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Keywords:

  • chemotherapy;
  • docetaxel;
  • gemcitabine;
  • small cell lung carcinoma

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

The goal of the current study was to evaluate the feasibility, toxicity, and efficacy of a novel combination of weekly docetaxel and gemcitabine for elderly patients and patients with poor performance status who had advanced-stage small cell lung carcinoma (SCLC).

METHODS

Previously untreated patients with advanced-stage SCLC were eligible for the current clinical trial. In addition, patients were required to be age > 65 years or to have poor performance status (Eastern Cooperative Oncology Group 2). All patients received 800 mg/m2 gemcitabine and 30 mg/m2 docetaxel intravenously on Days 1, 8, and 15. Courses were repeated at 28-day intervals.

RESULTS

Forty patients were enrolled in the current multicenter, community-based trial. Nine patients (23%) had partial responses to treatment. The median survival for the entire group was 4 months. Fourteen percent of patients were alive at 1 year. Myelosuppression was mild to moderate, with no episodes of neutropenia and fever. Grade 3/4 fatigue (25%) was the only common nonhematologic toxicity.

CONCLUSIONS

Although relatively well tolerated, the weekly regimen of gemcitabine and docetaxel possessed only modest activity in this group of patients with unfavorable prognosis. The regimen offered no potential advantages over standard treatment approaches and is not recommended for further development. Cancer 2004. © 2004 American Cancer Society.

The treatment of patients with advanced-stage small cell lung carcinoma (SCLC) remains difficult. In spite of the initial sensitivity of this malignancy to combination chemotherapy, disease recurrence and rapid progression occur in these patients, and second-line treatments typically are ineffective. Standard therapy with a platinum/etoposide regimen produces median survivals in the range of 8–9 months.1–3 In a recent randomized trial, treatment with a combination of cisplatin and irinotecan resulted in a median survival of 12.8 months and proved superior to the combination of cisplatin and etoposide.4 Results of that trial await confirmation.

A substantial percentage of patients with advanced-stage SCLC have poor performance status at the time of diagnosis or are elderly and have significant coexisting conditions. Even with treatment, the median survival is only 3–4 months for patients with poor performance status. These patients usually tolerate cisplatin-based regimens poorly. However, combination therapy with carboplatin and etoposide has proven to be more effective than single-agent etoposide.5, 6

Several of the newer antineoplastic agents, including taxanes, topoisomerase I inhibitors, and gemcitabine, have demonstrated single-agent activity in patients with advanced-stage SCLC.7–10 Gemcitabine and the taxanes, when administered weekly, have relatively favorable toxicity profiles in elderly patients.11–13 A recent study demonstrated that a weekly combination of docetaxel and gemcitabine was well tolerated and effective in the treatment of elderly patients and patients with poor performance status who had advanced-stage nonsmall cell lung carcinoma (NSCLC).14

In the current Phase II trial, we evaluated the efficacy and toxicity of a weekly regimen of docetaxel and gemcitabine as first-line treatment for elderly patients and patients with poor performance status who had advanced-stage SCLC. The trial was performed within the Minnie Pearl Cancer Research Network, a multicenter, community-based clinical trials group.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Eligibility

Patients were eligible for the trial if they had biopsy-proven SCLC and advanced-stage disease using standard staging criteria for SCLC. In addition, patients were required to be age > 65 years, have an Eastern Cooperative Oncology Group performance status of 2 (ECOG 2), or be a poor candidate for platinum-based chemotherapy due to a coexisting medical condition. No previous treatment with chemotherapy or radiotherapy was allowed. Patients with parenchymal brain metastases were eligible as long as they met other entry criteria. Additional entry criteria included adequate bone marrow function (absolute neutrophil count [ANC] > 1000/μL and platelet count > 100,000/μL), adequate liver function (normal bilirubin levels and transaminase levels < 2.5 times the upper limit of normal [ULN]), adequate renal function (serum creatinine levels ≤ 2.0 mg/dL), the absence of any other active neoplasms, and the absence of any preexisting Grade ≥ 3 neuropathy. Written informed consent was obtained from all patients before they joined the trial. The trial was approved by the institutional review board at Centennial Medical Center (Nashville, TN) and by the institutional review boards of all participating Minnie Pearl Cancer Research Network sites.

Pretreatment Evaluation

Patients underwent routine staging procedures according to the guidelines for SCLC. For all patients, complete histories were acquired, physical examinations were performed, and complete blood counts, chemistry profiles, and chest X-rays were obtained. In addition, all patients received computed tomographic scans of the head, chest, and abdomen, as well as radionuclide bone scans. Blood counts and chemistry tests were performed within 7 days of the start of treatment, and staging procedures were performed within 21 days of treatment initiation.

Treatment

Patients received 800 mg/m2 gemcitabine administered by 30-minute intravenous (i.v.) infusion followed by 30 mg/m2 docetaxel administered by 30-minute i.v. infusion on Days 1, 8, and 15. Treatment courses were repeated at 28-day intervals. Premedication before each dose of docetaxel included 8 mg dexamethasone orally on the morning of treatment, 8–10 mg dexamethasone orally or i.v. 30 minutes before docetaxel infusion, and 8 mg dexamethasone orally on the evening after treatment. Patients with brain metastases at the time of initial staging were allowed to receive whole-brain irradiation concurrently with the initiation of chemotherapy.

Patients were evaluated for response to treatment after completing 2 courses (8 weeks) of chemotherapy. Patients who had objective responses or stable disease at this time continued treatment courses for six cycles or until disease progression occurred.

Dose modifications were made with respect to both gemcitabine and docetaxel based on blood counts obtained on the scheduled day of treatment. Full doses for both drugs were administered if the ANC was > 1000/μL and the platelet count was > 100,000/μL. If the ANC was 500–1000/μL or the platelet count was 75,000–100,000/μL, a 75% dose of gemcitabine was administered along with full-dose docetaxel. Administration of both drugs was halted if the ANC was < 500/μL or if the platelet count was < 75,000/μL. If blood counts were inadequate on Day 1 of a scheduled treatment course, the beginning of the treatment course was delayed for ≤ 2 weeks. If omission of a dose on Day 8 or Day 15 was necessary, then this dose was not administered at a later date but rather omitted, with the length of the treatment cycle remaining constant at 28 days.

Patients who required hospitalization for treatment of neutropenia and fever received 75% doses of gemcitabine during subsequent courses, while the docetaxel doses remained at 100% intensity. The decision to continue administering full doses of docetaxel while reducing the gemcitabine dose was based on our previous experience with weekly docetaxel as a single agent. In elderly patients with advanced NSCLC, weekly docetaxel doses of 36 mg/m2 caused Grade 3/4 neutropenia in < 5% of all treatment courses.11 Although the use of cytokines was not a scheduled part of the current study regimen, administration of cytokines after an episode of neutropenia and fever was left to the discretion of the treating physician. However, cytokines could not take the place of a protocol-mandated dose reduction.

Liver function tests were monitored monthly in patients receiving weekly docetaxel and gemcitabine. Dosing of docetaxel was omitted if bilirubin levels increased above the ULN or if either alkaline phosphatase or transaminase levels were > 5 × the ULN. If other Grade 3/4 nonhematologic toxicity developed, treatment was withheld until the toxicity improved to better than Grade 2, after which further doses of the agent or agents were administered at 75% intensity.

Evaluation of Response

After the completion of two courses of chemotherapy, patients were reevaluated by repeating all scans and tests that had revealed abnormal results at study entry. Response categories were assigned using standard World Health Organization definitions. A complete response required the total disappearance of all clinically and radiologically detectable disease for ≥ 4 weeks. A partial response required reduction by ≥ 50% in the size of all evaluable lesions as measured by the products of the longest perpendicular tumor diameters, with no new lesions appearing for ≥ 4 weeks. Stable disease was defined as a reduction of < 50% or an increase of < 25% in lesion size, with no new lesions appearing. Patients with progressive disease experienced an increase of ≥ 25% in existing lesion size or the appearance of new lesions.

Overall survival was measured from the first day of treatment until death. All patients who received at least one dose of treatment were included in the toxicity analysis. Actuarial survival curves were constructed using the Kaplan–Meier method.15

The current nonrandomized Phase II study was designed to assess the feasibility, toxicity, and efficacy of this novel chemotherapy program for elderly patients and patients with poor performance status who had advanced-stage SCLC. The study was designed to accrue 40 patients, a number considered sufficient to adequately define the toxicity profile and to provide an estimate of the response rate within confidence limits of ±8%.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Characteristics

Between July 2000 and June 2002, 40 patients entered the current multicenter, community-based trial. Patients were entered by 15 participating sites in the Minnie Pearl Cancer Research Network. Patient characteristics are detailed in Table 1. The median age of the patient cohort was 72 years, and the majority of patients (60%) were male. In addition, 18 patients (45%) had poor performance status (ECOG 2). At the time of study entry, 22 patients (55%) had liver metastases, while 5 (13%) had brain metastases.

Table 1. Patient Characteristics (n = 40)
CharacteristicNo. of patients (%)
  1. ECOG: Eastern Cooperative Oncology Group.

Median age in yrs (range)72 (56–88)
Gender 
 Male24 (60)
 Female16 (40)
ECOG performance status 
 08 (20)
 114 (35)
 218 (45)
No. of metastatic sites 
 17 (18)
 215 (37)
 > 218 (45)
Site of treatment 
 Sarah Cannon Cancer Center (Nashville, TN)17 (43)
 Other network site23 (57)

Treatment Received

A combined total of 104 courses of treatment were administered to 40 patients. A median of 2.5 courses was received by each patient (range, 0–7 courses). Table 2 summarizes the treatment received by these 40 patients. Of the 40 patients, 29 (73%) received 2 courses (8 weeks) of treatment and were evaluated for response. Four patients had evidence of rapid tumor progression before completing two courses of treatment and were categorized as nonresponders. Seven additional patients did not complete two courses of treatment and were unevaluable for response (Table 2).

Table 2. Treatment Data
 No. of patients (%)
Total patients enrolled40
Evaluable patients (received ≥ 2 courses)29 (73)
Patients with rapid tumor progression before completion of two courses 4 (10)
Inevaluable patients 7 (17)
 Intercurrent illness4
 Treatment-related toxicity2
 Poor compliance1

The percentages of the planned docetaxel and gemcitabine doses actually administered were evaluated for the 29 patients who received 2 full courses of treatment. Thirteen patients were able to receive full doses of both drugs. The percentages of the planned doses actually received were as follows: 97% of the planned docetaxel dose and 87% of the planned gemcitabine dose on Day 1; 91% of the planned docetaxel dose and 82% of the planned gemcitabine dose on Day 8; and 74% of the planned docetaxel dose and 63% of the planned gemcitabine dose on Day 15. Day 15 doses were omitted for 14 of 40 patients (35%), almost always due to myelosuppression.

Treatment Efficacy

Nine of 33 evaluable patients (27%; 23% of the entire group) had partial responses to treatment. Five of 19 evaluable patients (26%) who had a favorable performance status (ECOG 0 or 1) had objective responses, compared with 4 of 14 patients (29%) who had a poor performance status. The median duration of objective response was 7 months (range, 4–7 months). The median progression-free survival for the entire group was 2 months. One patient was free of progressive disease at 1 year.

The actuarial overall survival for the 40 patients is shown in Figure 1. The median survival was 4 months, with 14% of patients alive at 1 year. No patient survived for 2 years. The median survival period and the 1-year actuarial survival rates for patients with favorable performance status were 6 months and 21%, respectively, compared with 3 months and 6% for patients with poor performance status (P = 0.06). Sixteen patients age were > 65 years and also had poor performance status (ECOG 2). In this group, the response rate was 19%, with a median survival of 3 months.

thumbnail image

Figure 1. Actuarial survival of 40 patients treated with docetaxel and gemcitabine. The median survival duration was 4 months, with a 1-year survival rate of 14%.

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Toxicity

Treatment-related toxicity data are summarized in Table 3. Only a limited number of patients experienced Grade 3/4 hematologic toxicity, and no hospitalization for the treatment of neutropenia and fever was required. Grade 3/4 nonhematologic toxicities included fatigue (25%) and dyspnea (20%); however, attribution of these symptoms to treatment rather than to SCLC itself was difficult. Other nonhematologic toxicity was uncommon. There were no treatment-related deaths.

Table 3. Treatment-Related Grade 3/4 Toxicitya
ToxicityNo. of patients (%)
  • a

    Among 40 patients receiving a combined total of 104 treatment courses.

  • b

    Seven percent of courses.

Hematologic 
 Leukopenia 6 (15)b
 Thrombocytopenia 7 (17)
 Anemia 2 (5)
 Platelet transfusion required 1 (2)
 Neutropenia/fever0
Nonhematologic 
 Fatigue10 (25)
 Dyspnea 8 (20)
 Nausea/emesis 4 (10)
 Myalgias0
 Peripheral edema0
Treatment-related death0

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The purpose of the current trial was to evaluate a novel, relatively well tolerated combination regimen for the treatment of patients with advanced-stage SCLC who were elderly and/or had poor performance status. Previous trials have documented poor tolerance of combinations of cisplatin and etoposide in this group of patients, as well as a short median survival duration (3–4 months). Docetaxel and gemcitabine have both exhibited substantial single-agent activity in patients with previously untreated advanced-stage SCLC. Docetaxel produced a 23% response rate in a group of 43 patients treated in a Southwest Oncology Group Phase II trial.8 Furthermore, gemcitabine, when evaluated as a single agent by the National Cancer Institute Canada Clinical Trials Group,10 produced a 30% response rate in a group of 23 patients with advanced-stage SCLC. The combination of docetaxel and gemcitabine, used at various doses and in various schedules, has been evaluated by a number of investigators in the treatment of advanced-stage NSCLC.14, 16–18 In general, this combination has been active and relatively well tolerated. In a previous Phase II trial involving patients with Stage IV NSCLC who were elderly or had poor performance status, we demonstrated that a weekly regimen containing docetaxel and gemcitabine could be administered with acceptable toxicity to most patients.14 In a group of 64 patients treated in our previous trial, there were no hospitalizations for treatment of neutropenia and fever, and only 1 death, caused by bilateral pulmonary infiltrates, was considered to be potentially related to treatment.

Although the combination of weekly docetaxel and gemcitabine exhibited some efficacy in the treatment of these patients with advanced-stage SCLC, the results of the trial generally were disappointing. Only 9 of the 40 patients who entered the trial (23%) had objective responses, and the overall median survival for the group was 4 months. As expected, the regimen produced only mild-to-moderate hematologic toxicity in most patients, although omission or reduction of the planned dose on Day 15 was frequently required due to myelosuppression. Since the initiation of the trial, additional experience with combinations of docetaxel and gemcitabine has indicated that dosing is better tolerated on a Day 1/Day 8 schedule that is repeated every 21 days. Although the use of a 21-day schedule may have reduced the myelosuppression observed in the current study, it appears unlikely that such a schedule change would have markedly improved the efficacy of this regimen.

In summary, the combination of weekly docetaxel and gemcitabine exhibited only modest activity in this group of patients with advanced-stage SCLC. On the basis of the current experience, we conclude that the study combination, although it is relatively well tolerated, offers no advantages over standard therapy. In addition, the results of the current study provide no compelling rationale for investigating the combination of docetaxel and gemcitabine as first-line treatment for younger patients with SCLC who have a more favorable performance status. Novel agents and combinations are urgently required before substantial improvements in the treatment of this malignancy can be expected.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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