Niho, Seiji MD*; Kubota, Kaoru MD*; Yoh, Kiyotaka MD*; Goto, Koichi MD*; Ohmatsu, Hironobu MD*; Nihei, Keiji MD†; Saijo, Nagahiro MD*; Nishiwaki, Yutaka MD*
Lung cancer is the leading cause of cancer-related deaths worldwide. In Japan, over 56,000 people died of lung cancer in 2003. Small cell lung cancer (SCLC) accounts for about 15% of all forms of lung cancer. SCLC has a more aggressive biologic behavior than non-small cell lung cancer. At the time of presentation, two-thirds of patients exhibit disseminated disease. SCLC is sensitive to chemotherapy, with a response rate of 70 to 80%. A clinical two-stage system proposed by the Veterans Administration Lung Study Group distinguishes limited-disease (LD) and extensive-disease (ED) in SCLC.1 LD is defined as being limited to one hemithorax, including mediastinal, contralateral hilar, and ipsilateral supraclavicular lymph nodes, whereas ED represents tumor spread beyond these regions. The current standard care for LD-SCLC is a combination of chemotherapy and thoracic radiotherapy (TRT). On the other hand, ED-SCLC is treated with chemotherapy alone. The original definition of LD was a tumor volume that could be encompassed by a reasonable radiotherapy plan. According to the International Association for the Study of Lung Cancer (IASLC)’s consensus report, on the other hand, the classification of LD-SCLC includes bilateral hilar and/or supraclavicular nodal involvement and ipsilateral pleural effusion.2 However, the indication for definitive TRT in patients with LD-SCLC and ipsilateral pleural effusion have not been thoroughly investigated. Recently, the IASLC proposed the seventh edition of the tumor, node, metastasis (TNM) classification for lung cancer. In the proposals, the presence of a pleural effusion is considered as M1 disease.3–6
Definitive TRT is contraindicated in lung cancer patients with malignant pleural effusion. We have sometimes treated SCLC cases in which the ipsilateral pleural effusion disappeared after induction chemotherapy. Should definitive TRT be indicated in SCLC patients if the ipsilateral pleural effusion disappears after induction chemotherapy? Since about 1998, we have routinely performed definitive TRT if the patient’s pleural effusion disappeared after induction chemotherapy. In this retrospective study, we investigated the clinical course and outcome of LD-SCLC patients with ipsilateral pleural effusion and examined the overall survival in patients who received chemotherapy and TRT, comparing with that of ED-SCLC or LD-SCLC patients without ipsilateral pleural effusion. We also applied the proposed seventh edition of the TNM stage to our cohort.
PATIENTS AND METHODS
We retrospectively reviewed the medical records of lung cancer patients who received treatment at the National Cancer Center Hospital East between July 1992 and December 2006. During this period 699 patients were newly diagnosed as having SCLC. Three-hundred and seventy-three patients were diagnosed as having LD-SCLC, and 326 were diagnosed as having ED-SCLC using conventional staging procedures, including a medical history and physical examination, chest radiography, computed tomography (CT) scan of the chest, CT scan or ultrasound of the abdomen, bone scan, and CT scan or magnetic resonance imaging of the brain. In this study, LD-SCLC was defined as disease limited to one hemithorax, including mediastinal, contralateral hilar, and supraclavicular lymph nodes, ipsilateral pleural effusion, and pericardial effusion; ED-SCLC was defined as tumor spread beyond these manifestations.2 Sixty-three of the 373 LD-SCLC patients (17, 95% confidence interval (CI): 13–21%) had ipsilateral pleural effusion. Thirty-seven SCLC patients underwent surgical resection as an initial treatment, and 13 patients received only TRT and/or best supportive care. Remaining 649 patients received chemotherapy as an initial treatment. Of these, 62 LD-SCLC patients had ipsilateral pleural effusion, and were included in this study. The patient characteristics are shown in Table 1. The breadth of the pleural effusion was measured using a CT scan of the chest (Figure 1). Cytologic examination of the pleural effusion prior to treatment was performed in 26 patients. Eleven patients had cytologically positive effusion. Ten patients also had pericardial effusion. Three patients had solid pleural tumor and pleural effusion detected on CT scan. Twenty-six patients had atelectasis. Of these, 14 patients received cytologic examination of the pleural effusion, and four patients had cytologically positive effusion.
We collected clinical data on the patients from their medical records; this data included the chemotherapy regimen that was received, the response to first-line chemotherapy, whether pleural effusion disappeared after first-line chemotherapy, and whether the patient underwent definitive TRT. The World Health Organization’s response criteria were used.7
Overall survival was defined as the interval between the start of treatment and death or the final follow-up visit. Median overall survival was estimated using the Kaplan-Meier analysis method.8 Survival data was compared among groups using a log-rank test. The breadth of pleural effusion was compared using the Mann-Whitney U test. All reported p values are two-sided.
The induction chemotherapy regimens were shown in Table 2. Most common regimen was cisplatin or carboplatin plus etoposide. In LD patients with ipsilateral pleural effusion, there were three complete responses, 43 partial responses, seven no changes, and six progressive diseases. Response was not evaluated in three patients because of early death. The response rate was 74% (95% CI: 62–84%). Ipsilateral pleural effusion disappeared after first-line chemotherapy in 34 patients (55, 95% CI: 42–68%).
Since about 1998, definitive TRT to the primary lesion and mediastinum was routinely performed in patients whose pleural effusion disappeared after chemotherapy. We divided the 62 patients in this study into three subgroups: group A included patients who received chemotherapy and TRT (n = 26), group B included patients who did not receive TRT in spite of the disappearance of pleural effusion after first-line chemotherapy (n = 8), and group C included patients who did not receive TRT and whose pleural effusion persisted after first-line chemotherapy (n = 28).
The median (range) breadth of pleural effusion was 11.2 cm (0.5–7.6 cm) in group A, 1.8 cm (0.5–5 cm) in group B, and 4 cm (0.7–9 cm) in group C. Combining group A and B, the median breadth of pleural effusion was 1.3 cm, which was significantly lower than that of group C (p = 0.0007) (Figure 2).
In group A, all but two patients received platinum-based chemotherapy. One patient received weekly cisplatin, vincristine, doxorubicin, plus etoposide (PE) therapy, and the other patient received cyclophosphamide, doxorubicin, PE alternating with cisplatin PE therapy. Three of the 26 patients in group A underwent TRT (twice daily, 45 Gy in total) concurrently with the first course of chemotherapy. The breadths of pleural effusion in those three patients were 0.7, 0.8, and 1.0 cm. Two, seven, and one patient underwent TRT (once daily, 50 Gy in total) concurrently with the second, third, and fourth courses of chemotherapy, respectively. Thirteen patients underwent TRT (once daily, 50 Gy in total) sequentially after chemotherapy. Six patients received prophylactic cranial irradiation (PCI) of 25 Gy.
Figure 3A showed the survival of the all 699 SCLC patients by the proposed seventh edition of TNM stage. Figure 3B showed the survival of the 649 SCLC patients who received chemotherapy as an initial treatment. The survival of LD patients with ipsilateral pleural effusion was intermediate between those of LD patients without effusion and ED patients (p < 0.0001). The median survival time in LD patients with ipsilateral pleural effusion was 11.8 months (95% CI: 9.2–16.6), and the 1, 2, 3 and 5-year survival rates were 48, 21, 10 and 8%, respectively. Four patients have survived for over 5 years. One patient had a cytologically negative pleural effusion, and cytologic examinations were not performed for the remaining three patients. Breadth of pleural effusion of these four patients ranged from 1.0 to 1.5 cm. Two of these four patients have not shown any progression for more than 5 years. One patient who received only chemotherapy as an initial treatment developed a local recurrence 3 years after the first-line treatment. This patient received concurrent chemoradiotherapy and achieved a complete response. Unfortunately, he developed brain metastasis 9 years after the first-line chemotherapy and received whole brain radiotherapy. The other patient developed cervicular and inguinal node metastases 8 months after the initiation of first-line chemotherapy and concurrent TRT with three courses of chemotherapy. This patient received second, third, and fourth-line chemotherapy, radiotherapy to the cervicular and inguinal node metastases, and surgical resection of the recurrent inguinal node metastasis. He has not shown any signs of progression for 3 years and 3 months after the final surgical resection of the metastatic inguinal node. All three patients who had solid pleural tumor died within 31 months.
Survival analyses for the subgroups in LD patients with ipsilateral pleural effusion are shown in Figures 4, 5 and Table 3. In group A, the median survival time was 19.2 months (95% CI: 16.7–27.9) and the 1 and 2-year survival rates were 81 and 38%, respectively. The median survival time of patients with cytologically positive and negative pleural effusion were 9.3 months (95% CI: 3.8–14.2) and 12.7 months (95% CI: 5.1–17.9), respectively. The median survival time of those patients whose pleural effusions were not examined cytologically was 12.9 months (95% CI: 9.2–18.4). This difference was not statistically significant (p = 0.1959).
Disease progression was confirmed in 21 of the 26 patients in group A. The sites of first disease progression included the brain (n = 10), regional lymph nodes (n = 5), primary lesion (n = 3), distal lymph nodes (n = 2), liver (n = 1), adrenal gland (n = 1), and bone (n = 1). Twelve (57%) were distant, seven (33%) were local-regional, and two (10%) were both local-regional and distant. Brain metastasis was the only site of recurrence in nine patients. These nine patients had not received PCI. At the time of disease progression, ipsilateral pleural effusion recurred in 10 of the 18 patients.
LD-SCLC with ipsilateral pleural effusion accounted for 9% of all the patients with SCLC (63 of 669 patients) and 17% of all the patients with LD-SCLC (63 of 373 patients). Twenty-six (41%) of the LD-SCLC patients with ipsilateral pleural effusion received chemotherapy and definitive TRT. The median survival time of these patients was 19.2 months (95% CI: 16.7–27.9), and the 1 and 2-year survival rates were 81 and 38%, respectively. This overall survival time was comparable to that of LD patients without ipsilateral pleural effusion.
Among the LD-SCLC patients with ipsilateral pleural effusion, the median survival time was 11.8 months (95% CI: 9.2–16.6), and the 1 and 2-year survival rates were 48 and 21%, respectively. This survival was intermediate between those of LD patients without ipsilateral pleural effusion and ED patients. An analysis of 2,580 patients treated in the Southwest Oncology Group trials demonstrated that the survival of patients with LD-SCLC and ipsilateral pleural effusion was not significantly different from that of patients with ED-SCLC and a single metastatic lesion. The median survival times were 13.0 and 12.0 months (p = 0.85), respectively.9 Thus, our data was compatible with that of the Southwest Oncology Group trials. Another analysis of 5,758 patients with SCLC from the IASLC database also demonstrated consistent results.10
According to the proposed seventh edition of the TNM classification for lung cancer, LD patients with ipsilateral pleural effusion will be classified as stage IV.3–6 However, prognosis of LD patients with ipsilateral effusion is better than that of ED patients with distant metastasis. If surgical cases such as clinical stage I cases were excluded, the simple staging system, LD or ED, seemed to be sufficient to select treatment strategy.
In our study, four LD patients with ipsilateral pleural effusion have survived for more than 5 years. Three patients received chemotherapy and TRT as an initial treatment. The remaining one patient received only chemotherapy as an initial treatment but received chemotherapy and TRT after a local recurrence. TRT probably contributed to local control and long-term survival in those LD-SCLC patients with ipsilateral pleural effusion. A previous systematic review demonstrated that an early timing of TRT contributed to a significant improvement in long-term survival, compared with a late timing.11 In patients whose ipsilateral pleural effusion disappears after chemotherapy, definitive TRT should be considered as early as possible.
Disease progression was confirmed in 21 out 26 patients (81%) who received chemotherapy and definitive TRT. The most common site of first failure was the brain. Nine of the 10 patients had not received PCI. In these nine patients, brain metastasis was the only site of recurrence. In LD-SCLC patients with ipsilateral pleural effusion who undergo chemotherapy and definitive TRT, PCI may further improve treatment outcome.
Cytologic examinations of the pleural effusion before treatment were only performed in 26 patients (42%). These cytologic results did not significantly affect overall survival. However, all nine patients with cytologically positive pleural effusion died within 31 months. A similar observation was reported in a cohort of IASLC database.10
Chemotherapy regimens were heterogeneous between LD and ED patients. More patients with ED received cisplatin and irinotecan containing regimens. However, response rates were similar between LD with ipsilateral pleural effusion and ED patients (74 and 76%).
In conclusion, long-term survival was achieved by LD-SCLC patients who underwent definitive TRT after their ipsilateral pleural effusion disappeared after induction chemotherapy. A prospective randomized trial is warranted to compare chemotherapy alone with chemoradiotherapy in LD-SCLC patients with ipsilateral pleural effusion. This work was supported in part by a Grant from the Ministry of Health, Labor, and Welfare for the 3rd term Comprehensive Strategy for Cancer Control and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor, and Welfare, Japan.
1. Zelen M. Keynote address on biostatistics and data retrieval. Cancer Chemother Rep 3
2. Stahel RA, Ginsberg R, Havemann K, et al. Staging and prognostic factors in small cell lung cancer: a consensus report. Lung Cancer
3. Rami-Porta R, Ball D, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol
4. Rusch VW, Crowley J, Giroux DJ, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol
5. Postmus PE, Brambilla E, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer. J Thorac Oncol
6. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol
7. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer
8. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc
9. Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Determinants of improved outcome in small cell lung cancer: an analysis of the 2,580-patient Southwest Oncology Group data base. J Clin Oncol
10. Shepherd FA, Crowley J, Van Houtte P, et al. The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol
11. Fried DB, Morris DE, Poole C, et al. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small cell lung cancer. J Clin Oncol