A Phase II trial of topotecan and gemcitabine in patients with previously treated, advanced nonsmall cell lung carcinoma
Article first published online: 5 SEP 2002
Copyright © 2002 American Cancer Society
Volume 95, Issue 6, pages 1274–1278, 15 September 2002
How to Cite
Rinaldi, D. A., Lormand, N. A., Brierre, J. E., Cole, J. L., Barnes, B. C., Mills, G., Yadlapati, S., Felicia Fontenot, M., Buller, E. J. and Rainey, J. M. (2002), A Phase II trial of topotecan and gemcitabine in patients with previously treated, advanced nonsmall cell lung carcinoma. Cancer, 95: 1274–1278. doi: 10.1002/cncr.10806
- Issue published online: 5 SEP 2002
- Article first published online: 5 SEP 2002
- Manuscript Accepted: 24 APR 2002
- Manuscript Revised: 23 JAN 2002
- Manuscript Received: 12 NOV 2001
- GlaxoSmithKline, Inc.
- nonsmall cell lung carcinoma
Multiple trials have been performed to evaluate second-line clinical chemotherapy in patients with advanced nonsmall cell lung carcinoma (NSCLC). However, no single agent or combination has demonstrated superior activity.
Patients with advanced NSCLC who had aready received one chemotherapeutic regimen were treated with topotecan (0.75 mg/m2 over 30 minutes, Days 1–5) and gemcitabine (400 mg/m2 over 30 minutes, Days 1 and 5) every 21 days.
Of 35 patients who were treated, 4 (11%) achieved a partial responses and 8 (23%) hadstable disease for at least four courses of treatment. The response rate for patients with refractory disease (progressing during frontline chemotherapy) was 18% (3 of 17) with 18% having stable disease for at least four courses of treatment. The median survival of the entire group was 7 months (range, 1.5–44 months) and 20% (7 of 35) of patients were alive 1 year from the initiation of topotecan and gemcitabine treatment. Patients with refractory disease had a median survival of 4½ months, with 6-month and 1-year survival rates of 47% and 18%, respectively. During Course 1, five patients (14%) developed Grade IV neutropenia and three patients (9%) developed Grade IV thrombocytopenia. Nonhematologic toxicity was relatively mild, with one patient developing Grade III side effects (fatigue) and eight patients (23%) developing Grade II nonhematologic side effects.
The combination of topotecan and gemcitabine demonstrated antitumor activity with a modest side effect profile in patients with advanced, previously treated NSCLC. Cancer 2002;95:1274–8. © 2002 American Cancer Society.
Topotecan (Hycamptin, GlaxoSmithKline, Inc., Middlesex, UK) is a semisynthetic derivative of the compound camptothecin. Its cytotoxic effect is due to inhibition of the enzyme topoisomerase I, which leads to double-strand DNA damage. Typically, it is administered intravenously as a single agent at a dose of 1.5 mg/m2 per day for 5 days, after which it is repeated every 21 days. The dose-limiting toxicity is neutropenia, with 40% of patients developing an absolute neutrophil count less than 500 cells/mm3. Other fairly common toxicities include thrombocytopenia, anemia, mild nausea, diarrhea, alopecia, headaches, paresthesias, and mild dyspnea. Three Phase II trials that evaluated topotecan in patients with untreated advanced nonsmall cell lung carcinoma (NSCLC) have been reported.1–3 Despite low clinical response rates (0–15%), the median periods of survival (7.6, 9, and 10.2 months) were comparable to those obtained with agents commonly used to treat advanced NSCLC. There are no published trials of topotecan in the second-line setting in patients with advanced NSCLC.1–5
Gemcitabine (Gemzar, Eli Lilly, Indianapolis, IN) is a pyrimidine analog with a cytotoxic effect due to competition with dCTP for incorporation into DNA, resulting in chain termination. Gemcitabine also inhibits ribonucleotide reductase, which is important in DNA synthesis. Typically, it is administered intravenously at a dose of 1000 mg/m2 per week over 30 minutes for 3 of 4 weeks. Neutropenia is the dose-limiting toxicity, but only about 6% of patients develop an absolute neutrophil count less than 500 cells/mm3. Other fairly common toxicities are anemia, thrombocytopenia, skin rash, fever, mild nausea and vomiting, mild dyspnea, lethargy, peripheral edema, and flulike syndrome. Gemcitabine has demonstrated a response rate ranging from 14% to 26%, with reported median survivals of 8–11.5 months as a single agent when used as frontline treatment for patients with advanced NSCLC. When used in a second-line setting, it has demonstrated response rates ranging from 0% to 21%, with median survivals of 5–8 months.6–10
The combination of topotecan and gemcitabine is potentially promising for patients with advanced NSCLC. Preclinical data suggest synergy between topotecan and gemcitabine on A549 lung carcinoma cell lines.11 Both agents have demonstrated preclinical and clinical activity against NSCLC. In addition, both are relatively well tolerated with fairly mild nonhematologic toxicity.
In our initial Phase I–II trial of topotecan and gemcitabine, 18 patients with advanced, previously treated NSCLC were treated with escalating doses of topotecan over 30 minutes on Days 1–5 and gemcitabine over 30 minutes on Days l and 5, of each 21-day treatment course. The primary reason for this schedule was patient convenience. The frequency of physician office visits impacts on patient quality of life during treatment. This schedule involved five visits on consecutive days, leaving 16 consecutive days in-between treatments. The maximally-tolerated dose (MTD) and doses recommended for Phase II clinical trials were 0.75 and 400 mg/m2 for topotecan and gemcitabine, respectively, with neutropenia and thrombocytopenia the dose-limiting toxicities. Partial responses were achieved in 3 of 17 patients (18%) with measurable disease. Six patients (32%) had disease stabilization for at least four courses of treatment. The median survival for the entire population was 10 months from the initiation of topotecan and gemcitabine treatment.12
The objectives of this study were to determine the antitumor activity and further define the qualitative and quantitative toxicities of topotecan and gemcitabine combination therapy, when administered to patients with advanced NSCLC previously treated with one chemotherapeutic regimen.
MATERIALS AND METHODS
All patients underwent a complete medical history, physical examination, and laboratory evaluation. Eligibility criteria included the following: 1) histologic or cytologic evidence of unresectable NSCLC; 2) patients had to be at least 18 years of age; 3) Eastern Cooperative Oncology Group performance status of 2 or less; 4) life expectancy of 12 weeks or more; 5) previous treatment with one chemotherapeutic regimen for advanced NSCLC; 6) no previous chemotherapy or radiotherapy for at least 3 weeks (at least 6 weeks for nitrosoureas or mitomycin C) and recovery from any significant toxicity associated with the most recent therapy; 7) adequate bone marrow function (white blood cell count of ≥ 3500/mm3 or granulocyte count ≥ 1500/mm3, platelet count ≥ 100,000/mm3, hemoglobin level ≥ 9 g/dL), hepatic function (bilirubin level ≤ 1.5 times the upper limit of normal, aspartate transaminase [AST] or alanine transaminase [ALT] less than or equal to three times normal [AST or ALT less than or equal to five times normal if due to malignancy]), and renal function (creatinine level ≤ 2.0 mg/dL or Clcreat ≥ 60 mL/min); and 8) written, informed consent. Exclusion criteria included 1) clinical evidence of active brain metastases, 2) serious preexisting medical conditions, which would prevent full compliance with the study, 3) pregnancy, and 4) previous topotecan or gemcitabine treatment.
Topotecan (0.75 mg/m2) was administered intravenously over 30 minutes on Days 1–5 and gemcitabine (400 mg/m2) was administered intravenously over 30 minutes on Days 1 and 5 only, immediately after the topotecan dose. Treatment courses were repeated every 21 days. Routine prophylactic antiemetic medications were not used unless the patient experienced nausea and/or vomiting during a preceding course of treatment. Prophylactic colony-stimulating factors were not used during Course 1.
Dose adjustments were based on the toxicity observed during the preceding course of treatment. A new cycle of treatment would begin when the granulocyte count was greater than or equal to 1.5 × 109/L, the platelet count was greater than or equal to 75 × 109/L, and the nonhematologic toxicity was Grade 1 or lower. Upon recovery, patients were re-treated based on the maximal toxicity experienced during the previous course of treatment (Table 1).
|AGC nadir (× 109/L)||Platelet nadir (× 109/L)||Topotecan||Gemcitabine|
|≥ 0.5||≥ 50||Full dose||Full dose|
|< 0.5||≥ 50||−1 Dose level||Full dose|
|Any||< 50||−1 Dose level||−1 Dose level|
|Nonhematologica||Grade III||−1 Dose level||−1 Dose level|
|Grade IV||−2 Dose levels||−2 Dose levels|
Disease assessment was performed after every other course of treatment (i.e., every 6 weeks). Standard response criteria were used.13 A complete response required disappearance of all evidence of disease for at least 4 weeks. A partial response required a 50% or greater decrease in the sum of the products of the diameters of all measured lesions for at least 4 weeks. There also could be no new lesions or increases in the size of any evaluable lesions. Progressive disease was defined as a greater than 25% increase in the sum of the products of the diameters of the measured lesions or the appearance of any new lesions. Stable disease was defined as not meeting criteria for a response or progressive disease.
Thirty-five patients were enrolled in the trial. Nine patients treated on the Phase I–II portion of the trial met the eligibility criteria and are included in this analysis. Their characteristics are listed in Table 2. One hundred twenty-five courses of treatment were administered, with a range of one to nine courses per patient. All patients were treated previously with paclitaxel and carboplatin for initial treatment of their advanced lung carcinoma. Of 35 patients, 4 (11%) achieved partial responses and 8 (23%) had stable disease for at least four courses of treatment. The median survival of the entire group was 7 months (range, 1.5–44 months) and 20% (7 of 35) of patients were alive 1 year from the initiation of topotecan and gemcitabine treatment. The response rate for both adenocarcinoma and squamous cell carcinoma was 7% (1 of 14) and two patients (14%) with each subtype had stable disease for at least four courses of treatment. The median survival for squamous cell carcinoma was 7½ months versus 5 months for adenocarcinoma, with 1-year survival rates of 21% (3 of 14) and 14% (2 of 14), respectively.
|No. of Phase II patients||26|
|No. of Phase I–II eligible patients||9|
|Median age (range)||61 (38–76)|
|ECOG performance status|
|Large cell carcinoma||5|
|Time to disease progression|
|≤ 6 mos||7|
|> 6 mos||11|
Seventeen patients had refractory disease, defined as progressing during frontline chemotherapy. Three patients (18%) achieved partial responses and three (18%) had stable disease for at least four courses of treatment. Patients with refractory disease had a median survival of 4½ months with a 6-month survival rate of 47% and a 1-year survival rate of 18%.
Neutropenia and thrombocytopenia were confirmed as the dose-limiting toxicities. During Course 1, Grade III and Grade IV neutropenia occurred in 20% and 14% of patients, whereas Grade III and Grade IV thrombocytopenia occurred in 23% and 9% of patients, respectively. Five patients were transfused with platelets during the study time. Thirteen patients were transfused with a total of 37 U of packed red blood cells during their study (Table 3).
Nonhematologic toxicity was relatively mild, with one patient developing Grade III side effects (fatigue) and eight patients (23%) developing Grade II nonhematologic side effects (Table 3). There was no evidence of cumulative toxicity.
Fluid retention during the treatment week was noted during our Phase I–II trial. Patients were weighed daily during their treatment week and given furosemide (20–40 mg intravenously) if they gained 1.35 kg or more from their Day 1 baseline weight. Thirteen patients (37%) received doses of furosemide during their study time.
Until recently, few published trials evaluated second-line chemotherapy in patients with NSCLC. However, over the last few years, a number of trials have been reported using both single agents and multidrug regimens.9, 10 These trials are difficult to compare due to the limited details regarding the characteristics of the treated patients. Frequently, important clinical factors, such as the response to frontline treatment and the timing of the initiation of second-line treatment, are not discussed. Patients whose disease progresses during frontline chemotherapy (refractory disease) are expected to have a poorer prognosis and, therefore, may be a more reliable measure of the effectiveness of a second-line treatment.
Gemcitabine has been evaluated in second-line clinical trials with separate results reported for patients with refractory disease.14, 15 Combining the data for these two trials, 148 patients were treated, 59 of whom had refractory disease. The overall response rate and median survival were 13.5% and 6 months, respectively. Only the trial by Crino et al.15 reported a 1-year survival rate of 45%. For patients with refractory disease, the combined response rate was 2%. Neither the median nor 1-year survival was reported for this subgroup of patients. Toxicity was relatively mild, with few patients developing Grade III or IV side effects (Table 4).
|Author||Agent||No. ALL||RR ALL (%)||MS ALL (mos)||1y OS ALL (%)||No. REF||RR REF (%)||MS REF (mos)||1y OS REF (%)|
|Sculier et al.14||GEM||65||6.2||3.9||—||35||0||—||—|
|Crino et al.15||GEM||83||19||7.8||45||24||4||—||—|
|Fossella et al.16||DOC||42||21||9.7||44||30||23||—||—|
|Fossella et al.17||DOC||121||6.7||5.7||32||24||5||—||—|
|Shepherd et al.18||DOC||55||5.5||7.5||37||10||0||—||—|
|Alexopoulos et al.19||DOC/GCSF||60||25||7.4||23||30||20||—||—|
|Gandara et al.20||DOC||80||16||7||25||47||17||5|
Docetaxel has been evaluated extensively in second-line clinical trials, with separate results reported for patients with refractory disease in several of these trials.16–20 Combining the data for these trials, 358 patients were treated, 141 of whom had refractory disease. The overall response rate, median survival, and 1-year survival rate were 13%, 7 months, and 31%, respectively. For patients with refractory disease, the combined response rate was 16%. Only the study by Gandara et al.20 reported a median survival of 5 months in this subgroup of patients. Grade IV neutropenia occurred in 66% of patients. Grade II and III–IV asthenia occurred in 28% and 10% of patients, respectively. Grade II and III–IV peripheral neuropathy developed in 15% and 4% of patients, respectively (Table 4).
In the current study, the 17 patients with refractory disease had a response rate of 18%, with a median survival of 4½ months. The 6-month and 1-year survival rates were 47% and 18%, respectively. Grade IV neutropenia occurred in 14% of patients and 9% of patients developed Grade IV thrombocytopenia. Grade II and III nonhematologic toxicity developed in 23% and 3% of patients, respectively. Antitumor activity is comparable to that reported with docetaxel, but with less toxicity. All of the patients in the current trial had been treated previously with both carboplatin and paclitaxel, whereas the docetaxel trials included patients who were treated predominantly with a platinum regimen without paclitaxel.
There did not appear to be a major difference in antitumor activity by histologic type in the current trial. However, the survival figures were somewhat higher for squamous cell carcinoma (median survival 7½ months vs. 5 months, 1-year survival rate 21% vs. 14%) albeit only 14 patients were treated with each histologic type. This is in contrast to our initial Phase I–II trial in which the combination was more active in patients with adenocarcinoma. In this trial, three of seven patients (43%) with adenocarcinoma and measurable disease achieved partial responses, compared with no responses in the six patients with squamous cell carcinoma, two patients with large cell carcinoma, or two patients with undifferentiated nonsmall cell carcinoma. The median survival from the start of topotecan and gemcitabine treatment for patients with adenocarcinoma was 11½ months, compared with 6 months for patients with nonadenocarcinoma subtypes.12
It is difficult to compare the reported Phase II and III trials of second-line chemotherapy in patients with NSCLC due to differences in patient characteristics and the variable natural history of the disease. Second-line treatment with topotecan and gemcitabine combines two classes of chemotherapeutic agents that are not used frequently in the frontline setting. This regimen has demonstrated antitumor activity with a modest side effect profile in patients with advanced, previously treated NSCLC.
- 3A phase II study of oral topotecan in advanced non-small cell lung cancer: useful symptom palliation and 10 month median survival [abstract]. Proc Am Soc Clin Oncol. 1999; 2033: 527A., , , et al.
- 4DNA Topoisomerase Inhibitors. In: PerryM, editor. The chemotherapy sourcebook. Baltimore: Williams and Wilkins, 1997: 425–433., .
- 5Topoisomerase interactive agents. In: DevitaVT, HellmanS, RosenbergSA, editors. Cancer: principles and practice of oncology, 6th ed. Philadelphia: Lippincott, Williams, and Wilkins, 2001: 416–425., .
- 6Investigational drugs. In: PerryM, editor. The chemotherapy sourcebook. Baltimore: Williams and Wilkins, 1997: 502–503., .
- 7Antimetabolites. In: DevitaVT, HellmanS, RosenbergSA, editors. Cancer: principles and practice of oncology, 6th ed. Philadelphia: Lippincott, Williams, and Wilkins, 2001: 402–404., , .
- 8Efficacy of single-agent gemcitabine in advanced non-small-cell lung cancer: a review. Semin Oncol. 1997; 24 (Suppl 7): 38–41., .
- 11Combined therapy with topotecan and gemcitabine in patients with inoperable or metastatic non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol. 1999; 1930: 500., , .
- 13World Health Organization. The WHO handbook for reporting results of cancer treatment. Geneva: World Health Organization, 1979.