Irinotecan (I) and cisplatin (P) are active chemotherapy agents with clinical synergy in non–small-cell lung cancer (NSCLC). We evaluated the efficacy of IP regimen as a salvage treatment of patients with NSCLC that progressed after nonplatinum-containing regimen(s).
Eligibility required histologically confirmed NSCLC, bidimensionally measurable disease, ECOG PS 0-2, and progressive disease after nonplatinum-based chemotherapy. Treatment consisted of I (65 mg/m2) and P (30 mg/m2) i.v. on Days 1 and 8 of a 21-day cycle, for a maximum of 6 cycles. An informed consent was obtained from all patients.
Between August 2002 and May 2004, 32 patients with median age of 56 years (range, 42–74) were enrolled. Twenty-four (75%) patients were men, and 28 (88%) had ECOG PS 0 or 1. Twenty-five patients had adenocarcinoma and 6 had squamous-cell carcinoma. All patients were evaluated for response and toxicity, and the response rate was 40.6%. After a median follow-up of 18.5 months, the median survival time was found to be 9.3 months, with a 1-year survival rate of 43.8%. Toxicities were moderate and manageable, with 47% G3 and 9% G4 neutropenia, 19% G3 diarrhea, and 22% G3 asthenia. There was no G4 nonhematologic toxicity.
Systemic chemotherapy is now considered a standard of care in the treatment of advanced non–small-cell lung cancer (NSCLC). ASCO guidelines recommend platinum-based or nonplatinum-based doublets for front-line chemotherapy.1 For a second-line treatment, several pivotal Phase III trials showed therapeutic benefit of docetaxel2 and erlotinib3 over best supportive care, and therapeutic equivalence between docetaxel and pemetrexed.4 Currently, docetaxel, pemetrexed, and erlotinib are considered the standard option.
However, recent development of more effective chemotherapy agents and palliative care have resulted in an apparent increase in the number of patients eligible for second-line therapy. Nevertheless, only a few trials have reported on the efficacy of combination chemotherapy in the second-line setting of NSCLC therapy, mostly with noncisplatin-containing regimens.5, 6 Conversely, as more and more patients are treated with nonplatinum-based doublets or triplets up front, there has been a growing need to explore the efficacy of platinum doublets, instead of such well-documented single agents as docetaxel.
In the current Phase II trial, we evaluated the efficacy of a platinum-based combination (i.e. irinotecan + cisplatin) in the second-line setting for the patients who had received nonplatinum-based front-line therapy. We first administered cisplatin, immediately followed by irinotecan on a weekly schedule for 2 consecutive weeks of a 3-week cycle. This administration sequence was designed to permit maximum synergy between these 2 drugs and preserve the maximum dose intensities of both agents.7 Here we report that the irinotecan and cisplatin combination had significant antitumor activity against the NSCLCs that have failed to respond or have recurred after nonplatinum-based first-line treatments.
MATERIALS AND METHODS
Eligibility included pathologically confirmed diagnosis of advanced or metastatic NSCLC that had progressed during or after 1 or more platinum-based regimens; age, 18–75 years; ECOG performance status, 0–2; 1 or more bidimensionally measurable lesion(s), defined as at least 1 cm by 1 cm by CT scan, MRI, or physical examination; a minimum of 21 days' lapse since any prior chemotherapy; estimated life expectancy of at least 12 weeks; adequate hematologic, renal, and hepatic functions, defined as white blood cell count ≥4000/μL, platelet count ≥150,000/μL, serum creatinine ≤1.5 mg/dL, serum bilirubin ≤1.5 mg/dL, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) up to 1.5 times the upper limit of normal levels. Prior radiation therapy was allowed as long as the irradiated area was not the only site of measurable disease and was completed at least 3 weeks before the enrollment in study.
Patients were excluded if there was severe comorbidity such as myocardial infarction within preceding 6 months or symptomatic heart disease, including unstable angina, congestive heart failure, or uncontrolled arrhythmia, and serious concomitant infection, including postobstructive pneumonia. The presence of CNS metastases, however, was not considered as an exclusion criterion, provided there were either no CNS symptoms or minor CNS symptoms that were well controlled with corticosteroids. This trial was approved by the Institutional Review Board of the National Cancer Center Korea, and written informed consent was obtained from all patients prior to entering the study. The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
Baseline and Treatment Assessment
All patients were screened for medical history and underwent a physical examination. Baseline assessments including complete blood cell count (CCBC), renal and liver function tests, urinalysis, and performance status were performed within 2 weeks before enrollment. Chest X-rays, chest and abdominal CT scans, brain MRI, and radionuclide bone scanning were performed within 4 weeks before enrollment. Physical examination and toxicity evaluation were done on each visit. Weekly CBC and blood chemistry were done. Response was documented by physical examination, chest X-ray prior to each treatment cycle, and a CT scan and/or MRI every 3 cycles or if disease progression was suspected. Response was assessed using World Health Organization criteria and National Cancer Institute Common Toxicity Criteria version 3.0. Patients were considered assessable for response if they completed at least 1 full cycle, and those who received a minimum of half a cycle were considered assessable for toxicity.
The treatment was given in the outpatient setting. The treatment consisted of irinotecan (I; 65 mg/m2) and cisplatin (C; 30 mg/m2) given intravenously (i.v.) on Days 1 and 8 of a 21-day cycle. Cisplatin was given first as a 30-min i.v. infusion, immediately followed by irinotecan i.v. over 90 min. Patients received standard i.v. hydration with 5% dextrose in normal saline or normal saline for 2 hours to assure adequate hydration before cisplatin administration. Cholinergic symptoms occurring during or within 1 hour after receiving irinotecan were treated with atropine (1 mg or as needed). Dexamethasone (10 mg) wasadministered intravenously as part of the pretreatment antiemetic regimen unless a contraindication to corticosteroid use was identified. Ondansetron (8mg) or granisteron (1 mg) (per physician preference) was given prior to each cisplatin dose. For delayed diarrhea, patients were instructed to take loperamide at the first sign of diarrhea (i.e., first poorly formed or loose stool or first episode of 1–2 more bowel movements than usual in 1 day) that occurred >12 hours after irinotecan administration in the following manner: 4 mg at the first onset of diarrhea, then 2 mg every 2 hours around the clock until diarrhea-free for at least 12 hours. During the night, patients were allowed to take 4 mg every 4 hours. During a course of treatment, the irinotecan dose on Day 8 was decreased by 10 mg/m2 for Grade 3 hematological toxicities and/or Grade 3 diarrhea and withheld for any Grade 4 toxicity. The cisplatin dose was decreased by half if the serum creatinine level was up to 2.0 mg/dL and withheld if it was >2.0 mg/dL. Both the agents were withheld if there was neutropenic fever.
For the next course of therapy, irinotecan was decreased in stepwise by 10 mg/m2-decrements to 55 or 45 mg/m2 in patients who experienced Grade 4 hematological toxicities or Grade 3 diarrhea and/or nonhematologic toxicities. The cisplatin dose was reduced by 50% for serum creatinine elevation up to 2.0 mg/dL and withdrawn for a serum creatinine >2.0 mg/dL. A total of 6 cycles of treatment were administered. Treatments were discontinued if the patient withdrew consent, had disease progression, experienced unacceptable drug toxicity not responding to dosage modification, or developed an intercurrent, noncancer-related illness that prevented therapy continuation or regular follow-up.
The minimax two-stage design described by Simon for a Phase II clinical trial was used to calculate the sample size,8 based on the following assumptions: alpha error, 0.1; beta error, 0.1; clinically uninteresting true response rate, 5%; and sufficiently promising true response rate, 20%. According to the two-stage design, this trial had to be stopped if no response was observed in the first 18 patients. Otherwise, a total of 32 patients were to be enrolled. The treatment was considered effective if 4 or more responses were observed in 32 evaluable patients.
Duration of response, time to progression, and survival were estimated using the Kaplan–Meier method. Survival was calculated from the first day of treatment to death. Time to progression was calculated from the first day of treatment to the date that disease progression was reported. Duration of response was calculated for all responders from the date of first documentation of response to the date that progressive disease was noted. Confidence intervals (CI) were constructed around the Kaplan–Meier estimates using Greenwood's variance formula. 95% Confidence intervals for response rate were calculated using methods for exact binomial confidence intervals. Dose intensity was calculated using the method of Hryniuk and Bush.9
Between August 2002 and May 2004, 32 patients were enrolled, and the patients' characteristics are shown in Table 1. The median age was 56 years (range, 42–74). Twenty-four patients (75%) were men and 28 patients (88%) had an ECOG PS of 0 or 1 while 25 patients (78%) had adenocarcinoma and 30 (94%) had Stage IV disease. Twenty-four patients (75%) had treatment-free interval less than 3 months. Twenty-two patients received IP chemotherapy after 1 regimen failure, which included gemcitabine and vinorelbine (16), docetaxel and capecitabine (4), and gemcitabine, vinorelbine, and capecitabine (2). Ten patients received 2 prior regimens. They were docetaxel plus capecitabine, followed by gemcitabine plus vinorelbine (5); gemcitabine plus vinorelbine, followed by gefitinib (3); and gemcitabine plus vinorelbine, followed by alimta (2).
The patients received a total of 143 cycles; the median number of cycles administered was 5.5 (range, 1–6 cycles), and 16 patients completed 6 cycles of chemotherapy. A delay in chemotherapy administration or dose reduction occurred in 49 cycles (36%) and 20 cycles (14%), respectively. The most common cause for the delay in chemotherapy administration was neutropenia (40 cycles). Twenty cycles required dose reduction mainly due to neutropenia (18 cycles), diarrhea (1 cycle), and asthenia (1 cycle). The average relative dose intensity was 84.2% for irinotecan and 84.6% for cisplatin.
Response and Survival
Thirteen of 32 patients achieved PR for an overall response rate of 40.6% (95% CI, 23.6–57.6%) (Table 2). After a median follow-up of 18.5 months, median time to progression was 3.6 months (Fig. 1A). Median survival time was 9.3 months and 1-year survival rate was 43.8% (95% CI, 26.6%–61.1%) (Fig. 1B). No single pretreatment characteristic, including sex (male vs. female), ECOG PS (0 vs. 1–2), histology (adenocarcinoma vs. nonadenocarcinoma), smoking history (never vs. ever), number of prior treatment regimens (1 vs. 2), best response of any prior treatment (PR vs. non-PR), treatment-free interval (<3 vs. ≥3 months), was predictive of tumor response or survival in this study (Tables 3–5).
Best response of any prior treatment (PR vs. non-PR)
Treatment-free interval (<3 vs. ≥3 mo)
Table 5. Multivariate Analyses to Predict Overall Survival (Cox Regression)
HR indicates hazard ratio; ACA, adenocarcinoma.
Sex (male vs. female)
ECOG (0 vs. 1 or 2)
Histology (ACA vs. non-ACA)
Smoking history (never vs. ever)
Maximum response in IP chemotherapy (PR vs. non-PR)
Prior treated regimen no. (1 vs. 2)
Best response of any prior treatment (PR vs. non-PR)
Treatment-free interval (<3 vs. ≥3 mo)
Twenty-six patients received salvage chemotherapy after disease progression on IP chemotherapy. This included gefitinib (13), gemcitabine plus vinorelbine (4), docetaxel (4), paclitaxel plus carboplatin (2), docetaxel plus capecitabine (1), capecitabine (1), and irinotecan plus cisplatin (1). Responses were evaluable in 26 patients, of whom 4 patients achieved PR (2 with gemcitabine plus navelbine, 1 with paclitaxel plus carboplatin, and 1 with docetaxel).
Hematologic and nonhematologic toxicities observed over the entire course of the study are summarized in Table 6. Hematologic toxicities were common. Grade 3 and 4 neutropenia were observed in 15 (46.9%) and 3 (9.4%) of 32 patients, respectively, with febrile neutropenia in only 1 patient. Grade 3 anemia was seen in 4 patients and Grade 3 thrombocytopenia was seen in 1 patient. Major nonhematologic toxicity was diarrhea and asthenia. Grade 3 diarrhea was observed in 6 patients (18.8%) and Grade 3 asthenia in 7 patients (21.9%). Grade 4 nonhematologic toxicity was absent. Overall toxicities were moderate and manageable. No treatment-related death was observed.
Table 6. Hematologic and Nonhematologic Toxicity (NCI-CTC Grade), by Patient
This is a nonrandomized Phase II study on irinotecan plus cisplatin in patients with advanced-stage NSCLC that progressed or failed to respond to noncisplatin-based chemotherapy. To date, docetaxel is the most well-documented second-line therapy for previously treated NSCLC. However, the results of docetaxel-based combination therapy have been disappointing in the second-line setting. In a randomized Phase II trial, Takeda et al.5 compared the single-agent docetaxel (60 mg/m2) on Day 1 with the combination of docetaxel (60 mg/m2) on Day 8 and gemcitabine (800 mg/m2) on Days 1 and 8 every 3 weeks. The trial was terminated early because of unexpected occurrence of interstitial lung disease, which resulted in 3 treatment-related deaths (5%) in the docetaxel/gemcitabine arm.5 In the other trial, a comparison between single-agent docetaxel and combination of docetaxel plus irinotecan failed to elucidate any benefit of combination therapy.6 After the treatment with docetaxel (75 mg/m2) every 3 weeks or docetaxel (30 mg/m2) in Days 1 and 8 in combination with irinotecan (60 mg/m2) on Days 1 and 8 every 3 weeks, there was no difference in overall survival (6.5 vs. 6.4 months) or 1-year survival rates (37% vs. 34%).6
We elected to use the irinotecan plus cisplatin combination in the current study for a simple practical reason. For our patient population, irinotecan was the only active agent left out to be used in a second-line setting because many of our patients were previously treated up front with nonplatinum-based regimens that contained such other active agents as gemcitabine, navelbine, and docetaxel. As a single agent, irinotecan generates objective tumor responses in approximately one-third of the patients with chemotherapy-naive advanced NSCLC.10 When given together with cisplatin, which has a different toxicity profile, irinotecan showed synergistic antitumor effect in vitro and significant antitumor activity in the first-line setting, as summarized in Table 7.7, 11–14 In a second-line setting, however, 2 Japanese studies showed conflicting results on its activity against NSCLC.15, 16 Negoro et al. treated 26 previously treated NSCLC patients with 100 mg irinotecan/m2 every week and observed no response while they reported a 34% response rate in chemotherapy-naive patients in the same study.15 Conversely, Nakai et al. has reported a 14% response rate among 22 previously treated NSCLC patients after second-line therapy with irinotecan at 200 mg/m2 given every 3–4 weeks.16 As a first-line therapy, the response rate was 31% in the same study. Taken together, it is quite remarkable to see the 40.6% objective response rate in the current trial of irinotecan and cisplatin combination, which outperformed our initial target response rate of 20%. It strongly suggests that this combination has synergistic antitumor effects and that there might be no cross-resistance between this combination and the agents used in the first-line setting.
Table 7. Phase II Trials of Irinotecan and Cisplatin in Chemo-Naïve Patients With Advanced NSCLC
In most clinical trials of irinotecan plus cisplatin combination, cisplatin was administered on a single triweekly or every 4-week administration schedule and irinotecan was given prior to cisplatin on Day 1 and thereafter as a single drug on Day 8 and 15 of a 28-day cycle. This combination of weekly irinotecan and triweekly or every 4-week cisplatin has shownpromising antitumor activity for advanced NSCLC.11–13 However, there is a growing body of evidence that suggests that the concurrent same-day administration of cisplatin and irinotecan, as demonstrated in the current study, may better exploit their therapeutic synergy and minimize toxicities.14, 17
The major mechanism of cisplatin resistance is through rapid repair of platinum-DNA adducts. This repair requires unscheduled DNA synthesis, which in turn requires uncoiling of the damaged section of DNA. This uncoiling would be facilitated by topoisomerase I. Thus, a logical method for combining a topoisomerase I inhibitor such as irinotecan with cispaltin would be to use a schedule that maximizes topoisomerase I inhibition after cisplatin administration, at the time when platinum-DNA adducts are undergoing attempted repair. This would ideally involve divided doses of cisplatin, each given immediately before a dose of the topoisomerase I inhibitor.17 In addition, the dose intensity of irinotecan and cisplatin is low in 28-day cycled schedule because of frequent toxicities of myelosuppression or diarrhea or both. Using the concurrent cisplatin and irinotecan administration schedule, we showed objective tumor responses in 47% of chemo-naive NSCLC patients with 1-year survival rate of 63.3%.14 In the current study, 40.6% of patients with previously treated NSCLC responded to the second-line irinotecan and cisplatin therapy, which is quite comparable to our first-line response rate and also the results of other trials wherein the irinotecan and cisplatin regimen was used in a front-line setting (Table 7).
In a second-line setting, Georgoulias et al. compared the irinotecan and cisplatin combination with cisplatin alone in NSCLC patients who were previously treated with taxanes/gemcitabine regimen.18 A total of 147 patients were randomized to receive either irinotecan (110 mg/m2) on Day 1 and 100 mg/m2 on Day 8 plus cisplatin (80 mg/m2) on Day 8 every 3 weeks or cisplatin (80 mg/m2) alone on Day 1 every 3 weeks. The combination of irinotecan and cisplatin resulted in a significantly higher response rate than did cisplatin alone (22.5% vs. 7.0%. P = .012), but no significant difference in the overall survival (median survival, 7.8 vs. 8.8 months; 1-year survival rates, 34.3% vs. 31.7%, respectively; P = .933). These results, taken together with the results of our study, confirmed the role of platinum-containing regimens in the second-line setting in terms of generating significantly higher response rates.
Historically, the median survival of patients with relapsed or refractory NSCLC was only 4.6 months if no active therapy is given other than best supportive care after first-line chemotherapy.2 In a most recent randomized trial that reported the efficacy of pemetrexed as second-line chemotherapy in comparison with docetaxel, the median survival time was 7.9 months with docetaxel and 8.3 months with pemetrexed.4 In the current study, we observed 9.3 months of median survival and 43.8% 1-year survival rate after the second-line treatment with irinotecan/cisplatin. Since many patients with relapsed or refractory NSCLC are unfit for second-line therapy, which introduces inherent selection bias, we have to take extra caution in interpreting the results of the current Phase II clinical trial. Nevertheless, it should be noted that in the current study, 75% of the patients had less than 3 months of treatment-free interval and 31% had received 2 prior regimens. Despite this refractory nature of the disease, we observed tumor responses in 9 of 23 (39%) patients whose disease progressed after the first-line therapy with gemcitabine/vinorelbine and 4 of 9 (44%) patients whose disease progressed after the first-line therapy with docetaxel/capecitabine. Although the number is small, it seems that the prior treatment with gemcitabine/vinorelbine or docetaxel/capecitabine had no adverse effect on the antitumor activity of irinotecan/cisplatin, which suggests the potential lack of cross-resistance between irinotecan/cisplatin and the other 2 regimens.
In conclusion, the irinotecan/cisplatin regimen is an active and well-tolerated second-line therapy for patients with advanced NSCLC who were pretreated with nonplatinum-based chemotherapy. As more patients are treated with nonplatinum-based doublets up front, there is more need to explore the platinum doublets instead of such single agents as docetaxel as the second-line therapy.