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Paclitaxel and Carboplatin in the Treatment of Small-Cell Lung Cancer Patients Resistant to Cyclophosphamide, Doxorubicin, and Etoposide: A Non–Cross-Resistant Schedule

From the Department of Pulmonary Diseases, University Hospital, Groningen; Vrije Universiteit, Amsterdam; and Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands.

Address reprint requests to H.J.M. Groen, MD, PhD, Department of Pulmonary Diseases, University Hospital, Hanzeplein 1, 9700 RB Groningen, the Netherlands; email h.j.m.groen{at}int.azg.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate the efficacy of paclitaxel and carboplatin (PC) in small-cell lung cancer (SCLC) patients resistant to cyclophosphamide, doxorubicin, and etoposide (CDE).

PATIENTS AND METHODS: We performed a phase II study with PC in SCLC patients who relapsed within 3 months after first-line treatment with CDE. Paclitaxel administration (175 mg/m² by a 3-hour intravenous infusion) was followed by a 30-minute infusion of carboplatin (area under the curve 7; Chatelut formula) once every 3 weeks for five cycles. Dexamethasone, clemastine, and ranitidine were standard premedication before every cycle.

RESULTS: Included were 35 patients (median age, 59 years; 16 with limited disease and 19 with extensive disease; Eastern Cooperative Oncology Group performance status of 1; median time off treatment 6 weeks) who were previously treated with CDE (n = 33), oral etoposide (n = 2), and reinduction CDE (n = 15); only one patient had received three CDE treatments of five cycles. The CDE regimen was followed by local thoracic radiotherapy in seven patients. Hematologic toxicity of grade 3 or 4, for leukopenia was 27% and 6%, for thrombocytopenia 21% and 13%, and for anemia 17% and 0%, respectively, for a total of 132 cycles. Two patients had neutropenic fever; no toxic death occurred. Nonhematologic toxicity was paresthesia CTC grade 3, diarrhea grade 4, and myalgia grade 3 in one patient each. Reversible paresthesia (CTC grade 1 and 2) in toes and fingers was reported in 69% of patients. Thirty-four patients were assessable for response: complete response in two patients, partial response in 23 patients, stable disease in eight patients, and progressive disease in one patient (response rate, 73.5%; 95% confidence interval, 59% to 88%). One patient was found to have atypical carcinoid at pathologic review and was excluded. Median time to progression was 21 weeks (range, 3 to 40 weeks). Median survival was 31 weeks (range, 6 to 112 weeks). One-year survival was 9%.

CONCLUSION: Second-line PC in CDE-resistant SCLC patients yields a high response rate and seems non–cross-resistant to CDE. Toxicity was mild in these poor-prognosis patients.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
DESPITE THE SLOW progress that has been made since the recognition that chemotherapy is the mainstay of treatment for patients with small-cell lung cancer (SCLC), for the majority of patients, cure remains an elusive goal, mainly because of the occurrence of drug-resistant relapses after an initial response to chemotherapy. The response rate (RR) of recurrent SCLC to second-line chemotherapy is highly dependent on the time between the completion of induction or first-line chemotherapy and tumor recurrence.¹ Patients who fail to respond to first-line chemotherapy or relapse within 3 months after completion of first-line chemotherapy tend to do poorly, whereas patients who relapse after a longer treatment-free period may yield RRs comparable to those achieved after first-line therapy, depending on the previous agents used.² Few drugs are capable of producing remissions in the salvage setting of resistant tumors, and survival is usually only a few weeks after initiation of second-line treatment.³ Therefore, this patient group is ideal to test new drugs on their ability to circumvent drug-induced resistance.³

Here, we describe the results of a phase II study of paclitaxel and carboplatin combination chemotherapy (PC) in SCLC patients failing or relapsing shortly after cyclophosphamide, doxorubicin, and etoposide polychemotherapy (CDE), which is the current standard chemotherapy for SCLC patients within the European Organization for Research and Treatment of Cancer Lung Cancer Study Group. Carboplatin was chosen because it has activity both as a single agent⁴ and in combination with vincristine⁵ and/or ifosfamide in patients resistant to CDE.⁶ Recently, we studied the single-agent activity of paclitaxel in SCLC patients resistant to CDE and observed a major RR of 29%,⁷ which is at the upper level of activity for any single agent in this setting reported to date. In addition, platinum compounds and paclitaxel exhibit synergistic activity, at least in vitro.⁸ Also, the PC combination has activity in non–small-cell lung cancer,^9-11 the latter not an uncommon pathologic feature of relapsing SCLC.^12,13 Our results indicate that in this poor-prognosis population, PC has major antitumor activity, suggesting that this combination should be tested as frontline therapy in SCLC.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The trial was approved by the local medical ethics committees. All patients gave informed consent before they were enrolled onto the study.

Eligibility Criteria
Patients were considered eligible when they met all of the following criteria: age between 18 and 75 years, histologic or cytologic proof of SCLC, last cytotoxic treatment less than 3 months before entry, Eastern Cooperative Oncology Group performance status 0 to 3, WBC count more than 3.0 x 10⁹/L, platelet count more than 100 x 10⁹/L (unless lower values were due to bone marrow involvement), creatinine clearance according to the Cockroft method more than 60 mL/min, bilirubin level less than 25 µmol/L, and bidimensionally measurable disease. Exclusion criteria included significant cardiac disease, uncontrolled infection, and concurrent cytotoxic therapy. Concurrent radiotherapy was allowed, provided that not all measurable lesions were included in the irradiated field.

Pretreatment Evaluation
Before chemotherapy, each patient was evaluated with a history and physical examination with assessment of performance status, a complete blood cell count, liver function tests and serum creatinine determination, ECG, chest x-ray and/or computed tomography of the chest and other staging procedures as indicated, including ultrasonography of the liver and bone scintigraphy.

Treatment
Paclitaxel (Taxol) was obtained from Bristol-Myers Squibb (Woerden, the Netherlands), as a concentrated sterile solution, 6 mg/mL in 5-mL ampules in polyoxyethylated castor oil (Cremophor EL) 50% and dehydrated alcohol. The calculated dose of paclitaxel was diluted in a minimum volume of 250 mL and a maximum volume of 1,000 mL of dextrose 5% or normal saline. To avoid acute allergic reactions, all patients received the following medication: dexamethasone 8 mg orally 12 and 6 hours before paclitaxel, clemastine 2 mg intravenous, (IV) push 30 minutes before paclitaxel, and cimetidine 300 mg IV push or ranitidine 50 mg IV push 30 minutes before paclitaxel. Paclitaxel 175 mg/m² was administered as a 3-hour IV infusion every 21 days. The subsequent dose was modified according to toxicity in the previous cycle for each individual patient. A dose reduction to 150 mg/m² was applied when the WBC count was less than 1.0 x 10⁹/L or platelet counts were less than 25 x 10⁹/L for more than 1 week or in the case of febrile neutropenia. Antiemetics were metoclopramide as needed in addition to dexamethasone, also administered to avoid hypersensitivity reactions to paclitaxel treatment, and occasionally ondansetron.

Carboplatin (Paraplatin; Bristol-Myers Squibb) was supplied as a lyophilized product that contained 150 mg carboplatin and 150 mg of mannitol as a bulking agent. Immediately before use, the content of each vial was reconstituted with 15 mL of water for injection, and the total dose was added to 250 mL of dextrose 5%. The dose of carboplatin in milligrams is calculated according to the formula: dose (mg) = carboplatin clearance (mL/min) x area under the curve (AUC). Carboplatin clearance is calculated according to the Chatelut formula,¹⁴ and AUC = 7. Carboplatin was administered after paclitaxel as a 30-minute IV infusion. The carboplatin dose was not reduced in view of the hematologic toxicity.

Therapy was administered for a maximum of five cycles. Patients went off study in the case of disease progression, incomplete hematologic recovery 2 weeks after scheduled retreatment, grade 3 neuropathy according to National Cancer Institute common toxicity criteria (CTC), or any other CTC grade 4 nonhematologic toxicity, except alopecia.

Evaluation Before and During Treatment
Before each new administration of paclitaxel and carboplatin, a physical examination, assessment of performance status, complete blood cell count, serum creatinine and liver function tests, ECG, chest x-ray, and any other investigation necessary for assessment of response were obtained. A complete blood cell count on day 14 was obtained between two cycles. Toxicity was scored using CTC criteria.

Response Assessment
A complete response was defined as the complete resolution of all signs of known disease for a minimum of 4 weeks. A partial response was defined as a more than 50% reduction in the sum of the products of the largest perpendicular diameters of all measurable lesions for a minimum of 4 weeks. Patients who failed to fulfill the criteria for partial response, in the absence of disease progression, were classified as having stable disease. Progression of disease was defined as an increase of more than 25% in the sum of the products of the largest perpendicular diameters of all measurable lesions or the occurrence of any new lesion. Response duration, time to progression, and survival time were measured from the date of initiation of therapy. All patients were considered assessable for toxicity.

Statistical Analysis
The minimum number of CDE-resistant SCLC patients to be accrued in this study was 20 for the first stage. If none of the original patients responded, the treatment would be considered inactive and the study would be terminated. If four or more responses were observed in the first group of patients, the study would be extended to 35 patients to limit confidence intervals. If one to three responses were observed, an additional 15 patients would be enrolled. The design permits the exclusion of an RR greater than 10.9% at the 90% confidence level if no response is observed in the first stage. With greater true RRs, the probability of declaring the treatment active is .82 at a true RR of 16%.¹⁵ The tumor RR is presented and median time to progression and survival were calculated according to the Kaplan-Meier product-limit method.

	RESULTS

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Patient Characteristics
From February 1996 to September 1997, a total of 35 patients were registered in three different Dutch hospitals. All patients were assessable for toxicity, and 34 patients were assessable for response; one patient was found to have atypical carcinoid at pathologic review after failing to respond to two cycles of PC. The characteristics of all patients are listed in Table 1. Their median age was 59 years (range 40 to 73 years), there were 24 men and 11 women, and the majority of patients (26 of 35) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Thirty-three patients had been treated with CDE as first-line therapy, and two patients had received oral etoposide followed by CDE after local relapse. Fifteen patients had received reinduction CDE before entering onto this study, and seven patients had received thoracic radiotherapy as part of their induction treatment. All patients relapsed within 3 months (median, 6 weeks; range, 0 to 11 weeks) after previous cytotoxic treatment. The median number of cycles administered to these patients was four (range, one to five). Fifteen patients (43%) received the planned five cycles of therapy. The remaining patients were taken off therapy before completing five cycles for the following reasons: ineligibility (n = 1), tumor progression (n = 7), or toxicity (n = 12).

Toxicity
A total of 132 cycles were administered. There were no treatment-related deaths. The principal toxicity was hematologic; toxicity is summarized in Table 2. Leukocytopenia CTC grade 3 was observed in 27% and grade 4 in 6% of cycles. Leukocyte recovery was complete in all patients by day 21. Two patients had to be hospitalized because of neutropenic fever and had subsequent dose reductions of paclitaxel as specified by the protocol. Thrombocytopenia grade 3 and 4 was encountered in 21% and 13% of cycles, respectively. There was a nonsignificant trend for more prolonged thrombocytopenia as patients were treated with more cycles of PC. Seven patients went off therapy because of incomplete platelet recovery by day 35. Four patients received platelet transfusions, but there were no bleeding episodes related to thrombocytopenia. Twenty-two patients received RBC transfusions.

Nonhematologic toxicities were generally modest (Table 3). Nausea and vomiting were well controlled with antiemetics. One patient experienced grade 4 diarrhea after two cycles of PC chemotherapy persisting for more than 4 weeks despite treatment with high-dose loperamide. Arthralgia and myalgia (grades 1 and 2) were observed in five patients despite treatment with nonsteroidal antiinflammatory drugs. In one patient, after the third cycle of PC, grade 3 myalgia was observed in conjunction with neuropathy grade 3, which resolved slowly after discontinuation of treatment. In 25 of 35 patients, neuropathy was encountered, usually after the second or third cycle of PC. Three patients went off therapy because of polyneuropathy despite an antitumor response. Acute or chronic cardiac, lung, renal, or skin toxicities were not observed; one patient had transient hepatic dysfunction, probably attributable to paclitaxel treatment. Hypersensitivity reactions were not observed, except for one transient and slight hypotension during intravenous infusion, which reacted promptly to volume expanders.

Response and Survival
Among the 34 assessable patients, there were two complete and 23 partial responses, with an overall RR of 73.5% (95% confidence interval, 59% to 88%). In addition, eight patients had disease stabilization, and one patient had progressive disease. Of the 25 responders to carboplatin and paclitaxel, 20 had a performance status of 0 or 1 and five had a performance status of 2 or 3. Twelve of these 25 patients responded to their first-line treatments. The relative RRs of patients originally diagnosed as having limited (n = 18) or extensive (n = 16) disease were 83% and 62%, respectively. The median time to progression was 21 weeks (range, 3 to 40 weeks). The majority of patients (n = 24) had a systemic relapse, including five patients with brain metastases and seven patients with isolated brain relapse. Thirteen patients received chemotherapy on relapse after PC, and eight patients received whole-brain radiotherapy. The median survival was 31 weeks (range, 6 to 112 weeks), with three patients remaining alive and in remission without additional treatment (Fig 1). The 1-year survival rate was 9% (95% confidence interval, 4% to 14%).

View larger version (12K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival curve of 34 patients with resistant SCLC treated with paclitaxel and carboplatin. For three patients who remained alive, the data were censored.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Despite an often impressive response to induction chemotherapy, most treated SCLC patients unfortunately become candidates for second-line treatment. Upon relapse, many of these patients are in good physical condition and are desirous of further treatment. The results of second-line treatment are dependent on several factors, including the interval between cessation of primary therapy and relapse, the nature of the response to primary therapy, and the drug composition of the primary chemotherapy.¹ Two distinct clinical patterns after induction chemotherapy can be observed. In some patients, the tumor is characterized as having drug sensitivity, with a tumor response duration of at least 3 months and more than a 50% chance of tumor response after reinduction chemotherapy¹⁶; in contrast, in drug-resistant patients, the tumors recur within 3 months and are resistant toward the drugs used in the induction phase. These patterns represent two different drug-induced biologic behaviors of SCLC that require treatment approaches circumventing specific drug-resistance mechanisms.² However, despite extensive research aimed at elucidating drug-induced resistance mechanisms in SCLC in vitro, it is unknown whether these mechanisms are also operative in vivo. Two small studies^17,18 reported induction of P-glycoprotein expression in recurrent SCLC in six of 10 and seven of 33 specimens. In one of these studies, there was also a significant increase in expression of the multidrug resistance–associated protein and a decrease of topoisomerase Iia in the recurrent SCLC specimen, all associated with drug resistance in vitro. In autopsy series after cytotoxic treatment, the frequency of mixed small-cell and large-cell carcinoma is often higher after treatment than is generally found at diagnosis,^12,13 and this histologic subtype is associated with poor response to chemotherapy. However, this finding may be biased by the fact that, during autopsy, larger amounts of tumor can be analyzed than at initial diagnosis. Thus, treatment of SCLC at relapse is often performed on a trial-and-error basis rather than guided by knowledge of the specific mechanisms of resistance involved.

Attempts to treat resistant SCLC have been made previously. Evidence of drug activity in previously treated patients with SCLC is considered when the RR exceeds 10%.¹⁵ Ifosfamide was administered to 14 patients, and six (43%) responded.¹⁹ In a previous study conducted by our group in similar resistant SCLC patients, single-agent paclitaxel showed a 29% objective RR.⁷ Treatment with single-agent topoisomerase I and II inhibitors such as topotecan²⁰ and chronic low-dose etoposide²¹ is associated with hardly any antitumor activity in resistant SCLC (12% and 6.4%, respectively). Treatment with two-drug combinations such as carboplatin and vincristine yielded a RR of 36% in CDE failures.⁵ Two studies of cisplatin and etoposide (EP) treatment after failure on cyclophosphamide, adriamycin, and vincristine (CAV) reported rather poor results: 23% and 28% RRs.^22,23 Three drug schedules with CAV²⁴ or vincristine, ifosfamide, and carboplatin⁶ showed a wide range of RRs in resistant SCLC (21% to 60%), probably owing to patient selection. The likelihood of tumor response to EP after CAV failure was 40% to 50% in patients whose tumor response was longer than 3 months.^25,26 In a similar patient group, reinduction CDE resulted in more than 50% objective responses.⁶ Conversely, CAV was rarely active in EP failures,^22,23,27 whereas 25% of patients failing both CAV and EP responded to chronic low-dose etoposide with short-lived remissions.²⁸

All of these studies show that only a minority of resistant SCLC patients may benefit from second-line treatment. The different studies are not easy to compare because of the inclusion of patients with different prognostic factors.²⁹ They also do not substantiate non–cross-resistance. The results described here, obtained with PC combination chemotherapy in this poor-prognosis subset of SCLC patients, compare favorably with the outcomes of the studies described above. PC treatment resulted in a 73% RR. Moreover, responses were often valuable and of relatively long duration. Duration of response and survival after second-line treatment in resistant SCLC patients is often not stated, but survival time has been reported to range from 2.8 to 4.7 months.^4-7,20,30 A troublesome feature of second-line treatment with paclitaxel in resistant SCLC is the number of brain relapses, either as the first site of recurrence or together with other systemic relapse. In this study, 12 patients (35%) had CNS disease at progression. One explanation for this finding may be that only carboplatin crosses the blood-brain barrier,³¹ whereas paclitaxel does not.³² In another study using carboplatin (AUC 5.0), paclitaxel (135 mg/m², 1-hour IV infusion), and prolonged etoposide in untreated SCLC patients, a high number of brain metastases (41%), either isolated or as the first site of progression, was also observed.³³

The applicability of our results to patients who received first-line etoposide platinum treatment is expected to be limited, owing to platinum resistance. In those patients, single-agent paclitaxel seems active, but combination treatment including paclitaxel should be explored.

Surprisingly large doses of both carboplatin and paclitaxel can be administered, even to pretreated patients, as observed in our study and reported by others.^33,34 Dose-intensity of these compounds may be important, as in two sequential studies in untreated SCLC patients, a survival advantage for the higher-dose regimen, carboplatin AUC 5.0, paclitaxel 135 mg/m² (1-hour IV infusion) versus carboplatin AUC 6.0 and paclitaxel 200 mg/m² (1-hour IV infusion), both with the same dose of etoposide, was found. In the phase II study reported here, the dose of carboplatin (AUC 7.0, Chatelut formula) and paclitaxel (175 mg/m², 3-hour IV infusion) induced mainly hematologic toxicity and was tolerable, and treatment was feasible in an outpatient setting. Nonetheless, 20% of the patients were forced to halt treatment because of inadequate platelet recovery by day 35. The most important nonhematologic toxicity was peripheral paresthesia shortly after paclitaxel infusions that subsided afterward, although it did not always disappear. The frequency of neurologic toxicity is comparable to that reported in studies with PC in non–small-cell lung cancer patients.

Until recently, no non–cross-resistant drugs have been found to be effective in SCLC patients resistant to CDE. In this study, we have shown that second-line PC in such patients results in high RRs and improved survival time, among the best reported to date. These results support the use of this combination as first-line treatment in SCLC. We have initiated a randomized phase III study in untreated extensive-disease SCLC patients to compare PC with CDE chemotherapy.

	NOTES

 
Paclitaxel was a gift of Bristol-Myers Squibb.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted August 3, 1998; accepted November 23, 1998.

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