Japanese Journal of Clinical Oncology 33:620-625 (2003)
© 2003 Foundation for Promotion of Cancer Research
Early Concurrent Chemoradiotherapy with Prolonged Oral Etoposide and Cisplatin for Limited-stage Small-cell Lung Cancer
1 Division of Hematology and Oncology, Department of Medicine, 2 Department of Radiation Oncology and 3 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Background: Combined chemoradiotherapy (CRT) is the standard treatment modality for limited-stage small-cell lung cancer (LSCLC), but the optimal timing of radiation is controversial. Prolonged oral etoposide has the advantage of prolonged exposure, which possibly leads to improved clinical outcome. We conducted a phase II trial of early concurrent CRT, starting from the very beginning of the first cycle of chemotherapy for previously untreated LSCLC.
Methods: Chemotherapy was given for six cycles, each consisting of oral etoposide (50 mg/m2 daily from day 1 to 14) and intravenous cisplatin (75 mg/m2 on day 1), every 3 weeks. Thoracic radiation therapy was given from day 1 of the first cycle of chemotherapy, administered at 2.0 Gy in 22 daily fractions to a total dose of 44 Gy.
Results: Forty-four patients were enrolled. The median age was 60 years (range, 42–77 years), including 15 patients (34%) over 65 years-of-age. We observed a complete response rate of 52% (95% CI, 37–67%), and an overall response rate of 88% in an intent-to-treat (ITT) analysis. Median overall survival was 14.9 months (95% CI, 11.4–18.3 months) and the median time to progression was 10.8 months (95% CI, 9.3–12.4 months) for the ITT population. In 220 cycles, grade 3–4 neutropenia was observed in 48% of cycles and grade 3–4 thrombocytopenia in 30% of cycles. Neutropenic fever was observed in 18 patients (41%).
Conclusions: Early concurrent CRT, starting from the very beginning of the first cycle of chemotherapy with prolonged oral etoposide and cisplatin failed to show any improvement in survival compared with other CRT regimens.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Combined chemoradiotherapy (CRT) for limited-stage small-cell lung cancer (LSCLC) has shown survival advantages over chemotherapy alone in two meta-analyses (1,2), and this approach is, therefore, the standard treatment option for LSCLC. According to the mathematical model of Goldie and Coldman, the most effective regimens should ideally be administered as early in the treatment course as possible in order to prevent the emergence of resistant clones (3). The repopulation of tumor cells between courses of chemotherapy and radiotherapy is regarded as one of the important mechanisms of resistance (4). Compared with late concurrent or sequential CRT, early concurrent CRT has the theoretical advantage of early administration of the most effective modalities of both radiation and chemotherapy, and can decrease the repopulation of tumor cells more efficiently. It has the potential disadvantage, however, of increased toxicity, which may compromise the delivery of systemic chemotherapy. Some trials to investigate the optimal timing of radiation therapy failed to show superiority of early radiation with respect to survival (5,6), whereas others reported results favoring early radiation (7–9). The trials applying early concurrent CRT with hyperfractionated radiation showed a 5-year-survival rate of 24–30% (8,9).
A regimen of 3-day or 5-day intravenous etoposide and platinum is most commonly used for LSCLC (10,11). The anti-tumor cytotoxicity of etoposide may be related to the prolonged exposure to low drug plasma concentrations, and prolonged oral etoposide can produce prolonged exposure (12,13). Therefore, prolonged administration of oral etoposide has a theoretical advantage in the anti-tumor efficacy over conventional intravenous administration. Furthermore, oral etoposide is convenient to administer and can be given on an outpatient basis. Prolonged oral etoposide has been widely studied in poor-risk or extensive-stage SCLC patients (14–18). A few studies have reported the role of prolonged oral etoposide concurrently with radiation in LSCLC (19,20). In a phase II trial using oral etoposide and cisplatin with concurrent radiation in locally advanced non-small-cell lung cancer, the regimen was feasible and showed favorable survival outcomes (21).
On the basis of theoretical advantage of early radiation and prolonged oral etoposide, we conducted a single-institution phase II trial of early concurrent CRT. Radiation was started from the very beginning of the first cycle of chemotherapy, with prolonged oral etoposide and cisplatin for LSCLC to evaluate its efficacy and safety.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Subjects
All patients entered in this trial had newly diagnosed, pathologically confirmed SCLC, and all had measurable limited-stage disease, defined as a tumor confined to one hemithorax, mediastinal, hilar or supraclavicular area, which could be encompassed within a single radiation port. History, physical examination, chest radiography, chest and upper abdomen computed tomography (CT) scan, bone scan and bone marrow examination were performed for staging. Other staging studies were performed if clinically indicated. All patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2. Other eligibility criteria included an absolute neutrophil count (ANC)
1500/µl, a platelet count 100 000/µl, aspartate aminotransferase/alanine aminotransferase (AST/ALT) 
2.5 x the upper normal limit (UNL), bilirubin 1 x UNL and serum creatinine 1.5 x UNL. Patients with a previous or concurrent malignancy other than LSCLC, a history of chemotherapy or radiation therapy, active infection, myocardial infarction within 6 months before entry, congestive heart failure or significant arrhythmia were ineligible. Written informed consent was obtained from all patients.
Study Protocol
End-points. The primary end-point of this trial was complete response (CR) rate. The secondary end-points were response rate, response duration, time to progression and overall survival.
Chemotherapy. One cycle of oral etoposide (50 mg/m2/day on days 1–14) and intravenous cisplatin (75 mg/m2 on day 1) combination chemotherapy was administered every 3 weeks, for six cycles. Etoposide was given in 25-mg tablets, so the calculated dose was rounded up to the nearest multiple of 25 mg, and was administered in two divided doses each day.
Subsequent doses were modified on the basis of hematologic and non-hematologic toxicities. Chemotherapy was withheld if the ANC was 1500/µl or the platelet count was 75 000/µl on day 1. In this case, the complete blood count (CBC) was repeated weekly and chemotherapy was restarted as soon as counts allowed at least 50% of the dose to be administered. Doses were adjusted or treatment discontinued if the creatinine level was >1 x UNL (cisplatin), the AST level was >5 x UNL or bilirubin level was >1.5 x UNL (etoposide), or if intractable nausea, vomiting or neurotoxicity developed (cisplatin).
Radiotherapy. Forty-four Gy of thoracic radiation therapy (TRT) was administered at 2.0 Gy/day in 22 daily fractions (excluding weekends and holidays) using the AP/PA portal arrangement. TRT was to begin concurrently with chemotherapy from day 1 of the first cycle. The radiation target volume included the primary tumor mass, the ipsilateral hilar and the mediastinal lymph nodes with 1.5–2.0-cm margins in all directions throughout TRT, and the radiation fields were reduced on an individual basis for responders during TRT. Prophylactic cranial irradiation (PCI) of 25 Gy in 10 daily fractions was administered to patients who achieved a CR after the planned six cycles of chemotherapy.
Follow-up tests. We went through history taking, physical examination, CBC, chemistry and simple chest radiography every cycle, and chest CT every other cycle for all patients during the treatment period. After the planned treatment, history taking, physical examination, CBC, serum chemistry and simple chest radiography were repeated every month for 6 months, then every 3 months for the next 18 months; chest CT was repeated every 3 months for 2 years.
Efficacy and Toxicity Assessment
CR was defined as the complete disappearance of all clinically detectable disease for at least 4 weeks. Partial response (PR) was defined as a 50% decrease in the sum of the products of the two longest perpendicular diameters of all measurable lesions for at least 4 weeks with no increase in size of any area of known malignant disease and no appearance of new areas of malignant disease. Stable disease (SD) was defined as regression not meeting the previous criteria for objective response, with no progression for a minimum of 3 months. Progressive disease (PD) was defined as a >25% increase in the sum of the products of the perpendicular diameters of all measurable lesions or the appearance of any new lesion.
Overall survival was calculated from the first day of treatment to the date of death or last follow-up. Duration of response was calculated from the date of its initial documentation to the date on which PD was first observed or of the last follow-up, with the group of responding patients. Time to progression was calculated from the first day of treatment to the date on which PD was first observed or of the last follow-up.
Statistical Analysis
Clinical efficacy was analyzed according to an intent-to-treat (ITT) analysis.
Descriptive statistics were reported as proportions and medians. Kaplan–Meier estimates were used in the analysis of all time-to-event variables (overall survival, duration of response, time to progression), and the 95% CI for the median time to event was computed.
The relative dose was calculated as the ratio of the dose actually delivered to the dose planned by the protocol. The dose intensity (DI) was calculated as the ratio of the total dose (expressed in milligrams) per meter squared of the patient, divided by the total treatment duration expressed in days. In this calculation, the end of treatment was considered to be 21 days after day 1 of the last cycle of chemotherapy. The relative DI was calculated as the ratio of the DI actually delivered to the DI planned by the protocol.
This study was designed as a phase II study, with CR rate as the primary end-point. According to Simon’s two-stage minimax design (22), a sample size of 40 was required to accept the hypothesis that the true CR rate is >70% with an 80% power and to reject the hypothesis that the true CR rate is <50% with 5% significance. At the first stage if there were fewer than nine CRs out of the initial 20 patients, the study would terminate.
SPSS for Windows (SPSS Inc, Chicago, IL) packages were used for statistical analysis.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Patient Characteristics
We enrolled 44 patients between September 1998 and January 2001 at the Samsung Medical Center, including 36 men and eight women, with a median age of 60 years (range, 42–77 years), including 15 patients (34%) >65 years-of-age. Forty patients (91%) had an ECOG PS of 0–1. Patient characteristics are outlined in Table 1.
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Efficacy
Forty-one patients were assessable for response after excluding three patients: one lost to follow-up after one cycle, one lost to follow-up after two cycles and one early death. According to ITT analysis, the CR rate was 52% (95% CI, 37–67%), the PR rate was 36%, and the overall response rate was 88% (95% CI, 78–98%) (Table 2). The median duration of response was 11.4 months (95% CI, 7.5–15.4 months) for complete responders and 7.4 months (95% CI, 6.7–8.1 months) for partial responders.
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The median follow-up period was 14.9 months (range, 0.2–46.7 months), and the median overall survival was 14.9 months (95% CI, 11.4–18.3 months) for the ITT population (Fig. 1). The 2- and 3-year survival rates were 26% and 20%, respectively. The median time to progression was 10.8 months (95% CI, 9.3–12.4 months) (Fig. 2).
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Toxicity
The major toxicities were hematologic (see Table 3). Eighteen patients (41%) experienced at least one neutropenic fever event and seven patients (16%) experienced repeated febrile episodes during neutropenia. The most common non-hematologic toxicity
grade 3 was esophagitis; grade 4 non-hematologic toxicity was not observed.
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There were two deaths (5%) from sepsis with neutropenia; these were considered to constitute treatment-related mortalities. One patient died after the first cycle of chemotherapy during TRT, and the other after the sixth cycle of chemotherapy.
Patterns of Failure
Of the 29 patients whose disease progressed during the follow-up period, 10 patients (34%) failed within the thorax only, five (17%) in combined thoracic and extra-thoracic sites and 14 (49%) in extra-thoracic sites only. The first site of failure was the central nervous system (CNS) for six patients (21%); the CNS was the only site of failure for five of these patients (17%).
Profile of Actual Chemotherapy Delivered
The median number of chemotherapy cycles administered per patient was six, and 31 patients (70%) received all six planned cycles of chemotherapy.
Of the 41 patients receiving more than one cycle of chemotherapy, the median delay in starting the second cycle was 10 days, mostly as the result of hematologic toxicity. The median delays in starting the third to sixth cycles ranged from 11 to 15 days, and multiple delays among individual patients were common.
Profile of Actual TRT and PCI Delivered
Forty-one out of 44 eligible patients received 44 Gy as planned. Three patients received <40 Gy because one died during TRT and the other two were lost to follow-up. Twenty-three patients achieved CR and 17 (74%) of them received PCI. Three patients refused PCI and three others did not undergo PCI due to early progression.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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We report in the present study the results of early concurrent CRT, starting from the very beginning of the first cycle of chemotherapy, with prolonged oral etoposide and cisplatin for LSCLC.
The CR rate of 52% in this study is similar to those of concurrent CRT with conventional fractionation, but inferior to that of concurrent CRT with hyperfractionation, irrespective of the timing of radiation. Perry et al. reported 49% and 58% (5), Work et al. 59% and 61% (6) and Murray et al. 64% and 56% (7) using early and late radiation with conventional fractionation. Jeremic et al. reported outstanding CR rates of 96% and 82% using early and late radiation with hyperfractionation (8).
We obtained a median overall survival of 14.9 months and a 2-year survival rate of 26%, which are no better than those of other reports using late concurrent CRT. Perry et al. reported median overall survival of 11.2 months (5), Work et al. reported 12.0 months (6), Murray et al. reported 16.0 months (7), Jeremic et al. reported 26 months (8) and Takada et al. reported 27 months (9).
When we initiated this study, we expected comparatively better results on the basis of the theoretical advantage of early concurrent CRT and prolonged oral etoposide. But the results we obtained were not superior to those of other trials using early or late concurrent CRT with conventional fractionation and intravenous combination chemotherapy. The main reason for the failure to show improved CR rate and survival is probably the decreased DI of chemotherapy. The present study reports a median delay of 10 days or more in administering chemotherapy, mainly due to bone marrow suppression, and a mean relative DI of 0.58 for etoposide and 0.62 for cisplatin. Early concurrent CRT may have resulted in more severe bone marrow suppression than expected, and a subsequent reduction in the actual DI, which was previously pointed out (5).
Severe bone marrow suppression is partly due to prolonged oral etoposide. In a previous phase III study comparing prolonged oral etoposide (50 mg/m2/day for 21 days) with intravenous etoposide in extensive-stage SCLC, prolonged oral etoposide showed a greater rate of severe hematologic toxicity but no difference in the objective response rate or in survival (16). But oral etoposide (50 mg/m2/day for 14 days) and cisplatin with concurrent radiation showed favorable survival outcomes and acceptable toxicity profiles in locally advanced non-small-cell lung cancer (21). Although we selected a 14-day schedule of oral etoposide, rather than 21-day, on the basis of the above results, unexpected severe bone marrow suppression, resulting in decreased DI, was observed. New drugs or conventional intravenous etoposide should be considered preferentially over prolonged oral etoposide for further investigation of LSCLC.
Recent data has shown the possible superiority of hyperfractionated radiation compared to conventional fractionation if delivered with the same dose (23), and the possible delivery of up to 70 Gy of radiation with standard fractionation (11). At this time, 44 Gy of standard fractionation (as delivered in this trial) might be considered a somewhat low dose, although this was not the case at the time of initiating this trial.
Early concurrent CRT, starting from the very beginning of the first cycle of chemotherapy with prolonged oral etoposide and cisplatin failed to show any improvement in survival compared with other CRT regimens. Another phase II study of early concurrent CRT with prolonged oral etoposide and platinum in LSCLC did not show a superior response rate or survival (20).
In order to improve the outcomes of LSCLC, future research is warranted to define the optimal timing of TRT in combination with chemotherapy as well as a better method of TRT delivery, the optimal dose of TRT and a more effective and less toxic chemotherapy regimen. Another single-institution, phase II trial of concurrent CRT, starting from the third cycle of chemotherapy, has shown very similar results to this study in terms of response rate and survival (24). We plan to perform a prospective, randomized clinical trial comparing concurrent CRT starting from the very beginning of the first cycle of chemotherapy with concurrent CRT starting from the third cycle of chemotherapy, using intravenous instead of oral etoposide and platinum, to define the optimal timing of TRT.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Early concurrent CRT, starting from the very beginning of the first cycle of chemotherapy with prolonged oral etoposide and cisplatin, showed a less-than-satisfactory outcome, with moderate toxicity. Future investigations need to address the optimal timing of TRT in combination with chemotherapy as well as a better method of TRT delivery, the optimal dose of TRT and a more effective and less toxic chemotherapy regimen.
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FOOTNOTES |
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+ For reprints and all correspondence: Keunchil Park, Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-gu, Seoul 135-710, Korea. E-mail: kpark{at}smc.samsung.co.kr
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Received July 14, 2003; accepted November 3, 2003
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