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II study of altered schedule of cisplatin and etoposide administration and concurrent accelerated hyperfractionated thoracic radiotherapy for limited-stage small-cell lung cancer
Lung Cancer (2003) 41, 13 /20
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Phase I/II study of altered schedule of cisplatin and etoposide administration and concurrent accelerated hyperfractionated thoracic radiotherapy for limited-stage small-cell lung cancer Yoshihiko Segawaa, Hiroshi Ueokab,*, Katsuyuki Kiurab, Masahiro Tabatab, Nagio Takigawaa,b, Yoshio Hirakic, Yoichi Watanabed, Toshiro Yoneie, Tomonori Moritakaf, Junichiro Hiyamag, Shunkichi Hirakid, Mitsune Tanimotob, Mine Haradab, for the Okayama Lung Cancer Study Group a
Department of Internal Medicine, National Shikoku Cancer Center, 13 Horinouchi, Matsuyama, Ehime 790-0007, Japan b Department of Internal Medicine II, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan c Department of Radiology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan d Department of Internal Medicine, Okayama Red Cross Hospital, 2-1-1 Aoe, Okayama 700-8607, Japan e Department of Internal Medicine, National Okayama Medical Center, 1711-1 Tamasu, Okayama 701-1192, Japan f Department of Internal Medicine, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime 790-0024, Japan g Department of Internal Medicine, Kure Kyosai Hospital, 2-3-28 Nishi-chuo, Kure, Hiroshima 737-0811, Japan Received 10 October 2002; received in revised form 12 February 2003; accepted 25 February 2003
KEYWORDS Limited-stage small-cell lung cancer; Concurrent chemoradiotherapy; Accelerated hyperfractionated thoracic radiation;
Summary To improve the efficacy of a combination of cisplatin and etoposide and concurrent accelerated twice-daily thoracic radiotherapy against limited-stage smallcell lung cancer, we conducted a phase I/II study using an altered schedule of chemotherapy administration. Chemotherapy consisted of four cycles of cisplatin (days 1 and 8) and etoposide (days 1, 2, 8, and 9) every 4 weeks. Accelerated hyperfractionated thoracic radiation (1.5 Gy twice daily /30 fractions, total dose of 45 Gy) was concurrently given with the first cycle of chemotherapy. The recommended doses of cisplatin and etoposide determined in the phase I study were 40 and 80 mg/m2, respectively. In the phase II study, the overall response rate was 100%
*Corresponding author. Tel.: /81-86-235-7229; fax: /81-86-232-8226. E-mail address: [email protected] (H. Ueoka). 0169-5002/03/$ - see front matter – 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0169-5002(03)00139-9
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Y. Segawa et al.
(complete response: 32%, partial response: 68%). By a median follow-up time of 29 months, median radiation-outfield progression-free survival was 13.4 months, while radiation-infield progression-free survival did not reach median value. The median overall survival time was 22.9 months, with survival rate of 48.4% at 2 years. Major toxicities were leukopenia and neutropenia (]/grade 3, 92% each). The local control and overall survival demonstrated in this study were excellent. However, the insufficient distant control suggests a need for development of more active chemotherapy regimens. – 2003 Elsevier Science Ireland Ltd. All rights reserved.
1. Introduction Small-cell lung cancer (SCLC) is a highly aggressive tumor and accounts for approximately 20% of all lung cancers. Limited-stage SCLC (LD-SCLC) clinically confined to one hemithorax has been of particular interest to many investigators, since it may be curable. During the past few decades, there has been definite progress in the treatment of LD-SCLC. Although median survival of 14 or more months was the goal of treatment of LD-SCLC in the early 1980s [1], recent studies have reported excellent outcomes surpassing 20 months of survival as a median value [2 /5]. This improvement in survival is not only attributable to integration of thoracic radiotherapy into the treatment of SCLC but also to recent more accurate staging of disease [6]. The establishment of standard chemotherapy consisting of platinum compound and etoposide has also contributed to this improvement [6,7]. The value of thoracic radiotherapy in treatment of SCLC was confirmed by the results of two metaanalyses in the early 1990s [8,9]. According to one of these analyses [8], 14% reduction of annual risk of death was observed in patients who underwent chemotherapy combined with radiotherapy, compared with that for those who underwent chemotherapy alone. In addition, more recent randomized studies addressing the effect of radiotherapy on SCLC have reported a significant advantage of the use of accelerated hyperfractionation over the standard radiation method [2] as well as that of early integration of radiotherapy into the entire course of treatment compared with late integration [3 /5]. The Okayama Lung Cancer Study Group has conducted a series of trials of SCLC treatment, and some of the results from these trials have constituted portions of important meta-analyses of SCLC during the last decade [8 /10]. This phase I/II study was designed to improve both local and distant control of the current standard regimen against LD-SCLC, by increasing the dose intensity of
chemotherapy and/or frequency of interaction between chemotherapy and radiotherapy via an altered schedule of chemotherapy dosing.
2. Patients and methods 2.1. Patient eligibility Patients with pathologically documented SCLC confined to one hemithorax and adjacent lymph nodes were eligible for this phase I/II study. Patients with contralateral hilar lymph node involvement or malignant pleural effusion were ineligible. Additional eligibility criteria for study entry were as follows: (1) age 75 years or less, (2) an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, (3) measurable lesion, (4) previously untreated disease, and (5) adequate functional reserve of bone marrow (leukocyte count ]/4000/ml, platelet count ]/ 100 000/ml, hemoglobin ]/9 g/dl), kidney (24-h creatinine clearance level ]/60 ml/min), liver (total serum bilirubin level 5/1.5 mg/dl, serum AST and ALT levels 5/2.5 times the upper limit of normal ranges) and lung (PaO2 ]/60 mmHg). Patients with active infection, severe heart disease, interstitial pneumonia, peripheral neuropathy, pregnancy, or active concomitant malignancy were excluded. Patients who had previously undergone chemotherapy or radiotherapy were also excluded. All patients underwent complete staging procedures for SCLC, which included acquisition of complete medical history, physical examination, complete blood cell count with differential, blood chemistry profile, chest radiograph, computed tomography (CT) of the chest and abdomen, CT or magnetic resonance imaging of the brain, radionucleotide bone scan and fiberoptic bronchoscopy. Neither bone marrow aspiration nor biopsy was required for staging in this study.
Modified Chemoradiotherapy for LD-SCLC
Written informed consent was obtained from all patients. Thirteen institutions participated in this study, and each of their Institutional Review Boards approved this study. The central registration office (Second Department of Internal Medicine, Okayama University Medical School) entered the patients in this study after verification of eligibility.
2.2. Treatment plan This study had a two-step design (phase I and phase II steps). In the phase I portion of this study, dose escalation of cisplatin and etoposide was conducted with concurrent administration of twice-daily thoracic radiation, to determine the maximal tolerated dose (MTD) of this combination and the recommended dose for the phase II study. In the phase II portion, the efficacy and feasibility of this treatment were assessed at a fixed dose of chemotherapy. Eligible patients in each step received four cycles of chemotherapy consisting of cisplatin (days 1 and 8) and etoposide (days 1, 2, 8, and 9) every 4 weeks. Cisplatin was intravenously administered over 1 h, followed by 1-h infusion of etoposide. The phase I part of this study began with cisplatin and etoposide at doses of 40 mg/m2 and 60 g/m2, respectively. These doses were increased as shown in Table 2. At least four patients were enrolled at each dose level. Dose-limiting toxicity (DLT) was assessed based on the data of the first cycle of chemotherapy and concurrent thoracic radiotherapy. If DLT was observed in three or four patients, this dose level was considered to be the MTD. If DLT was observed in one or two patients, four additional patients were accrued. When DLT developed in more than half of the patients, this dose level was also considered to be the MTD. The DLTs considered in this study included grade 4 leukopenia/neutropenia lasting 3 days or longer, neutropenic fever (grade 3 or 4 neutropenia with temperature of /38 8C), grade 4 thrombocytopenia, or any nonhematologic toxicities of grade 3 or higher, except for nausea/vomiting, anorexia, and general fatigue. Once the MTDs of cisplatin and etoposide were determined, further patient accrual for the phase II part of this study was continued at doses one level below the MTD. Based on the hematologic and nonhematologic toxicities observed, dose modification was performed in the following cycle of chemotherapy. Cisplatin and etoposide were administered at dose level /1 when grade 4 leukopenia/neutropenia lasting more than 3 days, neutropenic fever, or grade 4 thrombocytopenia developed. In addition,
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at the time of next cycle of chemotherapy, the drugs were administered at dose level /1 when leukocyte and platelet counts were 3000 /3900/ml and 75 000 /99 000/ml, respectively. Chemotherapy was not given until hematologic recovery when leukocyte and platelet counts were less than 3000 and 75 000/ml, respectively. Cisplatin dose was reduced to 30 mg/m2 when 24-h creatinine clearance level decreased below 60 ml/min but was ]/ 30 ml/min. Cisplatin was not given when 24-h creatinine clearance level was below 30 ml/min. After cisplatin administration, all patients received infusion of 2000 /2500 ml physiologic saline over 4 h. All patients received prophylactic antiemetic therapy using 5-hydroxytryptamine type 3 receptor blocker and/or dexamethasone. Granulocyte-colony stimulating factor (G-CSF) administration was permitted when grade 3 or higher leukopenia or neutropenia occurred (concomitant administration of radiation and G-CSF was not allowed). This administration was continued until the leukocyte or neutrophil count recovered to ]/ 10 000 or 5000/ml, respectively. Accelerated hyperfractionated thoracic radiotherapy was initiated on day 1 of chemotherapy, using a linear accelerator (6 /10 MeV). A radiation dose of 1.5 Gy was administered twice daily with at least a 6-h interfraction interval. A total of 45 Gy was delivered in 30 fractions over 3 weeks. The target volume for thoracic radiotherapy, which was determined by chest CT scan, included the gross tumor with a margin of 2 cm around the mass and the ipsilateral hilum, and the entire width of the mediastinum with a margin of 1 cm around the region of involvement extending inferiorly to 3 cm below the carina. The ipsilateral supraclavicular region was further included when involvement was confirmed by CT scan or palpation. When grade 4 leukopenia, neutropenia, or thrombocytopenia, or neutropenic fever occurred, radiation therapy was withheld until hematologic recovery was observed. In addition, when grade 3 or higher radiation esophagitis occurred, radiation therapy was withheld until it recovered to 5/grade 2. Prophylactic cranial irradiation (PCI) was considered indicated in patients who achieved a complete response (CR) or near CR, and was left to the discretion of the treating physician. PCI was begun within 4 weeks after the last chemotherapy.
2.3. Response and toxicity evaluation For evaluation of response and toxicity, all patients underwent a series of examinations consisting of complete blood cell count with differential, blood chemistry profile and chest
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radiograph at least weekly, and chest CT scan 4weekly. The same examinations (except bronchoscopy) as for staging were performed after the completion of treatment. Response was evaluated every 4 weeks in general. Response was assessed according to the ECOG criteria [11]. The response to treatment including eligibility and assessibility was determined for each patient by extramural reviewers. CR was defined as the disappearance of all measurable lesions for at least 4 weeks. Partial response was defined as a ]/ 50% decrease in the sum of the products of the greatest perpendicular diameters of all measurable lesions for at least 4 weeks without the development of new lesions. Progressive disease (PD) was defined as a ]/25% increase in the sum of the products of the perpendicular diameters of all measurable disease or the appearance of new lesions. Between B/50% decrease and B/25% increase in the sum of the products of the perpendicular diameters of all measurable lesions were defined as stable disease. Toxicities were also assessed using the ECOG criteria [11], and grading of acute esophageal toxicity due to radiation was evaluated in accordance with that of oral toxicity.
2.4. Statistical considerations The sample size of the phase II part of this study was determined based on the expectation of a CR rate of 70%, with a 95% confidence interval (CI) of 9/15%. Accrual of at least 36 patients was therefore required for this study. Statistical analyses were performed using the TM SPSS Base System and Advanced StatisticsTM programs (SPSS Inc, Chicago, IL). Survival time was defined as the period from initiation of treatment to death or last follow-up evaluation. In addition, progression-free survival time was defined as the period from initiation of treatment to PD. Patients who had no clinical evidence of relapse at death or at the last follow-up evaluation were considered censored cases. Survival curves were calculated using the method of Kaplan and Meier.
3. Results Between November 1995 and September 1999, 51 patients were entered into this study. Pretreatment patient characteristics are listed in Table 1. The groups of patients entered into the phase I or phase II part of this study had similar characteristics in terms of age and gender, although larger proportion of the patients entered into phase I study had lower performance status
Y. Segawa et al.
Table 1 Patient characteristics Characteristic
No. of patients entered No. of patients eligible Median age in years (range) Gender Male Female
No. of patients Phase I study
Phase II study
12 12 66.5 (50 /73)
39 37 66 (44 /75)
10 2
35 2
ECOG performance status 0 3 1 7 2 2
14 21 2
Weight loss B/5% ]/5%
33 4
9 3
Abbreviation: ECOG, Eastern Cooperative Oncology Group.
(ECOG 2) and more weight loss. In addition, most patients were men and had a good ECOG performance status of 0 or 1. All 12 patients were fully assessable for DLT in the phase I part of this study. However, two of 39 patients in the phase II study were excluded from analysis due to patient’s refusal of the protocol therapy or protocol violation.
3.1. Phase I study The number of patients who experienced DLT in the first cycle of chemotherapy and concurrent thoracic radiotherapy is shown in Table 2. Prolonged grade 4 neutropenia, neutropenic fever, and grade 3 radiation esophagitis were observed in this study. One patient receiving dose level 3 experienced both neutropenia and esophagitis. Although DLT occurred in only one of four patients at dose levels 1 and 2, all of the four patients experienced DLT at dose level 3, suggesting that this dose level was the MTD. The recommended doses of cisplatin and etoposide for the phase II part were thus considered to be 40 and 80 mg/m2 (dose level 2), respectively.
3.2. Phase II study Of the 37 patients eligible for the phase II part of this study, 29 completed four cycles of chemotherapy. The remaining eight patients received only three cycles because of toxicity (n /2, renal
Modified Chemoradiotherapy for LD-SCLC
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Table 2 DLT by dose level in phase I study Dose level Cisplatin Etoposide DLT (mg/m2) (mg/m2)
No. of patients
No. of patients with toxicity
Type of toxicity
1 2 3
40 40 50
60 80 80
4 4 4
1 1 4
Neutropenia (grade 4) Esophagitis (grade 3) Esophagitis (grade 3, n /2) Neutropenia (grade 4, n /2) Neutropenic fever (n /1)
4 5
60 60
80 100
/ /
/ /
Cisplatin and etoposide in each dose level were administered on days 1 and 8, and days 1, 2, 8, and 9, respectively. One patient entered to the dose level 3 developed both grade 3 esophagitis and grade 4 neutropenia.
disturbance and myelosuppression in one patient each), patient’s refusal (n /2), treatment-unrelated sudden death (n /1), physician’s discretion (n /1), and reasons not otherwise specified (n / 2). The percentages of actually delivered doses to the projected dose (mean9/S.D.) for cisplatin and etoposide were respectively 969/6% and 889/12% in the second cycle, 919/13% and 879/13% in the third cycle, and 909/14% and 899/12% in the fourth cycle. All of the patients completed thoracic radiation. However, a radiation therapy resting period was required for 16 patients, with a median duration of 12.5 days (range, 1 /34 days). The reasons for this included myelosuppression (n / 12), radiation esophagitis (n /2), myelosuppression plus esophagitis (n /1), and linear accelerator malfunction (n /1). Myelosuppression consisted mainly of neutropenia, with neutropenic fever occurring in four patients. PCI (30 Gy) was administered to 10 patients. All of the 37 patients had a response to this concurrent chemoradiotherapy, with 12 (32%; 95% CI, 25 /40%) achieving CR. By a median follow-up time of 29 months (range, 21 /57 months) for surviving patients, 26 (70%) had relapsed. Patterns of the initial treatment failure included radiationinfield progression in five (14%) patients, radiationoutfield progression in 18 (49%), and both infield and outfield progression in three (8%). In addition, the most common site of initial treatment failure was brain (n /12; n /1 with PCI, n /11 without PCI), and the second common site was the primary lesion (n /8). The progression-free survival curves are shown in Fig. 1. By a median follow-up time of 29 months, median radiation-outfield progressionfree survival was 13.4 months, while radiationinfield progression-free survival did not reach median value. The survival curve is shown in Fig. 2. At the time of analysis, 23 (62%) patients had died and 14 (38%)
were still alive. The cause of death was directly related to SCLC for 20 patients and unrelated for three (sudden death in two patients and refractory anemia probably related to treatment in one). The median survival time was 22.9 months with survival rate of 48.4% at 2 years. Toxicities observed in the 37 patients during treatment and the follow-up period are listed in Table 3. The major toxicity was myelosuppression. Both grade 3 or higher leukopenia and neutropenia occurred in 34 (92%) patients. Five (14%) patients experienced grade 3 neutropenic fever. In addition, grade 3 or higher thrombocytopenia and anemia occurred in 20 (54%) and 14 (38%) patients, respectively. G-CSF was administered to 32 (86%) patients and 97 (69%) of 140 entire chemotherapy cycles. Platelet and red blood cell transfusions were given to five (14%) and seven (19%) patients, respectively. Nonhematologic toxicities were generally mild, although grade 3 radiation esophagitis occurred in three (8%) patients. Grade 3 pulmonary toxicity occurred in only one (3%) patient. Overall, grade 3 or higher hematologic toxicity was observed in 35 (95%) patients, while grade 3 nonhematologic toxicity occurred in 8 (22%) patients.
4. Discussion The most active standard regimen currently available for the treatment of LD-SCLC is a combination of platinum compound and etoposide combined with up-front concurrent accelerated hyperfractionated thoracic radiation. This regimen has been established based on accumulating results from large randomized trials that compared the efficacy of twice-daily versus once-daily thoracic radiotherapy (intergroup trial 0096) [2] or the usefulness of early versus late integration of thoracic radiotherapy [3 /5]. Median survival times
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Y. Segawa et al.
Fig. 1
Radiation-infield and -outfield progression-free survival curves.
ranging from 23 to 34 months have been reported in standard chemoradiotherapy trials against LDSCLC [2,4,5]. This excellent outcome is primarily attributable to improvement in local control of this disease [2,4]. According to the intergroup trial, long-term local failure rate was only 36%. In our study, median survival was estimated to be 22.9 months. This is considered comparable to results of standard chemoradiotherapy trials, and also appears to be associated with similar local control rates in this study and those in standard chemoradiotherapy trials. However, this trial using an altered schedule of cisplatin and etoposide administration failed to show therapeutic efficacy compared with that using a standard schedule such as that in the intergroup trial, since distant control was quite insufficient. The median radiation-outfield progression-free survival was only 13.4 months in this study. A likely reason for this insufficient distant control was the relatively low
dose intensity of chemotherapy used in this study. The projected dose intensities of cisplatin and etoposide in the intergroup trial were 20 and 120 mg/m2/week, respectively. In contrast, the respective dose intensities in this study were 20 and 80 mg/m2/week. We considered that intensified interaction of chemotherapy and radiotherapy by frequent administration of cisplatin and etoposide was the major cause of severe myelosuppression despite the lower dose of etoposide in this regimen. On the other hand, nonhematologic toxicities such as esophaigitis were mild, which may be attributable to the frequent resting period of radiotherapy due to severe myelosuppression. In addition, it is clear that a considerable number of patients with indication for PCI did not receive this therapy (e.g., only seven patients achieving CR received PCI), because indication of PCI was left to the discretion of the treating physician in this study. The low rate of use of PCI influenced the
Fig. 2 Survival curve. Abbreviation: MST, median survival time.
Modified Chemoradiotherapy for LD-SCLC
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Table 3 Hematologic and nonhematologic toxicities in phase II study Toxicity
Leukopenia Neutropenia Thrombocytopenia Anemia Infection (neutropenic fever) Renal dysfunction Nausea/vomiting Diarrhea Constipation Stomatitis Liver dysfunction Pulmonary toxicity Dermatitis Hair loss Peripheral neurotoxicity Esophagitis Worst hematologic toxicity per patient Worst nonhematologic toxicity per patient Worst toxicity per patient
No. of patients with toxicities by grade
% of toxicities
1
2
3
4
]/ grade 3
0 0 5 6 0 8 16 3 3 3 4 3 1 15 6 20 0 1 0
3 3 11 6 10 2 16 3 0 2 1 3 5 9 0 6 2 26 2
13 10 14 12 5 0 1 0 0 0 2 1 1 / 0 3 10 7 10
21 24 6 2 0 0 1 0 0 0 0 0 0 / 0 0 25 1 25
92 92 54 38 14 0 5 0 0 0 5 3 3 / 0 8 95 22 95
finding of insufficient distant control, since the most common site of initial treatment failure was the brain in this study. Patients achieving CR or near CR should benefit from PCI, since a recent meta-analysis of PCI reported significant reduction in the annual risk of death for SCLC patients receiving this treatment [10] and a randomized clinical study has shown that daily fraction of 2 Gy to a total dose of 30 Gy have not given meanful neurotoxicity when compared to control group without PCI [12]. In order to further improve distant control in LDSCLC, it is a matter of great urgency that effective chemotherapeutic agents or their combinations be developed against SCLC. Concerning new approaches to chemotherapy in the concurrent chemoradiotherapy series, a combination of cisplatin, etopside, and ifosphamide [13], and of cisplatin, etopside, and paclitaxel [14,15] have been reported. However, treatment results from these trials were equivalent to those in the standard chemoradiotherapy trials [2,4,5]. Recently, a combination of cisplatin and irinotecan has been demonstrated to have more activity against extensive-stage SCLC than does a combination of cisplatin and etoposide [16]. It is difficult to employ this novel combination concurrently with thoracic radiation due to the higher-than-expected toxicities of this combined therapy [17]. However, it might be useful to employ this novel combination
as a second chemotherapy following the initial portion of concurrent chemoradiotherapy. In conclusion, this study using an altered schedule of cisplatin and etoposide administration yielded a treatment outcome comparable to those of standard concurrent chemoradiotherapy trials for LD-SCLC. In addition, distant treatment failure, especially brain metastasis, is a major obstacle to control of this disease. Therefore, more frequent use of PCI for responders by chemoradiotherapy seems to improve outcome of LD-SCLC.
References [1] Aisner J, Alberto P, Bitran J, et al. Role of chemotherapy in small cell lung cancer: a consensus report of the international association for the study of lung cancer workshop. Cancer Treat Rep 1983;67:37 /43. [2] Turrisi AT, Kim K, Blum R, et al. Twice-daily compared oncedaily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340:265 /71. [3] Murray N, Coy P, Pater JL, et al. Importance of timing for thoracic irradiation in the combined treatment of limitedstage small-cell lung cancer. J Clin Oncol 1993;11:336 /44. [4] Jeremic B, Shibamoto Y, Acimovic L, et al. Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: a randomized study. J Clin Oncol 1997;15:893 /900. [5] Takada M, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 2002;20:3054 /60.
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[6] Johnson DH. Management of small cell lung cancer: current status of the art. Chest 1999;116:525S /30S. [7] Albain KS, Crowley JJ, LeBlanc M, et al. Determinants of improved outcome in small-cell lung cancer: an analysis of the 2580-patient Southwest Oncology Group data base. J Clin Oncol 1990;8:1563 /74. [8] Pignon J, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992;327:1618 /24. [9] Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 1992;10:890 /5. [10] Aupe ´rin A, Arriagada R, Pignon J, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med 1999;341:476 /84. [11] Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649 /55. [12] Gregor A, Cull A, Stephens RJ, et al. Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: results of a multicentre randomised trial. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) and the Eur-
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[13]
[14]
[15]
[16]
[17]
opean Organization for Research and Treatment of Cancer (EORTC). Eur J Cancer 1997;33:1752 /8. Glisson B, Scott C, Komaki R, et al. Cisplatin, ifosfamide, oral etoposide, and concurrent accelerated hyperfractionated thoracic radiation for patients with limited small-cell lung carcinoma: results of Radiation Therapy Oncology Group trial 93-12. J Clin Oncol 2000;18:2990 /5. Levitan N, Dowlati A, Shina D, et al. Multi-institutional phase I/II trial of paclitaxel, cisplatin, and etoposide with concurrent radiation for limited-stage small-cell lung carcinoma. J Clin Oncol 2000;18:1102 /9. Bremnes RM, Sundstrøm S, Vilsvik J, et al. Multicenter phase II trial of paclitaxel, cisplatin, and etoposide with concurrent radiation for limited-stage small-cell lung cancer. J Clin Oncol 2001;19:3532 /8. Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002;346:85 / 91. Yokoyama A, Kurita Y, Saijo N, et al. Dose-finding study of irinotecan and cisplatin plus concurrent radiotherapy for unresectable stage III non-small-cell lung cancer. Br J Cancer 1998;78:257 /62.
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Phase I/II study of altered schedule of cisplatin and etoposide administration and concurrent accelerated hyperfractionated thoracic radiotherapy for limited-stage small-cell lung cancer Yoshihiko Segawaa, Hiroshi Ueokab,*, Katsuyuki Kiurab, Masahiro Tabatab, Nagio Takigawaa,b, Yoshio Hirakic, Yoichi Watanabed, Toshiro Yoneie, Tomonori Moritakaf, Junichiro Hiyamag, Shunkichi Hirakid, Mitsune Tanimotob, Mine Haradab, for the Okayama Lung Cancer Study Group a
Department of Internal Medicine, National Shikoku Cancer Center, 13 Horinouchi, Matsuyama, Ehime 790-0007, Japan b Department of Internal Medicine II, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan c Department of Radiology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan d Department of Internal Medicine, Okayama Red Cross Hospital, 2-1-1 Aoe, Okayama 700-8607, Japan e Department of Internal Medicine, National Okayama Medical Center, 1711-1 Tamasu, Okayama 701-1192, Japan f Department of Internal Medicine, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime 790-0024, Japan g Department of Internal Medicine, Kure Kyosai Hospital, 2-3-28 Nishi-chuo, Kure, Hiroshima 737-0811, Japan Received 10 October 2002; received in revised form 12 February 2003; accepted 25 February 2003
KEYWORDS Limited-stage small-cell lung cancer; Concurrent chemoradiotherapy; Accelerated hyperfractionated thoracic radiation;
Summary To improve the efficacy of a combination of cisplatin and etoposide and concurrent accelerated twice-daily thoracic radiotherapy against limited-stage smallcell lung cancer, we conducted a phase I/II study using an altered schedule of chemotherapy administration. Chemotherapy consisted of four cycles of cisplatin (days 1 and 8) and etoposide (days 1, 2, 8, and 9) every 4 weeks. Accelerated hyperfractionated thoracic radiation (1.5 Gy twice daily /30 fractions, total dose of 45 Gy) was concurrently given with the first cycle of chemotherapy. The recommended doses of cisplatin and etoposide determined in the phase I study were 40 and 80 mg/m2, respectively. In the phase II study, the overall response rate was 100%
*Corresponding author. Tel.: /81-86-235-7229; fax: /81-86-232-8226. E-mail address: [email protected] (H. Ueoka). 0169-5002/03/$ - see front matter – 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0169-5002(03)00139-9
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(complete response: 32%, partial response: 68%). By a median follow-up time of 29 months, median radiation-outfield progression-free survival was 13.4 months, while radiation-infield progression-free survival did not reach median value. The median overall survival time was 22.9 months, with survival rate of 48.4% at 2 years. Major toxicities were leukopenia and neutropenia (]/grade 3, 92% each). The local control and overall survival demonstrated in this study were excellent. However, the insufficient distant control suggests a need for development of more active chemotherapy regimens. – 2003 Elsevier Science Ireland Ltd. All rights reserved.
1. Introduction Small-cell lung cancer (SCLC) is a highly aggressive tumor and accounts for approximately 20% of all lung cancers. Limited-stage SCLC (LD-SCLC) clinically confined to one hemithorax has been of particular interest to many investigators, since it may be curable. During the past few decades, there has been definite progress in the treatment of LD-SCLC. Although median survival of 14 or more months was the goal of treatment of LD-SCLC in the early 1980s [1], recent studies have reported excellent outcomes surpassing 20 months of survival as a median value [2 /5]. This improvement in survival is not only attributable to integration of thoracic radiotherapy into the treatment of SCLC but also to recent more accurate staging of disease [6]. The establishment of standard chemotherapy consisting of platinum compound and etoposide has also contributed to this improvement [6,7]. The value of thoracic radiotherapy in treatment of SCLC was confirmed by the results of two metaanalyses in the early 1990s [8,9]. According to one of these analyses [8], 14% reduction of annual risk of death was observed in patients who underwent chemotherapy combined with radiotherapy, compared with that for those who underwent chemotherapy alone. In addition, more recent randomized studies addressing the effect of radiotherapy on SCLC have reported a significant advantage of the use of accelerated hyperfractionation over the standard radiation method [2] as well as that of early integration of radiotherapy into the entire course of treatment compared with late integration [3 /5]. The Okayama Lung Cancer Study Group has conducted a series of trials of SCLC treatment, and some of the results from these trials have constituted portions of important meta-analyses of SCLC during the last decade [8 /10]. This phase I/II study was designed to improve both local and distant control of the current standard regimen against LD-SCLC, by increasing the dose intensity of
chemotherapy and/or frequency of interaction between chemotherapy and radiotherapy via an altered schedule of chemotherapy dosing.
2. Patients and methods 2.1. Patient eligibility Patients with pathologically documented SCLC confined to one hemithorax and adjacent lymph nodes were eligible for this phase I/II study. Patients with contralateral hilar lymph node involvement or malignant pleural effusion were ineligible. Additional eligibility criteria for study entry were as follows: (1) age 75 years or less, (2) an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, (3) measurable lesion, (4) previously untreated disease, and (5) adequate functional reserve of bone marrow (leukocyte count ]/4000/ml, platelet count ]/ 100 000/ml, hemoglobin ]/9 g/dl), kidney (24-h creatinine clearance level ]/60 ml/min), liver (total serum bilirubin level 5/1.5 mg/dl, serum AST and ALT levels 5/2.5 times the upper limit of normal ranges) and lung (PaO2 ]/60 mmHg). Patients with active infection, severe heart disease, interstitial pneumonia, peripheral neuropathy, pregnancy, or active concomitant malignancy were excluded. Patients who had previously undergone chemotherapy or radiotherapy were also excluded. All patients underwent complete staging procedures for SCLC, which included acquisition of complete medical history, physical examination, complete blood cell count with differential, blood chemistry profile, chest radiograph, computed tomography (CT) of the chest and abdomen, CT or magnetic resonance imaging of the brain, radionucleotide bone scan and fiberoptic bronchoscopy. Neither bone marrow aspiration nor biopsy was required for staging in this study.
Modified Chemoradiotherapy for LD-SCLC
Written informed consent was obtained from all patients. Thirteen institutions participated in this study, and each of their Institutional Review Boards approved this study. The central registration office (Second Department of Internal Medicine, Okayama University Medical School) entered the patients in this study after verification of eligibility.
2.2. Treatment plan This study had a two-step design (phase I and phase II steps). In the phase I portion of this study, dose escalation of cisplatin and etoposide was conducted with concurrent administration of twice-daily thoracic radiation, to determine the maximal tolerated dose (MTD) of this combination and the recommended dose for the phase II study. In the phase II portion, the efficacy and feasibility of this treatment were assessed at a fixed dose of chemotherapy. Eligible patients in each step received four cycles of chemotherapy consisting of cisplatin (days 1 and 8) and etoposide (days 1, 2, 8, and 9) every 4 weeks. Cisplatin was intravenously administered over 1 h, followed by 1-h infusion of etoposide. The phase I part of this study began with cisplatin and etoposide at doses of 40 mg/m2 and 60 g/m2, respectively. These doses were increased as shown in Table 2. At least four patients were enrolled at each dose level. Dose-limiting toxicity (DLT) was assessed based on the data of the first cycle of chemotherapy and concurrent thoracic radiotherapy. If DLT was observed in three or four patients, this dose level was considered to be the MTD. If DLT was observed in one or two patients, four additional patients were accrued. When DLT developed in more than half of the patients, this dose level was also considered to be the MTD. The DLTs considered in this study included grade 4 leukopenia/neutropenia lasting 3 days or longer, neutropenic fever (grade 3 or 4 neutropenia with temperature of /38 8C), grade 4 thrombocytopenia, or any nonhematologic toxicities of grade 3 or higher, except for nausea/vomiting, anorexia, and general fatigue. Once the MTDs of cisplatin and etoposide were determined, further patient accrual for the phase II part of this study was continued at doses one level below the MTD. Based on the hematologic and nonhematologic toxicities observed, dose modification was performed in the following cycle of chemotherapy. Cisplatin and etoposide were administered at dose level /1 when grade 4 leukopenia/neutropenia lasting more than 3 days, neutropenic fever, or grade 4 thrombocytopenia developed. In addition,
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at the time of next cycle of chemotherapy, the drugs were administered at dose level /1 when leukocyte and platelet counts were 3000 /3900/ml and 75 000 /99 000/ml, respectively. Chemotherapy was not given until hematologic recovery when leukocyte and platelet counts were less than 3000 and 75 000/ml, respectively. Cisplatin dose was reduced to 30 mg/m2 when 24-h creatinine clearance level decreased below 60 ml/min but was ]/ 30 ml/min. Cisplatin was not given when 24-h creatinine clearance level was below 30 ml/min. After cisplatin administration, all patients received infusion of 2000 /2500 ml physiologic saline over 4 h. All patients received prophylactic antiemetic therapy using 5-hydroxytryptamine type 3 receptor blocker and/or dexamethasone. Granulocyte-colony stimulating factor (G-CSF) administration was permitted when grade 3 or higher leukopenia or neutropenia occurred (concomitant administration of radiation and G-CSF was not allowed). This administration was continued until the leukocyte or neutrophil count recovered to ]/ 10 000 or 5000/ml, respectively. Accelerated hyperfractionated thoracic radiotherapy was initiated on day 1 of chemotherapy, using a linear accelerator (6 /10 MeV). A radiation dose of 1.5 Gy was administered twice daily with at least a 6-h interfraction interval. A total of 45 Gy was delivered in 30 fractions over 3 weeks. The target volume for thoracic radiotherapy, which was determined by chest CT scan, included the gross tumor with a margin of 2 cm around the mass and the ipsilateral hilum, and the entire width of the mediastinum with a margin of 1 cm around the region of involvement extending inferiorly to 3 cm below the carina. The ipsilateral supraclavicular region was further included when involvement was confirmed by CT scan or palpation. When grade 4 leukopenia, neutropenia, or thrombocytopenia, or neutropenic fever occurred, radiation therapy was withheld until hematologic recovery was observed. In addition, when grade 3 or higher radiation esophagitis occurred, radiation therapy was withheld until it recovered to 5/grade 2. Prophylactic cranial irradiation (PCI) was considered indicated in patients who achieved a complete response (CR) or near CR, and was left to the discretion of the treating physician. PCI was begun within 4 weeks after the last chemotherapy.
2.3. Response and toxicity evaluation For evaluation of response and toxicity, all patients underwent a series of examinations consisting of complete blood cell count with differential, blood chemistry profile and chest
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radiograph at least weekly, and chest CT scan 4weekly. The same examinations (except bronchoscopy) as for staging were performed after the completion of treatment. Response was evaluated every 4 weeks in general. Response was assessed according to the ECOG criteria [11]. The response to treatment including eligibility and assessibility was determined for each patient by extramural reviewers. CR was defined as the disappearance of all measurable lesions for at least 4 weeks. Partial response was defined as a ]/ 50% decrease in the sum of the products of the greatest perpendicular diameters of all measurable lesions for at least 4 weeks without the development of new lesions. Progressive disease (PD) was defined as a ]/25% increase in the sum of the products of the perpendicular diameters of all measurable disease or the appearance of new lesions. Between B/50% decrease and B/25% increase in the sum of the products of the perpendicular diameters of all measurable lesions were defined as stable disease. Toxicities were also assessed using the ECOG criteria [11], and grading of acute esophageal toxicity due to radiation was evaluated in accordance with that of oral toxicity.
2.4. Statistical considerations The sample size of the phase II part of this study was determined based on the expectation of a CR rate of 70%, with a 95% confidence interval (CI) of 9/15%. Accrual of at least 36 patients was therefore required for this study. Statistical analyses were performed using the TM SPSS Base System and Advanced StatisticsTM programs (SPSS Inc, Chicago, IL). Survival time was defined as the period from initiation of treatment to death or last follow-up evaluation. In addition, progression-free survival time was defined as the period from initiation of treatment to PD. Patients who had no clinical evidence of relapse at death or at the last follow-up evaluation were considered censored cases. Survival curves were calculated using the method of Kaplan and Meier.
3. Results Between November 1995 and September 1999, 51 patients were entered into this study. Pretreatment patient characteristics are listed in Table 1. The groups of patients entered into the phase I or phase II part of this study had similar characteristics in terms of age and gender, although larger proportion of the patients entered into phase I study had lower performance status
Y. Segawa et al.
Table 1 Patient characteristics Characteristic
No. of patients entered No. of patients eligible Median age in years (range) Gender Male Female
No. of patients Phase I study
Phase II study
12 12 66.5 (50 /73)
39 37 66 (44 /75)
10 2
35 2
ECOG performance status 0 3 1 7 2 2
14 21 2
Weight loss B/5% ]/5%
33 4
9 3
Abbreviation: ECOG, Eastern Cooperative Oncology Group.
(ECOG 2) and more weight loss. In addition, most patients were men and had a good ECOG performance status of 0 or 1. All 12 patients were fully assessable for DLT in the phase I part of this study. However, two of 39 patients in the phase II study were excluded from analysis due to patient’s refusal of the protocol therapy or protocol violation.
3.1. Phase I study The number of patients who experienced DLT in the first cycle of chemotherapy and concurrent thoracic radiotherapy is shown in Table 2. Prolonged grade 4 neutropenia, neutropenic fever, and grade 3 radiation esophagitis were observed in this study. One patient receiving dose level 3 experienced both neutropenia and esophagitis. Although DLT occurred in only one of four patients at dose levels 1 and 2, all of the four patients experienced DLT at dose level 3, suggesting that this dose level was the MTD. The recommended doses of cisplatin and etoposide for the phase II part were thus considered to be 40 and 80 mg/m2 (dose level 2), respectively.
3.2. Phase II study Of the 37 patients eligible for the phase II part of this study, 29 completed four cycles of chemotherapy. The remaining eight patients received only three cycles because of toxicity (n /2, renal
Modified Chemoradiotherapy for LD-SCLC
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Table 2 DLT by dose level in phase I study Dose level Cisplatin Etoposide DLT (mg/m2) (mg/m2)
No. of patients
No. of patients with toxicity
Type of toxicity
1 2 3
40 40 50
60 80 80
4 4 4
1 1 4
Neutropenia (grade 4) Esophagitis (grade 3) Esophagitis (grade 3, n /2) Neutropenia (grade 4, n /2) Neutropenic fever (n /1)
4 5
60 60
80 100
/ /
/ /
Cisplatin and etoposide in each dose level were administered on days 1 and 8, and days 1, 2, 8, and 9, respectively. One patient entered to the dose level 3 developed both grade 3 esophagitis and grade 4 neutropenia.
disturbance and myelosuppression in one patient each), patient’s refusal (n /2), treatment-unrelated sudden death (n /1), physician’s discretion (n /1), and reasons not otherwise specified (n / 2). The percentages of actually delivered doses to the projected dose (mean9/S.D.) for cisplatin and etoposide were respectively 969/6% and 889/12% in the second cycle, 919/13% and 879/13% in the third cycle, and 909/14% and 899/12% in the fourth cycle. All of the patients completed thoracic radiation. However, a radiation therapy resting period was required for 16 patients, with a median duration of 12.5 days (range, 1 /34 days). The reasons for this included myelosuppression (n / 12), radiation esophagitis (n /2), myelosuppression plus esophagitis (n /1), and linear accelerator malfunction (n /1). Myelosuppression consisted mainly of neutropenia, with neutropenic fever occurring in four patients. PCI (30 Gy) was administered to 10 patients. All of the 37 patients had a response to this concurrent chemoradiotherapy, with 12 (32%; 95% CI, 25 /40%) achieving CR. By a median follow-up time of 29 months (range, 21 /57 months) for surviving patients, 26 (70%) had relapsed. Patterns of the initial treatment failure included radiationinfield progression in five (14%) patients, radiationoutfield progression in 18 (49%), and both infield and outfield progression in three (8%). In addition, the most common site of initial treatment failure was brain (n /12; n /1 with PCI, n /11 without PCI), and the second common site was the primary lesion (n /8). The progression-free survival curves are shown in Fig. 1. By a median follow-up time of 29 months, median radiation-outfield progressionfree survival was 13.4 months, while radiationinfield progression-free survival did not reach median value. The survival curve is shown in Fig. 2. At the time of analysis, 23 (62%) patients had died and 14 (38%)
were still alive. The cause of death was directly related to SCLC for 20 patients and unrelated for three (sudden death in two patients and refractory anemia probably related to treatment in one). The median survival time was 22.9 months with survival rate of 48.4% at 2 years. Toxicities observed in the 37 patients during treatment and the follow-up period are listed in Table 3. The major toxicity was myelosuppression. Both grade 3 or higher leukopenia and neutropenia occurred in 34 (92%) patients. Five (14%) patients experienced grade 3 neutropenic fever. In addition, grade 3 or higher thrombocytopenia and anemia occurred in 20 (54%) and 14 (38%) patients, respectively. G-CSF was administered to 32 (86%) patients and 97 (69%) of 140 entire chemotherapy cycles. Platelet and red blood cell transfusions were given to five (14%) and seven (19%) patients, respectively. Nonhematologic toxicities were generally mild, although grade 3 radiation esophagitis occurred in three (8%) patients. Grade 3 pulmonary toxicity occurred in only one (3%) patient. Overall, grade 3 or higher hematologic toxicity was observed in 35 (95%) patients, while grade 3 nonhematologic toxicity occurred in 8 (22%) patients.
4. Discussion The most active standard regimen currently available for the treatment of LD-SCLC is a combination of platinum compound and etoposide combined with up-front concurrent accelerated hyperfractionated thoracic radiation. This regimen has been established based on accumulating results from large randomized trials that compared the efficacy of twice-daily versus once-daily thoracic radiotherapy (intergroup trial 0096) [2] or the usefulness of early versus late integration of thoracic radiotherapy [3 /5]. Median survival times
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Y. Segawa et al.
Fig. 1
Radiation-infield and -outfield progression-free survival curves.
ranging from 23 to 34 months have been reported in standard chemoradiotherapy trials against LDSCLC [2,4,5]. This excellent outcome is primarily attributable to improvement in local control of this disease [2,4]. According to the intergroup trial, long-term local failure rate was only 36%. In our study, median survival was estimated to be 22.9 months. This is considered comparable to results of standard chemoradiotherapy trials, and also appears to be associated with similar local control rates in this study and those in standard chemoradiotherapy trials. However, this trial using an altered schedule of cisplatin and etoposide administration failed to show therapeutic efficacy compared with that using a standard schedule such as that in the intergroup trial, since distant control was quite insufficient. The median radiation-outfield progression-free survival was only 13.4 months in this study. A likely reason for this insufficient distant control was the relatively low
dose intensity of chemotherapy used in this study. The projected dose intensities of cisplatin and etoposide in the intergroup trial were 20 and 120 mg/m2/week, respectively. In contrast, the respective dose intensities in this study were 20 and 80 mg/m2/week. We considered that intensified interaction of chemotherapy and radiotherapy by frequent administration of cisplatin and etoposide was the major cause of severe myelosuppression despite the lower dose of etoposide in this regimen. On the other hand, nonhematologic toxicities such as esophaigitis were mild, which may be attributable to the frequent resting period of radiotherapy due to severe myelosuppression. In addition, it is clear that a considerable number of patients with indication for PCI did not receive this therapy (e.g., only seven patients achieving CR received PCI), because indication of PCI was left to the discretion of the treating physician in this study. The low rate of use of PCI influenced the
Fig. 2 Survival curve. Abbreviation: MST, median survival time.
Modified Chemoradiotherapy for LD-SCLC
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Table 3 Hematologic and nonhematologic toxicities in phase II study Toxicity
Leukopenia Neutropenia Thrombocytopenia Anemia Infection (neutropenic fever) Renal dysfunction Nausea/vomiting Diarrhea Constipation Stomatitis Liver dysfunction Pulmonary toxicity Dermatitis Hair loss Peripheral neurotoxicity Esophagitis Worst hematologic toxicity per patient Worst nonhematologic toxicity per patient Worst toxicity per patient
No. of patients with toxicities by grade
% of toxicities
1
2
3
4
]/ grade 3
0 0 5 6 0 8 16 3 3 3 4 3 1 15 6 20 0 1 0
3 3 11 6 10 2 16 3 0 2 1 3 5 9 0 6 2 26 2
13 10 14 12 5 0 1 0 0 0 2 1 1 / 0 3 10 7 10
21 24 6 2 0 0 1 0 0 0 0 0 0 / 0 0 25 1 25
92 92 54 38 14 0 5 0 0 0 5 3 3 / 0 8 95 22 95
finding of insufficient distant control, since the most common site of initial treatment failure was the brain in this study. Patients achieving CR or near CR should benefit from PCI, since a recent meta-analysis of PCI reported significant reduction in the annual risk of death for SCLC patients receiving this treatment [10] and a randomized clinical study has shown that daily fraction of 2 Gy to a total dose of 30 Gy have not given meanful neurotoxicity when compared to control group without PCI [12]. In order to further improve distant control in LDSCLC, it is a matter of great urgency that effective chemotherapeutic agents or their combinations be developed against SCLC. Concerning new approaches to chemotherapy in the concurrent chemoradiotherapy series, a combination of cisplatin, etopside, and ifosphamide [13], and of cisplatin, etopside, and paclitaxel [14,15] have been reported. However, treatment results from these trials were equivalent to those in the standard chemoradiotherapy trials [2,4,5]. Recently, a combination of cisplatin and irinotecan has been demonstrated to have more activity against extensive-stage SCLC than does a combination of cisplatin and etoposide [16]. It is difficult to employ this novel combination concurrently with thoracic radiation due to the higher-than-expected toxicities of this combined therapy [17]. However, it might be useful to employ this novel combination
as a second chemotherapy following the initial portion of concurrent chemoradiotherapy. In conclusion, this study using an altered schedule of cisplatin and etoposide administration yielded a treatment outcome comparable to those of standard concurrent chemoradiotherapy trials for LD-SCLC. In addition, distant treatment failure, especially brain metastasis, is a major obstacle to control of this disease. Therefore, more frequent use of PCI for responders by chemoradiotherapy seems to improve outcome of LD-SCLC.
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