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Phase II Study of Irinotecan Plus Cisplatin Induction Followed by Concurrent Twice-Daily Thoracic Irradiation With Etoposide Plus Cisplatin Chemotherapy for Limited-Disease Small-Cell Lung Cancer

From the Research Institute & Hospital, National Cancer Center, Goyang, Gyeonggi, Korea

Address reprint requests to Jin Soo Lee, MD, Center for Lung Cancer, National Cancer Center, 809 Madu1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do, 411-764, Korea; e-mail: jslee{at}ncc.re.kr

	ABSTRACT

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PURPOSE: Irinotecan plus cisplatin (IP) chemotherapy demonstrated a promising outcome with a high complete response (CR) rate in chemotherapy-naïve patients with extensive small-cell lung cancer (SCLC). We evaluated the efficacy of induction IP chemotherapy followed by concurrent etoposide plus cisplatin (EP) chemotherapy with twice-daily thoracic radiotherapy (TDTRT) in limited-disease SCLC (LD-SCLC).

PATIENTS AND METHODS: Between November 2001 and May 2003, 35 chemotherapy-naïve patients with LD-SCLC were enrolled. Thirty-three patients (94%) were male, and 29 (83%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median age was 63 years. Treatment consisted of two 21-day cycles of cisplatin 40 mg/m² and irinotecan 80 mg/m² intravenously (IV) on days 1 and 8 followed by two 21-day cycles of cisplatin 60 mg/m² IV on days 43 and 64, and etoposide 100 mg/m² IV on days 43 to 45 and 64 to 66, with concurrent TDTRT of total 45 Gy beginning on day 43.

RESULTS: All 35 patients were assessable for response. The objective response rate was 97% (CR, 3; partial response [PR], 31) after induction chemotherapy and 100% (CR, 15; PR, 20) after concurrent chemoradiotherapy (CCRT). After a median follow-up of 26.5 months, the median survival was 25.0 months (95% CI, 19.0 to 30.9) with 1- and 2-year overall survival rates of 85.7% and 53.9%, respectively. Median progression-free survival (PFS) was 12.9 months with a 1- and 2-year PFS of 58.5% and 36.1%, respectively. The most common toxicities were grade 3 or 4 neutropenia in 68% of patients during induction chemotherapy and 100% during CCRT. Febrile neutropenia occurred in 20% of patients during induction chemotherapy and 60% during CCRT.

CONCLUSION: IP induction chemotherapy followed by concurrent TDTRT with EP chemotherapy showed a promising activity with favorable 1- and 2-year survival rates. Based on the favorable outcome in this trial, this regimen should be evaluated in a large phase III trial.

	INTRODUCTION

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Concurrent chemoradiotherapy is the standard therapy for limited-disease small-cell lung cancer (LD-SCLC). Meta-analyses by Pignon et al¹ and Warde and Payne² found a modest but significant increase in survival after the combined therapy. While thoracic radiation therapy (TRT) is usually integrated in the treatment for LD-SCLC, controversy remains regarding dose, fractionation, and timing.^3,4 Recently, Fried et al⁵ evaluated the timing of TRT by meta-analytic techniques and observed a small but significant improvement in 2-year survival for early TRT, which was defined as beginning before 9 weeks after the initiation of chemotherapy and before the third cycle of chemotherapy. In a subgroup analysis, a greater difference was evident for hyperfractionated TRT and platinum-based chemotherapy, supporting the use of early TRT as a component of a combined-modality approach, specifically for platinum-based regimens with a hyperfractionated radiation schedule.

Despite the significant improvement in the outcome of LD-SCLC, long-term cure is possible in a small fraction of LD-SCLC. A great majority of patients eventually die as a result of systemic recurrence.^1,4,5 More efficacious chemotherapy is needed to improve the overall outcome of LD-SCLC. Irinotecan has been demonstrated to have significant activity against SCLC. A phase II study of irinotecan plus cisplatin (IP) chemotherapy reported an objective response rate of 86% for extensive SCLC (ED-SCLC) with a complete response (CR) rate of 26%.⁶ A subsequent randomized phase III trial for chemotherapy-naïve patients with ED-SCLC showed a statistically superior benefit of IP combination over standard etoposide plus cisplatin (EP) chemotherapy.⁷ These results prompted several IP studies in SCLC, including two randomized phase III trials in the United States.⁸

To exploit the potential enhancement of synergy by concomitant weekly administration of cisplatin and irinotecan, we conducted a phase II study of dose-intensified weekly concomitant administration of cisplatin and irinotecan in chemotherapy-naïve patients with ED-SCLC. This regimen showed a 97% overall response rate with high CR rate of 26%.⁹ On the basis of the proven superior antitumor activity of this regimen, we hypothesized that two cycles of induction chemotherapy of dose-intensified concomitant weekly administration of IP would further improve the outcome of patients with LD-SCLC. This single-arm pilot study was conducted to evaluate the long-term efficacy of induction IP chemotherapy followed by EP chemotherapy with concurrent twice-daily TRT (TDTRT) in chemotherapy-naïve patients with LD-SCLC.

	PATIENTS AND METHODS

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Eligibility
Eligible criteria were as follows: histologically confirmed SCLC; limited-stage disease; Eastern Cooperative Oncology Group performance status (ECOG PS) 2; age 18 years; adequate function of bone marrow (WBC 4000/L and platelet count 100,000/L), liver (bilirubin level 1.5 mg/dL), and kidney (creatinine level 1.5 mg/100 mL); at least one bidimensionally measurable tumor; absence of active infection; no prior chemotherapy or radiotherapy; no history of myocardial infarction in the last 6 months and no congestive heart failure or significant arrhythmia; and no prior second primary cancer, except skin cancer.

LD was defined as disease confined to one hemithorax, the ipsilateral supraclavicular fossa, or both. Patients with pleural effusion found on chest films were excluded, regardless of cytologic findings, as were patients with contralateral hilar or supraclavicular adenopathy.

All patients signed written informed consent. The study was approved by the institutional review board of our institution and was conducted in compliance with institutional review board regulations.

Assessment of Patients
All patients underwent a medical history and physical examination with PS evaluation. Laboratory assessments, including CBC, renal and liver function tests, and urinalysis, were conducted within 2 weeks before enrollment. Chest x-rays, chest and abdominal computed tomography (CT) scan, brain magnetic resonance imaging (MRI)or CT, and radionuclide bone scan were conducted within 4 weeks before enrollment.

CBC was repeated on days 8 and 15. Before each course, the medical history and physical examination, laboratory assessment, chest x-ray, weight determination, and toxicity evaluation were repeated. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 2.0.

Treatment
Treatment was given in the outpatient setting and the treatment schema is shown in Figure 1. Treatment consisted of 2 cycles of cisplatin 40 mg/m² and irinotecan 80 mg/m² given intravenously on days 1 and 8 of a 21-day cycle. The doses and schedule were based on the previously conducted phase II trial.

View larger version (29K): [in this window] [in a new window]   Fig 1. Treatment schema. IV, intravenously; TRT, thoracic radiation therapy.

Patients received standard intravenous hydration with 1,000 mL of 5% dextrose in normal saline or normal saline for 2 hours before cisplatin administration. A standard antiemetic combination of dexamethasone 20 mg and ondansetron 8 mg was administered by intravenous infusion before the administration of cisplatin.

Cholinergic symptoms that occurred during or within 1 hour after receiving irinotecan were treated with atropine (1 mg or as needed). Loperamide was provided for delayed diarrhea. Patients were instructed to begin taking loperamide at the first bout of diarrhea (ie, first poorly formed or loose stool, or first episode of one or two more bowel movements than usual in a day) that occurred more than 12 hours after irinotecan administration. Loperamide was administered in the following manner: 4 mg at the first onset of diarrhea, then 2 mg every 2 hours around the clock until the patient was free of diarrhea for at least 12 hours. During the night, patients were allowed to take 4 mg every 4 hours.

Dose Modification
During the treatment cycle, cisplatin, irinotecan, and etoposide were withheld for 1 week if, on the day of planned treatment, the WBC was less than 3 x 10⁹/L, the absolute neutrophil count was less than 1 x 10⁹/L, the platelet count was less than 100 x 10⁹/L, or if grade 2 nonhematologic toxicities were present. For initiation of a subsequent cycle of chemotherapy, patients were required to have a WBC 3 x 10⁹/L, a platelet count 100 x 10⁹/L, a serum creatinine concentration < 1.5 mg/dL, and adequate recovery from nonhematologic toxicities.

No adjustments were made to the cisplatin dose during treatment. All chemotherapy was withheld for 1 week if, on the planned treatment day, the creatinine concentration was > 1.5 mg/dL. Resumption of treatment was permitted when the creatinine concentration returned to 1.5 mg/dL

TRT
Accelerated TDTRT was administered as 30 doses of 1.5 Gy each over a period of 3 weeks. An interval of 6 hours or more was required between the two daily fractions of radiotherapy. Three dimensional conformal radiotherapy techniques were used in all patients and their targets were defined in accordance with International Commission on Radiation Units and Measurements Report (ICRU 50) as follows. Gross tumor volume (GTV) included prechemotherapy gross tumor volume and lymph nodes > 1 cm in short axis diameter observed on CT scans. Clinical target volume (CTV) included GTV and uninvolved mediastinal and ipsilateral hilar nodes. Planning target volume (PTV) included CTV plus a 10 to 15 mm margin. Elective irradiation of uninvolved supraclavicular fossa was not recommended. Three coplanar isocentric fields were used routinely to adequately cover the target volumes and to minimize doses to the lung and other healthy tissues (eg, spinal cord, esophagus, etc). At least one of these fields was designed to spare the spinal cord to avoid radiation myelitis. The daily total dose to spinal cord did not exceed 225 cGy during treatment. The treatments were delivered by linear accelerator with a 6 to 15 MV x-ray. The prescription dose was specified at the ICRU reference point (isocenter) of PTV without tissue heterogeneity corrections. Interruptions of TRT were discouraged, but it was interrupted when patients were hospitalized for neutropenic fever or sepsis.

Prophylactic Cranial Irradiation
Four weeks after completion of the planned treatment, responses were evaluated with chest x-ray and CT, brain MRI, and bone scan. Those who achieved a CR or near CR were offered prophylactic cranial irradiation (PCI). This treatment consisted of 10 doses of 2.5 Gy to the midplane of the brain over a 2-week period, for a total of 25 Gy.

Response Evaluation
Responses were evaluated every two cycles of chemotherapy using the same evaluation method. Objective tumor responses were evaluated according to the WHO criteria issued in 1979.¹⁰ CR was defined as the complete disappearance of all known measurable disease as determined by two observations 4 weeks apart with no new lesions. Partial response (PR) was defined as a 50% decrease in the sum of the products of the longest perpendicular diameters of all measured lesions compared with baseline and no appearance of new lesions. Progressive disease (PD) was defined as a 25% increase in the sum of products of all measurable lesions over the smallest sum observed (over baseline if no decrease) using the same technique performed at baseline, the appearance of a new lesion that had disappeared, a clear worsening of any assessable disease, or the appearance of any new lesion or site. Stable disease (SD) was defined as no significant change in disease status and no evidence of PD.

Post-treatment evaluation was performed every 2 months until death or PD. Treatment for PD was left to the discretion of the investigator.

Statistics
The sample size was calculated according to Simon's two-stage minimax design.¹¹ A targeted objective response rate of 80% versus an objective response rate of no interest of 60% with a power of 0.80 at a one-sided significance level of .05 was chosen, and accrual of 34 assessable patients was projected. All patients who received at least one course of therapy were considered assessable for toxicity, and all eligible patients who received at least one cycle of therapy were included for response evaluation.

The method of Kaplan and Meier¹² was used to estimate median overall survival (OS) and median progression-free survival (PFS). OS was measured from the date of the first chemotherapy administration to the date of death or last follow-up. PFS was measured from the date of first administration of the chemotherapy up to the date of disease progression or death from any cause or the date of last follow-up. All patients alive at the time of the analysis were censored at the date of the last follow-up. Duration of response was calculated from the day of the first demonstration of response until disease progression. CIs for survival were constructed around the Kaplan-Meier estimates using Greenwood's variance formula. 95% CIs for response rate were calculated using methods for exact binomial CIs (SPSS software, version 9.0; SPSS Inc, Chicago, IL). Dose-intensity was calculated by using the method of Hryniuk and Bush.¹³

	RESULTS

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Patient Characteristics
Thirty-five patients were accrued from November 2001 to May 2003. All patients were assessable for response and toxicity analysis. The characteristics of the 35 eligible patients are listed in Table 1. The median age was 63 years (range, 38 to 75 years). Thirty-three patients (94%) were male, 29 patients (83%) had an ECOG PS of 0 or 1, and 33 (94%) had weight loss < 5%.

As of September 2004, with a median follow-up time of 26.5 months, 17 patients died. The median PFS was 12.9 months (range, 4.7 to 29.2 months), and the median response duration was 11.3 months (range, 3.1 to 27.7 months). The median OS was 25.0 months (range, 5.7 to 30.2 months) with 1- and 2-year survival rates of 85.7% (95% CI, 74.1% to 97.3%) and 53.9% (95% CI, 36.3% to 71.6%), respectively. The Kaplan-Meier curves of PFS and OS of the assessable patients are shown in Figures 2 and 3.

View larger version (14K): [in this window] [in a new window]   Fig 2. Progression-free survival (PFS).

View larger version (15K): [in this window] [in a new window]   Fig 3. Overall survival

During induction chemotherapy, a total of 70 cycles of IP chemotherapy were administered with a median of two cycles per patient. The second cycle of induction chemotherapy was delayed for a median of 7 days in 19 (54%) of 35 patients. The most common cause for the delay was neutropenia (n = 15). Dose reduction was necessary in additional 13 cycles (37%), mainly due to neutropenia (n = 12). The mean dose-intensity was 41.6 mg/m²/week (78.0% of planned dose) for irinotecan, and 21.4 mg/m²/week (80.2% of planned dose) for cisplatin.

During concurrent chemoradiotherapy, a total of 67 cycles of EP were administered with a median of two cycles per patients. Three patients did not receive the second cycle of EP chemotherapy, and in 19 (59%) of 32 patients, the second cycle of EP chemotherapy was delayed for a median of 7 days. The most common cause for the delay was neutropenia (n = 18). Dose reduction was necessary in additional two patients (6%) due to neutropenia. The mean dose-intensity was 82.5 mg/m²/week (82.5% of planned dose) for etoposide, and 16.6 mg/m²/week (83.1% of planned dose) for cisplatin.

During concurrent chemoradiotherapy, all patients received total dose of 45 Gy. The median duration of TRT delivery was 22 days (range, 19 to 32 days). During concurrent treatment, only three patients (9%) interrupted TRT. Interruption was due to febrile neutropenia and was for a median duration of 3 days (range, 3 to 6 days).

Toxicity
Toxicity of induction IP chemotherapy is detailed in Table 2. Myelosuppresion was the most common toxicity, with grade 3 or 4 neutropenia occurring in 24 patients (68%), anemia in three patients (9%), and thrombocytopenia in one patient (3%). Toxicity of concurrent chemoradiotherapy is detailed in Table 3. Myelosuppression was the major toxicity again. The grade 3 or 4 neutropenia occurred in all 35 patients (100%), anemia in 18 patients (51%), and thrombocytopenia in 20 patients (57%).

Nonhematologic Toxicity
The most common nonhematologic toxicity of induction chemotherapy was diarrhea; 7 patients (20%) reported grade 3 or 4 diarrhea (Table 2). During concurrent treatment, esophagitis was the most common nonhematologic toxicity. Grade 3 esophagitis, defined as an inability to swallow solids, requiring narcotic analgesics or the use of feeding tubes, occurred in 10 patients (29%; Table 3). However, there was no report of esophageal stricture following acute esophagitis.

The median time to development of acute esophagitis was 31.5 days (range, 10 to 38 days) from the TRT starting date. The median duration of grade 3 esophagitis was 5.5 days (range, 3 to 20 days).

Grade 3 or 4 TRT-associated pneumonitis occurred in 3 patients (9%), and one patient died as a result of complicated pneumonitis. The time to development of pneumonitis was 100 days (range, 25 to 153 days) from the end of TRT.

Patterns of Relapse
Tumor relapse patterns, involving 22 of 35 total patients are presented in Table 4. Only five patients (23%) relapsed solely in locoregional sites. Distant relapses occurred in 17 patients, nine (41%) at distant site only, and eight (36%) at both local and distant sites. Brain was the most common site of distant relapse. Overall, eight patients developed brain metastasis, four as the only site of relapse. Of these, four patients had received PCI, two with CR and the other two with PR. The time from the end of all planned treatment to brain metastasis was 6.2, 8.5, 9.7, and 11.7 months for patients with PCI, respectively, and 1, 2.3, 5.5, and 7.4 months for the four patients without PCI, respectively. Compared with patients without PCI, the time to brain metastasis was longer in patients with PCI (P = .04).

	DISCUSSION

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Although there remains a debate regarding the optimal timing of concurrent radiotherapy, concurrent thoracic radiotherapy with EP chemotherapy has been widely accepted as the standard for the treatment of LD-SCLC.^1-5 However, the majority of patients still relapse and ultimately die as a result of distant metastasis. Therefore, more effective systemic chemotherapy is needed to improve the outcome for patients with LD-SCLC. In this trial, we evaluated the role of induction chemotherapy with dose-intensified concomitant weekly administration of IP hoping to improve the long-term outcome of patients with LD-SCLC.

This dose-intensified concomitant weekly administration of IP as an induction chemotherapy was very active, as shown by a 97% objective response rate after only two cycles of therapy. After concurrent chemoradiotherapy, virtually all patients achieved objective responses. Moreover, the median survival was 25.0 months (95% CI, 19.0 months to 30.9 months) with 1- and 2-year overall survival rates of 85.7% and 53.9%, respectively. Although this is a single-institution phase II trial, the survival data of this study are comparable to or even better than the results in the literature (Table 5).^14-19 These results suggest that addition of two cycles of induction IP chemotherapy to standard chemoradiotherapy with EP chemotherapy may have contributed to the improved survival in this study.

Another major toxicity of concurrent chemoradiotherapy is TRT-associated esophagitis. In a landmark Intergroup study,¹⁶ grade 3 esophagitis was significantly more frequent with twice-daily TRT, occurring in 27% of patients, as compared with 11% in the once-daily TRT. In this study, 10 patients (29%) developed grade 3 esophagitis, comparable to the Intergroup study. This suggests that IP induction chemotherapy did not worsen the magnitude of concurrent chemoradiotherapy-associated esophagitis.

With the concurrent treatment, the risk of local recurrence decreases; however, brain metastasis becomes one of the main types of treatment failure.^20,21 The risk of brain metastases in SCLC is approximately 50% at 2 years,^22-24 whereas, with a median follow-up time of 26.5 months, only 8 patients (23%) developed brain metastasis in our study, suggesting that dose-intensified IP induction chemotherapy may improve systemic control of disease.

In conclusion, IP induction chemotherapy followed by EP chemotherapy with concurrent TDTRT showed promising activity with favorable 1- and 2-year survival rates. On the basis of the favorable outcome in this trial, the role of induction IP chemotherapy in the treatment of LD-SCLC should be evaluated in a large phase III trial.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported in part by NCC Grant 0210140 from National Cancer Center, Korea.

Irinotecan was provided by Aventis Korea.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted December 22, 2004; accepted March 8, 2005.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Han, J.-Y. Articles by Lee, J. S. Search for Related Content PubMed PubMed Citation Articles by Han, J.-Y. Articles by Lee, J. S. Social Bookmarking                            What's this?