Head and neck squamous cell carcinoma: diagnostic performance of diffusion-weighted MR imaging for the prediction of treatment response.

PURPOSE: To determine the diagnostic performance of diffusion-weighted (DW) imaging for the prediction of treatment failure in primary head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: The study was approved by the local institutional ethics committee and conducted with informed written consent in patients with primary HNSCC treated with radiation therapy and chemotherapy. DW imaging of the primary tumor was performed before treatment in 37 patients and was repeated within 2 weeks of treatment in 30 patients. Histograms of apparent diffusion coefficients (ADCs) were analyzed, and mean ADC, kurtosis, skewness, and their respective percentage change were correlated for local failure and local control at 2 years by using the Student t test. Univariate and multivariate analyses of the ADC parameters, T stage, and tumor volume were performed by using logistic regression for prediction of local failure. RESULTS: Local failure occurred in 16 of 37 (43%) patients and local control occurred in 21 of 37 (57%) patients. Pretreatment ADC parameters showed no correlation with local failure. There was significant intratreatment increase in mean ADC and a decrease in skewness and kurtosis (P < .001, P < .001, P = .024, respectively) for the whole group of patients when compared with those before treatment. During treatment, primary tumors showed a significantly lower increase in percentage change of mean ADC, higher skewness, and higher kurtosis for local failure than for local control (P = .016, .015, and .040, respectively). These ADC parameters also were significant for predicting local failure with use of univariate but not multivariate analysis. CONCLUSION: Early intratreatment DW imaging has the potential to allow prediction of treatment response at the primary site in patients with HNSCC.

Pretreatment and early intratreatment prediction of clinicopathologic response of head and neck cancer to chemoradiotherapy using 1H-MRS.

PURPOSE: To determine if choline (cho) identified by proton magnetic resonance spectroscopy ((1)H-MRS) performed pretreatment and early in the course of treatment predicts clinicopathologic response of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: In all, 60 patients with HNSCC scheduled to undergo concurrent chemoradiotherapy or radiotherapy alone were recruited. (1)H-MRS was performed pretreatment and early intratreatment (2 weeks after start of treatment). Cho:creatine and cho:water ratios at each timepoint and change in the ratios between the two timepoints were correlated with locoregional failure, distant metastases, overall survival, and cancer-related death. Statistical analysis was performed using logistic regression and chi-square and a P-value of < 0.05 was considered statistically significant. RESULTS: Cho was identified in 47/49 successful pretreatment spectra and 42 of these 47 underwent successful (1)H-MRS early intratreatment, of which 21 showed persistent cho. Locoregional failure occurred in 15, distant metastases in 6, and death in 15 patients; the follow-up period in survivors ranged from 13-64 months (mean, 39 months). No statistically significant correlation was found between (1)H-MRS parameters and clinical endpoints. CONCLUSION: The pretreatment cho and change in cho early during a course of treatment did not predict clinical outcome.

Squamous cell carcinoma of the head and neck: diffusion-weighted MR imaging for prediction and monitoring of treatment response.

OBJECTIVE: To investigate the role of diffusion-weighted imaging (DWI) in predicting and monitoring chemoradiotherapy response in head and neck squamous cell carcinoma (HNSCC). METHODS: Diffusion-weighted imaging was performed pre-treatment (n = 50), intra-treatment (n = 41) and post-treatment (n = 20). Apparent diffusion coefficient (ADC) values were correlated with locoregional failure (LF). RESULTS: Locoregional failure occurred in 20/50 (40%) patients. A significant correlation was found between LF and post-treatment ADC (p = 0.02) but not pre- or intra-treatment ADC. Serial change in ADC was even more significant (p = 0.00001), using a fall in ADC early (pre- to intra-treatment) or late (intra- to post-treatment) to indicate LF, achieved 100% specificity, 80% sensitivity and 90% accuracy. CONCLUSIONS: Single ADC measurements pre- or intra-treatment did not predict response, but ADC post-treatment was a marker for LF. Serial change in ADC was an even stronger marker, when using an early or late treatment fall in ADC to identify LF.

Monitoring of treatment response after chemoradiotherapy for head and neck cancer using in vivo 1H MR spectroscopy.

Elevated choline (Cho) level has been documented on proton magnetic resonance spectroscopy ((1)H MRS) in head and neck squamous cell carcinoma and therefore percentage changes in Cho levels after chemoradiotherapy may serve as a marker of residual cancer in a post-treatment mass (PTM). Forty-six patients underwent (1)H MRS before treatment and the 30 patients with a PTM underwent repeat (1)H MRS at 6 weeks post-treatment. The percentage change in Cho/creatine and Cho/water ratios were correlated with residual cancer. The mean pretreatment Cho/creatine and Cho/water ratios were 2.24 and 1.20 x 10(-3), respectively. Cho persisted in four out of nine PTMs with residual cancer. Cho was absent in five out of nine PTMs with residual cancer and 21/21 PTMs without cancer. The number of PTMs with persistent Cho was too small to allow analysis of percentage change in ratios but the presence of Cho in a PTM showed significant correlation with residual cancer (p = 0.0046), producing a sensitivity, specificity, positive predictive value and negative predictive value of 44%, 100%, 100% and 81%, respectively. Therefore, the presence of Cho in a PTM may serve as a marker of residual cancer. Furthermore since so few PTMs contain Cho, a percentage change in Cho ratios may not be a useful method for monitoring treatment response.

Strong immunohistochemical expression of vascular endothelial growth factor predicts overall survival in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) has high morbidity and mortality, and its relationship with tumor angiogenesis as measured by microvessel density (MVD) or vascular endothelial growth factor (VEGF) expression has shown mixed results, with some, but not others, reporting correlation with outcome. METHODS: A retrospective study of 186 patients with HNSCC was performed. Patients were evaluated for MVD and VEGF and to correlate the levels with clinical parameters, including age at diagnosis, sex, site of tumor, stage, survival (disease free and overall), pathological tumor grade, and the presence of lymph node metastases. RESULTS: The 186 cancers included the following sites: oral tongue (n = 69), palate (n = 9), maxillary sinus (n = 8), floor of mouth (n = 13), oropharynx (n = 27), hypopharynx (n = 26) and larynx (n = 34). Over three-quarters of patients had advanced tumor (stage III/IV) and 58.6% had lymph node metastases. MVD and VEGF were assessed in 166 and 164 cases, respectively, but these were not correlated with site and grade. The 3-year overall and disease-free survival rates were 55.4% and 53.2%, respectively. Both univariate and multivariate survival analysis showed that advanced T stage, nodal metastasis, and strong VEGF intensity were independent adverse predictors for overall and disease-free survival. In stage IV disease, strong VEGF immunoreactivity was found to be the single adverse factor affecting the overall survival and a contributory factor for disease-free survival. CONCLUSIONS: VEGF immunoreactivity is a strong predictor of adverse outcome, particularly in locoregionally advanced disease.

New evidence for geographic variation in the role of human papillomavirus in tonsillar carcinogenesis.

AIMS: Our previous studies of tonsillar cancers from New South Wales, Australia, and Jilin Province in the north-east of China, provided evidence that the proportion of these cancers attributable to human papillomavirus (HPV) varies geographically. This study provides the first data on HPV in tonsillar cancers from Hong Kong. METHODS: A total of 49 Hong Kong tonsillar cancers were analysed for HPV DNA by PCR/sequencing and for p16(INK4A), retinoblastoma (pRb) protein, cyclin D1 and p53 expression by semiquantitative immunohistochemistry as evidence of virus causality. Results were compared with those from New South Wales and Jilin Province. RESULTS: Of the 31 Hong Kong cancers with amplifiable DNA, nine (29%) were HPV positive by PCR compared with 46% from New South Wales and 0% from Jilin Province. HPV positivity correlated with female gender, young age, over-expression of p16(INK4A) and loss of pRb and cyclin D1. Five-year disease-specific survival for patients with HPV positive and HPV negative cancers was 82 and 42%, respectively. Relationships between HPV status and cell protein expression in Hong Kong cancers were consistent with those from New South Wales and Jilin Province. The proportion of HPV-associated cancers reflected the relative incidence of oropharyngeal cancer in these regions. CONCLUSIONS: HPV is responsible for a small proportion of tonsillar cancers in Hong Kong patients. Differences in the proportions of tumours attributable to HPV in Hong Kong, New South Wales and Jilin Province may be due to environmental, cultural or genetic factors in the different populations.

Dose-response relationship of nasopharyngeal carcinoma above conventional tumoricidal level: a study by the Hong Kong nasopharyngeal carcinoma study group (HKNPCSG).

BACKGROUND AND PURPOSE: To define the dose-response relationship of nasopharyngeal carcinoma (NPC) above the conventional tumoricidal dose level of 66 Gy when the basic radiotherapy (RT) course was given by the 2D Ho's technique. PATIENTS AND METHODS: Data from all five regional cancer centers in Hong Kong were pooled for this retrospective study. All patients (n = 2426) were treated with curative-intent RT with or without chemotherapy between 1996 and 2000 with the basic RT course using the Ho's technique. The primary endpoint was local control. The prognostic significance of dose-escalation ('boost') after 66 Gy, T-stage, N-stage, use of chemotherapy, sex and age (< or =40 years vs >40 years) was studied. Both univariate and multivariate analyses were performed. RESULTS: On multivariate analysis, T-stage (P < 0.01; hazard ratio [HR], 1.58) and optimal boost (P = 0.01; HR, 0.34) were the only significant factors affecting local failure for the whole study population, and for the population of patients treated by radiotherapy alone, but not for patients who also received chemotherapy. The following were independent determinants of local failure for patient groups with different T-stages treated by radiotherapy alone: use of a boost in T1/T2a disease (P = 0.01; HR, 0.33); use of a boost (P < 0.01; HR, 0.60) and age (P = 0.01; HR, 1.02) in T3/T4 tumors. Among patients with T2b tumors treated by radiotherapy alone and given a boost, the use of a 20 Gy-boost gave a lower local failure rate than a 10 Gy-boost. There was no apparent excess mortality attributed to RT complications. CONCLUSIONS: Within the context of a multi-center retrospective study, dose-escalation above 66 Gy significantly improved local control for T1/T2a and T3/4 tumors when the primary RT course was based on the 2D Ho's technique without additional chemotherapy. 'Boosting' in NPC warrants further investigation. Caution should be taken when boosting is considered because of possible increase in radiation toxicity.

Cervical nodal metastases from head and neck squamous cell carcinoma: MRI criteria for treatment assessment.

BACKGROUND: The purpose of this study was to assess MRI criteria for detecting residual malignant head and neck squamous cell carcinoma (HNSCC) nodes after chemoradiotherapy (CRT). METHODS: One hundred and six metastatic nodes were assessed 6 weeks posttreatment by MRI for necrosis, extranodal neoplastic spread (ENS), size, and percentage of size change. Size measurements were reanalyzed after dividing posttreatment nodes into "discrete solid," "discrete necrotic," and "indiscrete" groups. Results were correlated with nodal response at 2 years. RESULTS: Eighty-three residual nodes were benign and 23 were malignant. Significant predictors of outcome were percentage of change in solid volume (total-necrotic volume; p = .0002) for all posttreatment nodes and percentage of change in total volume for "discrete solid" posttreatment nodes (p = .0003), the latter showing a ≤78% reduction of predicted residual malignant nodes with a negative predictive value (NPV) of 98.2% and positive predictive value (PPV) of 60%. Necrosis, ENS, and size of "discrete necrotic" and "indiscrete" nodes were not significant criteria. CONCLUSION: Necrosis and ENS were inaccurate criteria for residual malignant nodes and hindered the accuracy of size measurements. © 2016 Wiley Periodicals, Inc. Head Neck 38: E1598-E1604, 2016.

Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nonnasopharyngeal head and neck carcinomas.

PURPOSE: We investigated the detectability of EBV DNA in the plasma of patients with non-nasopharyngeal head and neck carcinomas (NNHNC). Previous studies have shown that EBV is present in the tumor tissue of some NNHNC. EXPERIMENTAL DESIGN: We recruited 101 patients with NNHNC and 48 healthy controls. Blood samples were taken from controls and patients before treatment. Tumor tissue samples were tested for the presence of EBV in the first 69 patients by in situ hybridization for small EBV-encoded RNA (EBER). Plasma EBV DNA was measured by real-time quantitative PCR in patients and controls. RESULTS: Squamous cell carcinoma (SCC) was the commonest histology (78 patients) followed by lymphoepithelial carcinoma (8 patients). EBER was detected in tumor cells in 7 of 69 patients tested. All of the EBER-positive tumors were lymphoepithelial carcinoma. Two controls (2 of 48; 4.2%) had detectable plasma EBV DNA. Plasma EBV DNA was detected in all of the patients with EBER-positive tumors, and in 23 of 94 (24.5%) patients with tumors of EBER-negative or unknown status. The proportion of plasma EBV DNA-positive cases in either group was significantly higher than that in the control group (P < 0.0027). Plasma EBV DNA concentrations in patients with EBER-positive tumors (median, 3827 copies/ml) were significantly higher than those in the controls (median, 0 copy/ml; P = 0.0001). Of patients with SCC, 21 (26.9%) had detectable plasma EBV DNA (median concentration, 34 copies/ml). Plasma EBV DNA concentrations in the whole group of patients with SCC (median, 0 copy/ml; interquartile range, 0-4 copies/ml) were also significantly higher than those in the controls (P = 0.001). CONCLUSIONS: Our data indicate that plasma EBV DNA reflects tumoral EBER status, and it may be of use as a tumor marker for EBER-positive NNHNC. The biological and clinical significance of low levels of circulating EBV DNA in the minority of patients with EBER-negative tumors remain to be elucidated.

DCE-MRI for Pre-Treatment Prediction and Post-Treatment Assessment of Treatment Response in Sites of Squamous Cell Carcinoma in the Head and Neck.

BACKGROUND AND PURPOSE: It is important to identify patients with head and neck squamous cell carcinoma (SCC) who fail to respond to chemoradiotherapy so that they can undergo post-treatment salvage surgery while the disease is still operable. This study aimed to determine the diagnostic performance of dynamic contrast enhanced (DCE)-MRI using a pharmacokinetic model for pre-treatment predictive imaging, as well as post-treatment diagnosis, of residual SCC at primary and nodal sites in the head and neck. MATERIAL AND METHODS: Forty-nine patients with 83 SCC sites (primary and/or nodal) underwent pre-treatment DCE-MRI, and 43 patients underwent post-treatment DCE-MRI, of which 33 SCC sites had a residual mass amenable to analysis. Pre-treatment, post-treatment and % change in the mean Ktrans, kep, ve and AUGC were obtained from SCC sites. Logistic regression was used to correlate DCE parameters at each SCC site with treatment response at the same site, based on clinical outcome at that site at a minimum of two years. RESULTS: None of the pre-treatment DCE-MRI parameters showed significant correlations with SCC site failure (SF) (29/83 sites) or site control (SC) (54/83 sites). Post-treatment residual masses with SF (14/33) had significantly higher kep (p = 0.05), higher AUGC (p = 0.02), and lower % reduction in AUGC (p = 0.02), than residual masses with SC (19/33), with the % change in AUGC remaining significant on multivariate analysis. CONCLUSION: Pre-treatment DCE-MRI did not predict which SCC sites would fail treatment, but post-treatment DCE-MRI showed potential for identifying residual masses that had failed treatment.

Accelerated fractionation radiotherapy and late intensification with 2 intra-arterial cisplatin infusions for locally advanced head and neck squamous cell carcinoma.

BACKGROUND: This study was established to determine the maximum tolerated dose of intra-arterial cisplatin (IAC) concurrent with accelerated fractionation radiotherapy for locally advanced head and neck squamous cell carcinoma (HNSCC). METHODS: We conducted a phase I study. Treatment consisted of 70 Gy/35 fractions/5.8 weeks and 2 weekly IAC infusions during the last 2 weeks. RESULTS: Ten patients were recruited. Two patients had stage III, 1 had stage IVa, and 7 had stage IVb disease. Three patients received IAC at 100 mg/m(2), 3 at 125 mg/m(2), and 4 at 150 mg/m(2). Nine patients received both planned infusions. Dose-limiting toxicity occurred at 150 mg/m(2) as transient grade 4 leukopenia and prolonged grade 3 acute skin reactions. The maximum tolerated dose was 125 mg/m(2). Six patients survived disease-free at 39 to 67 months. CONCLUSIONS: It was feasible to give IAC concurrent with accelerated fractionation radiotherapy for locally advanced HNSCC. The maximum tolerated dose of cisplatin was 125 mg/m(2).

Correlation of biomarkers in head and neck squamous cell carcinoma.

OBJECTIVE: To evaluate the relationship of functional magnetic resonance imaging (MRI) parameters, including choline/creatine ratio (Cho/Cr) and apparent diffusion coefficient (ADC) with protein expression of 10 common tumor and prognostic markers in head and neck squamous cell carcinoma. STUDY DESIGN: Cross-sectional study. SETTING: University hospital. SUBJECTS AND METHODS: The Cho/Cr and ADC obtained from 74 patients with head and neck squamous cell carcinoma were correlated with the expression level of the 10 protein markers as determined by immunohistochemistry. RESULTS: Cho/Cr showed significant positive correlations with cyclooxygenase 2 in primary tumors (r = 0.714), and epidermal growth factor receptor in metastatic cervical lymph nodes (r = 0.522). ADC showed significant (r = -0.591) negative correlation with human epidermal growth factor receptor 2 in metastatic cervical lymph nodes. CONCLUSION: There are relationships between protein and functional MRI markers. Future research in this direction may improve our understanding of the cancer micro-environment.

A broadly adaptive array of dose-constraint templates for planning of intensity-modulated radiation therapy for advanced T-stage nasopharyngeal carcinoma.

PURPOSE: To develop and validate adaptive dose-constraint templates in intensity-modulated radiotherapy (IMRT) planning for advanced T-stage nasopharyngeal carcinoma (NPC). METHOD AND MATERIALS: Dose-volume histograms of clinically approved plans for 20 patients with advanced T-stage NPC were analyzed, and the pattern of distribution in relation to the degree of overlap between targets and organs at risk (OARs) was explored. An adaptive dose constraint template (ADCT) was developed based on the degree of overlap. Another set of 10 patients with advanced T-stage NPC was selected for validation. Results of the manual arm optimization protocol and the ADCT optimization protocol were compared with respect to dose optimization time, conformity indices, multiple-dose end points, tumor control probability, and normal tissue complication probability. RESULTS: For the ADCT protocol, average time required to achieve an acceptable plan was 9 minutes, with one optimization compared with 94 minutes with more than two optimizations of the manual arm protocol. Target coverage was similar between the manual arm and ADCT plans. A more desirable dose distribution in the region of overlap between planning target volume and OARs was achieved in the ADCT plan. Dose end points of OARs were similar between the manual arm and ADCT plans. CONCLUSIONS: With the developed ADCT, IMRT treatment planning becomes more efficient and less dependent on the planner's experience on dose optimization. The developed ADCT is applicable to a wide range of advanced T-stage NPC treatment and has the potential to be applied in a broader context to IMRT planning for other cancer sites.

HER2 expression predicts improved survival in patients with cervical node-positive head and neck squamous cell carcinoma.

OBJECTIVE: To investigate the prognostic value of HER2 and p63 expression in head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: A case review of 186 HNSCCs from the oral tongue, palate, maxillary sinus, floor of mouth, oropharynx, hypopharynx, and larynx. SUBJECTS AND METHODS: All primary tumor specimens were evaluated by immunohistochemistry for HER2 and p63 expressions, which were correlated with clinical parameters including age, sex, grade, lymph node metastases, stage, and survival. RESULTS: One hundred forty-one patients had stage III-IV disease and 109 had lymph node metastases. For all cases, T and N stages were significant prognostic predictors for both overall and disease-free survivals. In the node-positive subgroup, T stage and HER2 expression were significant prognostic predictors for both overall and disease-free survivals. CONCLUSION: HER2 may be associated with longer survival in node-positive patients with HNSCC.

Survival outcome of patients with nasopharyngeal carcinoma with first local failure: a study by the Hong Kong Nasopharyngeal Carcinoma Study Group.

BACKGROUND: The purpose of this article is to report the overall survival (OS) outcome of patients with nasopharyngeal carcinoma (NPC) with local failure who received salvage treatment and to identify prognostic factors for OS. METHODS: Between January 1996 and December 2000, 2915 patients received primary radiotherapy (RT) with or without chemotherapy for nonmetastatic NPC. At a median follow-up of 3.1 years, 319 patients had developed local failure as the first failure, with or without synchronous regional/distant failure. OS was calculated from the start of primary RT. Univariate and multivariate analyses were performed to identify prognostic factors for OS in patients with isolated local failure. RESULTS: The T classification distribution of the local failure (rT classification) was as follows: 68 (21%) rT1 to T2a, 92 (29%) rT2b, 82 (26%) rT3, and 77 (24%) rT4. The rT classification was the same as the initial T classification in 82% of patients. Two hundred seventy-five patients (86%) had isolated local failure, and 232 (84%) of them did not have any distant metastasis or regional failure develop during follow-up. Salvage treatment was given to 200 patients (73%) with isolated local failure. One hundred fifty-nine patients (80%) received reirradiation (108 external beam RT [EBRT], 44 brachytherapy, and seven EBRT plus brachytherapy), 22 patients (11%) underwent nasopharyngectomy with or without postoperative RT, and 19 patients (9%) were treated with chemotherapy alone. Four patients died of RT complications, and one died of chemotherapy toxicity in the absence of active NPC. The 3-year actuarial OS for patients with isolated local failure was 74%. On multivariate analysis, advanced initial T classification (hazard ratio [HR], 1.44; p = .0006) and the use of salvage treatment (HR, 0.54; p = .0038) were independent prognostic factors. For the subgroups of patients who had the same recurrent and initial T classification, salvage treatment was associated with improved OS only in the subgroup with T1 to T2 local failure (n = 127; p = 0.0446), but not in the subgroups with T3 (n = 48) or T4 (n = 54) disease. CONCLUSIONS: Most patients with first local failure have localized disease. Salvage treatment is feasible in most of the patients with clinically isolated local failure. Patients who had early initial T classification have a more favorable prognosis. Subgroup analysis suggests that salvage treatment only prolongs survival in patients with T1 to T2 recurrent disease.

A Phase I-II study of sequential administration of topotecan and oral etoposide (toposiomerase I and II inhibitors) in the treatment of patients with small cell lung carcinoma.

BACKGROUND: Topotecan (9-dimethylaminomethyl-10-hydroxycampthothecin) is a new topoisomerase I inhibitor with promising efficacy in the treatment of patients with small cell lung carcinoma (SCLC). Combination with a topoisomerase II inhibitor may potentate the therapeutic effect of topotecan, although there has been conflicting preclinical information on the combination. The objectives of this study were to establish the maximum tolerated dose and to determine the efficacy of the sequential combination of intravenous topotecan and oral etoposide in the treatment of patients with SCLC. METHODS: Patients with histologically confirmed, limited or extensive stage SCLC were eligible. The dose escalation scheme of three cohorts (six patients per cohort) started at intravenous topotecan 0.5 mg/m(2) per day for 5 days and oral etoposide 50 mg twice daily for 7 days (21-day cycles). Subsequent dose levels involved escalation of topotecan to 0.75 mg/m(2) per day and 1.0 mg/m(2) per day for 5 days. A Phase II study was conducted at one dose level below the maximum tolerated dose. The authors alternated the drug sequence with each consecutive cycle and compared the hematologic toxicity between the two sequences. RESULTS: Thirty-six patients (21 patients with limited disease and 15 patients with extensive disease) received a total of 173 courses of sequential combination chemotherapy (topotecan --> etoposide, 88 courses; etoposide --> topotecan, 85 courses). The authors identified dose levels for the Phase II study as follows: topotecan, 0.75 mg/m(2) per day for 5 days; and etoposide, 50 mg twice daily for 7 days. The dose-limiting toxicity was neutropenia. At this dose level, the incidence of Grade 3-4 neutropenia and the incidence of Grade 3-4 thrombocytopenia were 25% and 10.9%, respectively. Two patients died from neutropenic sepsis. There was no significant difference in hematologic toxicities between the two sequences. Complete and partial response rates were 5.6% and 55.6%, respectively (limited disease, 9.5% and 66.75%; extensive disease, 0% and 40%, respectively). The median progression free survival was 31.9 weeks (limited disease, 36.1 weeks; extensive disease, 28.9 weeks; 95% confidence interval, 25.6-36.0 weeks), and the median overall survival was 52.4 weeks (limited disease, 54.9 weeks; extensive disease, 30.1 weeks; 95% confidence interval, 39.6-57.7 weeks). CONCLUSIONS: Combination therapy with topoisomerase I and II inhibitors is a safe and effective regimen for patients with SCLC. Future research on this combination should focus on an oral regimen for patients with extensive disease and poor tolerance to cisplatin. The authors recommend an oral dosage of topotecan at 1.2 mg/m(2) per day (equivalent to intravenous topotecan at 0.75 mg/m(2) per day) for 5 days followed by etoposide 50 mg twice daily for 7 days.