Phase II trial of weekly paclitaxel and gemcitabine for previously untreated, stage IIIB-IV nonsmall cell lung cancer


  • Informed consent was obtained from the subjects and/or guardians.



The purpose of the current study was to evaluate the efficacy and tolerance of the noncisplatin-based combination of paclitaxel and gemcitabine administered weekly for patients with untreated metastatic nonsmall cell lung cancer (NSCLC).


Patients with Stage IIIB/IV or recurrent NSCLC, a performance status of 0–2, and no prior chemotherapy exposure were eligible. Patients received gemcitabine 1000 mg/m2 and paclitaxel 85 mg/m2 on Days 1, 8, 15, 22, 29, 36 of an 8-week cycle until progression.


Thirty-nine eligible patients were enrolled. The median age was 66 years and 14 patients were ≥70 years old. Performance status was 2 in 13 (33%) and 29 patients (75%) had Stage IV. Five patients (12.8%) developed interstitial pneumonitis and 2 of these were responsive to steroid therapy. The overall response rate was 23.1%, with no complete responses. The median survival was 32 weeks and the 1-year survival was 32%.


This regimen of weekly paclitaxel and gemcitabine has modest activity in advanced NSCLC. Cancer 2006. © 2006 American Cancer Society.

Disseminated lung cancer is the major cause of cancer death in the US.1 Seventy percent of patients with nonsmall cell lung cancer (NSCLC) present with regional or distant disease and a majority of those with apparent limited stages experience recurrence distantly despite aggressive local therapy. Whereas cisplatin-based chemotherapy affects the outcome of systemic disease, median survival rates are modestly improved relative to best supportive care2 and the treatment is associated with substantial toxicity.3 Therefore, both improved activity and reduced toxicity are important attributes for future systemic therapies of NSCLC. One strategy to achieve these goals is to develop alternative noncisplatin-containing combination therapies using newer, and potentially more effective, agents. Paclitaxel and gemcitabine are reasonable candidates.

Paclitaxel has demonstrated substantial activity in advanced NSCLC. Single-agent treatment with a conventional 21-day schedule of administration has yielded response rates of 21% to 24% and 1-year survivals of 38% to 42%,4, 5 results comparable to combination treatment. Furthermore, paclitaxel compared with etoposide in cisplatin-based therapy yielded statistically superior rates of response and overall survival in a randomized trial of NSCLC.6 Despite these favorable results, the optimal dose, schedule, or combination of paclitaxel remains to be determined.

The Brown University Oncology Group developed a schedule of weekly paclitaxel administration to take advantage of its radiosensitizing and cell cycle-specific properties, which resulted in greater dose intensity and relatively less toxicity.7, 8 A Phase II trial at a maximum tolerated dose of 175 mg/m2/week for 6 of 8 week cycles achieved a 56% response rate and 1-year survival of 53% for Stage IIIB-IV NSCLC.9 Neuropathy occurred with increasing frequency and severity with cumulative dose, but became nonprogressive when patients received a 50% dose reduction for subsequent cycles.8 A similar, high-dose weekly study by the Cancer and Leukemia Group B (CALGB) achieved a comparable outcome with a 42% response rate and 2-year survival of 26%.10 It is unclear whether the greater frequency of weekly dosing or rapid administration of high doses was the greater contributor to this schedule's activity because a more moderately dosed, weekly schedule of paclitaxel at 85 mg/m2 has shown substantial activity in NSCLC.11

Gemcitabine, a novel deoxycytidine analog with properties similar to cytarabine,12 has a modest toxicity profile and notable activity in NSCLC. The combination of gemcitabine and cisplatin yielded improved response and survival compared with monotherapy with cisplatin.13 In addition, salvage therapy with gemcitabine achieved a response rate in previously treated patients with NSCLC14 that were similar to historical rates with docetaxel in the same setting. Taken together, these data with gemcitabine suggest broad activity and a degree of noncross-resistance with many of the agents used in the treatment of NSCLC.

We chose to study gemcitabine and paclitaxel as a noncisplatin doublet in NSCLC because of their demonstrated activity in NSCLC, their mild and relatively nonoverlapping toxicity profiles, and for their complementary weekly schedules of administration. The moderate-dose weekly schedule of paclitaxel was chosen as the base of this combination to lessen neurologic and hematologic toxicity. In addition, prior evaluation with this weekly schedule of paclitaxel has demonstrated platelet-sparing properties15, 16 and it was anticipated that this feature in combination therapy could mitigate thrombocytopenia associated with gemcitabine.


Eligibility Criteria

Eligibility requirements specified that the patients must have had histologically or cytologically documented NSCLC, a performance status (PS) of 0–2, an interval >2 weeks from the completion of radiation, measurable disease, and adequate organ function (granulocytes >1500/μL, hemoglobin >9 gm/dL, platelets >100,000/μL, serum glutamic oxaloacetic transaminase [SGOT] < twice the upper limit of institutional normal, and bilirubin <1.5 mg/dL). Stages were limited to Stage IIIB, Stage IV, or recurrent NSCLC. Central nervous system metastases were allowed only if previously treated and steroids had been discontinued for at least 1 week. No prior systemic therapy for metastatic disease was allowed. Previous malignancy was allowed if it was inactive after a disease-free interval of 1 year or consisted of nonmelanoma skin cancer. Institutional Human Subjects Committee standards were followed and written, informed consent was obtained before patient enrollment. Data audit of participating institutions was performed yearly by the Brown University Oncology Group Audit Committee.


Paclitaxel 85 mg/m2 was administered intravenously by 1-hour infusion, followed by gemcitabine 1000 mg/m2 intravenously (i.v.) over 30 minutes on a weekly schedule for 6 consecutive weeks followed by a 2-week rest without treatment. All patients received premedications consisting of diphenhydramine 25 mg i.v., ranitidine 50 mg i.v., and dexamethasone 20 mg orally given at bedtime on the day before and on the morning of chemotherapy infusion. This dose was decreased to 8 mg at the investigator's discretion on the second and subsequent cycles. The treatment was continued until the appearance of progressive disease.

Chemotherapy doses were modified on the day of treatment for toxicity. A complete blood count (CBC) and toxicity assessment were performed weekly during treatment. If the absolute neutrophil count was <1500/μL or platelets <75,000/μL, then paclitaxel was omitted for that day of treatment. Gemcitabine was given at 50% of the planned dose if there was an absolute neutrophil count <1500/μL or platelets <75,000/μL and omitted if the absolute neutrophil count <1000/μL or platelets <50,000/μL. Full doses were given on the next scheduled date of administration if the blood counts had returned to normal. Missed and omitted doses were not made up at a later date.

For neurologic toxicity, doses were adjusted for toxicity exceeding Common Toxicity Criteria (CTC) version 2 Grade 1. For Grade 2 toxicity, paclitaxel was reduced by 50%. This reduction was permanent for future doses and no retreatment at initial dose was allowed even if toxicity abated. For Grade 3–4 neurotoxicity on the day of treatment, paclitaxel was omitted. If the toxicity improved to Grade 2 or less, the paclitaxel was reinstituted at 50% of the original dose for all future doses. Gemcitabine was not reduced for neurologic toxicity.

Treatment was discontinued if a skin rash or anaphylaxis developed during treatment. A rechallenge of paclitaxel on the following week using double doses of dexamethasone and diphenhydramine and a decreased infusion rate of paclitaxel was allowed. For other Grade 3–4 toxicity, doses of both agents were held until recovery and reinstated at 75% of original dose.

Responses were evaluated at the end of each 8-week cycle. A complete response was defined as the resolution of all evaluable and measurable disease. A partial response was defined as a 50% decrease in the sum of the products of the biperpendicular diameters of any tumor masses reproducibly measured by chest X-ray, computed tomography (CT) scan, or magnetic resonance imaging (MRI) when compared with pretreatment measurements.

The primary objective of this trial was to determine if the response rate of weekly paclitaxel and gemcitabine in advanced NSCLC could exceed 50%. A 95% upper 1-sided confidence interval (normal theory method) was constructed for the observed response rate. Forty eligible patients were required to detect a difference in response rate between 30% and 50% with 80% power and P < .05. Survival was calculated by the Kaplan–Meier method.17


A total of 41 patients were enrolled in the trial from January 29, 1999 to September 7, 2000. Two patients were found ineligible due to incorrect pathology (melanoma) in 1 and ineligible liver enzymes in another. The characteristics of the remaining 39 patients are listed in Table 1. The median age was 66 (range, 44–86 years). There were 14 patients who were ≥70 years of age. Fully one-third of patients had PS 2, whereas the remaining two-thirds had PS 0–1. The majority of patients had adenocarcinoma, 1 had large cell carcinoma, 5 had squamous cell carcinoma, and 6 had NSCLC, not otherwise specified.

Table 1. Patient Characteristics
  1. ECOG, Eastern Cooperative Oncology Group.

Median age, y (range)66 (44–86)
Sex (%)
 Male23 (59)
 Female16 (41)
ECOG performance status (%)
 (0)14 (37)
 One (1)12 (30)
 Two (2)13 (33)
Stage (%)
 IIIB10 (25)
 IV29 (75)
Histology (%)
 Adenocarcinoma27 (69)
 Other12 (31)

Twenty-nine patients received the first full 8-week course of treatment. A second, third, and fourth cycle were administered to 13, 7, and 2 patients, respectively. One patient went on to receive 6 courses. The percent of delivered dose for the first 3 cycles was constant at 84% each cycle. The missed doses were due to scheduled dose reductions for relative neutropenia on the day of treatment.

Ten patients did not complete their first 8-week course of treatment as planned. One patient had an allergic reaction to paclitaxel on the first day and 1 had an allergic reaction to gemcitabine on the fourth dose. Two patients had an exacerbation of preexisting cardiac disease and were taken off protocol. Two patients had thrombotic events, 1 was preexisting. One refused further treatment and 1 had rapid progression of disease. Two further patients had pulmonary complications. With the exception of the latter 2 patients, described below, these discontinuations were attributed by the treating physicians as complications of comorbid conditions, disease progression, or drug allergy.

Overall, treatment-related toxicity was relatively modest (Table 2). Hematologic toxicities were the most common, but Grade 3–4 neutropenia occurred in only 20.5%. There were no episodes of febrile neutropenia. Grade 3–4 nonhematologic toxicities were less than 10% in all cases with the exception of pulmonary toxicity.

Table 2. Toxicity*
WHO Grade1234
  • *

    Numbers in parentheses are a percentage.

Anemia8 (20.5)7 (17.9)(8)0
Neutropenia4 (10)4 (10)5 (13)3 (7.7)
Thrombocytopenia12 (28.2)2 (5.1)1 (2.5)0
Nausea/vomiting3 (7.7)1 (2.5)1 (2.5)0
Alopecia04 (10.3)00
Neurotoxicity2 (5.1)1 (2.5)2 (5.1)0
Myalgia/arthralgia3 (7.7)000
Fatigue3 (7.7)3 (7.7)00
Hyperglycemia5 (12.8)3 (7.7)2 (5.1)0
Pulmonary1 (2.5)1 (2.5)2 (5.1)2 (5.1)
Cutaneous2 (5.1)000
Fever2 (5.1)3 (7.7)00

Pulmonary toxicity was potentially more frequent than expected. Five patients developed bilateral interstitial pneumonitis. Three occurred during the first cycle, another during the third cycle, and the fifth during the sixth cycle. All patients were treated with antibiotics, although no episodes of bacteremia were documented. A decrease in size of the primary tumor mass was noted in 2 patients and a borderline increase in another. Bronchoscopy was performed in 3 patients, but was nondiagnostic of a causative etiology. Three patients were treated with steroids acutely and 2 demonstrated rapid improvement in their clinical condition. These 2 patients appeared to have therapy-induced, steroid-responsive pneumonitis. Their condition stabilized and they received no further protocol chemotherapy. Two additional patients received steroids in the terminal phases of their pneumonitis and were not benefited. It was unclear if the events of pneumonitis that were not steroid-responsive were due to tumor progression, infection, or drug hypersensitivity that was primarily refractory to steroids or refractory due to late institution.

Partial responses were seen in 9 of 39 eligible patients and there were no complete responses for an overall response rate of 23.1% (95% confidence interval 9.9–36.3%). There were 10 patients (25.6%) with progression and 12 patients (35.8%) with stable disease. Nine patients who were not evaluated for response due to early study withdrawal for toxicity or physician-patient choice were categorized as nonresponders for calculation of response rate.

The median progression-free survival was 11.8 weeks. The median survival for eligible patients was 32.0 weeks. The 1-year survival was 32%. The survival based on PS was 51.1 weeks for PS = 0, 31.4 weeks for PS = 1, and 10.7 weeks for PS = 2.


The goal of palliative chemotherapy is to alleviate symptoms with maximum frequency and minimum side effects. The noncisplatin-containing combination of gemcitabine and paclitaxel used in this trial did not meet this goal due to a high dropout rate of patients during the first 8 weeks of therapy and by failing to achieve the optimistic rate of response (50%) defined a priori. Poor performance status, comorbidity, and toxicity were contributing factors.

The 1-year survival of 32% and response rate of 23% from this multi-institutional trial in metastatic NSCLC reflect both the intrinsic activity of the chemotherapy and patient factors. Because the toxicity of this regimen was perceived by the physicians enrolling in this trial as modest and tolerable for patients with low PS, 33% of patients enrolled in this study had PS = 2. Their median survival was only 10.7 weeks compared with 51.1 and 31.4 weeks for patients with PS = 0 or 1, respectively. Despite the large fraction of patients with PS = 2 enrolled to this trial, their exclusion still limits the median survival of the remaining patients with good PS between 31–51 weeks, parameters that do not support high activity. It remains to be determined how patients with PS = 2 should be treated: best supportive care, single-agent, nonplatinum doublets, or more aggressive, platinum-containing therapy.

Whereas the activity observed in this trial is modest, it is noteworthy that the combination of gemcitabine and paclitaxel has been shown in large randomized trials to have activity in advanced NSCLC that is not dissimilar from other platinum-based doublets including paclitaxel/carboplatin,18 paclitaxel/cisplatin,19 or gemcitabine/cisplatin.19 Both patient selection and/or schedule differences may account for the apparent improved activity noted in these randomized trials.

Overall, the treatment was reasonably tolerated, with the potential exception of pulmonary toxicity. There were 5 (12.8%) patients who developed bilateral interstitial infiltrates during the course of treatment and 2 of 3 of these patients who had early institution of steroids demonstrated a rapid improvement in radiographic and clinical condition. It is unclear if the earlier institution of steroids in the remaining 2 patients would have affected their outcome because their etiologies were never determined. Paclitaxel or gemcitabine are infrequently associated with drug-induced pneumonitis, but the combination of a taxane with gemcitabine appears to increase the rate. In 4 studies of this combination in lung cancer,20–23 interstitial pneumonitis occurred in 16 (13.3%) of 120 patients. Because a fraction of these may be due to steroid-responsive hypersensitivity reactions, it is strongly recommended that early institution of steroids be considered in the setting of pneumonitis with these agents.

The combination of weekly paclitaxel and gemcitabine has modest activity in advanced NSCLC and did not meet the desired level of response prospectively defined in this trial. Furthermore, adjustment for accrual of patients with poor performance status did not identify a population of patients who showed a survival advantage. Finally, the rate of pneumonitis was more frequent than we anticipated. For these reasons, we have chosen to not explore this schedule of this combination further for the treatment of advanced NSCLC.