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Phase II study of pegylated liposomal doxorubicin: Inactive in recurrent small-cell lung cancer
Annals of Oncology 11: 1395-1397,2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.
Original article Phase II study of pegylated liposomal doxorubicin: Inactive in recurrent small-cell lung cancer A Hellenic Cooperative Oncology Group Study E. Samantas,1 H. Kalofonos,2 H. Linardou,1 C. Nicolaides,3 N. Mylonakis,4 G. Fountzilas,5 P. Kosmidis6 & D. Skarlos1 Agii Anargiri' Cancer Hospital, Athens; 2Oncology Department, University of Patras, Patras; Oncology Department, University of Ioannina, loannina; ""Metaxas'Anticancer Hospital, Piraeus; 5Oncology Department, Aristoteleion' University of Thessaloniki, Thessaloniki; ^Oncology Department, 'Hygeia'Hospital, Athens, Greece
Results: No responses were seen but in three patients disease was stabilised for a median of three months. The median Purpose: Although clinical experience with liposomal doxo- number of cycles was 2 per patient, with 11 of 14 patients not rubicin is still limited in solid tumours, single agent Caelyx completing 6 cycles of Caelyx treatment. From those, five (pegylated liposomal doxorubicin) treatment has shown promis- patients were removed from the study after only one cycle due ing results in AIDS-related Kaposi's sarcoma, metastatic breast to rapid disease progression, and one was withdrawn after and ovarian cancer and anecdotally in other solid tumours. This three cycles due to prolonged toxicity. Overall, treatment was is thefirstreport of its use in small-cell lung cancer (SCLQ. The well tolerated with no episodes of grade 4 toxicity and only two objective of this multicenter phase II study was to evaluate the episodes of grade 3 toxicities: one of thrombocytopenia and safety, tolerance and anti-tumour activity of Caelyx as mono- one of prolonged palmar-plantar erythrodysesthesia (PPE). therapy in patients with recurrent SCLC. Conclusions: These results demonstrate limited activity of Patients and methods: A total of 14 patients with recur- Caelyx in this patient population, which may be related to the rent SCLC who had not received prior treatment with doxo- poor prognostic features of such patients. Our findings are in rubicin, were accrued into this phase II study. All patients had agreement with previous observations that doxorubicin-conprogressed or relapsed after first-line chemotherapy. All but taining combinations are rarely active in platinum/etoposide one had achieved objective responses to first-line treatment failures. However, as in other studies the favourable toxicity with median duration offivemonths (range 2-18 months) but profile of Caelyx is confirmed. half of them had experienced 'refractory' relapses (within 3—4 months). Study treatment consisted of Caelyx 50 mg/m2 Key words: liposomal doxorubicin, phase II, recurrent small(1-hour i.v infusion every 4 weeks for 6 cycles). cell lung cancer Summary
Although small-cell lung cancer (SCLC) is one of the most chemosensitive adult tumours, the initial dramatic responses to chemotherapy are commonly followed by drug-resistant relapses. The consistently poor prognosis of patients with recurrent SCLC demonstrates the need for investigation and development of novel agents in the second-line treatment of this disease [1]. Doxorubicin combinations (e.g., CAV or in European centers with etoposide and cyclophosphamide or analogues [2]) are used less as primary chemotherapy since the introduction of etoposide/cisplatin (EP) and considering its problematic toxicity profile, mainly when combined with radiotherapy. In the second-line setting although EP can achieve up to 40%-50% response rates after CAV failure, conversely CAV is rarely active in EP failures [3,4]. A doxorubicin formulation with improved tolerance would theoretically increase the drug's
therapeutic ratio and enhance its efficacy [5]. Pegylated liposomal doxorubicin (Caelyx) represents a unique formulation showing promising results in the treatment of several tumour types [5-8]. We present here the results of a multicenter phase II study of Caelyx monotherapy in SCLC patients failing or relapsing after first-line platinum-containing chemotherapy and therefore, potentially non-resistant to doxorubicin. The objective of the study was to evaluate the toxicity profile and efficacy of this novel agent in chemotherapy-refractory SCLC.
Patients and methods Patients over the age of 18, with WHO performance status ^ 2, an estimated life expectancy > 3 months and histologically confirmed SCLC, with disseminated disease, were eligible for study enrolment. Only one prior chemotherapy regimen and no past anthracycline
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 5, 2016
Introduction
1396 treatment was allowed. Left ventricular ejection fraction > 50% (by MUGA scan or echocardiography) and normal organ function were required. Toxicity was graded according to the NCI Common Toxicity Criteria ( C T Q , and response according to WHO standards. Local ethics committees in participating institutions approved the study and all patients enrolled gave written informed consent. Liposomal doxorobicin (Caelyx, provided by Schering-Plough) was administered at a dose of 50 mg/m 2 on day 1 of each cycle (one hour i.v. infusion) on an outpatient basis. Chemotherapy was repeated every four weeks for a total of six cycles and was discontinued in instances of disease progression, severe side effects or when radiotherapy was required. Patients were followed every two weeks for haematological toxicity. Disease re-evaluation was performed every two cycles, with appropriate radiological imaging of the documented measurable lesions. Complete or partial response would be re-confirmed four weeks later. All patients would be followed for a minimum of one year for survival. Standard dose adaptations for toxicity were applied, including increase of the dosing intervals for PPE, with 25% dose reduction in case of persisting > 2 weeks grade 1-2 PPE. For grade 3—4 toxicity persisting two weeks beyond the next scheduled dose, study drug was discontinued.
Results Fourteen patients with recurrent SCLC entered the trial between April 1998 and June 1999. Since no response was observed the study was terminated. Patients' characteristics are listed in Table 1. All had histologically confirmed SCLC and had relapsed or progressed following first-line platinum-containing chemotherapy. Only three patients completed six cycles of treatment; from the remaining, five patients were withdrawn after one cycle only due to rapid PD while one was withdrawn after three cycles due to prolonged toxicity. Toxicity was evaluable in 38 chemotherapy cycles with a median of two cycles per patient (range 1-6 cycles). There were no episodes of grade 4 toxicity while a patient was withdrawn from the study due to prolonged grade 3 PPE (Table 2). Disease was stabilised in three patients for three, three and four months, respectively, (median 3 months) whereas there were no responses seen. Two early tumour deaths were recorded (rapid disease deterioration after one and two cycles, respectively) while all the remaining patients had PD. Up to 1 March 2000, 12 patients have died, 6 of them of PD refractory to Caelyx as well as subsequent salvage therapies, consisting of topotecan (1 case), docetaxel/gemcitabine (2 cases), oral etoposide (1 case), carboplatin/oral etoposide (1 case), cyclophosphamide/epirubicin/vincristine (1 case). Apart from a short-lived (2 months) disease stabilisation in one case with taxotere/gemcitabine, all patients had PD. With a median follow-up of four months (range 1-20+) the median duration of survival was four months (range 1-20+).
14
Total number of patients enrolled Sex Male Female Age (years) Median Range WHO performance status 0,1 2 Disease stage at initial presentation Limited Extensive Response to first-line chemotherapy Complete response Partial response Progressive disease Duration of response to first-line chemotherapy (months) Median Range Radiotherapy Local thoracic PCI Sites of relapse Lung Locoregional lymph nodes Liver Bone Brain Adrenals Pleura Other (soft tissue thoracic wall)
13 1 61 46-75 11 3 9 5 2 11 1
3.5 0.5-19 9 9 2 10 7 4 2 1 2 1 1
Table 2. Toxicity details. Toxicity
Grade 1
Neutropenia Thrombocytopenia Anaemia Alopecia Nausea & Vomiting Fatigue PPE
1 4 1 1 1 1
Grade 2
Grade 3
Grade 4
Discussion A large number of novel anticancer agents, including taxanes, topoisomerase I inhibitors and innovative drug combinations for the treatment of refractory SCLC are currently being evaluated in clinical trials [10]. This report is the first on the use of Caelyx in recurrent SCLC. Although the study population is small, our results clearly demonstrate the limited activity of this drug as second-line monotherapy for SCLC. We recorded three disease stabilisations and no responses. This lack of activity may be partly related to the poor prognostic features of our population: more than half of our patients had 'refractory' relapses, with less than 3—4 months drug-free intervals, and most had disseminated disease at initiation of second-line treatment. It is
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 5, 2016
Study accrual was planned in two stages according to Gehan's design [9]. At the first stage at least one objective response was required out of 14 patients in order to accept the hypothesis that true response rate is 20% at the 5% level of significance. At the second stage in order to achieve a precision of 10% eleven more patients at the most would enter the study, depending on the number of responses of the first stage.
Table I. Patient and disease characteristics.
1397
Acknowledgement We thank Miss D. Katsala for technical assistance. References 1. Johnson DH. Treatment of relapsed small-cell lung cancer. Lung Cancer 1994; 11 (Suppl 1): 142-43. 2. Thatcher N, Girling DJ, Hopwood P et al. Improving survival without reducing quality of life in small-cell lung cancer patients by increasing the dose intensity of chemotherapy with gTanulocyte colony-stimulating factor support: Results of a British Medical Research Council Multicenter Randomised Trial. Medical Research Council Lung Cancer Working Party. J Clin Oncol 2000; 18: 395^104.
3. Roth BJ, Johnson DH, Einhom LH et al. Randomised study of cyclophosphamidc, doxorubicin, and vincristine vs. etoposidc and cisplatin vs. alterations of these two regimens in extensive stage SCLC: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1992; 10: 282-91. 4. Shepherd FA, Evans WK, MacCormick R et al. Cyclophosphamide, doxorubicin and vincristine in etoposide- and cisplatinresistant small-cell lung cancer. Cancer Treat Rep 1987; 71: 941^t 5. Gabizon A, Catane R, Uziely B et al. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 1994; 54: 987-92. 6. Stewart S, Jablonski H, Goebel FD et al. Randomised comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AEDS-related Kaposi's sarcoma. J C1in Oncol 1998; 16: 683-91. 7. Ranson MR, Carmichael J, O'Byrne K et al. Treatment of advanced breast cancer with sterically stabilised liposomal doxorubicin: Results of a multicenter phase II trial. J Clin Oncol 1997; 15: 3185-91. 8. Koukourakis MI, Koukouraki S, Giatromanolaki SC et al. Liposomal doxorubicin and conventionally fractionated radiotherapy in the treatment of locally advanced non-small-cell lung cancer and head and neck cancer. J Clin Oncol 1999; 17: 3512-21. 9. Machin D, Campbell MJ, Fayers PM, Pinol APY. Sample Size Tables for Clinical Studies. Oxibrd: Blackwell Science 1997. 10. 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 1999; 17: 658-67. 11. Garcia AA, Kempf RA, Rogers M, Muggia FM. A phase II study of Doxil (liposomal doxorubicin): Lack of activity in poor prognosis soft tissue sarcomas. Ann Oncol 1998; 9: 1131-3. 12. Gabizon A, Uziely B, Lotem M et al. Doxil in patients with pretreated metastatic breast cancer (MBQ: A dose-schedule finding study with pharmacokinetics. Proc ASCO 1997; 16: 147a. Received 2 May 2000; accepted 3 August 2000. Correspondence to • E. Samantas, MD Hellenic Cooperative Oncology Group 1, Laskaridou str. 11524 Athens Greece E-mail: [email protected]
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 5, 2016
notable that the three disease stabilisations were recorded in patients with 'sensitive', one-site relapses; all three had enjoyed meaningful drug-free intervals of six, seven, and seven months prior to relapse. However, disease stabilisations were only of a median of three months. Additionally, is noted that patients refractory to Caelyx did not respond to subsequent salvage therapies, and thus demonstrating the very limited therapeutic options in relapsed SCLC [1, 3, 4]. Nevertheless, in our study as well as in the majority of reports of Caelyx clinical use, the favourable toxicity profile is confirmed. Treatment was repeated every four weeks, as studies have indicated that skin toxicity is minimised when dosing interval is increased to four weeks [11, 12] and that could partly explain the lack of activity seen. The consistently poor outcome of patients with relapsed SCLC indicates the need for better patient selection and study design for the evaluation of novel agents in this setting. Based on our data, Caelyx seems nonactive as a single agent in the treatment of recurrent SCLC.
Original article Phase II study of pegylated liposomal doxorubicin: Inactive in recurrent small-cell lung cancer A Hellenic Cooperative Oncology Group Study E. Samantas,1 H. Kalofonos,2 H. Linardou,1 C. Nicolaides,3 N. Mylonakis,4 G. Fountzilas,5 P. Kosmidis6 & D. Skarlos1 Agii Anargiri' Cancer Hospital, Athens; 2Oncology Department, University of Patras, Patras; Oncology Department, University of Ioannina, loannina; ""Metaxas'Anticancer Hospital, Piraeus; 5Oncology Department, Aristoteleion' University of Thessaloniki, Thessaloniki; ^Oncology Department, 'Hygeia'Hospital, Athens, Greece
Results: No responses were seen but in three patients disease was stabilised for a median of three months. The median Purpose: Although clinical experience with liposomal doxo- number of cycles was 2 per patient, with 11 of 14 patients not rubicin is still limited in solid tumours, single agent Caelyx completing 6 cycles of Caelyx treatment. From those, five (pegylated liposomal doxorubicin) treatment has shown promis- patients were removed from the study after only one cycle due ing results in AIDS-related Kaposi's sarcoma, metastatic breast to rapid disease progression, and one was withdrawn after and ovarian cancer and anecdotally in other solid tumours. This three cycles due to prolonged toxicity. Overall, treatment was is thefirstreport of its use in small-cell lung cancer (SCLQ. The well tolerated with no episodes of grade 4 toxicity and only two objective of this multicenter phase II study was to evaluate the episodes of grade 3 toxicities: one of thrombocytopenia and safety, tolerance and anti-tumour activity of Caelyx as mono- one of prolonged palmar-plantar erythrodysesthesia (PPE). therapy in patients with recurrent SCLC. Conclusions: These results demonstrate limited activity of Patients and methods: A total of 14 patients with recur- Caelyx in this patient population, which may be related to the rent SCLC who had not received prior treatment with doxo- poor prognostic features of such patients. Our findings are in rubicin, were accrued into this phase II study. All patients had agreement with previous observations that doxorubicin-conprogressed or relapsed after first-line chemotherapy. All but taining combinations are rarely active in platinum/etoposide one had achieved objective responses to first-line treatment failures. However, as in other studies the favourable toxicity with median duration offivemonths (range 2-18 months) but profile of Caelyx is confirmed. half of them had experienced 'refractory' relapses (within 3—4 months). Study treatment consisted of Caelyx 50 mg/m2 Key words: liposomal doxorubicin, phase II, recurrent small(1-hour i.v infusion every 4 weeks for 6 cycles). cell lung cancer Summary
Although small-cell lung cancer (SCLC) is one of the most chemosensitive adult tumours, the initial dramatic responses to chemotherapy are commonly followed by drug-resistant relapses. The consistently poor prognosis of patients with recurrent SCLC demonstrates the need for investigation and development of novel agents in the second-line treatment of this disease [1]. Doxorubicin combinations (e.g., CAV or in European centers with etoposide and cyclophosphamide or analogues [2]) are used less as primary chemotherapy since the introduction of etoposide/cisplatin (EP) and considering its problematic toxicity profile, mainly when combined with radiotherapy. In the second-line setting although EP can achieve up to 40%-50% response rates after CAV failure, conversely CAV is rarely active in EP failures [3,4]. A doxorubicin formulation with improved tolerance would theoretically increase the drug's
therapeutic ratio and enhance its efficacy [5]. Pegylated liposomal doxorubicin (Caelyx) represents a unique formulation showing promising results in the treatment of several tumour types [5-8]. We present here the results of a multicenter phase II study of Caelyx monotherapy in SCLC patients failing or relapsing after first-line platinum-containing chemotherapy and therefore, potentially non-resistant to doxorubicin. The objective of the study was to evaluate the toxicity profile and efficacy of this novel agent in chemotherapy-refractory SCLC.
Patients and methods Patients over the age of 18, with WHO performance status ^ 2, an estimated life expectancy > 3 months and histologically confirmed SCLC, with disseminated disease, were eligible for study enrolment. Only one prior chemotherapy regimen and no past anthracycline
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 5, 2016
Introduction
1396 treatment was allowed. Left ventricular ejection fraction > 50% (by MUGA scan or echocardiography) and normal organ function were required. Toxicity was graded according to the NCI Common Toxicity Criteria ( C T Q , and response according to WHO standards. Local ethics committees in participating institutions approved the study and all patients enrolled gave written informed consent. Liposomal doxorobicin (Caelyx, provided by Schering-Plough) was administered at a dose of 50 mg/m 2 on day 1 of each cycle (one hour i.v. infusion) on an outpatient basis. Chemotherapy was repeated every four weeks for a total of six cycles and was discontinued in instances of disease progression, severe side effects or when radiotherapy was required. Patients were followed every two weeks for haematological toxicity. Disease re-evaluation was performed every two cycles, with appropriate radiological imaging of the documented measurable lesions. Complete or partial response would be re-confirmed four weeks later. All patients would be followed for a minimum of one year for survival. Standard dose adaptations for toxicity were applied, including increase of the dosing intervals for PPE, with 25% dose reduction in case of persisting > 2 weeks grade 1-2 PPE. For grade 3—4 toxicity persisting two weeks beyond the next scheduled dose, study drug was discontinued.
Results Fourteen patients with recurrent SCLC entered the trial between April 1998 and June 1999. Since no response was observed the study was terminated. Patients' characteristics are listed in Table 1. All had histologically confirmed SCLC and had relapsed or progressed following first-line platinum-containing chemotherapy. Only three patients completed six cycles of treatment; from the remaining, five patients were withdrawn after one cycle only due to rapid PD while one was withdrawn after three cycles due to prolonged toxicity. Toxicity was evaluable in 38 chemotherapy cycles with a median of two cycles per patient (range 1-6 cycles). There were no episodes of grade 4 toxicity while a patient was withdrawn from the study due to prolonged grade 3 PPE (Table 2). Disease was stabilised in three patients for three, three and four months, respectively, (median 3 months) whereas there were no responses seen. Two early tumour deaths were recorded (rapid disease deterioration after one and two cycles, respectively) while all the remaining patients had PD. Up to 1 March 2000, 12 patients have died, 6 of them of PD refractory to Caelyx as well as subsequent salvage therapies, consisting of topotecan (1 case), docetaxel/gemcitabine (2 cases), oral etoposide (1 case), carboplatin/oral etoposide (1 case), cyclophosphamide/epirubicin/vincristine (1 case). Apart from a short-lived (2 months) disease stabilisation in one case with taxotere/gemcitabine, all patients had PD. With a median follow-up of four months (range 1-20+) the median duration of survival was four months (range 1-20+).
14
Total number of patients enrolled Sex Male Female Age (years) Median Range WHO performance status 0,1 2 Disease stage at initial presentation Limited Extensive Response to first-line chemotherapy Complete response Partial response Progressive disease Duration of response to first-line chemotherapy (months) Median Range Radiotherapy Local thoracic PCI Sites of relapse Lung Locoregional lymph nodes Liver Bone Brain Adrenals Pleura Other (soft tissue thoracic wall)
13 1 61 46-75 11 3 9 5 2 11 1
3.5 0.5-19 9 9 2 10 7 4 2 1 2 1 1
Table 2. Toxicity details. Toxicity
Grade 1
Neutropenia Thrombocytopenia Anaemia Alopecia Nausea & Vomiting Fatigue PPE
1 4 1 1 1 1
Grade 2
Grade 3
Grade 4
Discussion A large number of novel anticancer agents, including taxanes, topoisomerase I inhibitors and innovative drug combinations for the treatment of refractory SCLC are currently being evaluated in clinical trials [10]. This report is the first on the use of Caelyx in recurrent SCLC. Although the study population is small, our results clearly demonstrate the limited activity of this drug as second-line monotherapy for SCLC. We recorded three disease stabilisations and no responses. This lack of activity may be partly related to the poor prognostic features of our population: more than half of our patients had 'refractory' relapses, with less than 3—4 months drug-free intervals, and most had disseminated disease at initiation of second-line treatment. It is
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 5, 2016
Study accrual was planned in two stages according to Gehan's design [9]. At the first stage at least one objective response was required out of 14 patients in order to accept the hypothesis that true response rate is 20% at the 5% level of significance. At the second stage in order to achieve a precision of 10% eleven more patients at the most would enter the study, depending on the number of responses of the first stage.
Table I. Patient and disease characteristics.
1397
Acknowledgement We thank Miss D. Katsala for technical assistance. References 1. Johnson DH. Treatment of relapsed small-cell lung cancer. Lung Cancer 1994; 11 (Suppl 1): 142-43. 2. Thatcher N, Girling DJ, Hopwood P et al. Improving survival without reducing quality of life in small-cell lung cancer patients by increasing the dose intensity of chemotherapy with gTanulocyte colony-stimulating factor support: Results of a British Medical Research Council Multicenter Randomised Trial. Medical Research Council Lung Cancer Working Party. J Clin Oncol 2000; 18: 395^104.
3. Roth BJ, Johnson DH, Einhom LH et al. Randomised study of cyclophosphamidc, doxorubicin, and vincristine vs. etoposidc and cisplatin vs. alterations of these two regimens in extensive stage SCLC: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1992; 10: 282-91. 4. Shepherd FA, Evans WK, MacCormick R et al. Cyclophosphamide, doxorubicin and vincristine in etoposide- and cisplatinresistant small-cell lung cancer. Cancer Treat Rep 1987; 71: 941^t 5. Gabizon A, Catane R, Uziely B et al. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 1994; 54: 987-92. 6. Stewart S, Jablonski H, Goebel FD et al. Randomised comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AEDS-related Kaposi's sarcoma. J C1in Oncol 1998; 16: 683-91. 7. Ranson MR, Carmichael J, O'Byrne K et al. Treatment of advanced breast cancer with sterically stabilised liposomal doxorubicin: Results of a multicenter phase II trial. J Clin Oncol 1997; 15: 3185-91. 8. Koukourakis MI, Koukouraki S, Giatromanolaki SC et al. Liposomal doxorubicin and conventionally fractionated radiotherapy in the treatment of locally advanced non-small-cell lung cancer and head and neck cancer. J Clin Oncol 1999; 17: 3512-21. 9. Machin D, Campbell MJ, Fayers PM, Pinol APY. Sample Size Tables for Clinical Studies. Oxibrd: Blackwell Science 1997. 10. 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 1999; 17: 658-67. 11. Garcia AA, Kempf RA, Rogers M, Muggia FM. A phase II study of Doxil (liposomal doxorubicin): Lack of activity in poor prognosis soft tissue sarcomas. Ann Oncol 1998; 9: 1131-3. 12. Gabizon A, Uziely B, Lotem M et al. Doxil in patients with pretreated metastatic breast cancer (MBQ: A dose-schedule finding study with pharmacokinetics. Proc ASCO 1997; 16: 147a. Received 2 May 2000; accepted 3 August 2000. Correspondence to • E. Samantas, MD Hellenic Cooperative Oncology Group 1, Laskaridou str. 11524 Athens Greece E-mail: [email protected]
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 5, 2016
notable that the three disease stabilisations were recorded in patients with 'sensitive', one-site relapses; all three had enjoyed meaningful drug-free intervals of six, seven, and seven months prior to relapse. However, disease stabilisations were only of a median of three months. Additionally, is noted that patients refractory to Caelyx did not respond to subsequent salvage therapies, and thus demonstrating the very limited therapeutic options in relapsed SCLC [1, 3, 4]. Nevertheless, in our study as well as in the majority of reports of Caelyx clinical use, the favourable toxicity profile is confirmed. Treatment was repeated every four weeks, as studies have indicated that skin toxicity is minimised when dosing interval is increased to four weeks [11, 12] and that could partly explain the lack of activity seen. The consistently poor outcome of patients with relapsed SCLC indicates the need for better patient selection and study design for the evaluation of novel agents in this setting. Based on our data, Caelyx seems nonactive as a single agent in the treatment of recurrent SCLC.