• Phase II trial;
  • gemcitabine;
  • docetaxel;
  • nonsmall cell lung carcinoma;
  • toxicity;
  • survival


  1. Top of page
  2. Abstract


The goals of the current study were to determine the safety and efficacy of a nonplatinum-containing doublet, gemcitabine and docetaxel, in the treatment of patients with chemotherapy-naive nonsmall cell lung carcinoma (NSCLC).


Thirty-two patients with advanced, chemotherapy-naive NSCLC were treated with gemcitabine (1000 mg/m2) and docetaxel (40 mg/m2) administered on Days 1 and 8 every 21 days. All patients were evaluable for toxicity and survival and 27 patients were evaluable for response.


This combination was extremely well tolerated with Grade 3 or 4 neutropenia occurring in 6 of 32 patients (19%) (grading was based on the National Cancer Institute Common Toxicity Criteria). There were two episodes of Grade 3 thrombocytopenia and no episodes of Grade 3 or 4 anemia. Grade 3 or 4 nonhematologic toxicities included nausea (occurring in 1 of 32 patients), diarrhea (occurring in 1 of 32 patients), fatigue (occurring in 10 of 32 patients), fluid retention (occurring in 2 of 32 patients), anorexia (occurring in 4 of 32 patients), and transaminitis (occurring in 2 of 32 patients). Six patients experienced Grade 3 pneumonitis that was at least possibly related to the combination of gemcitabine and docetaxel. There was 1 complete response and 7 partial responses for an overall response rate of 30%. The 1-year and median survivals were 35% and 7.9 months, respectively.


In the current study, the regimen of gemcitabine (1000 mg/m2) and docetaxel (40 mg/m2) administered on Days 1 and 8 every 21 days was well tolerated with manageable hematologic and nonhematologic toxicities. The responses were comparable to those achieved with platinum-based combination chemotherapy and the 2-year survival was an encouraging 19%. These data would support the further study of this nonplatinum doublet in patients with advanced NSCLC. Cancer 2002;95:1714–19. © 2002 American Cancer Society.

DOI 10.1002/cncr.10843

Lung carcinoma is the leading cause of cancer-related deaths in the U.S. and worldwide, accounting for 28% of all cancer deaths. It is predicted that for the year 2001, an estimated 184,600 new patients will be diagnosed with lung carcinoma and there will be 157,400 deaths from the disease in the U.S.1 It has been well established that cisplatin-based chemotherapy confers an improvement in overall survival compared with best supportive care and is an effective palliative treatment in patients with advanced nonsmall cell lung carcinoma (NSCLC).2, 3 In the late 1990s, a number of studies demonstrated that combination chemotherapy that added a newer chemotherapy agent (gemcitabine,4 vinorelbine,5 and paclitaxel6) to cisplatin offered a survival advantage over cisplatin alone. In a large-scale randomized Phase III study (Eastern Cooperative Oncology Group [ECOG] Study 1594), 1207 previously untreated patients with Stage IIIB NSCLC (according to the TNM staging system) with pleural or pericardial effusion or those with Stage IV NSCLC were randomized to 1 of 4 chemotherapy regimens that were comprised of 2 drugs: cisplatin and paclitaxel, cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel.7 No qualitative differences in outcome were observed for patients with Stage IIIB versus those with Stage IV disease. For all eligible patients, the median survival was 7.8 months, 8.1 months, 7.4 months, and 8.1 months, respectively, for the 4 treatment groups listed. The 1-year survival rate was 31%, 36%, 31%, and 34%, respectively, for each treatment group. The overall response rates were 21%, 22%, 17%, and 17%, respectively. The median time to disease progression was 3.4 months, 4.2 months, 3.7 months, and 3.1 months, respectively. This study concluded that there was no significant difference with regard to the primary endpoint of survival among the treatment groups. Compared with historic controls, these four newer chemotherapy regimens, which commonly are used in the U.S. and Europe, may offer a modest but clinically significant survival advantage. These data further reinforce the issue that there currently is no standard front-line regimen for the treatment of patients with Stage IV NSCLC. However, the majority of responses in NSCLC patients, even those achieved after combination chemotherapy, are partial responses and typically are of relatively short duration. In addition, neurotoxicity has been cumulative and disabling after the prolonged administration of paclitaxel, platinums, and vinca alkaloids. Therefore, it is highly desirable to identify treatments that are active with reduced toxicity.

We performed a Phase I study that evaluated the combination of gemcitabine and docetaxel administered together weekly on Days 1 and 8 every 21 days and found it to be a well tolerated regimen with a favorable myelosuppression profile and manageable nonhematologic toxicities.8 We evaluated the sequence of administration and did not find the sequence of the agents used to have any significant effect on the toxicity or pharmacokinetics of this regimen. In the patients who had received ≥ 2 prior chemotherapy regimens, the maximum tolerated dose (MTD) was 800 mg/m2 for gemcitabine and 40 mg/m2 for docetaxel, whereas the minimally pretreated patients (≤ 2 prior chemotherapy regimens) tolerated a higher dose of gemcitabine with an MTD of 1250 mg/m2 and an MTD for docetaxel of 40 mg/m2. We ultimately chose dose Level 3 of this Phase I study (gemcitabine at a dose of 1000 mg/m2 and docetaxel at a dose of 40 mg/m2) for this Phase II study.


  1. Top of page
  2. Abstract

Patient Selection

Inclusion criteria for the current study included patients who 1) had histologically or cytologically confirmed Stage IIIB disease (with malignant pleural effusion), Stage IV disease, or recurrent NSCLC; measurable disease (defined as any mass reproducibly measurable in 2 perpendicular dimensions by physical examination, X-ray, computed tomography [CT] scan, or magnetic resonance imaging [MRI] scan); 2) were age ≥ 18 years; 3) had an ECOG performance status (PS) of 0–2; 4) had adequate hematologic, hepatic, and renal function; and 5) had a negative pregnancy test and used effective means of contraception. Exclusion criteria included patients who had received prior chemotherapy for advanced or metastatic NSCLC or who had brain metastases (unless treated and clinically stable). Signed informed consent was obtained from all patients, and the Georgetown University Institutional Review Board approved the clinical protocol.

Treatment Plan

The purpose of this Phase II study was to evaluate a new combination chemotherapy regimen for the treatment of patients with advanced, chemotherapy-naive NSCLC. Patients received gemcitabine, 1000 mg/m2, and docetaxel, 40 mg/m2, on Days 1 and 8 every 21 days. Both gemcitabine and docetaxel were administered intravenously. Gemcitabine was administered over 30 minutes and was followed immediately by docetaxel, which was administered over 30 minutes. Treatment was administered on an outpatient basis. Premedication with 8 mg of dexamethasone was initiated 12 hours prior to each docetaxel infusion and continued every 12 hours for 4 doses. Patients were restaged every two cycles and continued to receive treatment if stable or responsive disease was observed. Patients were evaluated for response, survival, and toxicity. The study was conducted at Georgetown University Medical Center and within the Lombardi Extramural Consortium.

Patients were seen prior to the study and every 3 weeks before each subsequent cycle of chemotherapy. Standard laboratory tests, which included complete blood counts and a chemistry survey, were followed serially during the study. Imaging studies to evaluate possible tumor response were performed after every two cycles of treatment.

Dosage Schedule, Definition of Dose-Limiting Toxicity, and Dose Modification

In the current study, the dose-limiting toxicity (DLT) was defined as any Grade 3 toxicity (using the National Cancer Institute Common Toxicity Criteria) with the exception of myelosuppression. Dose-limiting myelosuppression was defined as Grade 4 myelosuppression (anemia, thrombocytopenia, neutropenia, or leukopenia) of ≥ 1-week duration or Grade 3/4 myelosuppression observed by Day 8 of each cycle. Patients in whom treatment was delayed due to Grade 3/4 myelosuppression were retreated with 75% of both the gemcitabine and docetaxel doses once hematologic toxicity had resolved to baseline eligibility requirements. Patients were allowed to receive granulocyte–colony-stimulating factor (G-CSF) after each cycle at the discretion of the investigator; however, G-CSF was not used routinely.


  1. Top of page
  2. Abstract

Patient Characteristics

A total of 32 patients were treated in the current study. Twenty-one men (66%) and 11 women (34%) were entered onto the study, and they ranged in age from 47–83 years. The majority of the patients treated in the current study had an ECOG PS of 0–1 (91%). Patient characteristics are shown in Table 1. All patients were evaluable for toxicity, and 27 patients completed 2 cycles of treatment and therefore were evaluable for response.

Table 1. Patient Characteristics
CategoryAll patients (n = 32)
  1. ECOG: Eastern Cooperative Oncology Group; PS: performance status.

Gender, no. (%) 
 Male21 (66)
 Female11 (34)
Age (yrs) 
ECOG PS (%) 
 06 (19)
 123 (72)
 23 (9)
Previous therapy 
 Radiation therapy15

Adverse Events

Patients were treated for a median of 3.85 cycles of chemotherapy (range, 0.5–8 cycles). Treatment delays occurred in 12 of the 32 patients and dose reductions were required in 4 patients. The reasons for treatment delays and dose reductions (primarily hematologic toxicities or fatigue) are shown in Table 2. The toxicities in the current study that were believed to be “possibly, probably, or definitely” related to gemcitabine and docetaxel are shown in Table 3.

Table 2. Treatment Summary
CategoryAll patients (n = 32)
Median no. of cycles (range)3.85 (0.5–8)
Treatment delays12
 Grade 3 fatigue4
 Grade 3/4 neutropenia3
 Grade 2 neutropenia/leukopenia3
 Grade 2 hypersensitivity reaction2
 Grade 2 thrombocytopenia1
Dose reductions4
 Grade 4 leukopenia1
 Grade 3 neutropenia > 1 wk1
 Grade 3 transaminitis1
 Grade 3 fatigue1
Table 3. Summary of Adverse Events
Adverse eventAll patientsa (n = 32)Worst toxicity gradeb
  • a

    Each patient was counted once for each adverse event and assigned the worst toxicity grade that was reported for that patient during the study. Treatment-related events were considered to be possibly, probably, or definitely related to treatment.

  • b

    National Cancer Institute Common Toxicity Criteria, Version 2.0, was used to grade adverse events.

 Granulocytopenia18 7533
 Leukopenia12 4314
 Thrombocytopenia12 7320
 Anemia10 7300
 Fatigue24 113100
 Anorexia15 7440
 Nausea13 9310
 Fluid retention12 8220
 Transaminitis12 8220
 Diarrhea10 6310
 Myalgias6 6000
 Pneumonitis6 0060
 Peripheral neuropathy4 0400

Significant myelosuppression was observed in a minority of patients with Grade 3 or 4 granulocytopenia, and was reported to occur in 6 of 32 patients (19%). G-CSF was not used routinely in the current study. Grade 3 thrombocytopenia was observed in 2 of the 32 patients and no Grade 3 or 4 anemia was observed. Fatigue was observed in 75% of the patients in the current study (24 of 32 patients) although it typically was mild in the majority of patients. Ten patients (31%) experienced Grade 3 fatigue, 4 of whom required treatment delay. There were no cases of Grade 4 fatigue reported. Fluid retention occurred in 12 of the 32 study patients (38%) and also was typically mild with only 2 cases of Grade 3 fluid retention reported (6%). Other toxicities included transaminitis, diarrhea, myalgia, and peripheral neuropathy; these toxicities also were mild to moderate and infrequent, and did not require intervention. One patient with Grade 3 transaminitis did require a dose reduction.

Six of 32 patients (19%) experienced symptoms and signs suggestive of hypersensitivity pneumonitis with bilateral pulmonary infiltrates, worsening respiratory distress, and hypoxia without evidence of progressive disease or infection. None of the patients who developed symptoms suggestive of treatment-related pneumonitis were continued on the current study. In some cases there was an elevation in temperature. The onset of symptoms and signs typically occurred after two to four cycles of chemotherapy. All patients were treated promptly with corticosteroids with resolution of their pneumonitis; there were no fatal cases of pneumonitis reported. It is interesting to note that five of the six patients who developed treatment-related pneumonitis previously had received chest/mediastinal radiation therapy for their NSCLC, suggesting a possible interaction with prior radiation therapy.

Responses and Survival

One of 27 evaluable patients achieved a complete response and 7 of the 27 patients achieved a partial response for an overall response rate of 30%. Ten patients (37%) had stable disease and 9 patients (33%) were found to have progressive disease. The median survival time was 241 days (7.9 months) and the 1-year, 2-year, and 3-year survival rates were 35%, 19%, and 6%, respectively (Fig. 1).

thumbnail image

Figure 1. Survival curve. SE: standard error.

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  1. Top of page
  2. Abstract

In the current Phase II study, the combination of gemcitabine (1000 mg/m2) and docetaxel (40 mg/m2), administered on Days 1 and 8 every 21 days was well tolerated without any reported cases of clinically significant fluid retention, myalgia, or neuropathy, and only mild fatigue and myelosuppression. The myelosuppression profile was favorable and Grade 3 or 4 neutropenia was observed in only 19% of patients. Only 2 of the 32 study patients (6%) experienced Grade 3 thrombocytopenia and no Grade 3 or 4 anemia was reported. Fatigue was observed in the majority of patients (24 of 32 patients [75%]), but it typically was mild to moderate, with no Grade 4 fatigue reported. Ten patients experienced Grade 3 fatigue, 4 of whom required a delay in treatment. Fluid retention occurred in 12 of the 32 patients and also was typically mild with only 2 cases of Grade 3 fluid retention reported. Other infrequent and manageable toxicities included transaminitis, diarrhea, myalgia, and peripheral neuropathy. One patient required a dose reduction for Grade 3 transaminitis.

It is important to address the risk of pneumonitis with the use of gemcitabine and docetaxel because this combination is emerging as an active treatment in a variety of solid tumors, including NSCLC. Gemcitabine structurally resembles cytarabine, which has been associated with noncardiogenic pulmonary edema.9 Gemcitabine has been reported to produce a mild and self-limited dyspnea in 5–8% of patients who are treated with it, although more severe pneumonitis and life-threatening pulmonary complications have been observed in only a minority of patients.10 Docetaxel has been associated with cumulative dose-dependent fluid retention,11 which is characterized by peripheral edema, pleural effusions, and ascites, although the risk of fluid retention is reduced significantly by steroid premedication. Hypersensitivity pneumonitis has been described only rarely.12, 13 The combination of gemcitabine and docetaxel has been studied in a number of different schedules of administration and pneumonitis has been observed in a minority of patients. The majority of published studies do not report any increase in pulmonary toxicity, although gemcitabine and docetaxel-related,14, 15 as well as gemcitabine and paclitaxel-16 related pneumonitis has been observed and reported. It is interesting to note that five of the six patients in the current study who developed treatment-related pneumonitis had received prior radiation therapy to the chest and mediastinum for NSCLC. This would suggest that there might be a predisposition to developing pneumonitis in patients who receive prior radiation therapy. The pneumonitis that developed typically occurred two to four cycles after the initiation of treatment; however, in two of the six patients, the pneumonitis did not become apparent until the fifth or sixth cycle of therapy. The pneumonitis responded well to corticosteroid therapy and a full recovery was observed in all six patients. Our approach to the potential toxicity of the gemcitabine and docetaxel combination would be to evaluate patients carefully for any deterioration in respiratory status that was not attributable to infection or progressive disease as a possible case of pneumonitis, particularly in those patients who received prior radiation. If the clinical picture were consistent with a possible pneumonitis, we would recommend discontinuing treatment with gemcitabine and docetaxel and initiating treatment with a tapering course of corticosteroids.

Other investigators have performed Phase II studies with gemcitabine and docetaxel in patients with chemotherapy-naive NSCLC14, 17–20 Response rates have ranged from 30% to 38% and the median survival has been reported to be as long as 13 months. The gemcitabine dosing and schedule in the previously published studies are comparable to those in the current study. In previously published studies, the docetaxel dose typically is given on either Days 1 or 8 (ranging in dosage from 65 to 100 mg/m2) rather than divided on Days 1 and 8 as in the current study. With the higher doses of docetaxel, G-CSF was used whereas at the lower doses (as in the current study), G-CSF was not used routinely. Georgoulias et al. performed a large, randomized Phase II study that compared gemcitabine (1100 mg/m2 on Days 1 and 8) and docetaxel (100 mg/m2 on Day 8) every 3 weeks versus docetaxel (100 mg/m2 on Day 1) and cisplatin (80 mg/m2 on Day 1) every 3 weeks.21 Both arms received G-CSF support. This was a study comprised of 406 patients and no significant differences in response (35% vs. 33%) or median survival (10 months vs. 9.5 months) were observed in the platinum-containing versus the nonplatinum-containing doublet. With G-CSF support, the gemcitabine and docetaxel combination demonstrated manageable myelosuppression with Grade 3 or 4 neutropenia reported to occur in 22% of patients and febrile neutropenia occurring in 11% of patients. The results of the current study provide supportive evidence that a nonplatinum-containing doublet has response and survival rates that are comparable to a more conventional platinum-containing combination regimen.

A combination of gemcitabine (800 mg/m2) and docetaxel (30 mg/m2) given on Days 1, 8, and 15 without G-CSF support has been evaluated in elderly patients or those with a poor PS. The response rate was 27% and the median survival was 7.5 months, with only 11% of patients reported to have Grade 3 or 4 leukopenia. Patients with an ECOG PS of 2 typically do not appear to have a survival benefit with combination chemotherapy. The increased predilection for chemotherapy-related toxicities in these patients may offset any benefit from chemotherapy. Retrospective reviews of prospective, randomized studies of cisplatin-based chemotherapy conducted by cooperative groups have shown that patients with a PS of 2 have a poorer survival. In the ECOG experience with 1960 evaluable patients from 5 trials studying cisplatin-based chemotherapy, a PS of 2 was associated with a statistically lower median survival of 3.3 months compared with 6.4 months in patients with a PS of 1 and 9.4 months in patients with a PS of 0 (P < 0.05).22, 23 The aforementioned limitations in the treatment of patients with an ECOG PS of 2 may be at least partially due to the toxicity of combination chemotherapy. The nonplatinum-containing gemcitabine and docetaxel doublet may be associated with reduced toxicity in this patient population.

We found the dosing and schedule of gemcitabine and docetaxel used in the current study to be active with a response rate of 30% and a median survival time of 241 days (7.9 months). The 1-year, 2-year, and 3-year survival rates were 35%, 19%, and 6%, respectively. These data are encouraging and are in keeping with typical response and survival rates with platinum-based combination chemotherapy. We also found the dosing and schedule used in the current study to be favorable in terms of myelosuppression as well as nonhematologic toxicity. These data merit further study of the combination of gemcitabine and docetaxel in patients with advanced NSCLC.


  1. Top of page
  2. Abstract
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