Annals of Oncology Advance Access originally published online on October 27, 2006
Annals of Oncology 2007 18(1):104-109; doi:10.1093/annonc/mdl353
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© 2006 European Society for Medical Oncology
lung cancer |
Randomised phase II study comparing topotecan/carboplatin administration for 5 versus 3 days in the treatment of extensive-stage small-cell lung cancer
1 Hamm-Kliniken, Bad Soden Salmünster
2 Klinikum Nuernberg-Nord, Nuernberg
3 Department of Medical Biometry and Informatics, University of Marburg and Giessen, Marburg
4 Department of Medical Biometry and Informatics, Johanniterkrankenanstalten Oberhausen, Oberhausen
5 Krankenhaus Luedenscheid, Leudenscheid
6 AK Hamburg-Harburg, Hamburg
7 St Johannes Hospital, Duisburg
8 Vogtlandklinikum, Plauen
9 GlaxoSmithKline, Munich
10 Department of Haematology and Oncology, Klinikum Kassel, Germany
* Correspondence to: Dr U. Seifart, Hamm-Kliniken, Brüder Grimm-Strasse, 20 63628 Bad Soden Salmünster, Germany. Tel: +49-6056-72109; Fax: +49-6056-72150; E-mail: dr.seifart{at}hamm-kliniken.de
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Abstract |
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Background: Topotecan is an active drug in small-cell lung cancer (SCLC). In our previous study, a combination of topotecan with cisplatin was associated with a median overall survival of 7.6 or 8.7 months, depending on the duration of treatment. We have replaced cisplatin by carboplatin in this trial, with the objective of creating a more convenient schedule for our patients. Furthermore, we have also compared the standard 5-day schedule with an experimental 3-day schedule.
Patients and methods: A total of 100 patients with metastatic disease were included. Patients were randomly assigned to receive either topotecan 0.75 mg/m2, days 1–5, and carboplatin AUC 5, day 5 (arm A) or topotecan 1.25 mg/m2, days 1–3, and carboplatin AUC 5, day 3 (arm B). Six cycles were given at a 3-week interval.
Results: A total of 91 patients were assessable for response. The response during therapy was 86.9% in arm A and 80.0% in arm B. Median survival in arm A was 11.8 months and in arm B 11.6 months (P = 0.37).
Conclusions: The combination of topotecan and carboplatin is active in extensive-disease SCLC. Toxicity and median survival were comparable in both arms. Three days of treatment seems to be similar to the 5-day regimen.
Key words: carboplatin, chemotherapy, extensive disease, small-cell lung cancer, topotecan
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Little progress has been made in the treatment of small-cell lung cancer (SCLC) during the past two decades. From 1981 to 1993, our multicentre study group carried out five randomised trials including 738 patients with metastatic disease without achieving clear improvements in survival time [1–5]. To overcome this stagnation, the introduction of new drugs into treatment protocols is necessary.
The first-line activity of topotecan (Hycamtin; GlaxoSmithKline, Philadelphia, PA), a semi-synthetic camptothecin, as single-agent in patients with metastatic SCLC, is shown in the study of Schiller et al. [6]. Remission rate was 39%, and the median survival was 10 months. Nevertheless, polychemotherapy is superior to single-agent treatment and platinum compounds can be regarded as the mainstay in the treatment of SCLC. Furthermore, topotecan and platinum show a synergistic effect in vitro [7, 8].
In our multicentre study [9], the combination of topotecan and cisplatin in extensive-disease (ED) SCLC patients was associated with a median overall survival of 7.6 or 8.7 months in a 3- or 5-day schedule, respectively. In this trial, vomiting and nausea were the main non-haematologic side-effect and we therefore decided to substitute cisplatin by carboplatin, to create a better tolerated schedule for our patients. Therefore, we have carried out a randomised phase II trial comparing topotecan/carboplatin administered for 5 versus 3 days in patients with ED SCLC.
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patients and methods |
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This multi-institutional phase II trial was started in February 2001 and during a 14-month recruitment period a total of 100 patients entered the trial.
Eligibility criteria were histologically confirmed SCLC, ED, defined as SCLC with metastatic distant-organ involvement [ED II (any T, any N, M1)] or malignant pleural effusion [ED I (T4, N3)], measurable disease, no prior chemotherapy or radiotherapy, age between 18 and 72 years, performance status (PS) of 70% or more according to the Karnofsky performance status, a life expectancy of at least 2 months and informed consent.
Patients were excluded from the study if prior radiotherapy, chemotherapy or surgical treatment had been given; if a previous malignant disease other than nonmelanoma skin cancer existed during the last 5 years; if symptoms and signs of intercurrent infection were found; if an human immunodeficiency virus-infection was diagnosed; if hypersensitivity to topotecan was known; if pregnancy could not be definitively excluded; in case of renal dysfunction (serum creatinine level 
1.5 mg/dl and creatinine clearance 
60 ml/min); hepatic disease (bilirubin level 2.0 mg/dl); advanced respiratory or cardiac failure or reduced bone marrow function (white blood cells 3500 x 109/l or platelet count 100 000 x 109/l).
The protocol and the patient-informed consent were approved by ethics review boards.
staging
Pre-treatment staging consisted of complete medical history, physical examination, electrocardiogram and standard laboratory parameters (blood counts, sodium, potassium, creatinine level, urea/nitrogen, creatinine clearance, aspartate aminotransferase, alkaline phosphatase and lactate dehydrogenase). A bronchoscopy with biopsy to obtain material for the histological examination (mediastinoscopy, thoracotomy or transthoracic needle biopsy were accepted due to the clinical situation) was done in each patient. A chest X-ray and computed tomography (CT) scan of the chest, ultrasound or CT of the abdomen, isotopic bone scan, CT or magnetic resonance imaging (MRI) of the brain and a unilateral iliac bone marrow biopsy was done in each patient.
The assessment of lung biopsy material was conducted at regional pathological institutes.
treatment
The treatment regimen of arm A consisted of topotecan at a dose of 0.75 mg/m2 as a 30-min infusion on days 1–5, followed by carboplatin AUC 5 as a 1-h infusion on day 5. In arm B, topotecan was given at a dose of 1.25 mg/m2 as a 30-min infusion on days 1–3, followed by carboplatin AUC 5 as a 1-h infusion on day 3. The treatment regimen is shown graphically in Figure 1. A total of six cycles at 3-week intervals were given to the responding patients. In case of progressive disease, treatment was stopped and the introduction of second-line therapy was left to the decision of the regional physician.
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evaluation before and during treatment
During treatment, blood counts were carried out on days 11 and 14 and afterwards at weekly intervals after each cycle. Before each subsequent course and 3 weeks after the last course, a complete physical examination, an evaluation of toxic side-effects due to therapy, a complete laboratory screen and an assessment of tumour response were conducted. Prior to each chemotherapy cycle, patients had to have normal blood counts with leukocytes >3500 x 109/l and platelets >100 000 x 109/l. Otherwise, treatment was postponed. If the blood count did not return to normal values within 2 weeks, further therapy was stopped and second-line therapy was started. The dose of topotecan in further cycles was adjusted according to the haematologic toxicity. The dose of topotecan was reduced by 0.25 mg/m2, if the nadir of the leukocytes was <1000 x 109/l or the nadir of platelets was <30 000 x 109/l on days 11 or 14. The dose of topotecan was increased by 0.25 mg/m2/day if the nadir of leukocytes was >3000 x 109/l and the nadir of platelets was >100 000 x 109/l on days 11 or 14. If the nadir was within these limits, the topotecan dose was not modified. Dose escalation of carboplatin was not permitted. No prophylactic growth factor use was recommended.
response assessment
When the treatment program was completed, a restaging scheme identical to the pre-treatment staging was carried out. Bronchoscopy was repeated only when a complete remission (CR) was suspected, and a second bone marrow biopsy was obtained only in patients with initial bone marrow involvement or in patients with suspected CR. The response to treatment was assessed according to World Health Organisation (WHO) recommendations [10].
statistical methods
All clinical data were monitored and collected by an independent monitoring company. Data management and final analysis were done with SAS software (SAS Institute, Inc., Cary, NC) version 8.02 and SAS Enterprise Guide version 2.05. The study results, including survival, tumour response, progression-free survival and toxic effects according to the WHO classification, were reported in a descriptive manner. Progression-free survival and survival time were measured from the day of randomisation.
Assuming an objective response rate of 55% in each group, the sample size was set to 42 assessable patients per group in order to get a 95% confidence interval (CI) with 15% precision. This pilot study is planned to investigate the effects of the two different regimens regarding as primary end point toxicity and remission rate but not to show statistically significant differences. Secondary end point was survival.
The remission rate was described exploratively in both therapy arms, with a 95% CI.
The survival curves shown were based on the Kaplan–Meier method [11]. Comparison of the two arms was carried out descriptively using the log-rank test [12].
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results |
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patient characteristics
During the 14-month recruitment period, 100 patients in 24 institutions across Germany entered the study. A total of 91 patients were assessable for response and 95 patients were assessable for toxicity. Baseline characteristics are listed in Table 1. Interestingly, both arms included 45 patients with central nervous system-metastasis. Selection for these patients did not take place.
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Nine patients (five in arm A and four in arm B) were not assessable for the following reasons: withdrawal of consent twice, side-effects twice, violation of inclusion criteria once, pleural empyema once and no information available thrice.
treatment schedule
Five or more cycles of chemotherapy were given to a total of 57 patients (Table 2). Of these, 31 received five or more cycles in arm A and 26 in arm B. Treatment was discontinued for the following reasons: death in five patients (two in arm A and three in arm B), progressive disease in 24 cases (13 in arm A and 11 in arm B), side-effects in five patients (two in arm A and three in arm B), patient's refusal in five cases (one in arm A and four in arm B) and other reasons in 10 cases (six in arm A and four in arm B) [gastrointestinal bleeding once, bad PS (two patients), pleural empyema once, violation of the inclusion criteria once, late haematologic recovery once, changing therapy because of lack of efficacy (once), no reasons in three patients] (Table 3).
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Topotecan doses were adjusted on the basis of the haematologic nadir on days 11 or 14 (dose reduction six patients in arm A and six patients; dose escalation 23 patients and 18 patients in arm A and arm B, respectively) (Table 4). In all cycles, the median weekly dose of topotecan given was 4.3 mg/m2 in arm A (range 1.25–8.75) and 3.95 mg/m2 in arm B (range 1.25–6.9) (P = 0.004) (Table 5).
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response
Response was assessed as the best response of all patients during therapy.
Response (CR and partial remission [PR]) during therapy is 86.9% in arm A—40 out of 46 (95% CI–73.7%–95.1%)—and 80.0% in arm B—36 out of 45 patients (95% CI–65.4%–90.4%) (Table 6).
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Ten patients (21.7%) achieved CR in arm A and seven patients (15.6%) in arm B. Thirty patients (65.2%) developed PR in arm A and 29 patients in arm B (64.4%). At restaging, progressive disease was seen in 4.4% in arm A (two patients) and in 8.9% in arm B (six patients).
Three patients died before restaging in arm A (two patients with lung emboli), and five patients in arm B (two pulmonary embolism and three cancer related). There was one therapy-related death in arm A (fever of unknown origin [FUO] during neutropenia after chemotherapy), while no therapy-related death was seen in arm B.
survival
Survival was analysed for all eligible patients.
The median survival in arm A was 11.8 months and in arm B 11.6 months (P = 0.37) The 1-year survival rate was found to be 39.2% and 40.8% for arms A and B, respectively. The survival curve for all patients is shown in Figure 2.
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toxicity
A total of 441 cycles were administered. There were two treatment-related deaths [one patient each in arms A and B (septicaemia during neutropenia)].
Haematologic toxicity was the main side-effect. Anaemia of WHO grade III or IV was seen in 20.8% (arm A) and 23.4% (arm B) (P = 0.763), and grade III/IV leukocytopenia was observed in 27.1% (arm A) and 21.3% (arm B) (P = 0.509). Grade III/IV thrombocytopenia was seen in 18.8% (arm A) and 23.4% (arm B) (P = 0.578).
Non-haematologic side-effects were generally moderate; relevant WHO grade III or IV side-effects were alopecia (29.8% arm A versus 18.6% in arm B, P = 0.218), vomiting (8.3% versus 17.8%, P = 0.175), nausea (15.6% versus 19.5%, P = 0.629), pain (13.3% versus 6.8%, P = 0.308) and constipation (10.4% versus 6.6%, P = 0.519). The incidences of side-effects are summarised in Table 7.
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discussion |
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Topotecan is known to have substantial activity in different solid tumours [13–21] and topotecan/cisplatin therapy can be carried out with acceptable toxicity and activity [22, 23]. Experience with topotecan in first-line treatment of SCLC, however, is still limited. In a previous multicentre study comparing topotecan/cisplatin for 3 versus 5 days [9], a median survival of 8.7 or 7.6 months, respectively, was shown in a patient population comparable to the present study. There, cisplatin 75 mg/m2 on day 5 in arm A and on day 3 in arm B was replaced by carboplatin AUC 5, in an attempt to lower the incidence of side-effects. Consequently, carboplatin/topotecan seems to be better tolerated than cisplatin/topotecan with respect to non-haematologic side-effects, as in the present study grade III and IV nausea [cisplatin: 26.2% (arm A)/28.6% (arm B) versus carboplatin: 15.6%/19.5%)], vomiting (WHO grade III and IV) [cisplatin: 7.2% (arm A)/28.6% (arm B) versus carboplatin: 8.3%/17.8%] and alopecia (WHO grade III and IV) [cisplatin: 47.6% in both arms versus carboplatin: 28.8%/23.4%] were found to be strongly reduced.
Because myelosuppression is one of the main side-effects of both topotecan and carboplatin, we expected a higher incidence of haematologic side-effects in the present study than in the older one. To our surprise, we found a lower rate of myelosuppression in the carboplatin study. Grade III and IV anaemia occurred in 20.9% (arm A) and in 23.4% (arm B) of patients, grade III and IV leukocytopenia in 27.1% (arm A) and 21.3% (arm B), while thrombocytopenia (WHO grade III and IV) was seen in 18.7% (arm A) and 23.6% (arm B) in the carboplatin study. In the cisplatin study, anaemia (WHO grade III and IV) was seen in 42.9% (arm A) and 21.4% (arm B), leukocytopenia in 54.3% (arm A) and 47.6% (arm B) and thrombocytopenia in 52.4% (arm A) and 40.4% (arm B) of all cases. The aetiology of these findings is not explained by our data. On one hand, we reduced the doses of topotecan in the current study—which may be responsible for the lower rate of haematologic and non-haematologic side-effects. On the other hand, cisplatin itself is responsible for more non-haemtologic side-effects. Another explanation for the lower haemtological side-effects in the present study is that cisplatin causes tubular damage in the kidney, so that topotecan stays longer in the bone marrow. This speculation is supported by the observation in the cisplatin study that the incidence of side-effects, especially the haematologic side-effects, was higher in arm A than in arm B. In the present study, we found no difference in the incidence of haematologic or non-haematologic side-effects between the two arms. Additional data from Rowinsky et al. [22] support our hypothesis. This trial showed that administration of cisplatin at the end of therapy caused significantly reduced haematologic toxicity. This observation was postulated to be due to subclinical renal tubular damage impairing the systemic clearance of topotecan. The dose reduction of topotecan between the two studies, however, does not provide a conclusive explanation for the difference in side-effects. Patients in arm A in the present study received more topotecan, due to the dose modification which was done, depending on the haematological nadir (Table 6), but we did not see a difference in side-effects.
The final proof of our speculation must be left to a separate trial, including measurements of topotecan levels during therapy.
The higher incidence of leukocytopenia in the cisplatin study may be responsible for the higher rate of infection in the older study than in the present study. In the current study, infection grades III and IV were seen in 6.1 (arm A) or 6.7% (arm B) of patients, while in the cisplatin trial 26.2% (arm A) and 11.9% (arm B) of patients developed an infection of grades III and IV. We did see two therapy-related deaths in the present study, compared with four in the previous study. All six patients died of neutropenia caused by chemotherapy and therefore it is evident that the lower haematologic side-effects were linked to a lower therapy-related fatality rate.
Other side-effects occurred at lower incidence and are not discussed here.
The response rate was higher in the present study [86.9% (arm A) and 80% (arm B); carboplatin] than in the older study [61.9% (arm A); 59.5% (arm B); cisplatin]. There is no statistically relevant difference between the two arms of the current study. The response rate of the present study, however, seems to be higher than the response rate of the older one. The response rate of the carboplatin study is similar to that described in the Sorensen et al. [23] trial and is in the upper range expected for first-line therapy in ED SCLC patients. This is particularly encouraging, in view of the high number of brain metastases in this trial.
Parallel to the better response rate, we observed a longer median survival in the carboplatin study [11.8 months (arm A), 11.6 months (arm B)] than in the cisplatin study [8.7 versus 7.6 months (arm A) versus (arm B)]. There is no evident difference between the two arms of the present study (P = 0.37), although these results are clearly in the upper level of what could be expected in this population. At the American Society of Clinical Oncology this year, Eckardt et al. [24] presented the data of one of the largest SCLC trials comparing oral topotecan/cisplatin versus etoposide/cisplatin. In this trial, a median survival of 39.9 or 40.3 weeks is described. This seems to be comparable to our topotecan/cisplatin study, but lower than the results of the current trial.
Our present study showed comparable results to those with the other topoisomerase I inhibitor, irinotecan. Noda et al. [25] described a median survival of 12.8 months in metastatic SCLC patients treated with irinotecan/cisplatin versus 9.4 months in patients who were treated with etoposide/cisplatin.
These trials indicate that a topoisomerase I inhibitor in combination with a platinum compound is effective in untreated SCLC patients.
The standard administration of topotecan in lung cancer and other solid tumours is still a 5-day schedule. A 3-day regimen is more convenient and acceptable to the patients than a 5-day treatment. Experience with a 3-day topotecan regimen has been restricted to a single randomised phase II study [9]. In this trial, there was no relevant difference between the two arms. The present study is the second investigation of a 3-day and a 5-day regimen in parallel, to analyse effects and toxicity. The regimens are similar in terms of toxicity, response rates and survival.
In summary, we have demonstrated that the combination of topotecan and carboplatin is active in ED SCLC. The haematologic and non-haematologic toxicity was tolerable and comparable to other topotecan schedules. Toxicity and response rate seem to be similar in both arms. Comparison to a very similar study with topotecan/cisplatin for 3 versus 5 days indicates that a 3-day regimen of topotecan and a platinum compound being more convenient for patients seems to be comparable to a 5-day regimen containing the same drugs.
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The work was supported by an unrestricted grant from GlaxoSmithKline, Munich, Germany.
Received for publication February 8, 2006. Revision received August 21, 2006. Accepted for publication August 23, 2006.
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References |
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