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Phase II Study of Paclitaxel, Ifosfamide, and Cisplatin as Second-Line Treatment in Relapsed Small-Cell Lung Cancer

From the Department of Medicine, Medical Oncology Unit, Helena-Venizelou Hospital, and Oncology Unit, Department of Pathophysiology, Laikon General Hospital, Athens University School of Medicine, Athens, Greece.

Address reprint requests to Christos Kosmas, MD, Medical Oncology Unit, Helena-Venizelou Hospital, 21 Apolloniou St, 163 41 Athens, Greece; email ckosm{at}ath.forthnet.gr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: The aim of the present phase II study was to evaluate the efficacy of the paclitaxel, ifosfamide, and cisplatin (PIC) combination in relapsed small-cell lung cancer (SCLC).

PATIENTS AND METHODS: Eligible patients were those with SCLC who had progressed or relapsed after therapy with carboplatin and etoposide (with or without chest radiotherapy). The PIC regimen consisted of paclitaxel 175 mg/m² on day 1, ifosfamide 5 g/m² divided over days 1 and 2, and cisplatin 100 mg/m² divided over days 1 and 2; PIC was given every 21 days with granulocyte colony-stimulating factor support.

RESULTS: Thirty-three patients (30 men and three women) were entered onto the study (median age, 62 years [range, 55 to 70 years]; median performance status, 1 [range, 0 to 2]). Metastatic sites at study entry included the lymph nodes (n = 13 patients), bone (n = 9), liver (n = 5), brain (n = 6), lung nodules (n = 8), adrenal glands (n = 9), and other (n = 2) Responses included eight complete remissions and 16 partial remissions (overall response rate, 73% [24 of 33 patients]). Five patients had stable disease and two had progressive disease. Median time to progression and overall survival were 21 and 28 weeks, respectively. The 1-year survival rate was 12%, with two patients alive without evidence of disease at 76 and 104 weeks since PIC initiation. Grade 3 and 4 toxicities included neutropenia in 30 patients (24 [73%] developed grade 4 neutropenia [ < 5 days]) and febrile neutropenia in six patients (18%); grade 3 or 4 thrombocytopenia was seen in nine patients (27%) . No grade 3 neuropathy was observed; grade 1 or 2 CNS toxicity was seen in five patients, there was no renal toxicity, grade 2 myalgias were seen in nine patients, grade 2 diarrhea was seen in one patient, and grade 3 nausea or vomiting was seen in seven patients. There were no treatment-related deaths.

CONCLUSION: In the present phase II study, the PIC combination seemed highly active and tolerable in patients with relapsed SCLC when it was administered as second-line treatment. Given the present experience, an evaluation of the PIC regimen as front-line treatment of SCLC is planned.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
SMALL-CELL LUNG cancer (SCLC) has been considered extremely sensitive to first-line cytotoxic chemotherapy, but relapse is largely unavoidable as a result of intrinsic or acquired drug resistance. Therefore, cure remains an elusive goal for the majority of patients, despite very high initial response rates. Response of recurrent SCLC to second-line chemotherapy highly depends on the interval between the completion of induction chemotherapy and the appearance of progressive disease.¹ As far as the current, standard, front-line induction regimens incorporate a platinum analog, cisplatin or carboplatin, combined with etoposide, the choice of drugs active in the salvage setting remains limited. Few drugs are capable of producing remissions in relapsed SCLC. Single-agent paclitaxel has probably demonstrated the highest activity among various agents in patients with SCLC resistant to cyclophosphamide, doxorubicin, and etoposide (CDE), with an observed response rate (RR) of 29%.² Similarly, ifosfamide has yielded significant single-agent activity, reaching the impressive figure of 43% RR in patients with resistant and sensitive SCLC.³ Moreover, paclitaxel in combination with carboplatin has obtained a RR of 73.5% in patients with SCLC resistant to CDE, by definition⁴ thus representing at present the most active phase II combination regimen in truly refractory disease.

Three-drug regimens may confer a meaningful benefit over two-drug regimens in SCLC, although the data are still not convincing. In fact, at least two three-drug regimens have been studied and found to be reasonable alternatives to two-drug regimens in patients with extensive SCLC. In one of these studies, by the Hoosier Oncology Group (HOG), the etoposide–cisplatin combination was compared with etoposide, ifosfamide, and cisplatin (VIP) and the results favored those patients receiving VIP, despite significantly more toxicity.⁵ The other trial was a phase II study by the Eastern Cooperative Oncology Group incorporating ifosfamide and carboplatin with prolonged oral etoposide (ICE) for an overall RR of 83%, including a complete remission (CR) rate of 23% and a 14% 2-year survival rate.⁶

Given the promising activity of the paclitaxel, ifosfamide, and cisplatin (PIC) combination in a variety of advanced or refractory solid tumors, as demonstrated by our group^7,8 as well as other investigators,^9-12 and the feasibility of the regimen at the doses delivered in our schedule with granulocyte colony-stimulating factor (G-CSF) support in a total outpatient setting, we decided to conduct a phase II study with this regimen in recurrent SCLC.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Patients with histologically confirmed SCLC who relapsed after prior chemotherapy with carboplatin and etoposide with or without chest radiotherapy were candidates for the present study. Eligibility criteria were as follows: (1) histologically confirmed SCLC not curable by other second-line chemotherapy and or radiotherapy; (2) World Health Organization performance status 2; (3) life expectancy 3 months; (4) adequate hematopoietic function (absolute neutrophil count > 1,500/µL and platelet count > 100,000/µL), liver function (bilirubin level < 1.5 mg/dL, AST/ALT concentrations < two times the upper normal limit unless caused by tumor, and serum albumin level > 3.0 g/dL), and renal function (blood urea nitrogen and creatinine concentrations < 1.5 times the upper normal limit [1.5 mg/dL in our laboratory or creatinine clearance > 50 mL/min]); (5) no previous chemotherapy; (6) absence of active coronary artery disease (in the form of unstable angina or myocardial infarction over the last 12 months), unstable diabetes mellitus, or peripheral neuropathy grade 2 by National Cancer Institute common toxicity criteria; (7) no prior irradiation to areas encompassing more than 30% of marrow-bearing bone, apart from emergency radiotherapy for superior vena cava obstruction, imminent vertebral or weight-bearing long bone fracture as a result of metastatic involvement, or symptomatic rapidly progressive brain metastases; and (8) presence of bidimensionally measurable disease outside a previously irradiated field, unless there was definite evidence of progression at this site. Patients with brain metastases that were asymptomatic or controllable with corticosteroids or prior irradiation were not excluded from treatment. Informed consent was obtained from each patient before study entry according to institutional policies.

Treatment Schedule
Eligible patients were treated as follows: paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) was administered at 175 mg/m² over 1 hour by intravenous (IV) infusion on day 1, after premedication consisting of dexamethasone 20 mg, dimethidene maleate (Fenistil; Novartis Pharma, Basel, Switzerland) 4 mg, and ranitidine 50 mg; all were administered by 30-minute IV infusion 1 hour before paclitaxel.⁷ Ifosfamide was administered at 5.0 g/m² IV in 1 hour over a 2-day period (on days 1 and 2, 2.5 g/m² per day; total dose, 5 g/m²) together with mesna uroprotection, at 40% of the ifosfamide dose, given by IV infusion before and at 3 and 6 hours after ifosfamide. Cisplatin was administered at 100 mg/m² IV in 30 minutes over a 2-day period (on days 1 and 2, 50 mg/m² per day; total dose, 100 mg/m²) with adequate, vigorous hydration before and after, mannitol and furosemide diuresis, and electrolyte replacement (potassium chloride 20 mEq and magnesium sulfate 8 mEq per L of posthydration solution. (Posthydration solution consisted of 0.9% normal saline or 1/2 normal saline plus 5% dextrose [D5/w].)

Supportive Care
Standard antiemetic medication included ondansetron given 1 hour before chemotherapy (at 24 mg IV), at 12 hours after chemotherapy on days 1 and 2 (at 8 mg orally), and after chemotherapy on days 3 through 5 (8 mg tid orally). Dexamethasone 20 mg IV was administered 1 hour before chemotherapy (on day 1 as paclitaxel premedication as well) on days 1 and 2 and after chemotherapy on days 3 through 5 (dexamethasone 4 mg tid or methylprednisolone 16 mg bid orally).⁷

Hematopoietic growth factors included G-CSF 5 µg/kg administered subcutaneously from day 4 until WBC count 10,000/µL and recombinant human erythropoietin 10,000 IU given subcutaneously three times a week (not on the days of chemotherapy) whenever the hemoglobin level dropped to 10.5 g/dL and continued until it was 12 g/dL.

Dose Modifications for Toxicity
The prerequisites for dose modifications were as follows: (1) any episode of grade 4 neutropenia of more than 7 days’ duration, (2) any episode of febrile neutropenia grade 3, (3) any episode of grade 4 thrombocytopenia requiring platelet transfusions, (4) any nonhematologic grade 3 or 4 toxicity, excluding nausea and vomiting, musculoskeletal and arthritic pain (myalgia/arthralgia syndrome), and alopecia.

The following guidelines were applied with respect to dose reductions for toxicity: (1) for neutropenia meeting the aforementioned criteria, paclitaxel and ifosfamide doses were reduced by 20% in subsequent cycles; if toxicity reappeared after a 40% total reduction from the starting dose in consecutive cycles, treatment was stopped, but the patient was assessed for toxicity and response. (2) For thrombocytopenia, cisplatin was reduced by 20%, in addition to paclitaxel and ifosfamide dose reductions as specified for neutropenia. (3) For grade 3 mucositis, the doses of paclitaxel and ifosfamide were reduced by 20% in subsequent cycles. (4) For neuropathy grade 3, treatment was interrupted. (5) For renal toxicity grade 3 toxicity (serum creatinine levels > three times normal), treatment was withheld until recovery (serum creatinine level < 1.8 mg/dL), with cisplatin and ifosfamide administered with more posthydration solution, mannitol diuresis, and hospitalization in subsequent cycles. If the glomerular filtration rate dropped to less than 40 mL/min, cisplatin and ifosfamide were omitted in subsequent cycles. However, no dose reductions or schedule modifications were required for renal toxicity in any patient on study. (6) For grade 3 CNS toxicity (ifosfamide encephalopathy), the dose of ifosfamide was reduced by 20% and more hydration with bicarbonates was anticipated in subsequent cycles. If encephalopathy reappeared, then ifosfamide was omitted from subsequent cycles.

If blood counts had not recovered to an absolute neutrophil count 1,500/µL and platelet count 100,000/µL on the day of therapy, treatment was withheld until recovery. After a maximum delay of 2 weeks, no further therapy was administered.

Pretreatment, Follow-Up Studies, and Response Evaluation
Tumor measurements were performed by physical examination and a specific radiologic test that documented measurable disease before treatment. Clinical examinations, full blood counts, biochemical tests, appropriate serum tumor marker measurements, and chest x-rays were carried out before each cycle of therapy. Blood counts were checked on days 8, 11, and 14 after each cycle and until full recovery. Response was evaluated after every two cycles of therapy. Patients who experienced toxic death despite objective responses at measurable sites were categorized as treatment failures. CR was defined as the disappearance of all signs and symptoms of disease for at least 1 month, with the documented disappearance of all known lesions by physical examination, x-rays, computed tomography scans, and bone scans and no new lesions. Partial remission (PR) was indicated by a decrease of 50% or greater (compared with pretreatment measurements) in the sum of the products of the two largest perpendicular diameters of all measurable lesions and no concomitant growth of new lesions for at least 1 month. There could be no deterioration of symptoms or performance status unless secondary to drug toxicity. Stable disease (SD) was indicated by a decrease of less than 50% or an increase in tumor size less than 25% over the original measurements. There could be no deterioration of symptoms or performance status unless secondary to drug toxicity. Progressive disease (PD) was defined as an increase of 25% or greater over the original measurements in the sum of the products of the two largest perpendicular diameters of any measurable lesions, and relapse was documented if, after a period of response, a former lesion reappeared or enlarged as above or a new lesion appeared.

A full staging evaluation had to be performed, as reported above, before treatment initiation. Follow-up disease evaluation was performed at approximate 3-month intervals after the end of treatment.

Statistical Methods
Patients who received at least two cycles of treatment were assessable for response unless they had definite evidence of progression after the first cycle. They were then categorized as having PD, and patients who had received at least one cycle of treatment were assessable for toxicity. Response duration was measured from the day of its initial documentation until PD; time to progression (TTP) was calculated from study entry until evidence of PD; overall survival was measured from the day of entry until last follow-up or death. The 95% confidence intervals (CIs) for RRs were calculated from the binomial distribution.¹³ Actuarial survival was estimated by the product-limit method of Kaplan and Meier.¹⁴ The trial was designed as a phase II study, with RR as the main end point. According to Simon’s two-stage minimax design,¹⁵ with a sample size of n = 33, our study had a 90% power to accept the hypothesis that the true RR is greater than 40% and 5% significance to reject the hypothesis that the true RR is less than 30%, if there were fewer than 19 responses. At the first stage, if there were fewer than five responses out of the initial 16 patients, the study would conclude that the anticipated RR is less than 30% and terminate. Therefore, the probability of accepting a therapy with a real RR less than 30% and the risk of rejecting a treatment with an RR of more than 40% would in both cases be less than 10%.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
The characteristics of the 33 patients entered onto this phase II study are listed in Table 1. All were pretreated with first-line carboplatin and etoposide, and the median time from the last chemotherapy cycle to the initiation of salvage PIC was 9 weeks (range, 3 to 38 weeks). All patients received at least one chemotherapy cycle and were therefore assessable for toxicity, and 30 received at least two cycles of treatment and were assessable for response. The three patients who received one cycle of PIC had definite evidence of progression after their first chemotherapy cycle and were therefore considered as having PD.

View larger version (12K): [in this window] [in a new window]   Fig 1. Response to first-line carboplatin/etoposide chemotherapy and subsequent outcome after salvage PIC at relapse according to the interval ( 3 months versus > 3 months) measured from the end of the prior carboplatin/etoposide administration.

View larger version (11K): [in this window] [in a new window]   Fig 2. Actuarial survival analysis of patients with relapsed SCLC treated with the PIC chemotherapy regimen (Kaplan-Meier plot). Tick marks indicate surviving patients at the particular time points (censored).

As 118 (71.5%) out of the total 165 cycles in the present study were administered without dose reductions or delays, it is conceivable that the administered median dose-intensities for each drug of the PIC combination were equal to the planned dose-intensities (for paclitaxel, 58.3 mg/m² per week [range, 42.4 to 58.3 mg/m²]; for ifosfamide, 1.67 g/m² per week [range, 1.21 to 1.67 g/m²]; for cisplatin, 33.3 mg/m² per week [range, 27.8 to 33.3 mg/m²]). The administered mean dose-intensity was 52.5 mg/m² per week for paclitaxel, 1.5 g/m² per week for ifosfamide, and 31.7 mg/m² per week for cisplatin. Eight patients in 37 treatment cycles required dose reductions for hematologic toxicity, and four cycles were delayed by 1 week to arrange transfusions for grade 3 anemia.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Despite great efforts put on clinical investigation over the past two decades, treatment options for patients with relapsed SCLC remain limited, while long-term survival has remained notoriously unchanged, with practically no survivors beyond 1 year.

Etoposide combined with platinum analogs remains the backbone on which newer agents should be added in attempts to improve the results of front-line chemotherapy in SCLC. Three-drug regimens that use ifosfamide, such as VIP and ICE, have demonstrated improved response rates and hint at survival prolongation over standard platinum/etoposide combinations.^5,6 However, the only positive randomized trial favoring the three-drug VIP regimen, carried out by HOG, has not yet been adopted by other cooperative groups in the United States. Moreover, all other studies are phase II trials suffering from several potential biases. It is not known at present with our study whether the combination of paclitaxel and ifosfamide alone would have yielded results similar to those found with PIC and therefore spared patients from exposure to high-dose cisplatin. However, since all of our patients were exposed to carboplatin during first-line chemotherapy, it can be argued that treatment with an adequate cisplatin dose aided by other synergistic drugs at relapse might, in a way, overcome resistance.

Impressive responses to induction chemotherapy occur in the majority of SCLC patients; however, most treated patients relapse and are candidates for some form of second-line treatment. The outcome of second-line chemotherapy in SCLC depends on several factors, including the interval between the end of front-line treatment and disease progression, the nature of response to induction therapy, and the cytotoxic drugs used during induction.¹ In general, patients who relapse at least 3 months after cessation of front-line chemotherapy retain the ability to respond to further treatment with the same drug combination or other active agents.¹⁶ In contrast, those with disease recurrence within 3 months after the end of induction chemotherapy are resistant to the agents used during induction and require some sort of non–cross-resistant drug combination.

Paclitaxel represents an established active cytotoxic agent against refractory/relapsed SCLC, with a 29% objective RR.² Ifosfamide and platinum compounds have demonstrated activity as single agents and as part of a combination in SCLC, both in first-line treatment and in the setting of relapsed/refractory disease.

Several groups have demonstrated that paclitaxel intensifies the cell-killing effects of DNA damage chemically induced by alkylating agents and cisplatin, provided that paclitaxel is given before these agents.¹⁷ In the clinical setting, paclitaxel has shown enhanced activity and possibly synergistic effects when combined with the alkylating agents cyclophosphamide and ifosfamide¹⁸ or with cisplatin.¹⁹ However, ifosfamide has been shown to synergize with platinum compounds by reversing intracellular mechanisms of resistance that would ultimately lead to increased DNA repair and/or detoxification of reactive intermediates of cisplatin, such as the glutathione/thiol systems. Depletion of the intracellular glutathione pool by 70% has been observed in peripheral-blood lymphocytes after ifosfamide administration.²⁰ It is thus theoretically conceivable that administration of ifosfamide and cisplatin might overcome resistance to cisplatin due to elevated glutathione concentrations. Therefore, given the in vitro and possible in vivo synergism between different two-drug combinations of paclitaxel, ifosfamide, and cisplatin, it is expected that the three-drug combination would exert a favorable cytotoxicity profile against a variety of advanced solid tumors. In addition, the safety of the 1-hour paclitaxel infusion schedule given with a short period of premedication, studied by our group and other investigators,^21-23 made the drug easy to administer in the outpatient setting; it also allowed us to incorporate paclitaxel into complex multidrug chemotherapy regimens, such as the PIC combination applied in the present study.

The rational for combining paclitaxel, ifosfamide, and cisplatin derives from both in vitro data and theoretical assumptions based on the properties of each individual cytotoxic agent to mediate its cellular damage. In brief, paclitaxel inhibits the energy-dependent enzymatic reactions, by disengaging activated intracellular phosphate (eg, ATP and GTP), required for the repair of the DNA damage induced by cisplatin (causing kinking of the DNA double helix) and oxazaphosphorine (cyclophosphamide and ifosfamide) alkylating agents (prevention of DNA strand separation and unwinding). These different types of DNA lesions caused by cisplatin and oxazaphosphorine cytostatics are repaired by the nucleotide excision repair and the mismatch repair pathways.²⁴

Preliminary evaluation of the PIC combination in the present study proved highly active in patients with relapsed/refractory SCLC, yielding an overall RR of 73% with a median TTP of 20 weeks, median survival time of 28 weeks, and 6-month survival rate of 51.5%, which at first sight seems very promising. A recent study evaluating the paclitaxel/carboplatin combination in SCLC after CDE failure demonstrated a similarly high RR (73%), with a median TTP of 21 weeks, median survival time of 31 weeks, and 1-year survival rate of 9%.⁴ Similarly, the 1-year survival rate was 12% in our study, with two patients surviving without recurrence at 18 and 24 months, which indicates that even in this group with a notoriously poor outcome, certain patients may derive prolonged control of their disease. Given that all patients included in the study of Groen et al⁴ had drug-resistant disease (relapsing < 3 months after the end of CDE) compared with 61% of the patients included in our study, it can be said that the results obtained in the former study with paclitaxel/carboplatin were more impressive. However, patients in our study were pretreated with etoposide/carboplatin, which definitely represents a more active, in terms of RR, front-line treatment than CDE; therefore, their disease was rather more refractory to platinum drugs. In contrast, CDE failures may indicate disease that is relatively non–cross-resistant to platinum drugs. Moreover, RRs to PIC according to the interval ( or > 3 months) from prior carboplatin/etoposide in our study did not differ significantly, although this is based on small numbers and the power to detect a potential difference was admittedly very low. Thoracic radiotherapy as part of the initial treatment of patients with limited or low-volume extensive disease (single extrathoracic metastasis eradicated) was administered to 42% of patients in our study versus 20% in the study of Groen et al,⁴ a factor that definitely impairs response to subsequent chemotherapy by conferring resistance to alkylating agents such as ifosfamide and cisplatin. A study using an approach similar to ours in the salvage setting was reported by HOG; it explored a daily oral etoposide, ifosfamide, and cisplatin (VoIP) regimen.²⁵ A high RR (55%) was observed in 42 assessable patients with a median TTP of 20 weeks and median overall survival of 29 weeks. These results, seen in the context of prior exposure to cisplatin/etoposide, seem particularly encouraging in the salvage setting, provide further support to our data with PIC, and lend credence to the application of three-drug, ifosfamide-containing combinations. However, it should be stressed that performance status plays a pivotal role in selecting patients with SCLC to be treated with aggressive combination regimens (three-drug), as most patients in the VIP,⁵ ICE,⁶ and VoIP²⁵ studies had a performance status of 0 or 1, similar to our study, in which only four patients had a performance status of 2. Therefore, it can be said that the encouraging results obtained in SCLC using aggressive combination regimens in the first-line or salvage setting pertain to a selected group of patients with a very good performance status.

Another important issue both in the study of Groen et al⁴ and our study is the high incidence of brain recurrences (35% v 21%, respectively) and, more particularly, that of isolated brain failures after successful salvage chemotherapy (20% v 15%), revealing a troublesome aspect of second-line treatment in SCLC. Given the limitation of interstudy comparisons, it can be said that fewer brain failures were observed with PIC than with paclitaxel and carboplatin, underscoring the role of ifosfamide and/or its combination with platinum in efficiently eradicating tumor subclones with a tendency to spread to the CNS. A recent meta-analysis of 21 phase III clinical trials conducted in North America between 1972 and 1994 revealed that there has been only a modest improvement in the survival of patients with extensive-stage SCLC using various standard chemotherapy or experimental regimens, thus pointing to the urgent need for new agents and their combination with active standard drugs in order to improve outcomes.²⁶

Another active agent in SCLC is topotecan, which has demonstrated significant antitumor activity as second-line therapy.²⁷ A recently completed phase I trial conducted at the Sarah Cannon Cancer Center (Nashville, TN) demonstrated a high activity of the topotecan, paclitaxel, and carboplatin combination in patients with pretreated, advanced SCLC (objective RR, 56%).²⁸

Despite the high incidence of grade 4 neutropenia (78%) in the present study, it can be stated that this was rarely prolonged (> 5 days) and therefore patients were unlikely to be exposed to the risks of febrile neutropenia. The 18% incidence of febrile neutropenia does not seem excessive and is comparable to the levels observed in other studies applying three-drug combinations of taxanes, etoposide, and cisplatin or carboplatin. However, it should be emphasized that G-CSF was given to all of our patients. Moreover, all patients with febrile neutropenia in the present study were managed successfully as outpatients with broad-spectrum antibiotics and their pyrexia did not exceed 3 days. The doses of both ifosfamide and cisplatin applied in the present study were higher than standard doses used in most studies of SCLC, ranging from 3.6 to 4.5 g/m² for ifosfamide and 60 to 80 mg/m² for cisplatin. It is possible, therefore, that using lower ifosfamide and cisplatin doses in the PIC combination in relapsed SCLC would result in a less toxic regimen and, most importantly, might obviate the need for routine growth factor, which makes PIC a somewhat cumbersome and expensive regimen. Other toxicities did not seem to be significant in the present study. Grade 3 myalgia/arthralgia after paclitaxel administration was rarely encountered in our study, possibly related to the fact that a standard dose of paclitaxel was applied.

In conclusion, the PIC combination at the doses and schedule applied in the present study seems to be a very active outpatient regimen in patients with relapsed/refractory SCLC and good performance status. However, given that toxicity in the present study, as in trials with similar three-drug regimens, was substantial, we have to keep in mind that second-line therapy for SCLC is largely palliative. We should therefore carefully weigh the risks and costs of any newly developed dose-intensive regimen against more simple treatments with active single agents. Although the present study provides valid phase II data for PIC applied as second-line treatment, the promising activity, TTP, and overall survival produced by the regimen lead us to suggest that it should be tested as front-line treatment or as reinduction after a successful conventional brief induction course (etoposide plus cisplatin or carboplatin) in patients with SCLC.

	NOTES

 
C. Kosmas and N.B.T. contributed equally to this work.

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Submitted April 26, 2000; accepted July 18, 2000.

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