Therapy of small cell lung cancer with emphasis on oral topotecan

Lung Cancer 70 (2010) 7–13

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Review

Therapy of small cell lung cancer with emphasis on oral topotecan Robert Pirker a,∗ , Peter Berzinec b,1 , Stephen Brincat c , Peter Kasan d , Gyula Ostoros e , Milos Pesek f , ¯ g , Gunta Purkalne h , Regina Rooneem i , Jana Skˇriˇcková j , Dana Stanculeanu k , Signe Plate Constanta Timcheva l , Valentina Tzekova m , Branko Zakotnik n , Christoph C. Zielinski a , Matjaz Zwitter o a

Department of Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria Department of Oncology, Specialised Hospital of St. Zoerardus Zobor, Nitra, Slovakia Sir Paul Boffa Hospital, Floriana, Malta d Department of Oncology, University Hospital Bratislava, Slovakia e National Korányi Institute for Tuberculosis and Pulmonology, Budapest, Hungary f Pneumology, Medical Faculty, Charles University, Plzen, Czech Republic g Riga Easten University Hospital, Riga, Latvia h Radiation and Chemotherapy Center, Paul Stradins Clinical University Hospital Riga, Latvia i North Estonia Regional Hospital, Cancer Centre, Department of Chemotherapy, Tallinn, Estonia j Department of Respiratory Diseases and TB, University Hospital, Brno, Czech Republic k Institute of Oncology, Bucharest, Romania l Specialized Hospital for Active Treatment in Oncology, Sofia, Bulgaria m Clinic of Chemotherapy, University Hospital Queen Joanna, ISUL, Sofia, Bulgaria n Division of Medical Oncology, Institute of Oncology Ljubljana, Slovenia o Department of Radiation Oncology, Institute of Oncology Ljubljana, Slovenia b c

a r t i c l e

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Article history: Received 9 March 2010 Received in revised form 18 May 2010 Accepted 23 May 2010 Keywords: Chemotherapy New drugs Thoracic radiotherapy Brain irradiation Second-line therapy Topotecan

a b s t r a c t Systemic chemotherapy plays the major role in the management of patients with small cell lung cancer. Cisplatin plus etoposide is the most widely used regimen and is considered as standard in patients with limited disease. Cisplatin plus irinotecan improved survival compared to cisplatin plus etoposide in a Japanese trial but failed to do so in two trials in Caucasians. Cisplatin plus topotecan had similar efficacy compared to cisplatin plus etoposide in patients with extensive disease. In the second-line setting, topotecan showed similar efficacy but better tolerability compared to cyclophosphamide, doxorubin plus vincristine. Oral topotecan was as efficacious as its intravenous formulation and was shown to improve survival compared to best supportive care alone in patients previously treated with chemotherapy. Thus topotecan is considered as the standard second-line chemotherapy in patients with small cell lung cancer.

1. Introduction Lung cancer is among the most common cancers [1,2]. In 2008 in Europe, 390,900 patients were newly diagnosed with lung cancer and 342,100 lung cancer deaths occurred which accounted for 19.9% of all cancer deaths [1]. Unless smoking prevalence decreases, lung cancer will remain common but avoidable [3]. Small cell lung cancer (SCLC) represents approximately 15–25% of all lung cancers [4] with a varying incidence in different countries [2,4,5]. Without treatment, SCLC is the most aggressive one of all lung cancer types. Patients with SCLC have a high propensity for early regional and distant metastases. Thus systemic chemother-

∗ Corresponding author. Tel.: +43 1 40400 4422; fax: +43 1 40400 4461. E-mail address: [email protected] (R. Pirker). 1 Co-authors according to alphabetical order. 0169-5002/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2010.05.020

© 2010 Elsevier Ireland Ltd. All rights reserved.

apy is the cornerstone of treatment, while local treatments such as surgery or radiotherapy alone rarely result in long-term survival [6]. SCLC should be staged according to the TNM staging system but is often still staged according to the Veteran’s Administration Lung Cancer Study Group as limited disease or extensive disease [7,8]. Hematogenous metastases usually involve the contralateral lung, liver, adrenal glands, brain, bones, and bone marrow. Limited disease SCLC carries a median survival of approximately 18–24 months [4,9] but is potentially curable with combined modality therapy which results in long-term disease-free survival in approximately 20–25% of patients [10,11]. Extensive disease SCLC is considered incurable. Median survival time is approximately 9–12 months and the 5-year survival rate is less than 3% [4,12]. Although SCLC is regarded as highly sensitive to both chemotherapy and radiotherapy, only modest improvement in survival has been achieved during the last 20 years [13].

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R. Pirker et al. / Lung Cancer 70 (2010) 7–13 Table 1 Chemotherapy protocols for the treatment of SCLC. Cisplatin and etoposide (PE) Carboplatin and etoposide (CE) Cyclophosphamide, doxorubicin, and vincristine (CAV) Cyclophosphamide, doxorubicin, and etoposide (CAE) Cyclophosphamide, doxorubicin, vincristine, and etoposide (CAVE) Ifosfamide, carboplatin, and etoposide (ICE) Etoposide, ifosfamide, and cisplatin (VIP)

2. Prognostic factors Pre-treatment prognostic factors for prolonged survival are good performance status, female gender and limited disease [14–17]. Extensive disease, performance status >2, and metastatic lesions of certain organs (liver, bone marrow, central nervous system) at the time of diagnosis are associated with worse outcome [14–17]. Several laboratory parameters including serum lactate dehydrogenase, serum sodium, alkaline phosphatase, serum bicarbonate, white blood cell count, platelet count, hemoglobin level and neurone-specific enolase were also shown to be important prognostic factors [15–20]. However, the prognostic values of these parameters depend on whether all or subsets of patients with SCLC are analyzed [15]. Patients who are confined to bed have increased morbidity and poorly tolerate aggressive therapy. Nevertheless, patients with poor performance status can still derive symptom relief and prolongation of survival from treatment. 3. General treatment principles First-line chemotherapy has to be aggressive and, therefore, consists of combination chemotherapy [21]. The protocols, which are used with different frequencies, are summarized in Table 1. These protocols result in response rates of 50–80% [22] and are superior to single-agent therapy with regard to symptom relief, quality of life, and survival [23,24]. In two meta-analyses, cisplatin-containing regimens have been shown to be more active than non-cisplatin-containing regimens [25,26]. Protocols containing either etoposide or etoposide combined with cisplatin were also found to result in a survival benefit [26]. Thus cisplatin plus etoposide is the most widely used protocol and is considered as the standard first-line chemotherapy in limited disease where it can be combined at full dose with thoracic radiotherapy [27]. Prophylactic cranial irradiation (PCI) has been established as standard treatment for patients who respond to initial treatment independent of tumour stage [28,29]. Fractions of 1.8–2.5 Gy are delivered up to a total dose of 25 Gy [30]. Higher-dose PCI (36 Gy) did not improve outcome in patients with limited-stage SCLC in complete remission after chemotherapy and thoracic radiotherapy [30]. In elderly patients, the absolute benefit of PCI, life expectancy and the presence of neurocognitive co-morbidities should be considered and discussed with the patients. Despite high response rates to first-line treatment, the majority of patients will progress and succumb to their disease. In patients with progressive disease, the focus has been on singleagent chemotherapy due to the better tolerance compared to combination chemotherapy. The drugs studied in these patients include topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine and vinorelbine, with topotecan being the best-characterized drug [31]. Despite improvements in both diagnosis and therapy during the past decades, the prognosis for patients with SCLC remains unsatisfactory. In order to improve outcome, new treatment strategies are

urgently needed and should be evaluated in clinical trials. Patients should be enrolled into these trials whenever possible. 3.1. Treatment in patients with limited disease For patients with limited disease SCLC, chemoradiotherapy remains the standard of care [4,32]. Cisplatin plus etoposide (PE) is the regimen of choice because it can be combined at full dose with thoracic radiotherapy and also has slightly superior activity compared with doxorubicin- or cyclophosphamide-containing regimens [4]. Patients usually receive 4–6 cycles of chemotherapy. Thoracic radiotherapy is given at a total dose of 45–60 Gy. Thoracic radiotherapy appears to be more effective when given early in the course of chemotherapy [32] and when given twice daily for 3 weeks versus once daily for 5 weeks [27]. Chemotherapy combined with radiotherapy twice daily resulted in 2-year and 5-year survival rates of 47% and 25% but was associated with a higher rate of grade 3 esophagitis (27% versus 11%) [27]. In patients treated with chemoradiotherapy and prophylactic cranial irradiation, clinical complete response rates of up to 50–60% of patients and 2-year survival rates up to nearly 50% can be achieved [27,33]. 3.2. Treatment in patients with extensive disease In patients with extensive disease SCLC, combination chemotherapy remains the cornerstone of treatment. Several protocols are used with varying frequencies in daily practice (Table 1). The currently accepted first-line therapy is a platinumbased therapy containing etoposide [25,26,34]. These protocols achieve objective responses in about 60–80% of patients and median survival times of 8–13 months [35]. Carboplatin plus etoposide seems to be as effective but less toxic (except for increased myelosuppression) than cisplatin plus etoposide [36–38]. Three-drug combinations did not improve survival, with the exception of the VIP protocol. The VIP protocol slightly improved survival compared to cisplatin plus etoposide in a randomized trial [39], but due to its greater toxicity has not been widely used in clinical practice. 4. New drugs In order to improve outcome of systemic chemotherapy in patients with extensive SCLC, several new drugs with a focus on topoisomerase-I- and topoisomerase-II-inhibitors have been investigated. 4.1. Irinotecan Irinotecan, a topoisomerase-I-inhibitor, has been studied in several randomized phase III trials. Cisplatin plus irinotecan was shown to be superior to cisplatin/etoposide in a Japanese phase III study with median survival times of 12.8 and 9.4 months, respectively, and 2-year survival rates of 19.5% and 5.2%, respectively [40]. Gastrointestinal toxicity was worse in patients treated with cisplatin/irinotecan, while hematotoxicity was more severe in patients treated with cisplatin/etoposide. In contrast to the Japanese trial, however, a North American/Australian study failed to show any improvement with a modified weekly regimen of cisplatin/irinotecan compared to cisplatin/etoposide in 331 patients with extensive disease SCLC [41]. The modified weekly irinotecan/cisplatin regimen resulted in less myelosuppression but more diarrhoea and vomiting. Another North American phase III trial, which included 620 patients and used the same regimen of cisplatin/irinotecan as the original Japanese study, also failed to demonstrate a survival benefit for

R. Pirker et al. / Lung Cancer 70 (2010) 7–13

cisplatin/irinotecan [42]. Thus both trials confirmed cisplatin plus etoposide as the reference standard regimen for SCLC in Caucasians. 4.2. Amrubicin Amrubicin, a fully synthetic anthracycline that inhibits DNA topoisomerase II, has also shown activity both as a single agent and in combination with cisplatin in SCLC. In two recent Japanese phase II studies [43,44], amrubicin resulted in response rates of more than 50%, with major responses in 8 of 16 patients with chemorefractory SCLC in one of these studies [43]. Myelosuppression was the major toxicity with leukopenia grades 3–4 occurring in 70% of the patients. Single-agent amrubicin also showed efficacy with an overall response rate of 21% in patients with platinum-refractory SCLC in a recent phase II trial in Caucasians [45]. Based on this encouraging efficacy, phase III-studies in both chemo-sensitive and chemo-refractory SCLC are ongoing [46].

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and quality of life were slightly better with cisplatin plus etoposide but these differences were of questionable clinical relevance. Thus the study met the predefined criteria for non-inferiority of ≤10% of cisplatin plus oral topotecan relative to cisplatin plus etoposide in the 1-year survival rate. Anemia grades 3–4 (38% versus 21%) and thrombocytopenia grades 3–4 (38% versus 23%) occurred more frequently with cisplatin plus oral topotecan, while neutropenia grades 3–4 occurred more frequently with cisplatin plus etoposide (59% versus 84%). Fever and infection occurring within 2 days approximate to grade 4 neutropenia was observed in 10% of patients on cisplatin plus etoposide versus 4% on cisplatin plus oral topotecan. With regard to non-hematologic toxicities, cisplatin plus oral topotecan led to a higher incidence of diarrhoea (33% versus 18%) but lower incidences of serum creatinine elevations (5% versus 12%) and alopecia (24% versus 40%). Thus this phase III trial study indicated similar efficacy but different toxicity profiles between cisplatin plus oral topotecan and cisplatin plus etoposide as first-line treatment for patients with extensive disease SCLC.

4.3. Topotecan Topotecan, a watersoluble, semisynthetic derivative of camptothecin, acts as a topoisomerase-I-inhibitor and, thereby, prevents DNA replication in cancer cells. The intravenous formulation of topotecan has shown activity against SCLC in several studies [47] and has been established as second-line therapy at the time of progression of SCLC (see below). In 2008, the results of a randomized phase III trial comparing cisplatin plus topotecan with cisplatin plus etoposide in patients with extensive disease SCLC have been reported [48]. A total of 795 patients were randomized to receive topotecan 1 mg/m2 i.v. daily on days 1–5 plus cisplatin 75 mg/m2 on day 1 or etoposide 100 mg/m2 daily days 1–3 plus cisplatin 75 mg/m2 on day 1 of 3week cycles. A third study arm of topotecan 1 mg/m2 daily days 1–5 plus etoposide 80–100 mg/m2 daily days 3–5 resulted in an increased number of treatment-related deaths due to hematotoxicity and was closed early. Compared to cisplatin plus etoposide, cisplatin plus topotecan was non-inferior with regard to survival but superior with regard to response rate and time to disease progression. However, grade 3/4 thrombocytopenia (5% versus 19%) and grade 3/4 anemia (7% versus 12%) and toxicity-related deaths (3% versus 5%) were higher with cisplatin plus topotecan. Thus cisplatin plus topotecan can be considered as a treatment option in patients with extensive disease SCLC. 4.3.1. Oral topotecan Oral topotecan has first been investigated as first-line monotherapy in a phase II feasibility study in 41 patients with extensive disease SCLC who due to age or concomitant illness were ineligible for standard therapy [49]. Patients initially received 2.0 mg/m2 per day for 5 days every 3 weeks, but the dose level was reduced to 1.7 mg/m2 per day due to myelosuppression. The overall response rate was 30%, including one complete response. Thus this trial suggested that oral topotecan has efficacy in patients with extensive disease SCLC. In a subsequent randomized phase III trial, the combination of cisplatin plus oral topotecan was compared with cisplatin plus etoposide in chemo-naïve patients with extensive disease SCLC [50]. Treatment consisted of oral topotecan 1.7 mg/m2 per day for 5 days with intravenous cisplatin 60 mg/m2 on day 5 or intravenous etoposide 100 mg/m2 per day for 3 days with intravenous cisplatin 80 mg/m2 on day 1 every 21 days. A total of 784 patients were randomized, 389 into the topotecan arm and 495 in the cisplatin/etoposide arm. Response rates (63% versus 69%) and overall survival (median 39.3 weeks versus 40.3 weeks; 1-year survival rates 31% in both groups) were similar between both groups. Time to disease progression (median 24 weeks versus 25 weeks, p = 0.02)

5. Treatment in patients with disease progression About 80% of limited disease patients and virtually all patients with extensive disease will relapse or progress. These patients have poor prognosis and symptom palliation as well as quality of life are primary considerations for them. Despite high response rates to first-line chemotherapy, response duration is usually short with a median progression-free survival of approximately 4 months for extensive disease [51]. Patients who relapse within 3 months after first-line therapy are considered as refractory, and patients who relapse more than 3 months after therapy as sensitive [51]. Refractory patients have lower response rates and a worse prognosis than those with sensitive disease. The treatment options for recurrent disease depend on the anatomic site of relapse, symptoms and previous treatments [4]. For local progression in the chest, palliative radiotherapy should be considered for patients without prior chest irradiation. Brain metastases are an important site of progression. The type of treatment depends on their numbers and symptoms, performance status of the patient, presence of symptoms outside the brain and previous treatments. Brain metastases are usually treated with radiotherapy, unless immediate systemic chemotherapy is required. Whole-brain irradiation is the preferred option in patients without previous cranial irradiation, while stereotactic radiotherapy might be considered in patients with prior cranial irradiation. Because intracranial metastases from SCLC may respond to chemotherapy like metastases in other organs [52,53], chemotherapy may also be considered in selected patients. Chemotherapy and whole-brain irradiation are usually administered in a sequential mode. Systemic progression is treated with systemic chemotherapy but radiotherapy also plays an important role in relief of symptoms from metastases, particularly in case of brain and bone metastases. Chemotherapy aims at palliation of cancer-related symptoms but may also improve survival. The possibility of a survival benefit was raised by a British study which suggested a survival benefit by second-line treatment in patients who had been pre-treated with short-term first-line chemotherapy but not in patients with previous long-term chemotherapy [54]. The choice of chemotherapy at relapse depends on performance status, type of and response to first-line therapy, and the treatment-free interval. Patients responding to initial treatment and progressing 6 months or more after the last chemotherapy can again be treated with the initial regimen [55,56]. Many patients with relapsed SCLC may not tolerate aggressive combination chemotherapy because of their co-morbidities, poor

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Table 2 Oral versus intravenous (i.v.) topotecan [62]. Topotecan

Number of patients Response rates Median survival time 1-year survival rate 2-year survival rate Neutropenia grade 4

Oral

i.v.

153 18% 33 weeks 33% 12% 47%

151 22% 35 weeks 29% 7% 64%

performance status, and/or older age [57]. In addition, cumulative toxicities of first-line chemotherapy such as nephrotoxicity, neuropathy, and bone marrow suppression, may limit the patient’s ability to tolerate therapy at the time of disease recurrence [58,59] and, therefore, have to be considered when selecting treatment for recurrent disease [30]. Intravenous topotecan has shown response rates and survival similar to cyclophosphamide/doxorubicin/vincristine (CAV) in relapsed, chemotherapy-sensitive SCLC [60]. However, topotecan caused less toxicity. Thus, in 1999 topotecan has been approved by the US Food and Drug Administration for the treatment of SCLC sensitive disease after failure of first-line chemotherapy. Intravenous topotecan has long been the only single agent approved for second-line chemotherapy of SCLC and has been the agent of choice for treatment of patients with SCLC who have relapsed within 2–6 months after completing first-line chemotherapy [55,56]. 5.1. Oral topotecan in patients with relapsed or resistant SCLC The proven efficacy of intravenous topotecan in SCLC led to the development of an oral formulation of topotecan in order to improve patient convenience and patient access. Oral topotecan was first compared with the standard intravenous topotecan in a phase II trial [61] and a phase III trial [62]. In these randomized studies, patients with relapsed, sensitive SCLC (defined as relapse more than 90 days after the end of first-line chemotherapy) received second-line therapy with either oral topotecan 2.3 mg/m2 per day for 5 days or intravenous topotecan 1.5 mg/m2 per day for 5 days every 21 days. In the phase II trial, the activities were similar but the incidences of grade 4 neutropenia were 35% versus 67% for the oral and intravenous formulations, respectively [61]. In the phase III trial, which randomly assigned 309 patients to treatment with either oral or intravenous topotecan, response rates as primary endpoint were 18% and 22%, respectively [62] (Table 2). Median survival and survival rates at 1 and 2 years were also similar (Fig. 1). Neutropenia grade 4 was less frequent with oral topotecan. Thus these trials demonstrated similar efficacy but reduced neutropenia for oral topotecan compared to intravenous topotecan. These findings together with the convenient administration make oral topotecan an interesting treatment option for patients with progressive SCLC. 5.1.1. Oral topotecan versus best supportive care Oral topotecan was compared with best supportive care alone in order to determine whether second-line chemotherapy can improve survival in patients with relapsed SCLC [63]. This phase III study enrolled 141 patients both refractory and sensitive to the first-line treatment and deemed unsuitable for further standard intravenous therapy. Patients were randomized into either oral topotecan 2.3 mg/m2 daily for 5 days every 21 days plus best supportive care (n = 71) or to best supportive care alone (n = 70). Patients receiving oral topotecan experienced greater symptom control and a survival benefit. Median survival times were 25.9 weeks versus 13.9 weeks (p = 0.01). In an intent-to-treat-analysis,

Fig. 1. Survival with oral versus intravenous topotecan in the intent-to-treat population [62].

survival as the primary endpoint was longer in the topotecan arm than in the best supportive care arm. The 6-month survival rates were 49% in the topotecan arm and 26% in the best supportive care arm (Fig. 2). The unadjusted hazard ratio for overall survival was 0.64 (95% CI, 0.45–0.90) for topotecan relative to best supportive care alone. Adjusted for stratification factors, the hazard ratio was 0.61 (95% CI, 0.43–0.87). Patients were stratified according to ≤60 days and >60 days in time to progression since first-line chemotherapy. Topotecan was active in both patients with resistant disease and those with sensitive disease. Topotecan was associated with an overall response rate of 7%, a median time to progression of 16.3 weeks, a better symptom control and a significantly slower worsening of quality of life. Benefits in survival and quality of life were seen in all subgroups including patients with poor performance status and patients with refractory disease (Fig. 3). Hematotoxicity was the main side effect with the following grade 3/4 toxicities: 61% neutropenia, 38% thrombocytopenia, and 25% anemia. Diarrhoea (6%) was the most common nonhematologic toxicity. All-cause mortality rates within 30 days of random assignment were 7% with topotecan and 13% with best supportive care. Thus this is the first trial, which indicated that second-line treatment with oral topotecan improves clinical outcome including survival. The trial also demonstrated that patients with resistant

Fig. 2. Survival benefit (p = 0.01) for oral topotecan plus best supportive care (BSC) versus BSC alone in patients with relapsed SCLC in the intent-to-treat population [63].

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Fig. 3. Oral topotecan plus best supportive care (BSC) versus BSC alone in patients with relapsed SCLC: subgroup analysis of survival [63].

disease also benefit from oral topotecan with regard to survival and quality of life [63]. 5.1.2. Safety and toxicity profile of oral topotecan The toxicity profile of oral topotecan was similar in the different clinical trials. Oral topotecan was generally well tolerated. Hematological toxicities were non-cumulative, with limited clinical sequelae, and non-hematological toxicities were predominately of grades 1 and 2. The incidence rates of grades 3 and 4 thrombocytopenia and anemia were similar for the oral and intravenous formulations, but there was a lower incidence of neutropenia with oral topotecan. However, these toxicities are usually predictable, of short duration, non-cumulative, and manageable with dose reductions or dose delays. Non-hematological toxicity is generally mild and mainly consists of gastrointestinal events, hair loss and fatigue. Of all possibly related non-hematologic events only diarrhoea is observed more frequently with oral than intravenous topotecan. Diarrhoea should be managed according to established guidelines [64]. Severe diarrhoea can effectively be prevented through careful monitoring and adequate intervention. The oral formulation of topotecan may provide a more convenient schedule for some patients, particularly if alternative regimens consist solely of intravenous medications. Indeed, a survey of 103 patients with incurable cancer revealed their preference of oral chemotherapy [65]. Given a choice of agents with similar efficacy, most patients would prefer oral agents to intravenous chemotherapy. The reasons for this preference include convenience, problems with intravenous access or needles, having control over the environment for taking chemotherapy, and the need for travel to receive intravenous chemotherapy [66]. Compliance with oral topotecan in clinical trials, evaluated by pill counts, has been high as shown in a retrospective analysis of compliance data from three randomized phase III trials of oral topotecan in lung cancer [67]. Compliance according to pill counts was in the range of 90.8–98.6% in the treated population, which also included patients >65 years and patients with poor performance status. 6. Treatment recommendations for extensive disease SCLC I. Treatment at initial diagnosis • Treatment decisions should consider performance status, comorbidity and organ functions of the patient but also sites of metastases. • Patients receive systemic chemotherapy. Platin plus etoposide is considered as standard protocol, while cyclophos-

phamide/doxorubicin/vincristine or other regimens may also be an option. • Documented brain metastases are usually treated with wholebrain radiotherapy unless they are small and immediate chemotherapy is indicated. • Prophylactic cranial irradiation (PCI) should be offered to patients responding to first-line chemotherapy. II. Treatment at progression • For treatment of disease progression the type of second-line therapy depends on site(s) of progression, response to as well as residual toxicity from first-line therapy, progression-free interval, performance status, co-morbidity, organ functions, and patient’s preference. • Systemic chemotherapy plays the major role for patients with systemic progress outside the brain: o Patients who progress six or more months after having completed first-line chemotherapy may benefit from retreatment with the initial regimen. o Topotecan, administered intravenously or orally, is the preferred treatment option for patients progressing after first-line chemotherapy and not suitable for re-treatment with the initial regimen. o Oral topotecan offers ease of administration and patient convenience. As a monotherapy, oral topotecan is administered at a dose of 2.3 mg/m2 daily for 5 days every 21 days. Side effects include non-cumulative myelosuppression and diarrhoea. o Palliative radiotherapy should be considered for local progression in the chest in patients without prior chest irradiation. Radiotherapy also plays an important role in palliation of symptoms of metastatic disease, particularly in case of brain and bone metastases. o Brain metastases are usually treated with whole-brain irradiation. The number as well as size of lesions, symptoms, performance status and symptoms outside the brain requiring immediate chemotherapy should be considered. Intracranial metastases from SCLC may also respond to chemotherapy. If both chemotherapy and radiotherapy are used in the treatment of brain metastases, they are commonly administered in a sequential mode.

Funding This project was made possible by unrestricted educational grants from GlaxoSmithKline.

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