Japanese Journal of Clinical Oncology Advance Access originally published online on April 10, 2007
Japanese Journal of Clinical Oncology 2007 37(3):181-185; doi:10.1093/jjco/hym005
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© 2007 Foundation for Promotion of Cancer Research
Concurrent Chemoradiotherapy for Limited-disease Small Cell Lung Cancer in Elderly Patients Aged 75 Years or Older
1 Divisions of Internal Medicine and Thoracic Oncology
2 Radiation Oncology, National Cancer Center Hospital, Tokyo
3 Department of Medical Oncology, Kinki University Nara Hospital, Ikoma, Nara, Japan
For reprints and all correspondence: Ikuo Sekine, Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan. E-mail: isekine{at}ncc.go.jp
Received July 19, 2006; accepted November 8, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Background: The optimal treatment for limited-disease small cell lung cancer (LD-SCLC) in patients aged 75 years or older remains unknown.
Methods: Elderly patients with LD-SCLC who were treated with chemoradiotherapy were retrospectively reviewed to evaluate their demographic characteristics and the treatment delivery, drug toxicities and antitumor efficacy.
Results: Of the 94 LD-SCLC patients treated with chemotherapy and thoracic radiotherapy at the National Cancer Center Hospital between 1998 and 2003, seven (7.4%) were 75 years of age or older. All of the seven patients were in good general condition, with a performance status of 0 or 1. Five and two patients were treated with early and late concurrent chemoradiotherapy, respectively. While the four cycles of chemotherapy could be completed in only four patients, the full dose of radiotherapy was completed in all of the patients. Grade 4 neutropenia and thrombocytopenia were noted in seven and three patients, respectively. Granulocyte-colony stimulating factor support was used in five patients, red blood cell transfusion was administered in two patients and platelet transfusion was administered in one patient. Grade 3 or more severe esophagitis, pneumonitis and neutropenic fever developed in one, two and three patients, respectively, and one patient died of radiation pneumonitis. Complete response was achieved in six patients and partial response in one patient. The median survival time was 24.7 months, with three disease-free survivors for more than 5 years.
Conclusion: Concurrent chemoradiotherapy promises to provide long-term benefit with acceptable toxicity for selected patients of LD-SCLC aged 75 years or older.
Key Words: elderly • small cell lung cancer • chemotherapy • radiotherapy
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Small cell lung cancer (SCLC) accounts for approximately 20% of all pulmonary neoplasms and 25–40% of patients with this disease are 70 years of age or older. The number of elderly patients with such disease are expected to increase with the growing geriatric population (1).
Because SCLC is highly sensitive to chemotherapy and radiotherapy, the standard treatment for limited-disease SCLC (LD-SCLC) has been a combination of platinum and etoposide with concurrently administered thoracic radiotherapy, as long as the patients are in good general condition (2, 3). Such elderly patients, however, may show decreased clearance of the anticancer agents commonly used for the treatment of SCLC, including cisplatin and etoposide, because of the decrease of the lean body mass, hepatic blood flow and renal function that are associated with aging. In addition, myelotoxicity is sometimes more severe in this population than in younger populations, because the absolute area of hematopoietic marrow decreases with age (4). Retrospective subset analyses of patients with LD-SCLC treated with concurrent chemotherapy and radiotherapy in phase III trials have shown that the percentage of patients in whom the planned number of chemotherapy cycles can be completed is usually 10% lower in patients 70 years of age or older as compared with that in younger patients (5). One study reported that myelotoxicity was more severe in elderly patients than in younger patients (5), while another reported no such difference between the patients of the two age groups (6). The delivery of thoracic radiotherapy was not influenced by age in these patients (7). However, 78–85% of patients in these analyses were aged between 70 and 75 years old and a few were over 80 years old. Thus, the most suitable treatment options for elderly patients with LD-SCLC aged 75 years or older still remain unknown.
The objective of this retrospective analysis was to evaluate the patient characteristics and the treatment delivery, toxicity and antitumor efficacy of the administered treatments in LD-SCLC patients 75 years of age or older who were treated with chemotherapy and thoracic radiotherapy.
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PATIENTS AND METHODS |
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We retrospectively reviewed the medical charts, chest X-rays and computed tomography (CT) scans of LD-SCLC patients aged 75 years or older. To evaluate the thoracic irradiation field, the standard initial field was defined as follows: the field including the primary tumor and involved nodes with a short axis length of 1 cm or more on CT scans with a 1.0–1.5 cm margin, and the subclinical ipsilateral hilum and bilateral mediastinal lymph node regions with a 1.0 cm margin. The supraclavicular lymph node regions were included only if there was tumor involvement of these nodes. Toxicity was graded according to the Common Terminology Criteria for Adverse Events, version 3.0, Japanese edition (8). The objective tumor response was evaluated according to the WHO criteria issued in 1979 (9). The overall survival time was measured from day 1 of chemotherapy to the date of death as a result of any cause or the date of the last follow-up.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Of the 94 LD-SCLC patients treated with chemotherapy and thoracic radiotherapy at the National Cancer Center Hospital between 1998 and 2003, seven (7.4%) were 75 years of age or older (Table 1). During this period, we had three other patients with LD-SCLC who were aged 75 years or older. They were treated with chemotherapy alone because of complications in two patients and refusal of intensive therapy in one patient. There were five males and two females, and four patients were between 75 and 79 years of age and three patients were 80 years old or older. Three patients presented with persistent cough, while the remaining four patients complained of no symptoms and were diagnosed based on the detection of an abnormal shadow on a plain chest X-ray obtained during a mass screening or routine health examination program. All the patients were in good general condition. One patient had a history of inferior wall myocardial infarction suffered 9 years prior to this admission. However, echocardiography at this admission revealed normal heart function with an ejection fraction of 73%. One patient had stage I pulmonary emphysema with % FEV1 predicted of 58%, but no abnormal findings on blood gas analysis. The % FEV1 predicted in other four patients was within 98% and 116%, and was not measured in the other two patients. A median (range) PaO2 level at the room air before treatment in the seven patients was 77.4 (66.9–87.2) Torr. A decreased creatinine clearance, 48.8 ml/min at a urine volume of 600 ml/day, was noted in one patient, while the other patients had a creatinine clearance of 78 ml/min or higher. Four and three patients had a performance status of 0 and 1, respectively, and five patients gave no history of loss of body weight. The diagnosis of small cell carcinoma was confirmed cytologically or histologically in all the patients.
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The chemotherapy regimens used were cisplatin at 80 mg/m2 on day 1 combined with etoposide at 100 mg/m2 on days 1–3 in four patients aged between 75 and 19 years. For patients aged 80 years of older, carboplatin was dosed to a target AUC of 5 by Calvert's formula on day 1 combined with etoposide at 80 mg/m2 on days 1–3 in two patients and cisplatin at 25 mg/m2 on days 1–3 combined with etoposide at 80 mg/m2 on days 1–3 in one patient (Table 2). These regimens have been reported to be used in a JCOG phase III trial for elderly patients with extensive SCLC (10). Four cycles of chemotherapy could be completed in four patients, whereas only three cycles could be completed in two patients and only one cycle could be completed in one patient. The reason for discontinuation of the chemotherapy in these patients was prolonged myelosuppression in two patients and patient refusal for continuation of treatment in one patient. The chemotherapy dose was reduced in the subsequent cycles in four patients. The reasons for the dose reduction were grade 4 thrombocytopenia in two patients, grade 4 leukopenia in one patient and both grade 4 thrombocytopenia and leukopenia in one patient. Thoracic radiotherapy was started concurrently with the chemotherapy in five patients (early concurrent chemoradiotherapy). Treatment began with chemotherapy alone in the remaining two patients, because of a mild cytology-negative pleural effusion in one patient and too large an irradiation volume in the other patient. Two cycles of chemotherapy reduced the tumor volume successfully in both the patients and thoracic radiotherapy was then added concurrently with the third and fourth cycles of chemotherapy (late concurrent chemoradiotherapy). Thoracic radiotherapy was delivered using photon beams from a liniac or microtron accelerator with energy between 6 and 20 MV at a single dose of 2 Gy once daily up to a total dose of 50 Gy in four patients aged between 78 years or older and at a single dose of 1.5 Gy twice daily up to a total dose of 45 Gy in three patients aged between 75 and 77 years. This selection of conventional or hyperfractionated radiotherapy was determined arbitrarily. The initial irradiation field was judged as the standard in six patients and reduced in one patient. A multi-leaf collimator and conventional lead blocks were used for shaping of the irradiation field. The median irradiation area was 169 cm2 (range, 95–278 cm2). The projected total radiation dose was administered in all the patients, but a treatment delay of 5 days or longer was observed in three patients. The criteria of radiotherapy suspension were white blood cell count < 1.0 x 109/L, platelet count < 20 x 109/L, esophagitis
grade 3, fever 38°C and performance status 3. The reason for the delay in the three patients was esophagitis, decreased platelet count and poor performance status.
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The hematological toxicities observed in the patients are summarized in Table 3. Grade 4 leukopenia, neutropenia and thrombocytopenia were noted in four, seven and three patients, respectively. Granulocyte-colony stimulating factor support was used in five patients, red blood cell transfusion was administered in two patients and platelet transfusion was administered in one patient. The non-hematological toxicities included grade 3 or more severe esophagitis, pneumonitis and neutropenic fever in one, two and three patients, respectively. One patient died of radiation pneumonitis that developed 4 months after the end of radiotherapy (Case No. 6).
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Of the seven patients, complete response was achieved in six patients and partial response in one patient (Table 3). However, prophylactic cranial irradiation was given in only one patient (Case No. 6). Three patients remained alive for more than 5 years without recurrence. The median survival of the seven patients was 24.7 months.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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The antitumor effects of the treatment regimens were reasonably good, with six complete responses and one partial response and three long-term disease-free survivors in spite of discontinuation/dose reduction of chemotherapy. This is perhaps mainly attributable to the strict selection of patients in good general condition. Thus, we believe that the standard chemoradiotherapy can be applied to LD-SCLC patients aged 75 years or older as long as they are in good general condition.
The general condition of elderly patients, however, varies widely from patient to patient. Thus, in many elderly patients 75 years of age or older, it may be better to reduce the treatment intensity, although it may be difficult to establish the standard schedule applicable to all elderly patients. There are four possible ways to modify the intensity of therapy: (1) administer chemotherapy alone; (2) change the relative timing of chemotherapy and radiotherapy; (3) decrease the drug doses and number of cycles of chemotherapy, and (4) decrease the dose and intensity of thoracic radiotherapy.
Chemotherapy alone versus chemotherapy and thoracic radiotherapy for LD-SCLC were compared in many randomized trials between the 1970s and 1980s. A meta-analysis of these trials demonstrated survival benefit of radiotherapy added to chemotherapy in younger populations of patients less than 65 years of age, but the benefit is still unclear in older patients (11). Although the findings of this meta-analysis indicated that the standard treatment in elderly patients with LD-SCLC might be chemotherapy alone, the result based on the old trials using cyclophosphamide and doxorubicin-based chemotherapy cannot be applied in the current medical setting, because chemotherapy regimens, irradiation delivery equipment and staging procedures have all evolved greatly over time.
The relative timing of chemotherapy and radiotherapy greatly influences the severity of toxicity. In late concurrent chemoradiotherapy that follows induction chemotherapy, the chemotherapy dose can be adjusted to suit each patient by evaluating the toxicity of the previous chemotherapy. In addition, the irradiation volume can be reduced by modifying the radiation treatment planning in accordance with the extent of tumor shrinkage during the induction phase. In the two patients treated by this approach in this study, the dose of the platinum drug during the concurrent chemoradiotherapy phase was reduced to 66–75% of the initial dose and that of etoposide was reduced to 50–75% of the initial dose. Sequential chemoradiotherapy consists of induction chemotherapy and subsequent radiotherapy. Because the two treatment modalities are administered separately, the treatment dose in each can be optimized for the elderly in this approach. A phase III study of concurrent versus sequential chemoradiotherapy in LD-SCLC patients younger than 75 years old revealed a 5-year survival rate of 24% in the concurrent arm and a 5-year survival rate of 18% with a lower incidence of toxicity in the sequential arm (2). The sequential schedule has not yet been evaluated in LD-SCLC patients 75 years of age or older.
A recent phase III trial showed that etoposide at 80 mg/m2 on days 1–3 combined with either carboplatin at AUC = 5 by Carvert's formula or cisplatin at 25 mg/m2 on days 1–3 was feasible and effective in elderly patients with extensive-disease SCLC (10). These regimens may, therefore, be applied for the treatment of LD-SCLC as well. The standard number of chemotherapy cycles administered is four. In many elderly patients, however, all four cycles cannot be completed. In two phase II studies of two cycles of chemotherapy and concurrent thoracic radiotherapy in elderly patients with LD-SCLC, 13–25% long-term survivors were noted (12,13). Thus, the optimal number of chemotherapy cycles in the elderly should be investigated in future trials.
Thoracic radiotherapy with accelerated hyperfractionation at a total dose of 45 Gy in 30 fractions, the standard schedule for LD-SCLC, was associated with grade 3–4 esophagitis in as high as 32% of the patients and grade 4 leukopenia in 44% of the patients (2,3,5). Thus, the conventional schedule at a total dose of 45–50 Gy in 25 fractions might be preferable in the elderly (3). The severity of esophagitis is also influenced by concomitant chemotherapy, the treatment schedule and the timing of thoracic radiotherapy.
In conclusion, concurrent chemoradiotherapy promises to offer long-term benefit with acceptable toxicity in selected patients of LD-SCLC aged 75 years or older. The optimal schedule and dose of chemotherapy and thoracic radiotherapy still remains to be established in this patient population.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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Acknowledgment |
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We would like to thank Mika Nagai for her assistance in the preparation of this manuscript.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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