in the treatment of elderly SCLC patients.

Phase I and pharmacologic study of oral (E)-2'-deoxy-2'-(fluoromethylene) cytidine: on a daily x 5-day schedule.

(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC), one of the most potent inhibitors of ribonucleoside diphosphate reductase, was selected for clinical development because of its novel mechanisms of action, and strong antitumor activity against experimental tumor models. This study was designed to determine the toxicities, maximum-tolerated dose (MTD), and pharmacokinetic profile of FMdC. FMdC was given orally for 5 consecutive days every 3 or 4 weeks in patients with advanced solid tumors. The starting dose was 8 mg/m2/day. Pharmacokinetic studies were carried out on days 1 through 5 of the first cycle. Ten patients with non-small cell lung cancer received 15 courses of FMdC at doses which were de-escalated from 8 mg/m2/day to 2 mg/m2/day because of unexpected severe toxicities at the starting dose level. Neutropenia was the dose-limiting toxicity. Thrombocytopenia and anemia were mild. Flu-like symptoms and fever were the common non-hematologic toxicities. The MTD was 4 mg/m2/day, since four of six patients developed grade 3-4 neutropenia. At the 4 mg/m2/day dose level, the mean terminal half-life, maximum plasma concentration (Cmax), plasma clearance, and mean residence time on day 1 were 3.20 h, 15.8 ng/ml, 2.91 l/h/kg, and 4.03 h, respectively. The recommended dose for phase II studies with this schedule is also 4 mg/m2/day for 5 days. Further investigations are necessary to establish optimal dosing schedules and routes for the administration of FMdC.

Transcutaneous needle biopsy of the lung.

PURPOSE: To evaluate the usefulness of transcutaneous needle biopsy (TCNB). MATERIAL AND METHODS: From May 1988 to December 1994, we performed TCNB under fluoroscopic control in 408 patients with mass lesions of the peripheral lung. The Surecut needle (1.5 mm) was selected mainly because of its ability to obtain specimens large enough for histological examination. Of the 408 patients, 286 had had previous bronchofiberscopic examinations but no definite diagnosis had been reached. RESULTS: A definite diagnosis was obtained by TCNB in 305 (74.7%) of 408 cases (251 malignant neoplasms, 54 benign lesions). In malignant neoplasms, the pathological diagnosis based on cytology and histology together was more reliable than that based on cytology alone. Although the complications of this procedure (such as pneumothorax) were within the range of acceptability, care should be taken to avoid air embolism and the seeding of cancer cells along the needle tract. CONCLUSION: TCNB with the Surecut needle is a useful procedure with relatively low risk.

CODE chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer.

Sixty-three patients with extensive-stage small-cell lung cancer were randomized to receive either cyclophosphamide, vincristine, doxorubicin and etoposide (CODE) alone or CODE plus recombinant human granulocyte colony-stimulating factor (rhG-CSF). rhG-CSF administration in support of CODE chemotherapy resulted in increased mean total received dose intensity for all drugs (P = 0.03) with a significant improvement in survival (P = 0.004).

[Risk of second primary cancer in two-year survivors of small cell lung cancer].

A total of 498 patients with small cell lung cancer received chemotherapy with or without chest irradiation at Osaka Prefectural Habikino Hospital from October 1977 through December 1991. Sixty-one who survived for more than two years were evaluated to determine the incidence and anatomic patterns of redevelopment of small cell lung cancer and development of second primary cancers. The numbers of expected cancers were estimated by cumulating person years of observation from 2 years after the start of treatment for small cell lung cancer to the date of death. Second primary cancers were observed in seven patients (four cases of non-small cell lung cancer, two of gastric cancer, and one of prostate cancer). The risk of a second primary cancer was 3.2 times greater than in the general population (95% Cl: 1.3-6.6). the relations between occurrence of a second primary cancer and family history of cancer, smoking history, smoking cessation after treatment of small cell lung cancer, and thoracic irradiation were studied. Occurrence of a second primary cancer correlated with family history (relative risk 7.5, 95% Cl: 1.5-22) and smoking cessation (relative risk 3.2, 95% Cl: 1.2-6.9). Long-term survivors were more likely to have a second primary cancer than a relapse of small cell lung cancer. Therefore, long-term survivors should be closely monitored for second primary cancers. Meta-analyses of studies done at several institutions may provide more detailed information on the occurrence of second primary cancers after small cell lung cancer.

Determinants of myelosuppression in the treatment of non-small cell lung cancer with cisplatin-containing chemotherapy.

Data on 16 potential risk factors for myelosuppression were assessed in 134 patients who received either vindesine and cisplatin (VP) or mitomycin C, vindesine and cisplatin (MVP) for inoperable stage III or IV non-small cell lung cancer in a randomized trial. Determinant factors for myelosuppression were evaluated by using univariate analysis and the logistic regression model. Recursive partitioning and amalgamation (RPA) was also used to define patient subgroups frequently suffering from severe bone marrow toxicity. Overall, 33 (25%) of 134 patients experienced at least one episode of grade 4 leukopenia. In univariate analysis, age, body surface area, serum creatinine, and pretreatment hemoglobin concentration were associated with severe leukopenia. A multivariate analysis using the logistic regression method showed that only raised creatinine level was an independent predictor for grade 4 leukopenia (P = 0.049). The RPA model generated three distinct subgroups based on age, body surface area and regimen. The three subgroups were distinguished by the frequency of severe (grade 4) leukopenia (50%, 25%, and 2.4%, respectively) (P < 0.001). Grade 4 leukopenia occurred more frequently in patients in class 3 (age > or = 65 years and treatment with MVP). The RPA model was useful in identifying the risk factors for myelosuppression induced by cisplatin-based chemotherapy, and in defining patient subgroups with elevated risk of toxicity.

Pro-gastrin-releasing peptide (31-98) as a tumour marker of small-cell lung cancer: comparative evaluation with neuron-specific enolase.

We attempted to clarify whether serum levels of a carboxy-terminal fragment of ProGRP, ProGRP(31-98), could serve as a more accurate tumour marker in patients with SCLC than neuron-specific enolase (NSE). ProGRP(31-98) and NSE were measured retrospectively in 101 newly diagnosed untreated patients with SCLC, 111 with non-small-cell lung cancer (NSCLC) and 114 patients with non-malignant lung diseases. ProGRP(31-98) and NSE levels were determined using a sandwich enzyme-linked immunosorbent assay. Sensitivity in SCLC patients was 72.3% for ProGRP(31-98) and 62.4% for NSE. Comparing the area under curve (AUC) of 'receiver operator characteristics' of ProGRP(31-98) with that of NSE, ProGRP(31-98) was the more powerful marker in the diagnosis of SCLC (P = 0.0001). Serum levels of ProGRP(31-98) were higher in the 40 patients with extensive disease than in the 61 patients with limited disease (P = 0.0082). ProGRP(31-98) was significantly higher in patients with pure small-cell carcinoma than in patients with mixed small-cell/large-cell carcinoma (P = 0.02). In serial measurement in 16 patients responding to treatment, a high degree of correlation was noted between the decrease in serum ProGRP(31-98) levels and clinical response during the second week after treatment (P = 0.0045). These results indicate that the determination of serum ProGRP(31-98) levels plays an important role in the diagnosis and treatment of SCLC patients.

Randomised trial for the prevention of delayed emesis in patients receiving high-dose cisplatin.

Despite recent advances in control of acute emesis following cisplatin-based chemotherapy regimens, delayed emesis remains a significant cause of treatment-related morbidity and factors associated with delayed emesis have not yet been evaluated. A prospective randomised trial was conducted to compare the efficacy and toxicity of granisetron, dexamethasone plus prochlorperazine with granisetron alone in controlling cisplatin-induced delayed emesis and to identify the important factors that influence its occurrence and severity. Seventy cisplatin-naive patients with inoperable solid tumors participated in the trial. Patients who received 80 mg m-2 or 100 mg m-2 of cisplatin were randomly assigned to receive either granisetron 40 micrograms kg-1 intravenously (i.v.) on day 1, dexamethasone 20 mg i.v. on days 2 and 3 and prochlorperazine 5 mg orally thrice daily on days 1-5 or granisetron 40 micrograms kg-1 i.v. on day 1 alone. There was no difference in their acute antiemetic efficacy. A combination regimen was more effective than granisetron alone in preventing delayed symptoms, with superior rates of complete plus major responses of 77% vs 51% (P = 0.0460). Treatment arm was the only determinant factor for the occurrence of delayed emesis (P = 0.0101).

Significance of serum neuron-specific enolase as a predictor of relapse of small cell lung cancer.

We conducted a prospective study to evaluate the significance of serum neuron-specific enolase (NSE) as a predictor of relapse of small cell lung cancer (SCLC). Patients entered into the study were drawn from those who had shown a complete or partial response to first-line chemotherapy with a concurrent decline in the NSE level to less than 10 ng/ml. When the serum NSE level increased to more than 15 ng/ml, the patient was restaged on the basis of clinical, radiological, and bronchoscopic examinations. During the period from August 1988 to December 1990, 57 patients with SCLC were enrolled and followed up until May 1992. Of these patients, 45 had clinical relapses, and 14 (31%) of them showed a clear elevation of the serum NSE level prior to the clinical recognition of relapse. Although one false-positive case was noted, this involved only a transient elevation of the NSE level. In patients who showed increased NSE levels, the relapses occurred in more difficult to detect silent sites such as the adrenal gland, liver, and deep lymph nodes. In addition, the percentage of patients demonstrating high NSE levels who were able to benefit from salvage chemotherapy was higher than for those who did not (RHO < 0.05). Our results indicate that serial NSE measurements are useful for the early prediction of SCLC relapse and should help to facilitate early administration of salvage chemotherapy for affected patients.

Measurement of cytokeratin 19 fragments as a marker of lung cancer by CYFRA 21-1 enzyme immunoassay.

Soluble cytokeratin fragment 19 levels were measured with an enzyme immunoassay method developed by Boehringer Mannheim (Enzymun-Test CYFRA 21-1) in the serum of 185 patients with lung cancer [149 with non-small-cell lung cancer (NSCLC) and 36 with small-cell lung cancer (SCLC)] and 97 patients with benign lung diseases in order to determine its clinical usefulness in the diagnosis of lung cancer and follow-up of treatment. We used the cut-off value of 3.5 ng ml-1, established by the Japan CYFRA research group. This cut-off value is based on calculations using the receiver operating characteristic approach instead of using the 95% specificity approach recommended by other authors. The resulting sensitivity and specificity for the group of all lung cancer patients were 65.4% and 84.5% respectively. The sensitivity was highest (76.1%) for squamous cell carcinoma and lowest (44.4%) for SCLC. For NSCLC patients, when CYFRA 21-1 levels were analysed by node (N) factor, patients who presented with mediastinal lymph node metastasis (N2 or N3) demonstrated higher serum CYFRA 21-1 levels (5.6; interquartile range 3.2-11.5 ng ml-1) than patients without mediastinal node metastasis (N0 or N1, 3.9; interquartile range 2.2-10.0 ng ml-1; Mann-Whitney U-test, P = 0.0373). We compared the discriminatory power of CYFRA 21-1 with that of other tumour markers including carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and neuron-specific enolase (NSE). The area under the curve (AUC) of each ROC curve was calculated using the CLABROC program for statistical analysis. CYFRA 21-1 appeared to have the most discriminatory power of the markers tested in the diagnosis of lung cancer. In serial measurements of 14 patients receiving chemotherapy or radiotherapy, a high degree of correlation was noted between serum levels of CYFRA 21-1 and extent of clinical response (Wilcoxon, P = 0.0093).

Phase I and pharmacologic study of irinotecan and etoposide with recombinant human granulocyte colony-stimulating factor support for advanced lung cancer.

PURPOSE: We conducted a phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with etoposide, a topoisomerase II inhibitor, and recombinant human granulocyte colony-stimulating factor (rhG-CSF) support because of the overlapping neutrophil toxicity of both drugs. The aim was to determine the maximum-tolerated dose of CPT-11 combined with a fixed dose of etoposide in patients with advanced lung cancer, as well as the dose-limiting toxicities of this combination. PATIENTS AND METHODS: Twenty-five patients with stage III or IV lung cancer, 15 (60%) with prior chemotherapy, were treated at 4-week intervals using CPT-11 (90-minute intravenous infusion on days 1, 8, and 15) plus etoposide (80 mg/m2 intravenously on days 1 to 3). In addition, rhG-CSF (2 micrograms/kg/d) was given from day 4 to day 21, except on the days of CPT-11 administration. The starting dose of CPT-11 was 60 mg/m2, and it was escalated in 10-mg/m2 increments until the maximum-tolerated dose was reached. RESULTS: The maximum-tolerated dose of CPT-11 was 90 mg/m2, since two of the three patients developed grade 3 to 4 leukopenia or grade 3 to 4 diarrhea during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the dose-limiting toxicities, while thrombocytopenia was only a moderate problem. Elimination of CPT-11 was biphasic, with a mean +/- SD beta half-life of 18.17 +/- 9.09 hours. The mean terminal half-life of 7-ethyl-10-hydroxycamptothecin (SN-38; the major metabolite of CPT-11) was 43.40 +/- 37.84 hours. There was one complete response (5%) and eight partial responses (38%) among 21 assessable patients, for an overall response rate of 43%. The response rates for small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) were 58% (seven of 12 patients) and 22% (two of nine patients), respectively. CONCLUSION: The combination of CPT-11 and etoposide with rhG-CSF support seems to be active against lung cancer, especially SCLC, with acceptable toxicity. The recommended dose for phase II studies in previously untreated patients is 80 mg/m2 of CPT-11 (days 1, 8, and 15) and 80 mg/m2 of etoposide (days 1 to 3) plus 2 micrograms/kg of rhG-CSF (days 4 to 21, except when CPT-11 is given). In addition, 70 mg/m2 of CPT-11 appears to be the appropriate dose for previously treated patients receiving this regimen.

Phase I study of irinotecan and cisplatin with granulocyte colony-stimulating factor support for advanced non-small-cell lung cancer.

PURPOSE: Since leukopenia was one of the dose-limiting toxicities of the combination of irinotecan (CPT-11) and cisplatin in a previous trial, we conducted a phase I trial to investigate whether support with recombinant human granulocyte colony-stimulating factor (rhG-CSF) would permit further intensification of the CPT-11 dose in combination with a fixed cisplatin dose. PATIENTS AND METHODS: Twenty previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) were treated with CPT-11 on days 1, 8, and 15 in combination with cisplatin 80 mg/m2 intravenously on day 1. In addition, rhG-CSF (2 micrograms/kg/d) was administered on days 4 to 21, except on the days of CPT-11 treatment. The starting dose of CPT-11 was 70 mg/m2, and the CPT-11 dose was escalated in 10-mg/m2 increments until the maximum-tolerated dose was reached. RESULTS: Diarrhea was the dose-limiting toxicity at 90 mg/m2. Two of six patients experienced either grade 3 or 4 diarrhea or grade 3 leukopenia during the first course of therapy at this dose level. Modest escalation of the CPT-11 dose from 80 to 90 mg/m2 resulted in a marked increase in the plasma concentration of 7-ethyl-10-hydroxycamptothecin (SN-38). Occurrence of diarrhea was well correlated with the peak plasma concentration (Cmax) of SN-38 (P = .035). There were 10 partial responses (50%) among 20 patients. CONCLUSION: The recommended dose for phase II studies is 80 mg/m2 of CPT-11, and 80 mg/m2 of cisplatin plus rhG-CSF. With the use of rhG-CSF, the CPT-11 dose can be increased 33% above that in the original regimen (60 mg/m2 of CPT-11 and 80 mg/m2 of cisplatin).