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The Burgeoning Role of Paclitaxel in Advanced Pulmonary Malignancy

^a Thoracic Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA; ^b Johns Hopkins Oncology, Baltimore, Maryland, USA

Correspondence: Corey J. Langer, M.D., Department of Medical Oncology, Fox Chase Cancer Center, Central and Shelmire Avenue, Philadelphia, Pennsylvania 19111, USA. Telephone: 215-728-2985; Fax: 215-728-3639; e-mail: c_langer{at}oberon.fccc.edu or dogbusby{at}aol.com

	Abstract

Top Abstract Single-Agent Studies Paclitaxel-Cisplatin... Paclitaxel-Carboplatin... Three-Hour Paclitaxel... One-Hour Paclitaxel-Carboplatin... Cooperative Group Trials Alternative Schedules Novel Paclitaxel Combinations Locally Advanced NSCLC: The... Carboplatin-Paclitaxel-RT... Cisplatin-Paclitaxel RT... Earlier-Stage Disease Small Cell Carcinoma of... References

 
Historically, the treatment of advanced non-small cell lung cancer (NSCLC) with cisplatin-based therapy has been a nearly futile effort. Median survival was seldom greater than six months, and fewer than 20% of those with metastatic NSCLC survived more than one year. In addition, toxicity often equaled, if not exceeded, benefit. Over the past five years, however, we have witnessed an explosion of new agents in advanced lung carcinoma. These new agents—in particular the taxanes, gemcitabine, vinorelbine, and topoisomerase I inhibitors—have breathed new life into clinical research. The therapeutic gains, though modest, are real. Paclitaxel, to a large extent, given either alone or in combination with platinols, has led the charge.

Key Words. NSCLC (Non-small cell lung cancer) • Paclitaxel • Chemotherapy • Metastatic disease • Paclitaxel-carboplatin combination

	Single-Agent Studies

Top Abstract Single-Agent Studies Paclitaxel-Cisplatin... Paclitaxel-Carboplatin... Three-Hour Paclitaxel... One-Hour Paclitaxel-Carboplatin... Cooperative Group Trials Alternative Schedules Novel Paclitaxel Combinations Locally Advanced NSCLC: The... Carboplatin-Paclitaxel-RT... Cisplatin-Paclitaxel RT... Earlier-Stage Disease Small Cell Carcinoma of... References

 
The efficacy of paclitaxel in non-small cell lung cancer (NSCLC) was demonstrated in the early 1990s when the Eastern Cooperative Oncology Group (ECOG) conducted a randomized phase II trial of new agents, including merbarone, pirazantrone and paclitaxel. In this study, paclitaxel at a dose of 250 mg/m² every three weeks yielded a 21% response rate, which, though modest, was the best to date of all single agents tested in the ECOG trials [1]. In addition, the paclitaxel arm yielded a one-year survival rate of 40%. Although the survival curves were not formally compared, a clear trend toward improvement was observed for the paclitaxel arm compared to the other two agents, both of which proved inactive and which yielded one-year survival rates of 23% and 22%, respectively, comparable to the historic controls of the ECOG. A confirmatory trial conducted at MD Anderson Cancer Center using 200 mg/m²/24 h every three weeks yielded a response rate of 25% and a one-year survival rate of 38.5% [2]. Yoneda and colleagues from Japan used a lower dose of paclitaxel (150 mg/m² over 24 h every three weeks) and observed a response rate of 20% in 15 evaluable patients [3].

In 1993 and 1994, evidence emerged documenting the utility and convenience of short infusion paclitaxel in breast cancer and ovarian cancer [4, 5]. Response rates appeared to be equivalent to those found with longer infusions, but myelosuppression was markedly reduced. Gatzemeier and colleagues were among the first to report the efficacy of three-h infusion in advanced NSCLC [6]. From September 1993 through May 1994, 43 patients with advanced disease received paclitaxel 225 mg/m² over three h every three weeks. The objective response rate was 21% (confidence intervals: 10%-33%), comparable to results obtained with 24-h infusion (Table 1). However, the pattern of toxicity was markedly different: 56% developed polyneuropathy, 63% manifested myalgias and arthralgias, while only one patient developed grade 3 or 4 neutropenia. Median survival duration was 10 months. Others have confirmed the efficacy of three-h infusion. Tester and colleagues from Albert Einstein Medical Center in Philadelphia demonstrated a 30% response rate in 20 patients at a dose of 200 mg/m² every three weeks [7]. Sekine and colleagues in Japan observed a 38% response rate in 60 assessable patients with chemo-naive, unresectable stage III or IV NSCLC at a dose of 210 mg/m² every three weeks [8]. Median survival for all patients enrolled was 11.2 months, and the one-year survival rate was 48%. The incidence of grade 4 neutropenia, at 50%, was higher than that observed in the Gatzemeier study. Alberola and colleagues from Spain observed a 36% response rate using a dose of 210 mg/m² every three weeks [9]. Also, Ranson and colleagues cited a 19% response rate and a 43% one-year survival rate in 21 patients with stage III or IV NSCLC treated with paclitaxel at 200 mg/m² every three weeks [10]. However, in an Australian study, paclitaxel at a lower dose (175 mg/m²/3 h every three weeks) was less active, with a 10% objective response rate observed in 51 patients. The median progression-free survival was three months, and median overall survival 6.7 months; yet the estimated one-year survival rate proved to be 40% [11]. The accumulated data suggest a threshold effect for dose-response using short infusion, with optimal activity observed at doses of 200 mg/m², but there is no obvious link between dose and survival rate.

	Paclitaxel-Cisplatin Combinations

Top Abstract Single-Agent Studies Paclitaxel-Cisplatin... Paclitaxel-Carboplatin... Three-Hour Paclitaxel... One-Hour Paclitaxel-Carboplatin... Cooperative Group Trials Alternative Schedules Novel Paclitaxel Combinations Locally Advanced NSCLC: The... Carboplatin-Paclitaxel-RT... Cisplatin-Paclitaxel RT... Earlier-Stage Disease Small Cell Carcinoma of... References

 
ECOG Study
Investigators at Johns Hopkins demonstrated that paclitaxel 135 mg/m²/24 h could be given safely with cisplatin 75 mg/m² without growth factor support [14]. With the addition of G-CSF, the paclitaxel dose could be safely escalated to 250 mg/m² [15]. In addition, in these phase I studies a number of patients with advanced NSCLC responded to treatment. These observations led directly to a phase III trial under the auspices of ECOG, in which the "standard" regimen, 75 mg/m² cisplatin and 100 mg/m²/d x 3 etoposide, was compared with both iterations of cisplatin and paclitaxel at the separate maximally tolerated doses (MTDs) identified by the Hopkins group [16]. Patients with stage IIIB or stage IV NSCLC with good performance status (ECOG PS 0-1) were enrolled. The cisplatin dose was fixed in each arm at 75 mg/m². In a 16-month period ending in December of 1994, 574 patients proved evaluable. Stage IIIB patients constituted 19% of the group and were equally distributed across all three treatment arms. Each cisplatin-paclitaxel combination yielded a significantly higher objective response rate than the etoposide-cisplatin combination, although there was no obvious dose-response relationship for paclitaxel. Similarly, the high- and low-dose paclitaxel arms yielded superior median survival rates of 10.1 and 9.6 months, respectively, versus 7.4 months for the etoposide arm, with no obvious difference in survival rate based on paclitaxel dose. One-year survival rates for the high-dose paclitaxel and low-dose paclitaxel arms and the non-taxane arm were 40%, 37%, and 32%, respectively (Table 2). By the Wilcoxan model and log rank tests, the paclitaxel arms combined yielded a statistically significant improvement in survival over etoposide-cisplatin (p = 0.012). Toxicities were more pronounced for the high-dose arm: severe neuropathy occurred at roughly double the incidence found in the low-dose and non-taxane arms, while myelosuppression was equivalent, most likely due to the protective effects of G-CSF (Table 3). A subanalysis stratified by stage demonstrated a more profound impact for taxane-based therapy on survival for those with stage IIIB disease than for those with stage IV disease [17]. Specifically, taxane-based therapy yielded a median survival of 13.1 months, and a one-year survival rate of 58.1% in stage IIIB patients, as opposed to eight months and 38.9%, respectively, for stage IIIB patients receiving etoposide-cisplatin (p = 0.064). Cella and colleagues have analyzed quality-of-life data from this trial [18]. The treatment outcome index (TOI) derived from FACT-L, in particular its alteration over the first six weeks of therapy, was more predictive of survival than baseline performance status, stage, regimen, or weight loss (Table 4).

Pirker and colleagues observed a 35% response rate in 20 patients using paclitaxel dosed at 175 mg/m²/3 h on day 1 followed by cisplatin 50 mg/m² daily x 2 [20]. Cumulative neurotoxicity again proved protocol-limiting. The response rate proved consistent with the 34% response rate observed by Belli and colleagues in a phase I-phase II trial of paclitaxel at 225 mg/m², in combination with cisplatin at doses as high as 120 mg/m² [21].

Perol and colleagues evaluated paclitaxel 200 mg/m² over three h followed by cisplatin 100 mg/m² day 1 [22]. Forty-two patients received 146 cycles of therapy. The incidence of grade 4 neutropenia was only 10%, and there was no evidence of febrile neutropenia. Nineteen of 32 patients had some degree of neuropathy; in three it proved to be grade 3. The objective response rate was 50%, with one CR. Again, cumulative polyneuropathy proved to be the limiting toxicity. Although myelosuppression was substantially less pronounced than with 24-h infusion, non-hematologic toxicity of short-infusion paclitaxel, especially neuropathy and myalgias-arthralgias, proved clearly more toxic in combination with cisplatin, the neurotoxic platinol.

The only randomized study evaluating the utility of cisplatin and short-infusion paclitaxel originated in the EORTC. In combination with a fixed dose of cisplatin 80 mg/m², Giaccone and colleagues compared paclitaxel 175 mg/m²/3 h to their prior standard, teniposide 100 mg/m² days 1, 3, and 5 [23]. Three hundred and thirty-two patients were accrued. The overall response rate to the paclitaxel combination was 44%, as opposed to 30% for the teniposide regimen. However, there was no difference in median survival (9.2 months), one- or two-year survival rates. Neuropathy was more pronounced in the taxane-containing regimen, but the taxane arm proved superior to the teniposide arm in terms of quality of life, fatigue, appetite, and myelosuppression. Consequently, the authors concluded that paclitaxel and cisplatin in combination offered superior palliation compared to teniposide paired with an identical dose of cisplatin and have designated the former the investigational arm for subsequent studies.

The EORTC and ECOG trials have established the ascendancy of paclitaxel-cisplatin as the "standard" approach in advanced NSCLC.

	Paclitaxel-Carboplatin Combinations

Top Abstract Single-Agent Studies Paclitaxel-Cisplatin... Paclitaxel-Carboplatin... Three-Hour Paclitaxel... One-Hour Paclitaxel-Carboplatin... Cooperative Group Trials Alternative Schedules Novel Paclitaxel Combinations Locally Advanced NSCLC: The... Carboplatin-Paclitaxel-RT... Cisplatin-Paclitaxel RT... Earlier-Stage Disease Small Cell Carcinoma of... References

 
24-Hour Paclitaxel-Carboplatin Combinations (Table 5)
Unlike cisplatin, its analog carboplatin results in markedly reduced nonhematologic toxicity. In a five-arm phase III randomized trial of cisplatin combinations and analogs (ECOG 1583), initial therapy with carboplatin, despite one of the lowest response rates (9%), resulted in the best median survival (31.4 weeks versus 25.8 weeks or less for the other arms) and the least toxicity (3% incidence of grade 4 toxicity, compared with 13% or higher for each of the other arms) [24]. A Cancer and Leukemia Group B (CALGB) trial [25] of carboplatin in a mixed group of stage III and IV patients yielded a somewhat higher response rate (16%), and an EORTC trial demonstrated equivalent median survival, albeit at a slightly lower response rate, for the carboplatin-etoposide combination compared with standard cisplatin-etoposide, with decreased toxicity for the carboplatin regimen [26].

Fox Chase Cancer Center
In order to avoid the synergistic neurotoxicity of combination cisplatin and paclitaxel, a number of investigators have combined carboplatin, the non-neurotoxic platinol, with paclitaxel. Langer and colleagues have published the results of their initial effort combining carboplatin at a fixed AUC of 7.5, with paclitaxel 24-h infusion [29]. The paclitaxel dose was escalated on an intra-patient basis from 135 mg/m² per cycle to a maximum dose of 215 mg/m² by cycle 3. Fifty-four patients with advanced NSCLC were enrolled; 53 proved evaluable. In the absence of growth factor support, neutropenia proved dose-limiting during the first cycle, with 7 of 54 patients hospitalized for febrile neutropenia. The routine implementation of G-CSF during the second and subsequent cycles abrogated neutropenia as a clinically meaningful side effect. Not surprisingly, G-CSF did not benefit thrombocytopenia or anemia, both of which proved cumulative and substantially more pronounced in those who had been previously irradiated. Of those enrolled, more than 50% achieved full-dose paclitaxel by the third cycle, and 70% of those still on study by cycle 5 reached full paclitaxel dose. However, the majority of responses were observed within two cycles of treatment, before the maximum paclitaxel dose was achieved, calling into question the necessity of boosting the paclitaxel dose above 175 mg/m² by 24-h infusion. Myalgias, arthralgias, and sensory neuropathy proved cumulative, with maximum incidence rates of 36% and 38%, respectively, but grade 3 toxicity was rare. Only one patient had to be removed from the study because of neurotoxicity. The majority of patients finished all six planned cycles. The final response rate was 62%, the one-year survival rate 64%, and the two-year survival rate 15% [30].

Vanderbilt
Johnson and colleagues of Vanderbilt instituted a phase I/II study of the same regimen using conventional BSA dosing of 300 mg/m² carboplatin in combination with 135 mg/m²/24 h paclitaxel at four-week intervals [31]. Myelosuppression, specifically neutropenia, was unpredictable and dose-limiting. In a subsequent cohort, the carboplatin dose was converted to AUC dosing (AUC 6), and the median leukocyte nadirs rose from 1,600 to 3,600/ml. In turn, improved tolerance permitted a third cohort to be evaluated at an escalated paclitaxel dose of 175 mg/m² in combination with a carboplatin AUC of 6. In this third group which received the MTD, the response rate was 39%. The overall median survival for all patients was 38 weeks, and the one-year survival rate 32%.

University of Maryland
Belani and colleagues at the University of Maryland mounted a similar phase I/II trial of paclitaxel (24-h infusion) at three-week intervals, combined with carboplatin at progressively higher AUC [32]. At an AUC of 7, the maximally tolerated paclitaxel dose without G-CSF was 175 mg/m²; with G-CSF it was 200 mg/m². The response rate was 56%. Long-term survival data, however, have not been reported.

	Three-Hour Paclitaxel-Carboplatin

Top Abstract Single-Agent Studies Paclitaxel-Cisplatin... Paclitaxel-Carboplatin... Three-Hour Paclitaxel... One-Hour Paclitaxel-Carboplatin... Cooperative Group Trials Alternative Schedules Novel Paclitaxel Combinations Locally Advanced NSCLC: The... Carboplatin-Paclitaxel-RT... Cisplatin-Paclitaxel RT... Earlier-Stage Disease Small Cell Carcinoma of... References

 
With the expectation of reduced myelosuppression and improved patient convenience, a number of investigators, both from North America and abroad, have evaluated the combination of three-h paclitaxel and carboplatin in NSCLC, citing response rates and survival comparable to those in 24-h studies. Table 6 summarizes these results.

Johns Hopkins
Rowinsky et al. at Johns Hopkins mounted a similar phase I study of paclitaxel (three-h infusion) followed by carboplatin in chemotherapy-naive patients with stage IV NSCLC [35]. The initial dose of paclitaxel was 175 mg/m²; the starting dose of carboplatin targeted an AUC of 7 mg/ml/min. The doses of each agent were escalated in sequential cohorts, and treatment was given at three-week intervals. Twenty-three patients with a median age of 63 (range: 44-78) were accrued. All had ECOG PS 0-1. Dose-limiting neutropenia and thrombocytopenia were observed consistently at paclitaxel dose of 225 mg/m² and a carboplatin AUC of 9. The MTDs were paclitaxel 225 mg/m² and a carboplatin AUC of 7. Seven of 19 patients with measurable tumor had bona fide partial or complete response. Rowinsky indicated that further escalation of paclitaxel dose above 225 mg/m² would be feasible with G-CSF support, but he recognized that progressive neuropathy would likely preclude clinically tolerable dose escalation and did not proceed with this approach.

University of Colorado
Bunn and colleagues [36] have treated patients with advanced, unresectable stage IIIB and IV NSCLC with paclitaxel via three-h i.v. infusion, followed by carboplatin (30-min infusion). Patients were assigned to seven sequential treatment groups, with the paclitaxel dose increased from 135 to 225 mg/m², and the carboplatin dose escalated from 250 to 400 mg/m². Pharmacokinetic dosing of carboplatin based on the Calvert formula was not implemented. Forty-two patients with a median age of 61 years were accrued. All but four (90%) had stage IV disease. Ten (24%) had ECOG PS 2. Adenocarcinoma was the predominant histology. There was a 7% cycle-specific incidence of grade IV neutropenia. Two patients only required G-CSF. There was only one episode of grade IV thrombocytopenia, corroborating the data generated by Natale and others. Nonhematologic toxicities, including fatigue and neurotoxicity, were relatively mild. However, allergic reactions prompted protocol discontinuation in four separate patients. An apparent dose-response relationship was observed. At the highest dose levels (paclitaxel 175-200 mg/m²), 6 of 12 evaluable patients responded.

EORTC
Giaccone and colleagues of the EORTC combined paclitaxel, at an initial dose of 100 mg/m²/3 h, with a fixed carboplatin dose of 300 mg/m², at four-week intervals in chemotherapy-naive NSCLC patients [37]. The paclitaxel dose was ultimately increased to 225 mg/m², and carboplatin sequentially escalated to 400 mg/m². Sixty-two patients were accrued to this study. Hematologic toxicities were minimal to moderate. At paclitaxel doses in excess of 200 mg/m², non-hematologic toxicities, specifically myalgias/osteoarthralgias, and peripheral neuropathy were apparent. In 50 evaluable patients, the response rate was only 12%. Of note, however, 5 of the 6 responses were observed at paclitaxel doses 175 mg/m², again suggesting a relative dose-response or dose-threshold effect for short-infusion paclitaxel.

Other Studies
Paccagnella and colleagues mounted a similar phase I-II dose-escalating study [38]. The paclitaxel dose was initially fixed at 175 mg/m² and combined with escalating doses of carboplatin, starting at 175 mg/m² and going up to 300 mg/m². Of twenty patients in this group, five responded (OR = 25%). A subsequent cohort received a fixed dose of paclitaxel of 200 mg/m², in combination with escalating doses of carboplatin from 400 mg/m² to 500 mg/m². The response rate in this group of eight evaluable patients was 38%. Grade 4 myelosuppression was not observed during the first cycle in the higher-dose cohort and was observed in only 19% of subsequent cycles.

In a similar study, Morere and colleagues from France documented a clear correlation between the retrospective calculation of first-cycle carboplatin AUC and response [39]. Patients received paclitaxel in escalating doses from 100 mg/m² to 250 mg/m², and carboplatin at doses of either 325 mg/m² or 350 mg/m² every three weeks. Thirty-five patients were accrued. The overall response rate was 23.5%. Grade 3 and 4 neutropenia occurred in only 40%. There were only two episodes of febrile neutropenia, and only 4% of cycles were associated with grade 3 or 4 thrombocytopenia. Using the Calvert formula, the median AUC in responders was 6.2; it was 4.8 in nonresponders (p = 0.017). Similar results were observed for the Chateaulut formula, with a median AUC of 5.1 in responders and a median AUC of 3.7 in non-responders (p = 0.035).

Tonato and colleagues mounted a similar phase I/II study, with escalation of paclitaxel from 130 mg/m² by 10 mg/m² increments to a maximum dose of 235 mg/m², combined with escalating doses of carboplatin and observed a response rate of 32% in 45 advanced-disease patients [40]. Dose-limiting toxicity, consisting primarily of acute and subacute neuromuscular pain, was observed at a carboplatin dose of 375 mg/m² and a paclitaxel dose of 235 mg/m². The suggested doses for the phase II study were 375 mg/m² and 225 mg/m², respectively. Finally, Kosimidis and colleagues are prospectively evaluating the role of paclitaxel dose intensification; patients receive a fixed dose of carboplatin and are randomly assigned to either 175 mg/m² or 225 mg/m² of paclitaxel every three weeks [41].

	One-Hour Paclitaxel-Carboplatin Infusion

Top Abstract Single-Agent Studies Paclitaxel-Cisplatin... Paclitaxel-Carboplatin... Three-Hour Paclitaxel... One-Hour Paclitaxel-Carboplatin... Cooperative Group Trials Alternative Schedules Novel Paclitaxel Combinations Locally Advanced NSCLC: The... Carboplatin-Paclitaxel-RT... Cisplatin-Paclitaxel RT... Earlier-Stage Disease Small Cell Carcinoma of... References

 
Fox Chase Cancer Center
Greco and Hainsworth have demonstrated that the toxicity and pharmacokinetics of one-h paclitaxel infusion are comparable to those of three-h infusion [12]. In addition, one-h paclitaxel infusion has generated comparable response rates [13]. In an attempt to reduce myelosuppression, eliminate the cost of overnight hospitalization for paclitaxel and obligatory G-CSF usage, and improve convenience, investigators at Fox Chase Cancer Center in 1994 mounted a follow-up study of combination carboplatin and one-h paclitaxel, in lieu of 24-h infusion (Table 7) [42]. The carboplatin dose was fixed at an AUC of 7.5. Paclitaxel was initially administered at a dose of 175 mg/m², with intrapatient dose escalation of 35 mg/m²/cycle over serial cycles to a maximum dose of 280 mg/m² by cycle 4 (Table 8). Without the routine use of colony-stimulating factor, myelosuppression proved comparable to that found in the original 24-h paclitaxel study. However, nonhematologic toxicities became more prominent. Myalgias and arthralgias were much more common, although not necessarily more severe than those observed in the 24-h study, and cumulative peripheral sensory neuropathy proved both more common and more severe, with grade 3 toxicity occurring in six of the first 20 patients enrolled (30%), obligating at least three to be removed from the study in the absence of disease progression. The major response rate of 55% proved similar to that observed in the 24-h trial. Moreover, the one-year survival rate was 45% in this cohort of 22 patients, and the two-year survival rate was 18%. Because of severe neurotoxicity, the treatment schema was revised: at an identical dose of carboplatin, a subsequent cohort of patients received a lower starting dose of paclitaxel (135 mg/m²), which was escalated on an intrapatient basis to a maximum dose of 215 mg/m², recapitulating the dose escalation schema used in the original 24-h study. Myelosuppression was considerably less severe. Myalgias, arthralgias, and neuropathy again proved cumulative but were not as severe as observed in the original high-dose one-h cohort. The incidence of grade 3 neuropathy was 9% in this cohort, compared with 30% in the high-dose one-h study, and 2% in the original 24-h study. However, the response rate dropped to 27%, although the one-year survival rate remained in range at 47% (Table 8).

Ottawa
Evans and colleagues combined carboplatin at an AUC of 6 with more modest doses of paclitaxel: 175 mg/m² during the first cycle. A provision to escalate the paclitaxel dose to 225 mg/m² over successive cycles was included. Thirty-six patients proved evaluable. Partial responses were observed in 10 of 35 patients (29%). Median survival was 6.5 months, and the one-year survival rate was 31%. 14% of patients sustained grade 3 neuropathy, a rate comparable to that observed in cohort B of the Fox Chase study. Median progression-free survival was 3.4 months [44].

Sarah Cannon Cancer Center
Hainsworth, Greco and colleagues have also assessed one-h paclitaxel in combination with carboplatin. Again, the carboplatin was fixed at an AUC of 6; the initial dose of paclitaxel at 225 mg/m², however, was higher than that used in any other one-h combination study [45]. Of the first 100 evaluable patients accrued, the response rate to date has been 40%, with 3% complete remissions. Median survival was eight months, and the one-year survival rate was 40%. Again, grade 3 neuropathy has been observed in 15% of patients, usually after four or more cycles of therapy. It is not clear to what extent this toxicity may have obligated treatment termination in the absence of disease progression. Review of these data suggests little difference between one- and three-h paclitaxel infusion, although the possible exacerbation of nonhematologic toxicity, potentially attributable to a higher peak concentration of the agent, cannot be discounted.

	Cooperative Group Trials

Top Abstract Single-Agent Studies Paclitaxel-Cisplatin... Paclitaxel-Carboplatin... Three-Hour Paclitaxel... One-Hour Paclitaxel-Carboplatin... Cooperative Group Trials Alternative Schedules Novel Paclitaxel Combinations Locally Advanced NSCLC: The... Carboplatin-Paclitaxel-RT... Cisplatin-Paclitaxel RT... Earlier-Stage Disease Small Cell Carcinoma of... References

 
ECOG 1594 (Table 9), with a targeted accrual of 1,200 patients, compares the carboplatin-paclitaxel regimen to the new ECOG "standard combination" of paclitaxel 135 mg/m²/24 h and cisplatin 75 mg/m² and to two other cisplatin combinations: gemcitabine 1 gm/m² days 1, 8 and 15 and cisplatin 100 mg/m² day 1; or docetaxel 75 mg/m² combined with cisplatin 75 mg/m².

These three trials represent "state-of-the-art therapy." As of March, 1998, the SWOG trial has completed accrual. The ECOG trial is more than 50% accrued, and the CALGB study has just been initiated. Although the studies are different, a common theme weaves through each. Even though paclitaxel-carboplatin is not a standard regimen, it has become in many areas the de facto community standard, and it is being evaluated in each of these cooperative group studies. Unanswered issues, however, persist. Twenty-four hour infusion, though clearly less convenient, more expensive, and more myelosuppressive, may be superior to 3 h infusion. This issue, however, is not currently being addressed in a randomized fashion in advanced NSCLC. In addition, identification of the precise threshold dose needed for optimal response and survival in short-infusion studies has not occurred, although the Kosimidis study should help elucidate this issue. Higher doses of paclitaxel (200-225 mg/m²), although possibly more effective, are clearly more neurotoxic.

	Alternative Schedules

Top Abstract Single-Agent Studies Paclitaxel-Cisplatin... Paclitaxel-Carboplatin... Three-Hour Paclitaxel... One-Hour Paclitaxel-Carboplatin... Cooperative Group Trials Alternative Schedules Novel Paclitaxel Combinations Locally Advanced NSCLC: The... Carboplatin-Paclitaxel-RT... Cisplatin-Paclitaxel RT... Earlier-Stage Disease Small Cell Carcinoma of... References

 
Rhode Island
Akerley and colleagues at Rhode Island Hospital in Providence conducted a phase I study of weekly paclitaxel in patients with chemotherapy-naive metastatic NSCLC [46]. Twenty-six patients were entered at six sequential dose levels (100, 125, 135, 150, 175, and 200 mg/m² per week) administered weekly for six consecutive weeks, followed by a two-week break. The median age was 65 (range: 37-80); 24 of 26 completed the first eight-week cycle. Dose-limiting toxicity consisting of neutropenia occurred in four of six patients at 200 mg/m² weekly and in two of six at 175 mg/m². However, only one evaluable patient required admission for febrile neutropenia. Other toxicities included rash, pulmonary infiltrates, myalgia, and neuropathy. Nine of 24 patients (38%) demonstrated objective responses. The author and colleagues concluded that the MTD of paclitaxel in this regimen was 175 mg/m² per week, a two-fold increase in dose-intensity compared to standard every-three-week regimens; based on these results, they launched a follow-up phase II study [47]. Doses were modified on a weekly basis for ANC below 1,500 and grade 2 neuropathy. Twenty-five patients were fully evaluable. All but two had ECOG PS 0-1. A total of 96% had stage IV disease. The majority had previously received RT. 44% had prior CNS involvement. The major response rate was 56%, with a median duration of six months. The one-year survival rate using this single-agent schedule was 53%. Four patients did not complete the first eight-week cycle for reasons unrelated to toxicity. Excluding these patients, 83%, 75%, 58%, and 50% of intended doses were delivered during cycles 1 through 4.

NCI-Navy
Based on preclinical studies demonstrating enhanced cytotoxicity in NSCLC and SCLC cell lines for continuous paclitaxel infusion (96 h), compared with shorter infusions [48], Georgiadis, Johnson, and colleagues have taken an opposite tack [49]. Fifty patients, 42 with NSCLC and eight with SCLC, received a fixed dose of cisplatin, initially 60 and later 80 mg/m², in conjunction with paclitaxel administered over 96 h. In successive cohorts, the paclitaxel dose was escalated from 80 mg/m²/96 h to a maximum dose of 180 mg/m². In the absence of G-CSF support, dose-limiting neutropenia was observed in two of six patients at 140 mg/m²/96 h and cisplatin 80 mg/m². With G-CSF support and an identical dose of cisplatin, dose-limiting mucositis and fatal neutropenia were observed at 180 mg/m²/96 h. In addition, in five patients who received six or more cycles of treatment, significant peripheral neuropathy developed. The authors concluded that the MTD of 96-h infusion paclitaxel without growth factor support was 120 mg/m²/96 h, and with G-CSF 160 mg/m²/96 h. Of 32 NSCLC patients with measurable disease, the objective response rate was 55%, with two complete remissions and 16 partial remissions. For the entire NSCLC cohort of 42 patients, median time to progression was five months and median survival duration 10 months. The actuarial one-year survival rate was 41%. Of eight SCLC patients, the response rate was 50% and the median survival 11 months.

	Novel Paclitaxel Combinations

Top Abstract Single-Agent Studies Paclitaxel-Cisplatin... Paclitaxel-Carboplatin... Three-Hour Paclitaxel... One-Hour Paclitaxel-Carboplatin... Cooperative Group Trials Alternative Schedules Novel Paclitaxel Combinations Locally Advanced NSCLC: The... Carboplatin-Paclitaxel-RT... Cisplatin-Paclitaxel RT... Earlier-Stage Disease Small Cell Carcinoma of... References

 
Paclitaxel has been combined with agents other than carboplatin. Masters et al. reported on the combination of paclitaxel, ifosfamide, and vinorelbine, based on previous activity in vivo in an ifosfamide-paclitaxel trial and data demonstrating preclinical vinorelbine-paclitaxel synergy [50]. In combination with a fixed dose of ifosfamide 1.2 gm/m² daily for three days, vinorelbine 20 mg/m² daily for three days, and G-CSF support, paclitaxel was escalated across sequential cohorts. However, a dose of 175 mg/m²/3 h proved too toxic. The MTD was 135 mg/m². Grade 3-4 neutropenia was ubiquitous, with nearly one-quarter of the patients experiencing neutropenic fever. Nine of 54 patients (17%) experienced partial response to treatment, suggesting that the addition of a third drug to either combination (ifosfamide-paclitaxel or ifosfamide-vinorelbine) exacerbated toxicity without expanding benefit. This was particularly noteworthy in that two prior studies of doublet therapy with paclitaxel and ifosfamide yielded comparable, if not superior, activity, with decreased toxicity [51, 52]. Vokes and colleagues from the University of Chicago evaluated ifosfamide at a dose of 1.6 gm/m² daily for three days, in combination with escalating dose of paclitaxel (24 h) at 135-300 mg/m², with G-CSF support. The recommended phase II dose was 200 mg/m². The overall response rate was 12% [51]. The NCI of Canada mounted a similar phase I/II study, combining ifosfamide at a dose of 3-4 gm/m² on day 1 only, with paclitaxel administered over 3 h with doses ranging from 100 to 225 mg/m², without G-CSF support [52]. Dose-limiting toxicity (DLT) was not encountered, but a decision was made to halt dose escalation at 225 mg/m² in light of cumulative neurotoxicity. The overall response rate in 40 patients was 21%, but this increased to >30% in those receiving paclitaxel doses 150 mg/m². Median survival was 9.1 months, and the projected one-year survival exceeds 30%.

The CALGB is currently mounting a randomized phase II study of paclitaxel-ifosfamide and vinorelbine-ifosfamide in chemotherapy-naive NSCLC, and the NCI-Canada is mounting a phase II study of the paclitaxel-ifosfamide combination.

Other phase I/II studies have evaluated the combination of paclitaxel-ifosfamide with either carboplatin or carboplatin-etoposide. In the three-drug regimen, the MTD of paclitaxel was 135 mg/m²/3 h, carboplatin AUC 6, and ifosfamide 3 gm/m² days 1 and 2 [53]. In the four-drug regimen, the ifosfamide was fixed at 2 gm/m² daily for three days, and etoposide at 75 mg/m² daily for three days, with carboplatin 300 mg/m² administered on day 2, and paclitaxel on day 1, administered over 24 h at doses escalating from 75 to 225 mg/m² [54]. Twenty-six percent of patients required admission for febrile neutropenia. However, because DLT was defined as grade 4 neutropenia or thrombocytopenia lasting seven days or more, a formal MTD was not established. The response rate for this regimen was 27%, but median survival exceeded one year and was similar in stage III and IV subsets.

Breton and colleagues evaluated vinorelbine, days 1 and 5 every three weeks in combination with paclitaxel by one-h infusion [55]. DLT was observed at paclitaxel dose of 135 mg/m² and vinorelbine at 20-25 mg/m², prompting dose reduction of paclitaxel of 100 to 115 mg/m², in combination with vinorelbine 20 mg/m². Objective responses were observed in 24% of patients. For phase II evaluation, the recommended dose of paclitaxel was 115 mg/m² day 1, and vinorelbine 20 mg/m² days 1 and 5 every three weeks.

Georgoulias, Kourousis, and colleagues evaluated a combination of paclitaxel and gemcitabine in patients whose tumors had progressed after first-line cisplatin-based chemotherapy [56]. Patients received gemcitabine 900 mg/m² on days 1 and 8, and paclitaxel 175 mg/m² on day 8 over three h. G-CSF was given prophylactically days 9-15, and treatment was repeated at three-week intervals. Twenty-six patients, 23 with stage IV disease and three with stage IIIb disease, were enrolled. Grade 3 and 4 neutropenia occurred in only 9% of patients, and there were no episodes of grade 3 or 4 edema or thrombocytopenia. Fifty-five percent of patients, however, experienced grade 2 or 3 neurotoxicity or fatigue. The overall response rate was 28.5% in this previously treated group, including one CR. Median survival duration was eight months. Responses were confined to squamous cell histology.

	Locally Advanced NSCLC: The Interaction of Paclitaxel and Radiation

Top Abstract Single-Agent Studies Paclitaxel-Cisplatin... Paclitaxel-Carboplatin... Three-Hour Paclitaxel... One-Hour Paclitaxel-Carboplatin... Cooperative Group Trials Alternative Schedules Novel Paclitaxel Combinations Locally Advanced NSCLC: The... Carboplatin-Paclitaxel-RT... Cisplatin-Paclitaxel RT... Earlier-Stage Disease Small Cell Carcinoma of... References

 
Over the past decade, data have clearly emerged in locally advanced NSCLC, demonstrating the benefits of chemotherapy combined with local measures, in particular radical thoracic radiation (XRT). Three separate studies have demonstrated a survival benefit for induction chemotherapy followed by definitive radiation compared with radiation alone, with improvements primarily in systemic control [57-59]. In addition, three other studies have demonstrated a radiosensitizing benefit to concurrent chemotherapy and radiation versus radiation alone, with improved local control and enhanced survival rates [60-62]. A seventh study has demonstrated the superiority for concurrent chemoradiation over sequential chemotherapy followed by radiation, although these results have not yet been confirmed by other investigators [63].

Paclitaxel stabilizes microtubulin polymers, leading to an accumulation of cells in the G₂ and M interface of the cell cycle, at which point radiation sensitization presumably is maximal [64]. Paclitaxel may also enhance radiation sensitization by stimulating apoptosis. In preclinical cell lines, including lung, ovary, cervix, and astrocytoma, the radiation enhancement ratio of paclitaxel is 50% higher than with XRT alone [65]. Finally, it is logical to introduce agents with proven activity and benefit in advanced disease to earlier stages where the chance for cure may be enhanced.

Choy and colleagues mounted a phase I trial in patients with locally advanced NSCLC, employing radical thoracic RT (60 Gy) in conjunction with weekly paclitaxel administered over three h, approximately three to four h prior to XRT (Table 10) [66]. Dose escalation was instituted conservatively. The starting dose of paclitaxel was 10 mg/m² weekly, and was escalated to DLT. At 70 mg/m² weekly, grade 4 esophagitis requiring hospitalization was observed in two of three patients. However, at a paclitaxel dose of 60 mg/m² weekly, only one of seven patients experienced grade 3 esophagitis, prompting designation of 60 mg/m² weekly as the MTD.

	Carboplatin-Paclitaxel-RT Combinations

Top Abstract Single-Agent Studies Paclitaxel-Cisplatin... Paclitaxel-Carboplatin... Three-Hour Paclitaxel... One-Hour Paclitaxel-Carboplatin... Cooperative Group Trials Alternative Schedules Novel Paclitaxel Combinations Locally Advanced NSCLC: The... Carboplatin-Paclitaxel-RT... Cisplatin-Paclitaxel RT... Earlier-Stage Disease Small Cell Carcinoma of... References

 
In a subsequent study reported at ASCO in 1997, Choy and colleagues reported the mature results of a phase II trial of concurrent radiation, weekly radiosensitizing paclitaxel, and carboplatin [68]. Thirty-nine patients with stage III NSCLC from five separate institutions received radical thoracic RT (66 Gy) in conjunction with weekly carboplatin (AUC 2) and paclitaxel 50 mg/m² over one h. Two additional cycles of systemically dosed paclitaxel (200 mg/m²) and carboplatin (AUC 6) were administered on an "adjuvant basis" after the completion of concurrent chemoradiation. The incidence of grade 3 and grade 4 esophagitis during concurrent chemoradiation was 50% and 28%, respectively; grade 3 pneumonitis was 8.5%. The overall response rate was 75%, the one-year survival rate was 52%, and the two-year survival rate was 40%, despite the inclusion of poor prognosis patients, some with weight loss exceeding 5%. Choy's current trial employs hyperfractionated RT in conjunction with concurrent paclitaxel and carboplatin [69].

Belani and colleagues mounted a similar study combining slightly lower doses of paclitaxel (45 mg/m²/3 h weekly) with carboplatin (100 mg/m² weekly) and concurrent radical thoracic RT: 60-65 Gy [70]. An actuarial three-year survival rate of 38% has been reported. Esophagitis was less pronounced than that observed in the Choy study, with less than 10% incidence of grade 3 esophagitis, although identical toxicity criteria were not used.

Langer and colleagues assessed the role of sequential induction chemotherapy with paclitaxel and carboplatin followed by concurrent chemoradiation (Table 11) [71, 72]. Thirty-five patients at Fox Chase Cancer Center and its network affiliates received two cycles of paclitaxel (175-225 mg/m²/3 h) and carboplatin (AUC 7.5) with G-CSF support followed by radical thoracic RT (60 Gy) starting day 43. As part of a phase I evaluation, Fox Chase patients also received concurrent paclitaxel and carboplatin during XRT, administered for two cycles on days 43 and 64. Myelosuppression and neurosensory toxicity proved mild during induction therapy. In the 17 patients who received concurrent chemoradiation, esophagitis was nearly ubiquitous but seldom severe, correlating consistently with the length of esophagus in the RT portal. It proved grade 2 or worse in six of seven patients with esophageal exposure 16 cm, but grade 1 in all six patients with esophageal exposure 16 cm. The paclitaxel dose during RT has been escalated across sequential cohorts from 67.5 mg/m² to 175 mg/m², and the carboplatin dose escalated from an AUC of 3.75 to an AUC of 5. DLT has not yet been observed. The median survival of all patients enrolled on this study to date is 14.3 months; for those formerly enrolled on the phase I dose escalation study, it is seventeen months.

	Cisplatin-Paclitaxel RT Combinations

Top Abstract Single-Agent Studies Paclitaxel-Cisplatin... Paclitaxel-Carboplatin... Three-Hour Paclitaxel... One-Hour Paclitaxel-Carboplatin... Cooperative Group Trials Alternative Schedules Novel Paclitaxel Combinations Locally Advanced NSCLC: The... Carboplatin-Paclitaxel-RT... Cisplatin-Paclitaxel RT... Earlier-Stage Disease Small Cell Carcinoma of... References

 
Myers et al. from the University of Alabama have reported the relatively mature results of a phase I/II study of concurrent cisplatin and paclitaxel with radical thoracic RT (60 Gy) for two cycles followed by two additional cycles of cisplatin-paclitaxel [77]. Forty patients (90% PS 0, 1; 35% 5% weight loss) have been accrued. Of 40 patients, 23 had stage IIIa disease. DLT was observed at a paclitaxel dose of 170 mg/m² in conjunction with cisplatin 75 mg/m². At this dose, four of nine patients experienced grade 3 esophagitis and there was a 56% incidence of cycle-specific neutropenic fever. In addition, six of nine patients at this dose level required treatment delays. The MTD was finally designated at a paclitaxel dose alternating between 135 and 170 mg/m² every other cycle. Grade 2 early pulmonary toxicity was observed in 4 of 31 evaluable patients. The overall response rate was 86%, and the one-year survival rate 64%.

Greco and Hainsworth have also reported the results of a phase II effort in locally advanced NSCLC, using induction therapy with cisplatin 60 mg/m² weeks 1 and 4, etoposide 100 mg/m² days 1, 2, and three in weeks 1 and 4, and paclitaxel 135 mg/m² over one h weeks 1 and 4, followed by concurrent thoracic RT beginning day 43, to a total dose of 60 Gy, cisplatin 5 mg/m² and etoposide 25 mg/m² daily days 43-46, 49-53, 64-67, 70-74, and paclitaxel 135 mg/m² days 43 and 64 [78]. Overall response rate in 33 patients was 82%; median survival was 17 months. With a minimum follow-up to date of 13 months in 53 patients, the projected two-year survival rate is 36%. Of note, seven patients had malignant pleural effusions at the onset.

Frasci and collaborators mounted a phase I/II study of weekly paclitaxel and cisplatin and concurrent XRT [79]. In conjunction with hyperfractionated XRT, doses of 45 mg/m² and 35 mg/m², respectively, on a weekly basis proved dose-limiting with unacceptable incidence of severe esophagitis. But the same doses proved tolerable in combination with standard, single-daily fractionated XRT. The projected median survival in 25 patients is 16 months, and the one-year survival rate is 66%.

Vokes and colleagues [80] from the CALGB are mounting a randomized phase II trial of three different cisplatin-based combinations, both prior to and during radiation in stage IIIb NSCLC. Patients receive two cycles of induction cisplatin-gemcitabine, cisplatin-vinorelbine, or cisplatin-paclitaxel, followed by concurrent radical RT (66 Gy) and two additional cycles of identical chemotherapy. The cisplatin dose is fixed at 80 mg/m² every three weeks. In the paclitaxel arm, the relevant doses are 225 mg/m²/3 h days 1 and 22 during the induction period, and 135 mg/m² days 43 and 64 during XRT. In this arm, the incidence of grade 3 and 4 granulocytopenia to date is 20% and 30%, and grade 3 esophagitis is 30%. Responses to the paclitaxel-cisplatin arm have been comparable to those of the other two regimens. This study is targeted to accrue 150 patients.

Finally, Niell and colleagues have mounted a phase I/II study of sequential and concurrent chemoradiation in locally advanced NSCLC [81]. The dose of cisplatin was fixed at 100 mg/m² every three weeks for two courses, and paclitaxel (one-h infusion) was escalated from 150 to 250 mg/m². The projected MTD of paclitaxel was 225 mg/m². Dose-limiting neurotoxicity was not observed. Twenty-one patients underwent concurrent chemoradiation; 17 have completed therapy. The paclitaxel dose during this phase was administered weekly at 40 mg/m² over one h in combination with weekly cisplatin 30 mg/m². Of the first 20 accrued, all but three patients experienced some degree of esophagitis; grade 3 esophagitis was observed in 20%. Of 22 evaluable patients, 13 (59%) obtained a PR to induction therapy. Of note, there was no weight loss restriction on this study, which included patients with PS 2. Median age was 65.

The Radiation Therapy Oncology Group (RTOG) is about to initiate a study in good-prognosis patients (KPS 70; 5% weight loss), evaluating induction therapy with paclitaxel and carboplatin followed by concurrent chemoradiation with the same two agents administered at weekly intervals, with or without amifostine as an esophageal protectant. The ECOG is planning to launch a parallel study evaluating similar induction therapy followed by either standard RT alone or hyperfractionated accelerated radiation, and the CALGB will be assessing induction therapy with this regimen followed by either XRT alone or concurrent XRT and weekly paclitaxel-carboplatin. To date, all completed efforts have been phase II, single-arm studies. The ultimate gauge of paclitaxel's utility in conjunction with XRT will need to await the results of carefully conducted, phase III trials against conventional combined modality programs.

	Earlier-Stage Disease

Top Abstract Single-Agent Studies Paclitaxel-Cisplatin... Paclitaxel-Carboplatin... Three-Hour Paclitaxel... One-Hour Paclitaxel-Carboplatin... Cooperative Group Trials Alternative Schedules Novel Paclitaxel Combinations Locally Advanced NSCLC: The... Carboplatin-Paclitaxel-RT... Cisplatin-Paclitaxel RT... Earlier-Stage Disease Small Cell Carcinoma of... References

 
Rice and colleagues from the Cleveland Clinic have mounted a phase II study of accelerated hyperfractionated radiation and concurrent cisplatin and paclitaxel followed by surgical resection [82]. Forty-five patients with locally advanced NSCLC received a single preoperative course of 24-h paclitaxel (175 mg/m²) day 1 and a four-day continuous infusion of cisplatin (20 mg/m² daily) concurrent with accelerated fractionated radiation (AFR) at a dose of 1.5 Gy bid for total dose of 30 Gy. Induction was completed in 12 days, and surgery accomplished four weeks later. Of evaluable patients, 89% experienced some degree of mucositis, 20% sustained grade 3 esophagitis, and 40% had neutropenic fever. Objective responses were observed in 24 of 45 patients. Forty proceeded to surgery, and 32 underwent complete surgical resection. Pathologic complete remissions were observed in five patients. Overall, 14 patients (30%) had pathologic downstaging. There were no perioperative deaths. Two-year relapse-free survival was 47%, and overall survival was 65%. Median survival has not yet been reached. There were no significant survival differences for patients with stage IIIa or IIIb disease. Eighteen percent of patients have experienced recurrence: one local and seven distant, including six in the CNS, of whom five did not recur outside the brain.

The RTOG and, independently, Fox Chase Cancer Center are conducting phase II trials of concurrent chemoradiation in completely resected stage II/IIa NSCLC, modeled after the experience to date with induction paclitaxel-carboplatin followed by chemoradiation in unresectable stage IIIa/b disease. In both instances, chemoradiation begins after recovery from surgery, with two cycles of chemotherapy given during radiation and two cycles administered after radiation is completed. RTOG 97-05 mandates the administration of 50.4 Gy in 28 fractions. During radiation, the dose of carboplatin is AUC 5, and the dose of paclitaxel is 135 mg/m² (cycles one and two). After radiation, the doses are AUC 6 and 225 mg/m², respectively (cycles three and four).

In earlier-stage disease (Ib, IIa, IIb), Pisters and colleagues are mounting a multi-institutional phase II trial of induction paclitaxel (225 mg/m²/3 h), and carboplatin (AUC 6), every three weeks for two cycles prior to surgery [83], followed by three cycles after surgery in patients with T2N0, T1N1, T2N1, and T3N0-1 disease. Eligible patients are required to have a negative mediastinoscopy. To date, 31 patients have been accrued, with responses observed in 19 of 27 evaluable patients, including 1 CR. There has been no increase in perioperative morbidity, and no treatment-induced deaths. Others are mounting similar efforts [84].

Finally, the CALGB and RTOG jointly are mounting an intergroup phase III randomized trial of adjuvant carboplatin-paclitaxel (four cycles) versus observation in patients with surgically resected, pathologically proven T2N0 NSCLC. The cooperative group studies will determine definitively whether this commonly used regimen yields a survival advantage in the early-stage adjuvant setting.

	Small Cell Carcinoma of the Lung (SCLC)

Top Abstract Single-Agent Studies Paclitaxel-Cisplatin... Paclitaxel-Carboplatin... Three-Hour Paclitaxel... One-Hour Paclitaxel-Carboplatin... Cooperative Group Trials Alternative Schedules Novel Paclitaxel Combinations Locally Advanced NSCLC: The... Carboplatin-Paclitaxel-RT... Cisplatin-Paclitaxel RT... Earlier-Stage Disease Small Cell Carcinoma of... References

 
Although combined chemoradiation yields long-term survival rates of 15%-25% in limited disease, SCLC generally remains a devastating illness. Patients with extensive disease, who constitute the majority of those newly diagnosed with SCLC, have median survival rates of 7 to 10 months with conventional platinol-etoposide therapy (PE). Hence, it is this group in which new cytotoxic agents such as paclitaxel must first be tested to best gauge efficacy and tolerance.

Ettinger and colleagues from the ECOG were the first to report the efficacy of paclitaxel in extensive-stage SCLC (Table 12) [85, 86]. Paclitaxel was dosed at 250 mg/m² over 24 h every three weeks. Thirty-six patients with chemotherapy-naive disease were accrued to this window-of-opportunity study and received a maximum of two to four cycles of therapy. Patients with disease progression or stable disease after two cycles or partial remission after four cycles were placed on "salvage" chemotherapy, consisting of standard-dose etoposide and cisplatin. Thirty-four patients were evaluable for toxicity and 32 for response. The median age was 63 (range: 40-78). Twenty-eight of 34 patients had good performance status: ECOG PS 0-1. Eleven PR (34%) were observed, and an additional six patients (19%) had stable disease, with at least three of these patients experiencing 50% shrinkage of their tumor; however, because of a mandatory switch in therapy, four-week follow-up measurements on paclitaxel could not be obtained. Therefore, by strict criteria, these patients were not considered partial responders. The median survival in this study was 45 weeks. Major toxicity included leukopenia, grade 4, in 90%.

Addition of Paclitaxel to Standard Etoposide-Cisplatin Regimen
Bunn and Kelly were among the first to combine paclitaxel with standard therapy: paclitaxel was added to a fixed dose of cisplatin 80 mg/m² day 1 and to etoposide at an initial dose of 50 mg/m² days 1 through 3 [88]. The starting dose of paclitaxel was 135 mg/m² over three h. DLT was observed at a paclitaxel dose of 200 mg/m² and an etoposide dose of 80 mg/m² i.v. day 1, and 160 mg/m² orally days 2 and 3. Of the first 19 patients accrued, all but one responded (94%). The CR rate was 21%. Myelosuppression was cumulative; five of six patients at dose level 3 required growth factor at some point, and three of seven patients at the fourth dose level experienced febrile neutropenia. Nonhematologic toxicities were mild. The median survival was 10.8 months, and, as reported at the International Association for the Study of Lung Cancer (IASLC), the one- and two-year survival rates were 39% and 19%, respectively.

Glisson and colleagues from MD Anderson have mounted a phase I/II study of paclitaxel, in combination with cisplatin and etoposide [89]. The cisplatin dose was fixed at 75 mg/m² i.v. day 2, etoposide given at 80 mg/m² i.v. days 2 through 4, and paclitaxel started at 130 mg/m² i.v. day 1. Twenty-six patients were eligible for evaluation. There were 20 partial responses (77%) and five CR (19%). Median progression-free and overall survival were 33 and 62 weeks, respectively. Grade 4 neutropenia occurred during 48% of treatment courses and neutropenic fever during 6% of treatment courses.

Levitan identified a paclitaxel MTD of 170 mg/m²/3 h in combination with cisplatin 60 mg/m² and etoposide 80 mg/m²/d x 3 with G-CSF support. The overall response rate in eight patients was 88%, with one CR [90].

Carboplatin Combinations
Other investigators in an attempt to avoid the nonhematologic toxicity of cisplatin, have substituted carboplatin in this combination. Hainsworth and colleagues from the Sarah Cannon Cancer Center in Nashville, Tennessee have mounted one of the largest efforts evaluating paclitaxel in combination in SCLC [91]. The first study evaluated 38 patients, 15 with limited disease [LD], 23 with extensive disease [ED]. Treatment (PET) consisted of paclitaxel 135 mg/m² i.v. one-h infusion day 1, combined with carboplatin AUC 5 day 1, and etoposide 50 mg alternating with 100 mg every other day for 10 days. This treatment was repeated at 21-day intervals. Limited-stage patients received RT beginning day 42. Median survival for ED patients in this cohort was eight months, and for LD patients 17 months, with two-year overall survival rates of 10% and 38%, respectively. Grade 4 leukopenia occurred during only 7% of treatment courses, and hospitalizations for febrile neutropenia occurred during only 11% of courses. The lack of substantial myelosuppression led the investigators to revamp the trial. From January 1995 through June 1996, 79 patients received higher doses of paclitaxel, 200 mg/m² day 1, and carboplatin AUC 6. The overall response rate in ED patients improved from 65% to 84%, and median survival improved from eight months to 10 months. In addition, LD patients sustained a higher CR rate (71% versus 40%). Median survival has not yet been observed at 15 months. The incidence of grade 3 or 4 leukopenia rose from 22% to 38%, but was still acceptable. This effort has lead to a phase III trial at Sarah Cannon and affiliates evaluating PET versus PE, with accrual 50% completed.

Gatzemeier and colleagues have evaluated the combination of carboplatin and oral etoposide with paclitaxel [92]. Twenty-six patients have been accrued since April 1996. Etoposide was administered at 100 mg daily, days 2 through 8, with carboplatin at an AUC of 5 day 1; paclitaxel was given at 175 mg/m² over one h day 1. The overall response rate was 81%, with 39% CR. Myelosuppression was relatively mild. There were no episodes of grade 3 nonhematologic toxicity. Progression and survival data have not been reported.

Non-Etoposide Combinations
Finally, other investigators have evaluated the role of paclitaxel in non-etoposide combinations. Jett and colleagues from the University of Pittsburgh examined combination topotecan 1 mg/m² for 30 min daily for five days and paclitaxel 135 mg/m² i.v. over 24 h on day 5 with G-CSF support [93]. Eligibility was restricted to ED SCLC. Eighteen patients were enrolled. Median age was 65. The patient-specific incidence of grade 3 and 4 neutropenia was 89%, over 78% of treatment courses. Ninety-two percent of patients experienced grade 4 thrombocytopenia. The overall response rate was 66%, and the median survival was promising at 59 weeks.

Nair and Marschke from the North Central Treatment Group have evaluated cisplatin 75 mg/m² combined with paclitaxel at either 135 mg/m² or 175 mg/m² [94]. Twenty-three patients were treated at the lower dose, 48 patients at the higher dose. Seventy-one percent of evaluable patients in the low-dose group, and 89% of evaluable patients at the higher dose had major responses to treatment. The median times to progression in these two groups were 145 days and 167 days, respectively, and the median survivals were 239 days and 267 days, respectively. The estimated one-year survival rates were 24% in the low-dose group and 38% in the high-dose group.

Current efforts of the RTOG in limited SCLC focus on combining standard hyperfractionated RT beginning day 1 with etoposide, cisplatin, and paclitaxel (RTOG 9609). As of October 1997, this trial has accrued 33 of 52 targeted patients. The ECOG will be assessing the same chemotherapy combination, but XRT will be delayed until day 43 after two cycles of chemotherapy have been given and will be administered on a once-daily basis.

Paclitaxel is clearly an active agent in SCLC and is compatible with other drugs. In combination with standard therapy, median survivals in ED exceeding one year have been observed. At face value, these results appear to be superior to typical survival rates observed in extensive SCLC. Whether the addition of paclitaxel to standard therapy will prove superior to standard therapy alone, either in ED or LD, will be determined by the results of phase III trials. To this end, the North American intergroup has proposed a study comparing standard cisplatin 80 mg/m² and etoposide 80 mg/m² days 1, 2, and 3 to the same combination, with paclitaxel 175 mg/m² day 1 added based on the work of Bunn, Kelly, Glisson, and Levitan. We eagerly await the initiation of this study.

	References

Top Abstract Single-Agent Studies Paclitaxel-Cisplatin... Paclitaxel-Carboplatin... Three-Hour Paclitaxel... One-Hour Paclitaxel-Carboplatin... Cooperative Group Trials Alternative Schedules Novel Paclitaxel Combinations Locally Advanced NSCLC: The... Carboplatin-Paclitaxel-RT... Cisplatin-Paclitaxel RT... Earlier-Stage Disease Small Cell Carcinoma of... References

 

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