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Phase III Trial Comparing Supportive Care Alone With Supportive Care With Oral Topotecan in Patients With Relapsed Small-Cell Lung Cancer

Mary E.R. O'Brien, Tudor-Eliade Ciuleanu, Hristo Tsekov, Yaroslav Shparyk, Branka ueviá, Gabor Juhasz, Nicholas Thatcher, Graham A. Ross, Graham C. Dane, Theresa Crofts

From the Royal Marsden Hospital, Sutton; Christie Hospital, Manchester; GlaxoSmithKline, Harlow, United Kingdom; Institutul Oncologic, Cluj-Napoca, Romania; Active Treatment Hospital, Varna, Bulgaria; Lviv State Oncology, Lviv, Ukraine; Klinika za plune bolesti Jordanovac, Zagreb, Croatia; and Margit Kórház, Csorna, Hungary

Address reprint requests to Mary O'Brien, MD, FRCP, Royal Marsden Hospital, National Health System Trust, Sutton Surrey, SM2 5 PT, England; e-mail: mary.o'brien{at}rmh.nhs.uk

	ABSTRACT

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PURPOSE: For patients with small-cell lung cancer (SCLC), further chemotherapy is routinely considered at relapse after first-line therapy. However, proof of clinical benefit has not been documented.

PATIENTS AND METHODS: This study randomly assigned patients with relapsed SCLC not considered as candidates for standard intravenous therapy to best supportive care (BSC) alone (n = 70) or oral topotecan (2.3 mg/m²/d, days 1 through 5, every 21 days) plus BSC (topotecan; n = 71).

RESULTS: In the intent-to-treat population, survival (primary end point) was prolonged in the topotecan group (log-rank P = .0104). Median survival with BSC was 13.9 weeks (95% CI, 11.1 to 18.6) and with topotecan, 25.9 weeks (95% CI, 18.3 to 31.6). Statistical significance for survival was maintained in a subgroup of patients with a short treatment-free interval ( 60 days). Response to topotecan was 7% partial and 44% stable disease. Patients on topotecan had slower quality of life deterioration and greater symptom control. Principal toxicities with topotecan were hematological: grade 4 neutropenia, 33%; grade 4 thrombocytopenia, 7%; and grade 3/4 anemia, 25%. Comparing topotecan with BSC, infection grade 2 was 14% versus 12% and sepsis 4% versus 1%; other grade 3/4 events included vomiting 3% versus 0, diarrhea 6% versus 0, dyspnea 3% versus 9%, and pain 3% versus 6%. Toxic deaths occurred in four patients (6%) in the topotecan arm. All cause mortality within 30 days of random assignment was 13% on BSC and 7% on topotecan.

CONCLUSION: Chemotherapy with oral topotecan is associated with prolongation of survival and quality of life benefit in patients with relapsed SCLC.

	INTRODUCTION

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The majority of patients with small-cell lung cancer (SCLC) who are treated with standard chemotherapy experience relapse within 1 year of treatment. At relapse, patients are routinely considered for further chemotherapy, and there is evidence that this is associated with symptom improvement in patients who have a relatively long treatment-free interval (TFI) after first-line therapy (considered sensitive disease).^1,2 Patients with short TFI (or resistant SCLC) are less likely to achieve objective tumor response than patients with sensitive SCLC,³ and for them the risks versus benefits of chemotherapy at relapse are ill defined.

Topotecan (Hycamtin; GlaxoSmithKline, Research Triangle Park, NC) inhibits the cut-and-repair nuclear enzyme topoisomerase I. The intravenous formulation is active against relapsed ovarian cancer and SCLC.^4-8 An oral formulation of topotecan has similar efficacy to the intravenous formulation in patients with relapsed SCLC.^9-11 In a phase III study of patients with relapsed sensitive SCLC, response rates with oral and intravenous topotecan were 18.3% and 21.9%, respectively.¹¹

In order to define the actual risk and benefit associated with chemotherapy at relapse with SCLC, a randomized study was conducted. Patients unsuitable for standard intravenous chemotherapy received either oral topotecan plus best supportive care (topotecan) or best supportive care alone (BSC) and were evaluated for survival, quality of life (QOL), and adverse experiences.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Patient Selection
Patients were randomly assigned 1:1 using a centralized automated registration and randomization system (JhoyLink, Paris, France),¹² stratified by sex, performance status (PS 0/1 or 2), TFI ( 60 days or > 60 days), and presence of liver metastases.

Because of the possibility of being randomly assigned to BSC alone, only patients considered unsuitable for further intravenous chemotherapy were recruited. Unsuitability was based on local policy concerning the unproven risk and benefit in patients with resistant (short TFI) SCLC and assessed on an individual basis by the attending oncologist. Initially excluded from the protocol were patients who had a TFI of longer than 90 days for whom treatment with BSC alone was not acceptable. However, as the study progressed, it became apparent that some patients with sensitive SCLC refuse further chemotherapy because of the risk of toxicity or become unsuitable for standard chemotherapy because of comorbidities. The protocol was therefore amended to allow the inclusion of such patients. As the population was stratified at random assignment, the final study population is comprised of two predefined subsets according to TFI. A minimum of 45 days was required after initial chemotherapy to ensure bone marrow recovery.

Other eligibility criteria included extensive or limited SCLC, one prior chemotherapy regimen, age 18 years, PS (Eastern Cooperative Oncology Group scale) of 0, 1, or 2, hemoglobin 9.0 g/dL, WBC count 3,500/mm³, platelets 100,000/mm³, neutrophils 1,500/mm³, calculated creatinine clearance 60 mL/min, serum bilirubin 2.0 mg/dL AST and ALT and alkaline phosphatase five times upper limit of normal with liver metastases or two times without, at least 24 hours since last radiotherapy, and at least 3 months since last immunotherapy.

Exclusion criteria were symptomatic CNS metastases, concomitant or previous malignancies within the last 5 years (except SCLC and adequately treated nonmelanoma skin cancer, cervical carcinoma in situ, or localized low-grade prostate cancer), infection, severe comorbidities, gastrointestinal conditions or drugs affecting gastrointestinal absorption, prior topotecan therapy, or hypersensitivity or other contraindication to the study drugs.

The protocol was approved by the institutional review board/ethics committee at each site, and each patient provided written informed consent.

Interventions
All patients had equal access to supportive care measures including analgesics, antibiotics, corticosteroids, appetite stimulants, antidepressants, RBC transfusions, deep relaxation therapy, and palliative radiotherapy or surgical procedures. All therapies with potential systemic antitumor effect (including immunotherapies) were excluded. Topotecan hydrochloride was supplied in capsules containing the equivalent to 0.25 mg or 1.00 mg of the anhydrous free base (GlaxoSmithKline, Middlesex, United Kingdom) and was dosed 2.3 mg/m²/d on days 1 through 5 every 21 days according to marrow recovery. Compliance was documented by returned capsule count. At least four treatment cycles were recommended, depending on tolerability and response, in order to ensure that patients received optimal benefit from topotecan.

Dose Delays and Modifications
Topotecan therapy was delayed if the following parameters were not met: hemoglobin more than 9.0 g/dL, neutrophils more than 1,000/mm³, platelets more than 100,000/mm³, or recovery from other clinically significant nonhematologic toxicity.

To ensure optimal topotecan exposure, individual dose adjustments were prescribed in the protocol. The topotecan dose was reduced by 0.4 mg/m²/d for neutrophils less than 500/mm³ associated with fever/infection or lasting 7 days, neutrophils 500 to 900/mm³ lasting beyond day 21, platelets less than 25,000/mm³, or grade 3/4 nonhematologic toxicity excluding grade 3 nausea and grade 3/4 vomiting. The minimum topotecan dose was 1.5 mg/m²/d; delays of more than 2 weeks at this dose resulted in withdrawal. Conversely, topotecan dose increases in increments of 0.4 mg/m² were permitted up to a maximum dose of 3.1 mg/m²/d if no toxicity higher than grade 2 occurred during the previous course.

Assessments
Baseline evaluations included medical history and examination, documented evidence of progressive disease, symptom assessment questionnaire (Patient Self Assessment [PSA]) and QOL evaluation. The PSA resembles the approach used in the well-validated and referenced Lung Cancer Symptom Scale,¹³ evaluating the degree to which patients experienced nine common and clinically relevant symptoms using a Likert scale for severity (from 1 [not at all] to 4 [very much]). The EuroQol-5 Dimensions Health Questionnaire (EQ-5D), is an evaluation of five health status dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The evaluation is a rating from 1 (no problem) to 3 (an extreme problem), and a visual analog scale ranging from 0 (worst imaginable) to 100 (best imaginable health state).^14,15

Patients on both study arms were evaluated at similar intervals: before each course of topotecan or approximately every 21 days for patients on the BSC arm. At each visit, the patient was interviewed and examined and completed the PSA and EQ-5D. PS was recorded and palliative measures documented. In the topotecan arm, toxicity (according to National Cancer Institute Common Toxicity Criteria) was evaluated and blood counts were obtained. During treatment, blood counts were obtained on day 8 and blood chemistries on day 15. Hematologic and biochemical toxicities were assessed from laboratory values; all other toxicities were from investigator-reported adverse events. Radiographic disease assessment was only required in the topotecan arm after three courses and thereafter only to confirm response or progressive disease. Response was assessed according to WHO criteria. Independent review of responses was not conducted. Poststudy follow-up occurred at least every 2 months for the full duration of survival.

The primary end point was overall survival (all cause mortality). Secondary end points were response rate, time to disease progression (TTP), patient symptom assessment, QOL evaluation, and safety.

Statistical Methods
Efficacy assessments were based on all randomly assigned patients, the intent-to-treat population. Safety and QOL assessments were based on all patients who received at least one postrandom assignment evaluation on the BSC arm or one dose of topotecan.

This trial was designed to detect a 66.7% difference in median survival. The expected survival in the BSC arm was 12 weeks. The estimated median survival in the BSC plus oral topotecan arm was 20 weeks. Although initial sample size calculations determined that 220 patients (110 per arm) were needed to assess a survival benefit for topotecan with 90% power and a significance level of .05, recruitment was slower than expected. A formal protocol amendment was implemented to terminate the study once 125 deaths had been reported, thus providing 80% power to assess a survival benefit for topotecan at a .05 significance level. This point was reached when 141 patients had been recruited. No interim analyses were conducted.

Overall survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. Analyses of all secondary end points were descriptive; no adjustments were made for multiplicity. For the topotecan group, response rates were summarized along with a binomial 95% CI and TTP was summarized by Kaplan-Meier estimates. All P values are two sided.

For the PSA, a generalized estimating equations model using PROC GENMOD version 8.1 (SAS Institute, Cary, NC) was fitted to longitudinal symptom data across visits to estimate the treatment effect on each of the symptoms (response was categorized as favorable or unfavorable). A logit link function along with exchangeable correlation structure was used for fitting the model. The rate of change in EQ-5D score in each arm was evaluated with a longitudinal analysis using a mixed model with change from baseline in score as response. Visual analog scale results were summarized using descriptive statistics.

	RESULTS

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Patients
Patients were recruited from 40 centers in Europe, Canada, and Russia. Between November, 2000, and March, 2004, a total of 141 patients were randomly assigned: 70 to BSC and 71 to topotecan. Patient demographics were well matched between arms, particularly with respect to the major prognostic variables of PS and sex (Table 1). The median TFI after first-line therapy was 90 days on BSC and 84 days on topotecan. The most commonly received first-line chemotherapeutic agents were cisplatin or carboplatin (77% of patients in the BSC group and 80% in the topotecan group) and etoposide (74% in the BSC group and 76% in the topotecan group), consistent with current guidelines.^16-18

Topotecan dose reduction occurred in 16 courses (8%) primarily due to hematologic toxicity (13 courses, 6%). Dose delays occurred in 41 topotecan courses (20%) most commonly for hematologic toxicity (25 courses, 12%). Dose escalation of topotecan occurred in 39 courses (14%). The median topotecan dose intensity achieved was 3.77 mg/m²/wk representing 98% of the scheduled dose.

Some patients who were randomly assigned to receive BSC alone withdrew consent and elected to receive standard intravenous chemotherapy. In all, 13 patients in each arm (18.3% on BSC and 18.6% on topotecan) received poststudy chemotherapy either alone or in combination with other therapy such as radiotherapy and surgery. In addition, poststudy radiotherapy alone was received by seven patients (10%) in the topotecan arm and one patient (1%) in the BSC arm. Crossover to topotecan was not allowed by protocol.

Supportive Care
Palliative medications and radiotherapy were used more frequently in the BSC group, while transfusions were used more frequently in the topotecan group (Table 3).

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier estimates for overall survival in the intent-to-treat population (log-rank P = .01). The unadjusted hazard ratio for overall survival was 0.64 (95% CI, 0.45 to 0.90) for topotecan relative to best supportive care alone. Adjusted for stratification factors, the hazard ratio was 0.61 (95% CI, 0.43 to 0.87).

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Subgroup analysis of survival according to the stratification factors of sex, performance status (PS), time to progression from prior therapy, and presence of liver metastases.

The overall response rate to topotecan was 7% and a further 44% of patients achieved stabilization of disease, which was confirmed after no less than 56 days (Table 4). Reponses according to the prospectively defined stratification of TFI 60 days versus more than 60 days, as well as according to TFI 90 days versus more than 90 days are presented in Table 4.

The most commonly occurring grade 3/4 nonhematologic toxicities were diarrhea (6%), fatigue (4%), vomiting (3%), and dyspnea (3%) in the topotecan group and dyspnea (9%), fatigue (4%), and cough (2%) in the BSC group. Toxic deaths occurred in four patients (6%) in the topotecan arm with three due to hematologic toxicity. Of these three deaths, one was attributed to severe cytopenia and infection, one to neutropenia and pneumonia, and one to neutropenia and thrombocytopenia. All cause mortality within 30 days of random assignment was 7% in the topotecan arm (five patients: progressive disease, one; drug toxicity, three; other reason, one) and 13% in the BSC arm (nine patients, all due to progressive disease). Patients on BSC were at greater risk of death compared with patients on topotecan at all stages of the study.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
This study has successfully quantified the clinical benefit associated with active chemotherapy in patients with relapsed SCLC. Treatment with oral topotecan prolonged survival and improved QOL compared with BSC alone and the improvements can be considered clinically and statistically significant. In patients with sensitive SCLC, the study confirms the previous observation of survival benefit and symptom palliation associated with active chemotherapy. More importantly, the treatment dilemma concerning patients with short TFI or PS 2 is also resolved. This study suggests that with oral topotecan the benefits of therapy outweigh the risks in all patient groups and therefore all subgroups of patients with relapsed SCLC (sensitive or resistant) should now be considered for this treatment.

Two randomized studies have shown that similar clinical activity is achieved with either oral or intravenous topotecan in SCLC.^9,10 In a different setting, a survey of patients showed that patients prefer oral over intravenous chemotherapy in the palliative setting if clinical activity is not compromised.¹⁹ Thus, physicians treating patients with recurrent SCLC would have an effective oral option when patients identify this preference.

With the median survival of the treated group at 25.9 weeks and the fact that around 50% of these patients in both arms had a good PS of 0 to 1 at study entry, and 42% and 59%, respectively, of patients had a TFI longer than 90 days, one could argue that this was a group of patients who should have been offered standard intravenous chemotherapy. We did not collect data on specific comorbidities or the reasons why individual patients were not offered standard intravenous chemotherapy by their oncologists. However, one recent study suggests that our study was indeed a real clinical situation. Sundstrom et al²⁰ randomly assigned and treated patients at diagnosis with either etoposide and cisplatin or cyclophosphamide, epirubicin, and vincristine; at relapse patients received the alternate, crossover regimen. Of 286 patients randomly assigned initially, only 120 were suitable for second-line therapy; the remaining 166 patients received BSC. In the group offered BSC alone, 38% had a PS of 0 to 1 and 43% had a TFI longer than 3 months—very similar to our trial group. The median survival in the crossover arms were 3.9 and 4.5 months, respectively, for etoposide and cisplatin and cyclophosphamide, epirubicin, and vincristine.²⁰

Other important clinical issues have been addressed. The number of patients deriving benefit from oral topotecan exceeds the 7% who achieved a partial response. This response rate is lower than that reported in previous studies with patients selected on their sensitivity to previous treatments. This corroborates previous suggestions that stabilization of disease as measured by WHO criteria is associated with clinical benefit,²¹ though we accept that the data on symptom control in both arms is less reliable than if a placebo had been included. The natural course of untreated SCLC has been defined, and this study will provide the benchmark against which future treatment strategies in this indication can be judged.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Mary E.R. O'Brien GlaxoSmithKline GlaxoSmithKline Tudor-Eliade Ciuleanu GlaxoSmithKline Yaroslav Shparyk GlaxoSmithKline Branka ueviá GlaxoSmithKline GlaxoSmithKline Nicholas Thatcher GlaxoSmithKline GlaxoSmithKline Graham A. Ross GlaxoSmithKline GlaxoSmithKline Graham C. Dane GlaxoSmithKline GlaxoSmithKline Theresa Crofts GlaxoSmithKline GlaxoSmithKline

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Mary E.R. O'Brien, Graham A. Ross, Graham C. Dane, Theresa Crofts Financial support: Graham A. Ross, Graham C. Dane Administrative support: Graham A. Ross, Graham C. Dane Provision of study materials or patients: Mary E.R. O'Brien, Tudor-Eliade Ciuleanu, Yaroslav Shparyk, Branka ueviá, Gabor Juhasz, Nicholas Thatcher, Graham A. Ross, Graham C. Dane Collection and assembly of data: Tudor-Eliade Ciuleanu, Yaroslav Shparyk, Graham A. Ross, Graham C. Dane Data analysis and interpretation: Mary E.R. O'Brien, Hristo B. Tsekov, Nicholas Thatcher, Graham A. Ross, Graham C. Dane, Theresa Crofts Manuscript writing: Mary E.R. O'Brien, Nicholas Thatcher, Graham A. Ross, Theresa Crofts Final approval of manuscript: Mary E.R. O'Brien, Tudor-Eliade Ciuleanu, Branka ueviá, Gabor Juhasz, Nicholas Thatcher, Graham A. Ross Other: Graham A. Ross [Medical monitoring of data during study conduct]

 

	NOTES

 
Supported by GlaxoSmithKline, Middlesex, United Kingdom.

Presented in part at the International Association for the Study of Lung Cancer’s 11th World Conference on Lung Cancer, Barcelona, Spain, July 3-6, 2005.

The trial was designed by the sponsor (G.S.K.) who held and analyzed the data. The contents of this article were reviewed and approved by all authors.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
1. Spiro SG, Souhami RL, Geddes DM, et al: Duration of chemotherapy in small cell lung cancer: A cancer research campaign trial. Br J Cancer 59:578-583, 1989[Medline]

2. von Pawel J, Depierre A, Hans K, et al: Topotecan (Hycamtin^TM) in small cell lung cancer (SCLC) after failure of first line therapy: Multicentre phase II study. Eur J Cancer 33:S229, 1997 (suppl 8; abstr 1038)

3. Giaccone G: Identification of new drugs in pretreated patients with small cell lung cancer. Eur J Cancer 25:411-413, 1989

4. ten Bokkel Huinink W, Gore M, Carmichael J, et al: Topotecan vs paclitaxel in relapsed ovarian cancer. J Clin Oncol 15:2183-2193, 1997[Abstract/Free Full Text]

5. Ardizzoni A, Hansen H, Dombernowsky P, et al: Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: A phase II study in patients with refractory and sensitive disease. J Clin Oncol 15:2090-2096, 1997[Abstract/Free Full Text]

6. Depierre A, von Pawel J, Hans K, et al: Evaluation of topotecan (Hycamtin^TM) in relapsed small cell lung cancer (SCLC): A multicentre phase II study. Lung Cancer 18:35, 1997 (suppl 1; abstr 126)[Medline]

7. Eckardt J, Gralla R, Palmer MC, et al: Topotecan (T) as second-line therapy in patients (Pts) with small cell lung cancer (SCLC): A phase II study. Ann Oncol 7:107, 1996 (suppl 5; abstr 513P)[Free Full Text]

8. von Pawel J, Schiller JH, Shepherd FA, et al: Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 17:658-667, 1999[Abstract/Free Full Text]

9. von Pawel J, Gatzemeier U, Pujol JL, et al: A phase II comparator study of oral versus intravenous topotecan in patients with chemosensitive small cell lung cancer. J Clin Oncol 19:1743-1749, 2001[Abstract/Free Full Text]

10. Eckardt JR, Von Pawel J, Hainsworth JD, et al: Single agent oral topotecan (PO) versus intravenous topotecan (IV) in patients (pts) with chemosensitive small cell lung cancer (SCLC): An international phase III study. Proc Am Soc Clin Oncol 22:619, 2003 (abstr 2488)

11. Gralla RJ, Eckardt J, von Pawel J, et al: Quality of life with single agent oral topotecan vs intravenous topotecan in patients with chemosensitive small cell lung cancer (SCLC): An international phase III study. Lung Cancer 41:S237, 2003 (suppl 2; abstr P-578)

12. Freedman LS, White SJ: On the use of Pocock and Simon's method for balancing treatment numbers over prognostic factors in the controlled clinical trial. Biometrics 32:691-694, 1976[CrossRef][Medline]

13. Hollen PJ, Gralla RJ, Kris MG, et al: Quality of life assessment in individuals with lung cancer: Testing the Lung Cancer Symptom Scale (LCSS). Eur J Cancer 29A:S51-S58, 1993 (suppl 1)

14. Brooks R: EuroQol: The current state of play. Health Policy 37:53-72, 1996[CrossRef][Medline]

15. The EuroQol Group: EuroQol: A new facility for the measurement of health-related quality of life. Health Policy 16:199-208, 1990[CrossRef][Medline]

16. Bunn P, Cullen M, Fukuoka M, et al: Chemotherapy in small cell lung cancer: A consensus report. Lung Cancer 5:127-134, 1989[CrossRef]

17. Small cell lung cancer: START –State of the Art Oncology in Europe. American Italian Cancer Foundation, NY, Instituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy, 2002

18. National Comprehensive Cancer Network: Clinical practice guidelines in oncology: Small cell lung cancer, Version 1.2006, 2006. http://www.nccn.org/professionals/physician_gls/PDF/sclc.pdf

19. Liu G, Franssen E, Fitch MI, et al: Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 15:110-115, 1997[Abstract/Free Full Text]

20. Sundstrøm S, Bremnes RM, Kaasa S, et al: Second-line chemotherapy in recurrent small cell lung cancer: Results from a crossover schedule after primary treatment with cisplatin and etoposide (EP-regimen) or cyclophosphamide, epirubicin, and vincristin (CEV-regimen). Lung Cancer 48:251-261, 2005[CrossRef][Medline]

21. Cesano A, Lane SR, Poulin R, et al: Stabilization of disease as a useful predictor of survival following second-line chemotherapy in small cell lung cancer and ovarian cancer patients. Int J Oncol 15:1233-1238, 1999[Medline]

Submitted March 28, 2006; accepted September 25, 2006.

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