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Simultaneous chemoradiotherapy with irinotecan and cisplatin in limited disease small cell lung cancer: A phase I study
Lung Cancer (2006) 53, 183—188
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Simultaneous chemoradiotherapy with irinotecan and cisplatin in limited disease small cell lung cancer: A phase I study Gunther Klautke a,∗, Sebastian F¨ ahndrich b, Sabine Semrau a, Claudia B¨ uscher a, Christian Virchow b, Rainer Fietkau a a b
Department of Radiotherapy, University Hospital, University of Rostock, S¨ udring 75, 18059 Rostock, Germany Department of Pneumology, University Hospital, Rostock, Germany
Received 14 February 2006; received in revised form 21 April 2006; accepted 24 April 2006
KEYWORDS Small cell lung cancer; Limited disease; Simultaneous chemoradiotherapy; Irinotecan; Early radiotherapy
Summary Introduction: Early radiotherapy concurrent with chemotherapy appears to have prognostic benefits in patients with limited disease SCLC. Irinotecan/cisplatin have been shown to be superior to a standard treatment with etoposide/cisplatin in extensive disease SCLC. The present phase I study aims to assess the feasibility of irinotecan/cisplatin administered concurrently with radiotherapy. Patients and methods: Twelve patients were treated concurrently with conventional fractionated radiotherapy (1.8—45 Gy + 9 Gy (RP)) and two cycles of irinotecan (40/50/60 mg/m2 , Day 1/8/15, 29/36/43) and cisplatin (20 mg/m2 , Days 1—3, 29—31), and four cycles of consolidation chemotherapy (CT). In addition, patients in complete remission (CR) received prophylactic cranial irradiation (PCI). Dose-limiting toxicity (DLT) was defined as any case grade III/IV nonhematological toxicity (esophagitis grade IV), grade IV leukopenia or grades III/IV thrombopenia (CTC) during RCT. Results: No DLT was observed; an irinotecan dose of 60 mg/m2 is recommended. 3/12 patients developed grade III leukopenia, one grade II pneumonitis. The predominant toxicity was esophagitis, grade II in 7/12 patients, grade III in 5/12. After RCT 7/12 patients were in CR, systemic progression was not observed during RCT. Conclusion: Concurrent RCT with irinotecan (60 mg/m2 ) and cisplatin followed by four cycles of CT can be safely administered. © 2006 Elsevier Ireland Ltd. All rights reserved.
1. Introduction ∗ Corresponding author. Tel.: +49 381 4949001; fax: +49 381 4949002. E-mail address: [email protected] (G. Klautke).
Small cell lung cancer (SCLC) is characterized by a rapid tumor doubling time, a high rate of local tumor recurrence, and the early formation of distant metastases. For prog-
0169-5002/$ — see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2006.04.012
184 nostic and treatment planning purposes, SCLC is classified according to tumor extent: limited disease (LD) SCLC is restricted to the initial ipsilateral hemithorax region and to the ipsi- and contralateral mediastinal and supraclavicular lymph node region, whereas distant metastases are present in extensive disease (ED) SCLC. Chemotherapy is an important pillar of treatment in both stages of the disease. Despite the good chemosensitivity of the disease, local recurrences occur in up to 90% of cases treated by chemotherapy alone [1]. Two meta-analyses of LD—SCLC treatment showed that additional local irradiation can significantly improve the local recurrence rate as well as the overall survival rate [2,3]. Several studies and metaanalyses have shown that early radiotherapy concomitant with chemotherapy has prognostic advantages for patients with LD—SCLC [4—6]. The combination of etoposide plus cisplatin or carboplatin is regarded as the standard form of chemotherapy in these patients [7—9]. However, this drug combination proved to be inferior to irinotecan plus cisplatin in a Japanese phase III study of patients with ED—SCLC [10]. Their irinotecan + cisplatin group achieved better response rates (objective remission 85% versus 67%) and a significantly better median survival time (12.8 months versus 9.4 months; p = 0.002). The results of a similar study with different dosages were presented at the ASCO 2005 [11]; the investigators did not observe any advantages in regard to survival, but acute toxicity was lower in the group treated with irinotecan. This phase I study was designed to determine the feasibility and maximum tolerable dose, i.e., dose-limiting toxicity, of irinotecan when used in combination with cisplatin and radiotherapy as part of a simultaneous chemoradiotherapy regimen. It was also designed to provide preliminary data on response rates.
2. Patients and methods 2.1. Patient characteristics From 1 November 2003 to 1 June 2005, five female and seven male patients, aged 44—66 years (median 63 years) with histologically confirmed SCLC were recruited into the study.
2.2. Inclusion criteria Limited disease SCLC according to the definition of the Veterans Administration Lung Cancer Study Group (VALG): primary tumor, localisized at one hemithorax region, with or without involved ipsilateral or/and contralateral mediastinal lymph nodes, with or without involved supracavicular lymph nodes, with or without pleural effusion; Karnofsky performance status of 70% or higher; adequate liver (bilirubin <1.25 times normal, GOT and GPT <3 times normal), kidney (creatinine <1.25 times normal, creatinine clearance >60 ml/min), lung (diffusion capacity >60%, FEV1 >1.4l) and bone marrow function (Hb >11 g/dl, leukocytes >3000 (mm3 )−1 , platelets >100,000 (mm3 )−1 ). CT scans of the chest and abdomen, bone scintigraphy, and MRI of the neurocranium were carried out for tumor staging.
G. Klautke et al.
2.3. Exclusion criteria Prior chemotherapy, secondary malignancy and contraindications to irinoteca and cisplatin or to chemotherapy and radiotherapy in general. Of the 12 cases treated, 2 were classified stage cT2, 2 stage cT3, and 8 stage cT4. Ipsilateral lymph nodes were involved in seven patients (cN2), and both ipsi- and contralateral nodes were affected in the remaining five cases (cN3). The tumors were moderately differentiated (G2) in 3/12 cases, and poorly differentiated (G3) in 9/12 cases. Neuron-specific enolase (NSE) levels were elevated in all cases. The mean time between histological confirmation and the start of treatment was 13 days. The necessary diagnostic examinations and treatment planning measures, including radiotherapy planning and determination of the patient’s suitability for chemotherapy, were carried out during this period.
2.4. Radiotherapy In all cases, three-dimensional treatment planning was performed using planning CT scans with contrast enhancement and a 0.5 cm slice thickness. The second-order target volume includes the primary tumor, the mediastinal lymph drainage area with the hilar lymph node stations on both sides and, in the case of upper lobe involvement, the ipsilateral supraclavicular lymph drainage area. The safety margin to the lung was 1 cm. In patients with atelectasis or a large tumor volume, irradiation planning was repeated with a current planning CT in order to adjust radiotherapy according to treatment response so as to protect the healthy lung tissue. The first-order planning target volume included the primary tumor and involved lymph nodes (>1.5 cm in CT) as well as a 1 cm safety margin. Radiotherapy was performed as multi-field irradiation with individual collimated fields. The patients received conventionally fractionated radiotherapy, with individual doses ranging from 1.8 Gy (PR) to 45 Gy, and a 9 Gy boost. We decided not to use hyperfractionated, accelerated radiation since it is associated with higher acute toxicity. A total dose of 54 Gy was delivered because the German Cancer Society recommends a total radiation dose in conventionally fractionation from more than 45—50 Gy, and the total dose of 54 Gy is biologically equivalent to 45 Gy in a hyperfractionated accelerated fractionation. The tolerance doses for organs at risk, e.g., the lung and the spinal cord, were taken into consideration. After completion of RCT and consolidation chemotherapy, prophylactic cranial irradiation (PCI) was carried out in patients who had achieved a histologically confirmed complete remission as determined in subsequent restaging assessments, including cranial MRI. PCI was administered using single doses of 1.8 Gy (RP) and a total dose of 36 Gy applied to two coplanar opposed lateral fields.
2.5. Chemotherapy Weekly 90-min infusions of irinotecan were administered on Days 1, 8 and 15 at doses of either 40, 50 or 60 mg/m2 , depending on the elected dose level; in the case of cisplatin, fixed doses of 20 mg/m2 were administered on Days 1—3.
Concurrent RCT with irinotecan and cisplatin in limited disease SCLC The next cycle began on Day 28; a total of six chemotherapy cycles (two simultaneous with radiotherapy and four as consolidation chemotherapy) were planned. Blood counts were performed twice weekly and prior to each chemotherapy cycle. In cases where leukocytes were <3000 (mm3 )−1 or platelets <100,000 (mm3 )−1 , chemotherapy was postponed until the counts rose to the threshold levels. If RCT at a given irinotecan dose did not induce any dose-limiting toxicity in three patients, then the irinotecan dose was increased to the next higher level for the next patients. If dose-limiting toxicity occurred, then the same dose level was used in the next three patients. Except for hair loss and esophagitis, dose-limiting toxicity was defined as any type of nonhematological toxicity more severe or equivalent to CTC grade III, any case of CTC grade III thrombocytopenia, and CTC grade IV neutropenia leading to complications (temperature over 38.5 ◦ C, clinical signs of infection) or persisting for more than 7 days. Consolidation chemotherapy was carried out using the same irinotecan dose as in cycles 1 and 2 of radiochemotherapy.
2.6. Supportive care Because of the intensity and dose density of treatment, special consideration was given to supportive care which was administered early and symptom-oriented. Grade II esophagitis was treated with analgesics in accordance with the WHO staging scheme, and the patients were placed on formula diets for additional enteral nutrition. The patients were switched to parenteral home nutrition early, i.e., as soon as they became unable to feed themselves properly or did not accept enteral nutrition. Red cell concentrates were transfused when hemoglobin values dropped below 10 g/dl; it was also permissible to administer erythropoietin after completion of radiochemotherapy. Patients whose leukocyte levels dropped below 1500 were allowed to receive granulocyte-stimulating agents. Prophylactic doses of dexamethasone 8 mg and ondansetron 8 mg were administered intravenously prior to the administration of cisplatin.
2.7. Statistical analysis The closing date for inclusion in the statistical analysis was 1 August 2005. All patients had completed induction chemoradiotherapy and consolidation chemotherapy by that time.
Table 1
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The data sets were analyzed using SPSS 12.0 software for personal computers. All patients gave their written informed consent to participate in the study. The study had been approved by the local ethics committee.
3. Results 3.1. Toxicity Dose-limiting toxicity did not occur at any of the dose levels investigated in this study. For safety reasons six patients were treated at the highest dose level. Hence, the recommended dose of irinotecan is 60 mg/m2 on Days 1, 8 and 15 in combination with 20 mg/m2 of cisplatin on Days 1, 2 and 3 (repetition of each Day 29) and conventional, fractionated radiotherapy. Of the 12 patients treated, 3 developed CTC grade III leukopenia and 2 developed CTC grade II thrombopenia during RCT. The median hemoglobin value before RCT was 13.5 g/dl; this dropped to a median of 11.6 g/dl by the end of treatment; during RCT, the nadir was a median of 10.6 g/dl. The well-known side effects of high-dose irinotecan, e.g., cholinergic syndrome and acute diarrhea, did not occur in this study; prophylactic doses of atropine were not given prior to irinotecan administration. Clinically, the most prominent acute toxicity was esophagitis: 7/12 patients treated developed CTC grade II esophagitis and 5/12 developed grade III esophagitis during RCT. These cases of esophagitis persisted for 3—4 weeks after completion of RCT (see Table 1 for toxicity during RCT). Lung function tests (FEV1 and diffusion capacity) were performed prior to chemoradiotherapy and at least 6 weeks after completion of RCT. None of the patients experienced a deterioration of lung function, and in two cases, FEV1 and/or diffusion capacity even increased. One patient developed clinical and radiological signs of grade II pneumonitis, which responded well to prednisolone and did not lead to any further complications. One patient developed a rapidly progressive worsening of vision after the fourth cycle of chemotherapy. MRI scans and an ophthalmology consultation did not reveal any clear reason for this; platinum-induced neurotoxicity was assumed to be the most probable cause. Chemotherapy was discontinued at the request of the patient. The patient’s vision
Toxicities occurring during radiochemotherapy and dose levels at which they occurred
Dose-limiting toxicity Diarrhea, CTC stage III/IV Leukopenia, CTC stage II; Thrombopenia, CTC stage II Esophagitis, CTC stage II Esophagitis, CTC stage III Pneumonitis, CTC stage II Worsening of vision CTC, common toxicity criteria.
Dose level 1
Dose level 2
Dose level 3
0/3 0/3 0/3 0/3 3/3 0/3 1/3 0/3
0/3 0/3 2/3 2/3 1/3 2/3 0/3 1/3
0/6 0/6 1/6 0/6 3/6 3/6 0/6 0/6
186 stabilized at the lower level and does not cause any major impairment of his everyday activities.
G. Klautke et al. Table 2 Response to and efficacy of treatment at the various dose levels
3.2. Feasibility of treatment It was possible to administer the complete concurrent chemoradiotherapy regimen to all patients. There was no need to compromise the radiotherapy or chemotherapy dose. It was possible to administer the second cycle of chemotherapy at the scheduled time. The irradiation fields were regularly adjusted in accordance with tumor response. Including the planned reduction after 45 Gy, the irradiation field size was reduced twice in 2/12 patients, three times in 3/12 patients, four times in 3/12 patients, and five times in 4/12 patients. The first course of consolidated chemotherapy (CT) after chemoradiotherapy (=third chemotherapy cycle) could be administered on schedule in all patients; after the fourth chemotherapy cycle (second CT cycle), chemotherapy had to be postponed for 3—10 days in four patients with leukocyte counts <3000 (mm3 )−1 or platelet counts <100,000 (mm3 )−1 . Prophylactic treatment with G-CSF was not used in this study, but was allowed by the protocol if felt necessary to reduce the risk of infections by leucocyte counts <1500 (mm3 )−1 . After the fourth cycle of chemotherapy this intervention was required in four patients (once in two patients and twice in two patients). Overall, 10 of the 12 patients treated were able to receive all six scheduled cycles of chemotherapy (two during and four after radiotherapy). One patient dropped out of chemotherapy after only four cycles due to a deterioration of his vision, and one patient died after the fifth chemotherapy cycle. Thus, it is possible to administer the same dose of chemotherapy in the same dose density and the same dose of radiotherapy by using early concurrent chemoradiotherapy as it is when administer chemotherapy and radiotherapy sequentially.
3.3. Response to and efficacy of treatment A first restaging evaluation (bronchoscopy and CT of the chest and abdomen) was performed after completion of chemoradiotherapy and one cycle of consolidated chemotherapy. Seven of the 12 patients were found to be in complete remission (CR); after completion of chemotherapy, bronchoscopy and CT of the chest and liver did not show any signs of renewed tumor progression in any of these seven patients in CR. However, the MRI examination performed prior to prophylactic irradiation of the neurocranium revealed asymptomatic cerebral metastases in three of the seven patients. Therefore, only 4/7 received the planned prophylactic cranial irradiation (PCI), and the remaining 3/7 received therapeutic cranial irradiation (2—40 Gy). The other 5/12 patients were found to be in partial remission (PR). Thus, the treatment response, defined as an objectively measurable remission, was 100%. None of the patients developed distant metastases during RCT. Because of the consolidated chemotherapy, none of the patients in partial remission was able to achieve complete remission.
CR at first restaging (without cranial MRI) CR after RCT + CT (with cranial MRI) Local recurrence Cerebral metastases Hepatic metastases Death (tumor-related) Death (intercurrent)
Level 1
Level 2
Level 3
2/3
0/3
5/6
1/3
0/3
3/6
1/3 1/3 0/3 1/3 0/3
0/3 0/3 1/3 1/3 1/3
0/6 2/6 1/6 0/6 0/6
CT, consolidation chemotherapy; CR, complete remission; MRI, magnetic resonance imaging; and RCT, radiochemotherapy.
Tumor progression has been detected in 6 of the 12 patients so far. After 12 months, one patient still at the first dose level developed a local recurrence in the region that was irradiated at 54 Gy. After it was determined that no distant metastases were present, this patient again received chemoradiotherapy, this time using etoposide plus cisplatin. Cerebral metastases were detected in three patients with otherwise complete remission, and two other patients developed liver metastases after 7 and 9 months. Three of the 12 patients have died to date. One, treated at the second dose level, developed a new occurrence of liver metastases; her general condition then deteriorated rapidly, and the patient died after 7 months. The second died of cerebral metastases after 15 months. The third died of pneumonia exacerbated by chronic bronchitis 1 month after completion of chemotherapy. In the latter case, imaging studies had not revealed any signs of pneumonitis, and the patient’s lung function had even improved after chemoradiotherapy (see Table 2 for summary of response and efficacy data). Due to the small number of cases and the brevity of the follow-up period, the statistical data on progression-free survival and one-year survival must be assessed with caution. At the time of analysis, the median time to progression was 12 months, and a 1-year survival rate of 91 ± 7% had been achieved. The median survival time had not yet been reached at a median follow-up of 13.5 ± 5 months.
4. Discussion When administered in combination with cisplatin (20 mg/m2 on Days 1—3) and radiotherapy for treatment of limited disease SCLC, the maximum tolerable dose of irinotecan is 60 mg/m2 on Days 1, 8 and 15. The chemotherapy dose used in the present study was therefore identical to that used in Noda’s phase III study of patients with extensive disease SCLC [10]. This demonstrates that early administration of radiotherapy in conjunction with chemotherapy does not necessitate a dose compromise, i.e., dose reduction. However, intensive supportive care is required for prevention and treatment of esophagitis. The rate of esophagitis depends on the irradiated volume of the esophagus and the total radiation dose, the fractiona-
Concurrent RCT with irinotecan and cisplatin in limited disease SCLC tion and the applied chemotherapeutic agents. So it is difficult to compare the rates of esophagitis of different studies. Turrisi [8] reported a rate of grade III/IV esophagitis in a hyperfractionated accelerated radiation schedule of 32%. We choose a conventional fractionation schema with the aim of reducing the rate of esophagitis but used a total radiation dose with comparable biological efficacy. The radiation volume was different in the two studies, the contralateral hilus was not included in the study of Turrisi, radiation of the supraclavicular fossa was also forbidden. Thus, the rate of grade III esophagitis in our study of 42% may be explained by these radiotherapeutic factors as well as a stronger radiosensitizing potential of irinotecan compared to etoposide used by Turrisi. This form of early radiotherapy makes it possible to improve overall survival without the need for further intensification of treatment. In one meta-analysis [5], early radiotherapy improved 2-year survival by 60% and 3-year survival by 49%. Another meta-analysis [6] has confirmed these findings. The most recent meta-analysis on this subject [12] was unable to demonstrate such clear benefits of early radiotherapy for 2- and 3-year survival, but did show a statistically significant advantage for 5-year survival. In the present study, we elected to use conventional fractionation due to uncertainties regarding the optimal form of fractionation during concurrent chemoradiotherapy. To shed light on this issue, Turrisi [8] conducted a randomized comparison study of concurrent chemoradiotherapy with etoposide plus cisplatin in patients with limited disease SCLC; some of them received conventional fractionated radiotherapy (1.8—45 Gy), while others received hyperfractionated, accelerated radiotherapy (2 × 1.5—45 Gy). Median survival in the group of patients receiving hyperfractionated, accelerated radiotherapy was significantly higher than in the other group (23 months versus 19 months; p = 0.04); however, the prevalence of grade 3 esophagitis was significantly higher (27% versus 11%; p < 0.001). The relatively low dose (45 Gy) used in the conventional treatment arm is a source of criticism of this study. Other investigators [13,14] have since shown that local control is significantly better at conventional fractionated radiotherapy doses of 50 Gy and higher than at 40 and 45 Gy, respectively, and that these higher doses also have a positive effect on total survival. A phase I study [15] to find the maximum tolerable radiation dose in hyperfractionated, accelerated radiotherapy versus conventional fractionated radiotherapy administered simultaneously with chemotherapy indicated that the maximum tolerable dose was 45 Gy in hyperfractionated, accelerated radiotherapy and 70 Gy in conventional fractionated radiotherapy. The corresponding 2- and 3-year survival rates were 52 and 25% and 54 and 35%, respectively. Although the combination of irinotecan plus cisplatin proved to be superior to standard treatment with etoposide plus cisplatin in Noda’s study of extensive disease SCLC, few data are available on the efficacy of irinotecan plus cisplatin in limited disease SCLC. In one phase II study [16], a total of 75 patients with either limited disease SCLC (n = 40) or extensive disease SCLC (n = 35) were treated with irinotecan (60 mg/m2 on Days 1/8/15) and cisplatin (60 mg/m2 on Day 1). Patients with limited disease (LD) received thoracic irradiation after four cycles of chemotherapy. In the LD group,
187
the treatment response, as defined by objectively measurable parameters (objective remission, OR), was 83% (complete remission: 30%); the time to progression was a median 8 months; the median survival time was 14.3 months. In our small-scale phase I study, an objective remission rate of 100% was achieved; local complete remission was observed in 7/12 patients (58%), and complete remission, including the cerebrum, was achieved in 4/12 patients (33%). The time to tumor progression in our patients was a median 12 months. The better remission rates and median tumor-free survival times achieved in our study at otherwise identical dosages could be attributable to our strategy of early radiotherapy administration. As can be seen in Table 2, three patients developed brain metastases. This could be a hint that the concentration of the chemotherapy in the CSF and brain is too low to prevent the manifestation of brain metastases. Therefore, one has to consider prophylactic cranial irradiation sooner in the treatment schedule in patients with complete response after chemoradiotherapy, for example together with the first course of consolidation chemotherapy. A second Japanese research group [17] conducted a phase I study comparable to ours. They also administered 60 mg/m2 of cisplatin on Day 1 and increased the initial irinotecan dose of 40 mg/m2 on Days 1, 8, and 15—50 or 60 mg/m2 . Their treatment protocol provided for four treatment cycles. In each case, radiotherapy was started on Day 2 of chemotherapy and was administered in three series of 20 Gy (10 × 2 Gy) to yield a total dose of 60 Gy. In their study, fatigue was indicated as the dose-limiting toxicity, and the recommended dose of irinotecan was 40 mg/m2 . Doselimiting toxicities were defined differently in our study; however, we did not observe any marked symptoms of fatigue in our patients, who received intensive supportive care in the form of transfusions and/or erythropoietin at Hb levels below 10 g/dl. The response rate in Oka’s study (4/16 complete remission, 11/16 partial remission, 1/16 stable disease) was somewhat lower than in our group; this was probably due to the fact that their split course radiotherapy technique has unfavorable biological and radiooncological effects on the tumor. In our study, 1 of 12 patients developed symptomatic grade II radiogenic pneumonitis, which responded well to medication and no longer requires treatment. In contrast, pneumonitis, among other things, was a dose-limiting toxicity observed in a phase I/II study of non-small cell lung cancer (NSCLC) patients treated with weekly doses of irinotecan concurrent with a thoracic irradiation dose of 60 Gy [18]. These differences in the rates of pneumonitis might be related to the fact that radiation volume was regularly adjusted in accordance with the individual tumor response. Likewise, radiation planning was repeated whenever atelectasis was observed. In conclusion, the present study demonstrates that radiotherapy concurrent with two cycles of chemotherapy consisting of irinotecan (60 mg/m2 on Days 1/8/15) plus cisplatin (20 mg/m2 on Days 1—3) followed by four cycles of consolidation chemotherapy with the same doses of the drugs can be safely administered. The high response rates and the efficacy of this treatment regimen are now being further investigated in a subsequent phase II study.
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Acknowledgment Supported in part by a grant from Aventis Pharma GmbH, Bad Soden am Taunus, Germany.
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G. Klautke et al. [10] Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, Yokoyama A, et al. Japan clinical oncology group: irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002;346(2): 85—91. [11] Hanna NH, Einhorn L, Sandler A, Langer C, Hariharan S, Ansari R, et al. Randomized, phase III trial comparing irinotecan/cisplatin (IP) with etoposide/cisplatin (EP) in patients (pts) with previously untreated, extensive-stage (ES) small cell lung cancer (SCLC). ASCO 2005 [Abstract 7004]. [12] Pijls-Johannesma MC, De Ruysscher D, Lambin P, Rutten I, Vansteenkiste JF. Early versus late chest radiotherapy foe limited stage small cell lung cancer. Cochrane Database Syst Rev 2005;25(1). [13] Tada T, Minakuchi K, Koda M, Masuda N, Matsui K, Kawase I, et al. Limited-stage small cell lung cancer: local failure after chemotherapy and radiation therapy. Radiology 1998;208(2):511—5. [14] Roof KS, Fidias P, Lynch TJ, Ancukiewicz M, Choi NC. Radiation dose escalation in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2003;57(3):701—8. [15] Choi NC, Herndon II JE, Rosenman J, Carey RW, Chung CT, Bernard S, et al. Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated—–accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer. J Clin Oncol 1998;16(11):3528—36. [16] Kudoh S, Fujiwara Y, Takada Y, Yamamoto H, Kinoshita A, Ariyoshi Y, et al. Phase II study of irinotecan combined with cisplatin in patients with previously untreated smallcell lung cancer. West Japan lung cancer group. J Clin Oncol 1998;16(3):1068—74. [17] Oka M, Fukuda M, Kuba M, Ichiki M, Rikimaru T, Soda H, et al. Phase I study of irinotecan and cisplatin with concurrent splitcourse radiotherapy in limited-disease small-cell lung cancer. Eur J Cancer 2002;38(15):1998—2004. [18] Takeda K, Negoro S, Kudoh S, Okishio K, Masuda N, Takada M, et al. Phase I/II study of weekly irinotecan and concurrent radiation therapy for locally advanced non-small cell lung cancer. Br J Cancer 1999;79(9—10):1462—7.
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journal homepage: www.elsevier.com/locate/lungcan
Simultaneous chemoradiotherapy with irinotecan and cisplatin in limited disease small cell lung cancer: A phase I study Gunther Klautke a,∗, Sebastian F¨ ahndrich b, Sabine Semrau a, Claudia B¨ uscher a, Christian Virchow b, Rainer Fietkau a a b
Department of Radiotherapy, University Hospital, University of Rostock, S¨ udring 75, 18059 Rostock, Germany Department of Pneumology, University Hospital, Rostock, Germany
Received 14 February 2006; received in revised form 21 April 2006; accepted 24 April 2006
KEYWORDS Small cell lung cancer; Limited disease; Simultaneous chemoradiotherapy; Irinotecan; Early radiotherapy
Summary Introduction: Early radiotherapy concurrent with chemotherapy appears to have prognostic benefits in patients with limited disease SCLC. Irinotecan/cisplatin have been shown to be superior to a standard treatment with etoposide/cisplatin in extensive disease SCLC. The present phase I study aims to assess the feasibility of irinotecan/cisplatin administered concurrently with radiotherapy. Patients and methods: Twelve patients were treated concurrently with conventional fractionated radiotherapy (1.8—45 Gy + 9 Gy (RP)) and two cycles of irinotecan (40/50/60 mg/m2 , Day 1/8/15, 29/36/43) and cisplatin (20 mg/m2 , Days 1—3, 29—31), and four cycles of consolidation chemotherapy (CT). In addition, patients in complete remission (CR) received prophylactic cranial irradiation (PCI). Dose-limiting toxicity (DLT) was defined as any case grade III/IV nonhematological toxicity (esophagitis grade IV), grade IV leukopenia or grades III/IV thrombopenia (CTC) during RCT. Results: No DLT was observed; an irinotecan dose of 60 mg/m2 is recommended. 3/12 patients developed grade III leukopenia, one grade II pneumonitis. The predominant toxicity was esophagitis, grade II in 7/12 patients, grade III in 5/12. After RCT 7/12 patients were in CR, systemic progression was not observed during RCT. Conclusion: Concurrent RCT with irinotecan (60 mg/m2 ) and cisplatin followed by four cycles of CT can be safely administered. © 2006 Elsevier Ireland Ltd. All rights reserved.
1. Introduction ∗ Corresponding author. Tel.: +49 381 4949001; fax: +49 381 4949002. E-mail address: [email protected] (G. Klautke).
Small cell lung cancer (SCLC) is characterized by a rapid tumor doubling time, a high rate of local tumor recurrence, and the early formation of distant metastases. For prog-
0169-5002/$ — see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2006.04.012
184 nostic and treatment planning purposes, SCLC is classified according to tumor extent: limited disease (LD) SCLC is restricted to the initial ipsilateral hemithorax region and to the ipsi- and contralateral mediastinal and supraclavicular lymph node region, whereas distant metastases are present in extensive disease (ED) SCLC. Chemotherapy is an important pillar of treatment in both stages of the disease. Despite the good chemosensitivity of the disease, local recurrences occur in up to 90% of cases treated by chemotherapy alone [1]. Two meta-analyses of LD—SCLC treatment showed that additional local irradiation can significantly improve the local recurrence rate as well as the overall survival rate [2,3]. Several studies and metaanalyses have shown that early radiotherapy concomitant with chemotherapy has prognostic advantages for patients with LD—SCLC [4—6]. The combination of etoposide plus cisplatin or carboplatin is regarded as the standard form of chemotherapy in these patients [7—9]. However, this drug combination proved to be inferior to irinotecan plus cisplatin in a Japanese phase III study of patients with ED—SCLC [10]. Their irinotecan + cisplatin group achieved better response rates (objective remission 85% versus 67%) and a significantly better median survival time (12.8 months versus 9.4 months; p = 0.002). The results of a similar study with different dosages were presented at the ASCO 2005 [11]; the investigators did not observe any advantages in regard to survival, but acute toxicity was lower in the group treated with irinotecan. This phase I study was designed to determine the feasibility and maximum tolerable dose, i.e., dose-limiting toxicity, of irinotecan when used in combination with cisplatin and radiotherapy as part of a simultaneous chemoradiotherapy regimen. It was also designed to provide preliminary data on response rates.
2. Patients and methods 2.1. Patient characteristics From 1 November 2003 to 1 June 2005, five female and seven male patients, aged 44—66 years (median 63 years) with histologically confirmed SCLC were recruited into the study.
2.2. Inclusion criteria Limited disease SCLC according to the definition of the Veterans Administration Lung Cancer Study Group (VALG): primary tumor, localisized at one hemithorax region, with or without involved ipsilateral or/and contralateral mediastinal lymph nodes, with or without involved supracavicular lymph nodes, with or without pleural effusion; Karnofsky performance status of 70% or higher; adequate liver (bilirubin <1.25 times normal, GOT and GPT <3 times normal), kidney (creatinine <1.25 times normal, creatinine clearance >60 ml/min), lung (diffusion capacity >60%, FEV1 >1.4l) and bone marrow function (Hb >11 g/dl, leukocytes >3000 (mm3 )−1 , platelets >100,000 (mm3 )−1 ). CT scans of the chest and abdomen, bone scintigraphy, and MRI of the neurocranium were carried out for tumor staging.
G. Klautke et al.
2.3. Exclusion criteria Prior chemotherapy, secondary malignancy and contraindications to irinoteca and cisplatin or to chemotherapy and radiotherapy in general. Of the 12 cases treated, 2 were classified stage cT2, 2 stage cT3, and 8 stage cT4. Ipsilateral lymph nodes were involved in seven patients (cN2), and both ipsi- and contralateral nodes were affected in the remaining five cases (cN3). The tumors were moderately differentiated (G2) in 3/12 cases, and poorly differentiated (G3) in 9/12 cases. Neuron-specific enolase (NSE) levels were elevated in all cases. The mean time between histological confirmation and the start of treatment was 13 days. The necessary diagnostic examinations and treatment planning measures, including radiotherapy planning and determination of the patient’s suitability for chemotherapy, were carried out during this period.
2.4. Radiotherapy In all cases, three-dimensional treatment planning was performed using planning CT scans with contrast enhancement and a 0.5 cm slice thickness. The second-order target volume includes the primary tumor, the mediastinal lymph drainage area with the hilar lymph node stations on both sides and, in the case of upper lobe involvement, the ipsilateral supraclavicular lymph drainage area. The safety margin to the lung was 1 cm. In patients with atelectasis or a large tumor volume, irradiation planning was repeated with a current planning CT in order to adjust radiotherapy according to treatment response so as to protect the healthy lung tissue. The first-order planning target volume included the primary tumor and involved lymph nodes (>1.5 cm in CT) as well as a 1 cm safety margin. Radiotherapy was performed as multi-field irradiation with individual collimated fields. The patients received conventionally fractionated radiotherapy, with individual doses ranging from 1.8 Gy (PR) to 45 Gy, and a 9 Gy boost. We decided not to use hyperfractionated, accelerated radiation since it is associated with higher acute toxicity. A total dose of 54 Gy was delivered because the German Cancer Society recommends a total radiation dose in conventionally fractionation from more than 45—50 Gy, and the total dose of 54 Gy is biologically equivalent to 45 Gy in a hyperfractionated accelerated fractionation. The tolerance doses for organs at risk, e.g., the lung and the spinal cord, were taken into consideration. After completion of RCT and consolidation chemotherapy, prophylactic cranial irradiation (PCI) was carried out in patients who had achieved a histologically confirmed complete remission as determined in subsequent restaging assessments, including cranial MRI. PCI was administered using single doses of 1.8 Gy (RP) and a total dose of 36 Gy applied to two coplanar opposed lateral fields.
2.5. Chemotherapy Weekly 90-min infusions of irinotecan were administered on Days 1, 8 and 15 at doses of either 40, 50 or 60 mg/m2 , depending on the elected dose level; in the case of cisplatin, fixed doses of 20 mg/m2 were administered on Days 1—3.
Concurrent RCT with irinotecan and cisplatin in limited disease SCLC The next cycle began on Day 28; a total of six chemotherapy cycles (two simultaneous with radiotherapy and four as consolidation chemotherapy) were planned. Blood counts were performed twice weekly and prior to each chemotherapy cycle. In cases where leukocytes were <3000 (mm3 )−1 or platelets <100,000 (mm3 )−1 , chemotherapy was postponed until the counts rose to the threshold levels. If RCT at a given irinotecan dose did not induce any dose-limiting toxicity in three patients, then the irinotecan dose was increased to the next higher level for the next patients. If dose-limiting toxicity occurred, then the same dose level was used in the next three patients. Except for hair loss and esophagitis, dose-limiting toxicity was defined as any type of nonhematological toxicity more severe or equivalent to CTC grade III, any case of CTC grade III thrombocytopenia, and CTC grade IV neutropenia leading to complications (temperature over 38.5 ◦ C, clinical signs of infection) or persisting for more than 7 days. Consolidation chemotherapy was carried out using the same irinotecan dose as in cycles 1 and 2 of radiochemotherapy.
2.6. Supportive care Because of the intensity and dose density of treatment, special consideration was given to supportive care which was administered early and symptom-oriented. Grade II esophagitis was treated with analgesics in accordance with the WHO staging scheme, and the patients were placed on formula diets for additional enteral nutrition. The patients were switched to parenteral home nutrition early, i.e., as soon as they became unable to feed themselves properly or did not accept enteral nutrition. Red cell concentrates were transfused when hemoglobin values dropped below 10 g/dl; it was also permissible to administer erythropoietin after completion of radiochemotherapy. Patients whose leukocyte levels dropped below 1500 were allowed to receive granulocyte-stimulating agents. Prophylactic doses of dexamethasone 8 mg and ondansetron 8 mg were administered intravenously prior to the administration of cisplatin.
2.7. Statistical analysis The closing date for inclusion in the statistical analysis was 1 August 2005. All patients had completed induction chemoradiotherapy and consolidation chemotherapy by that time.
Table 1
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The data sets were analyzed using SPSS 12.0 software for personal computers. All patients gave their written informed consent to participate in the study. The study had been approved by the local ethics committee.
3. Results 3.1. Toxicity Dose-limiting toxicity did not occur at any of the dose levels investigated in this study. For safety reasons six patients were treated at the highest dose level. Hence, the recommended dose of irinotecan is 60 mg/m2 on Days 1, 8 and 15 in combination with 20 mg/m2 of cisplatin on Days 1, 2 and 3 (repetition of each Day 29) and conventional, fractionated radiotherapy. Of the 12 patients treated, 3 developed CTC grade III leukopenia and 2 developed CTC grade II thrombopenia during RCT. The median hemoglobin value before RCT was 13.5 g/dl; this dropped to a median of 11.6 g/dl by the end of treatment; during RCT, the nadir was a median of 10.6 g/dl. The well-known side effects of high-dose irinotecan, e.g., cholinergic syndrome and acute diarrhea, did not occur in this study; prophylactic doses of atropine were not given prior to irinotecan administration. Clinically, the most prominent acute toxicity was esophagitis: 7/12 patients treated developed CTC grade II esophagitis and 5/12 developed grade III esophagitis during RCT. These cases of esophagitis persisted for 3—4 weeks after completion of RCT (see Table 1 for toxicity during RCT). Lung function tests (FEV1 and diffusion capacity) were performed prior to chemoradiotherapy and at least 6 weeks after completion of RCT. None of the patients experienced a deterioration of lung function, and in two cases, FEV1 and/or diffusion capacity even increased. One patient developed clinical and radiological signs of grade II pneumonitis, which responded well to prednisolone and did not lead to any further complications. One patient developed a rapidly progressive worsening of vision after the fourth cycle of chemotherapy. MRI scans and an ophthalmology consultation did not reveal any clear reason for this; platinum-induced neurotoxicity was assumed to be the most probable cause. Chemotherapy was discontinued at the request of the patient. The patient’s vision
Toxicities occurring during radiochemotherapy and dose levels at which they occurred
Dose-limiting toxicity Diarrhea, CTC stage III/IV Leukopenia, CTC stage II; Thrombopenia, CTC stage II Esophagitis, CTC stage II Esophagitis, CTC stage III Pneumonitis, CTC stage II Worsening of vision CTC, common toxicity criteria.
Dose level 1
Dose level 2
Dose level 3
0/3 0/3 0/3 0/3 3/3 0/3 1/3 0/3
0/3 0/3 2/3 2/3 1/3 2/3 0/3 1/3
0/6 0/6 1/6 0/6 3/6 3/6 0/6 0/6
186 stabilized at the lower level and does not cause any major impairment of his everyday activities.
G. Klautke et al. Table 2 Response to and efficacy of treatment at the various dose levels
3.2. Feasibility of treatment It was possible to administer the complete concurrent chemoradiotherapy regimen to all patients. There was no need to compromise the radiotherapy or chemotherapy dose. It was possible to administer the second cycle of chemotherapy at the scheduled time. The irradiation fields were regularly adjusted in accordance with tumor response. Including the planned reduction after 45 Gy, the irradiation field size was reduced twice in 2/12 patients, three times in 3/12 patients, four times in 3/12 patients, and five times in 4/12 patients. The first course of consolidated chemotherapy (CT) after chemoradiotherapy (=third chemotherapy cycle) could be administered on schedule in all patients; after the fourth chemotherapy cycle (second CT cycle), chemotherapy had to be postponed for 3—10 days in four patients with leukocyte counts <3000 (mm3 )−1 or platelet counts <100,000 (mm3 )−1 . Prophylactic treatment with G-CSF was not used in this study, but was allowed by the protocol if felt necessary to reduce the risk of infections by leucocyte counts <1500 (mm3 )−1 . After the fourth cycle of chemotherapy this intervention was required in four patients (once in two patients and twice in two patients). Overall, 10 of the 12 patients treated were able to receive all six scheduled cycles of chemotherapy (two during and four after radiotherapy). One patient dropped out of chemotherapy after only four cycles due to a deterioration of his vision, and one patient died after the fifth chemotherapy cycle. Thus, it is possible to administer the same dose of chemotherapy in the same dose density and the same dose of radiotherapy by using early concurrent chemoradiotherapy as it is when administer chemotherapy and radiotherapy sequentially.
3.3. Response to and efficacy of treatment A first restaging evaluation (bronchoscopy and CT of the chest and abdomen) was performed after completion of chemoradiotherapy and one cycle of consolidated chemotherapy. Seven of the 12 patients were found to be in complete remission (CR); after completion of chemotherapy, bronchoscopy and CT of the chest and liver did not show any signs of renewed tumor progression in any of these seven patients in CR. However, the MRI examination performed prior to prophylactic irradiation of the neurocranium revealed asymptomatic cerebral metastases in three of the seven patients. Therefore, only 4/7 received the planned prophylactic cranial irradiation (PCI), and the remaining 3/7 received therapeutic cranial irradiation (2—40 Gy). The other 5/12 patients were found to be in partial remission (PR). Thus, the treatment response, defined as an objectively measurable remission, was 100%. None of the patients developed distant metastases during RCT. Because of the consolidated chemotherapy, none of the patients in partial remission was able to achieve complete remission.
CR at first restaging (without cranial MRI) CR after RCT + CT (with cranial MRI) Local recurrence Cerebral metastases Hepatic metastases Death (tumor-related) Death (intercurrent)
Level 1
Level 2
Level 3
2/3
0/3
5/6
1/3
0/3
3/6
1/3 1/3 0/3 1/3 0/3
0/3 0/3 1/3 1/3 1/3
0/6 2/6 1/6 0/6 0/6
CT, consolidation chemotherapy; CR, complete remission; MRI, magnetic resonance imaging; and RCT, radiochemotherapy.
Tumor progression has been detected in 6 of the 12 patients so far. After 12 months, one patient still at the first dose level developed a local recurrence in the region that was irradiated at 54 Gy. After it was determined that no distant metastases were present, this patient again received chemoradiotherapy, this time using etoposide plus cisplatin. Cerebral metastases were detected in three patients with otherwise complete remission, and two other patients developed liver metastases after 7 and 9 months. Three of the 12 patients have died to date. One, treated at the second dose level, developed a new occurrence of liver metastases; her general condition then deteriorated rapidly, and the patient died after 7 months. The second died of cerebral metastases after 15 months. The third died of pneumonia exacerbated by chronic bronchitis 1 month after completion of chemotherapy. In the latter case, imaging studies had not revealed any signs of pneumonitis, and the patient’s lung function had even improved after chemoradiotherapy (see Table 2 for summary of response and efficacy data). Due to the small number of cases and the brevity of the follow-up period, the statistical data on progression-free survival and one-year survival must be assessed with caution. At the time of analysis, the median time to progression was 12 months, and a 1-year survival rate of 91 ± 7% had been achieved. The median survival time had not yet been reached at a median follow-up of 13.5 ± 5 months.
4. Discussion When administered in combination with cisplatin (20 mg/m2 on Days 1—3) and radiotherapy for treatment of limited disease SCLC, the maximum tolerable dose of irinotecan is 60 mg/m2 on Days 1, 8 and 15. The chemotherapy dose used in the present study was therefore identical to that used in Noda’s phase III study of patients with extensive disease SCLC [10]. This demonstrates that early administration of radiotherapy in conjunction with chemotherapy does not necessitate a dose compromise, i.e., dose reduction. However, intensive supportive care is required for prevention and treatment of esophagitis. The rate of esophagitis depends on the irradiated volume of the esophagus and the total radiation dose, the fractiona-
Concurrent RCT with irinotecan and cisplatin in limited disease SCLC tion and the applied chemotherapeutic agents. So it is difficult to compare the rates of esophagitis of different studies. Turrisi [8] reported a rate of grade III/IV esophagitis in a hyperfractionated accelerated radiation schedule of 32%. We choose a conventional fractionation schema with the aim of reducing the rate of esophagitis but used a total radiation dose with comparable biological efficacy. The radiation volume was different in the two studies, the contralateral hilus was not included in the study of Turrisi, radiation of the supraclavicular fossa was also forbidden. Thus, the rate of grade III esophagitis in our study of 42% may be explained by these radiotherapeutic factors as well as a stronger radiosensitizing potential of irinotecan compared to etoposide used by Turrisi. This form of early radiotherapy makes it possible to improve overall survival without the need for further intensification of treatment. In one meta-analysis [5], early radiotherapy improved 2-year survival by 60% and 3-year survival by 49%. Another meta-analysis [6] has confirmed these findings. The most recent meta-analysis on this subject [12] was unable to demonstrate such clear benefits of early radiotherapy for 2- and 3-year survival, but did show a statistically significant advantage for 5-year survival. In the present study, we elected to use conventional fractionation due to uncertainties regarding the optimal form of fractionation during concurrent chemoradiotherapy. To shed light on this issue, Turrisi [8] conducted a randomized comparison study of concurrent chemoradiotherapy with etoposide plus cisplatin in patients with limited disease SCLC; some of them received conventional fractionated radiotherapy (1.8—45 Gy), while others received hyperfractionated, accelerated radiotherapy (2 × 1.5—45 Gy). Median survival in the group of patients receiving hyperfractionated, accelerated radiotherapy was significantly higher than in the other group (23 months versus 19 months; p = 0.04); however, the prevalence of grade 3 esophagitis was significantly higher (27% versus 11%; p < 0.001). The relatively low dose (45 Gy) used in the conventional treatment arm is a source of criticism of this study. Other investigators [13,14] have since shown that local control is significantly better at conventional fractionated radiotherapy doses of 50 Gy and higher than at 40 and 45 Gy, respectively, and that these higher doses also have a positive effect on total survival. A phase I study [15] to find the maximum tolerable radiation dose in hyperfractionated, accelerated radiotherapy versus conventional fractionated radiotherapy administered simultaneously with chemotherapy indicated that the maximum tolerable dose was 45 Gy in hyperfractionated, accelerated radiotherapy and 70 Gy in conventional fractionated radiotherapy. The corresponding 2- and 3-year survival rates were 52 and 25% and 54 and 35%, respectively. Although the combination of irinotecan plus cisplatin proved to be superior to standard treatment with etoposide plus cisplatin in Noda’s study of extensive disease SCLC, few data are available on the efficacy of irinotecan plus cisplatin in limited disease SCLC. In one phase II study [16], a total of 75 patients with either limited disease SCLC (n = 40) or extensive disease SCLC (n = 35) were treated with irinotecan (60 mg/m2 on Days 1/8/15) and cisplatin (60 mg/m2 on Day 1). Patients with limited disease (LD) received thoracic irradiation after four cycles of chemotherapy. In the LD group,
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the treatment response, as defined by objectively measurable parameters (objective remission, OR), was 83% (complete remission: 30%); the time to progression was a median 8 months; the median survival time was 14.3 months. In our small-scale phase I study, an objective remission rate of 100% was achieved; local complete remission was observed in 7/12 patients (58%), and complete remission, including the cerebrum, was achieved in 4/12 patients (33%). The time to tumor progression in our patients was a median 12 months. The better remission rates and median tumor-free survival times achieved in our study at otherwise identical dosages could be attributable to our strategy of early radiotherapy administration. As can be seen in Table 2, three patients developed brain metastases. This could be a hint that the concentration of the chemotherapy in the CSF and brain is too low to prevent the manifestation of brain metastases. Therefore, one has to consider prophylactic cranial irradiation sooner in the treatment schedule in patients with complete response after chemoradiotherapy, for example together with the first course of consolidation chemotherapy. A second Japanese research group [17] conducted a phase I study comparable to ours. They also administered 60 mg/m2 of cisplatin on Day 1 and increased the initial irinotecan dose of 40 mg/m2 on Days 1, 8, and 15—50 or 60 mg/m2 . Their treatment protocol provided for four treatment cycles. In each case, radiotherapy was started on Day 2 of chemotherapy and was administered in three series of 20 Gy (10 × 2 Gy) to yield a total dose of 60 Gy. In their study, fatigue was indicated as the dose-limiting toxicity, and the recommended dose of irinotecan was 40 mg/m2 . Doselimiting toxicities were defined differently in our study; however, we did not observe any marked symptoms of fatigue in our patients, who received intensive supportive care in the form of transfusions and/or erythropoietin at Hb levels below 10 g/dl. The response rate in Oka’s study (4/16 complete remission, 11/16 partial remission, 1/16 stable disease) was somewhat lower than in our group; this was probably due to the fact that their split course radiotherapy technique has unfavorable biological and radiooncological effects on the tumor. In our study, 1 of 12 patients developed symptomatic grade II radiogenic pneumonitis, which responded well to medication and no longer requires treatment. In contrast, pneumonitis, among other things, was a dose-limiting toxicity observed in a phase I/II study of non-small cell lung cancer (NSCLC) patients treated with weekly doses of irinotecan concurrent with a thoracic irradiation dose of 60 Gy [18]. These differences in the rates of pneumonitis might be related to the fact that radiation volume was regularly adjusted in accordance with the individual tumor response. Likewise, radiation planning was repeated whenever atelectasis was observed. In conclusion, the present study demonstrates that radiotherapy concurrent with two cycles of chemotherapy consisting of irinotecan (60 mg/m2 on Days 1/8/15) plus cisplatin (20 mg/m2 on Days 1—3) followed by four cycles of consolidation chemotherapy with the same doses of the drugs can be safely administered. The high response rates and the efficacy of this treatment regimen are now being further investigated in a subsequent phase II study.
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Acknowledgment Supported in part by a grant from Aventis Pharma GmbH, Bad Soden am Taunus, Germany.
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