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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 1  |  Page : 238-243

Survival and prognostic factors in limited stage small cell lung cancer: A retrospective study from northeast Turkey


Department of Radiation Oncology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey

Date of Web Publication13-Apr-2016

Correspondence Address:
Özlem Aynaci
Karadeniz Technical University, Faculty of Medicine, Department of Radiation Oncology, Trabzon - 61080
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.151446

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 > Abstract 


Aim of the Study: The purposes of this retrospective study were to identify survival rates for limited stage small cell lung cancer (LD-SCLC) and analyze treatment outcomes and influencing factors on survival.
Materials and Methods: We conducted data from patients diagnosed with LD.SCLC between January 1998 and December 2012 at our institution. Dermographic information, treatment modalities, pretreatment clinical asessment, were recorded. Most of the patients. (88.4%) were treated with curative intent. The survival probabilties were asessed by Kaplan.Meier analysis. Cox regression was used to assess prognostic factors on overall survival and disease.free survival.
Results: A total of 129 patients were examined as a LD-SCLC. The median age was 60 (range; 31–86). Median follow-up time was 9.4 (SE ± 20.5) months and the median overall survival was 13.9 months [95% cumulative incidence (CI): 10.1–17.6]. On multivariate analysis, concurrent chemotherapy [HZ: 2.7 (95% CI: (1.0–7.2)] (P = 0.037) and doses of radiation therapy (<50, ≥50) [HZ: 1.4 (95% CI: (1.0–2.2)] (P = 0.046) were statistically significant on overall survival. With regard to multivariate anlaysis age (<60, ≥60) [HZ: 2.2 (95% CI: (0.6–3.7)] (P = 0.011), doses of radiation therapy (<50, ≥50) [HZ: 2.7 (95% CI: (1.0–7.2)] (P = 0.046), precense of surgery [HZ: 15.3 (95% CI: (1.5–152)] (P = 0.020), prophilactic cranial radiation therapy (PCI) [HZ: 2.3 (95% CI: (1.1–4.5)] (P = 0.014), and presence of concurrent chemoradiotherapy [HZ: 3.0 (95% CI: (1.3–6.8)] (P = 0.008) were important variable affecting disease-free survival.
Conclusion: For LD-SCLC patients concurrent chemoradiation therapy and 50. Gy and over doses radiation therapy provided improvement on overall and disease.free survival.

Keywords: Chemoradiotherapy, chemotherapy, LD-SCLC


How to cite this article:
Aynaci Ö, Canyilmaz E, Serdar L, Kandaz M, Bahat Z, Yoney A. Survival and prognostic factors in limited stage small cell lung cancer: A retrospective study from northeast Turkey. J Can Res Ther 2016;12:238-43

How to cite this URL:
Aynaci Ö, Canyilmaz E, Serdar L, Kandaz M, Bahat Z, Yoney A. Survival and prognostic factors in limited stage small cell lung cancer: A retrospective study from northeast Turkey. J Can Res Ther [serial online] 2016 [cited 2019 Dec 11];12:238-43. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/238/151446




 > Introduction Top


Cancer which makes up an important proportion of deaths is a worldwide health problem.[1] Lung cancer accounts for 13% of the whole cancer sites and 18% of the deaths depend on the cancer.[2] It is divided into two main different histologies: Small cell lung cancer (SCLC) and non-SCLC. Over the past several decades, among lung cancer subtypes, the prevalance of SCLC was 20%, but this percentage has been decreasing perhaps because of smoking cessation and the proliferation of low-tar cigarettes. Currently, this proportion acoounts for approximately 10%.[3],[4]

Owing to aggressive nature of SCLC, the majority of patients present as bulky mediastinal mass with mediastinal nodal involvement or extrathoracic extension.[5] SCLC is staged as limited stage (LD) and extensive stage in accordance with Veteran's Administration Lung Cancer Study Group. Limited stage disease which is limited to one hemitorax, regional mediastinal lymph nodes, and ipsilateral supraclavicular lymph nodes treated with chemotherapy and radiation therapy curatively. Patients who were not correspond to this definition are identified as extensive stage.

SCLC is more sensitive chemotherapy and radiotherapy than non-SCLC and also SCLC grows up more quickly and metastases to regionel and distant sites earlier.[6],[7],[8] If SCLC was not treated, the median survival ranged from 2 to 4 months.[9]

Because of variable incidences nowadays, we analyzed limited stage SCLC patients who applied to our department. Dermographic features, different treatment modalities, clinical courses of treated patients, and survival ratios of cases were examined in this report.


 > Materials and Methods Top


Patients

This retrospective study used patient files in our clinic. The data were acquired from the patient files of 1,696 patients who had been diagnosed lung cancer and treated with radiation therapy or chemotherapy during the period from January 1998 to December 2012.

For this report, we limited our analyses to 129 patients with a SCLC histology who have limited stage. The patient's information was obtained by history, directly and/or by phone calls made to patients or patient's relatives. We record data about dermographic information, chemotherapy regimen, radiation therapy information, lokal recürrens status, distant metastasis status. Patients were staged in accordance with either the staging system of the Veterans Administration Lung Cancer Study or American Joint Committee on Cancer staging system.

Treatment

Radiation therapy was performed with curative or palliative intent to 126 patients in our analysis. By the time June 2011, patients was treated two-dimensional treatment through the Co 60 or Linear accelerator (6–10 MV); and after June 2011, three-dimensional conformal or intensity modulated radiation therapy was applied through the Lineer accelerator (6–18 MV) to the patients. While the radiation therapy field included gross tumor as defined by chest computed tomography (CT) scan and involved lymph nodes and elective nodes in two-dimensional treatment modality. In the three-dimensional treatment, the target volume was included gross tumor and involved lymph nodes in radiation therapy field. Two types of radiothareapy schdule were used as 30 Gy in 15 fractions and 25 Gy in 10 fractions with using two opposite fields in prophilactic cranial irradiation.

In this analysis, chemotherapy was used as both concurrently and sequentually. Cisplatin and etoposide (EP) regimen was the main combination in LD-SCLC. Surgery may be an option for selected patients with early stages but only two patient underwent surgery in this study.

End points

The primary endpoint of the study was overall survival and was measured from the date of the diagnosis to the date of death from any cause. In the absence of a date of diagnosis, instead of that we recorded the beginning date of radiation therapy. We measured disease-free survival from the date of diagnosis to the date of local recurrence/progression or distant metastasis.

Statistics

Our data evaluation and statistical analyses were performed using statistical package of social sciences (SPSS) version 13 software. Overall survival and progression-free survival were calculated by using Kaplan–Meier method. The log rank test was used in the analyzing differences between subgroups. The Cox regression analysis were performed to predict the factors with independent prognostic significance on survival.


 > Results Top


Patient population

In the period from 1998 to 2012, a total of 129 patients were examined as a LD-SCLC. The median age was 60 (range; 31–86). There was a strong predominance of males (125 patients, 97%) compared with females. A large part of patients was diagnosed by brochoscopic biopsy (73.4%) [Table 1].
Table 1: Patient and tumor characteristic

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Treatment features

Most of patients (88.4%) was treated with curative intent. Patients with the Eastern Cooperative Oncology Group (ECOG) performance status 3–4; inadequate hematological, liver, and kidney function; severe dyspnea; ≥60 age were candidate for palliative radiation therapy. The average radiation therapy dose was 50 (range 34–71) Gy in the curative treatment. Fifteen (11.2%) patients who were administered to curative therapy didn't complete their total radiation course. With the aim of palliative treatment a fraction of 3 Gy/day, total of 30 Gy was applied. One patient of these did not finish radiation therapy. After a day, he died. The EP combination is the most commonly (80.9%) used first line chemotherapy regimen in our study. The second common multi agent regimen was cyclofosfamide, adriamicin, and vincristin (CAV) (6.4%). Only 9 (7%) of the 129 patients receive concurrent chemoradiotherapy. While seven (77.7%) of these received EP regimens, a patient received carboplatin and paclitaxel, and one patient received sisplatin and docataxel. Forty-one of patients (31.2%) received prophilactic cranial radiation therapy (PCI). Thirty-three patients could be analyzed according to distant metastases. PCI was administered to 17 of them. While brain metastases arised in 13 (81.3%) patients, 4 (23.5%) patients does not develop brain metastases. Doses were ranged from 30 Gy in 20 fractions to 25 Gy in 10 fractions [Table 2].
Table 2: Treatment features characteristics

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Treatment-related acute adverse effects were identified in 90 (69.8%) patients. The most common acute toxicity was esophagitis in 35 (38.9%) patients. When we evaluated all acute toxicities, grade 2 toxicity is common and developed in 42 (70%) patients. Late toxicities were assessed in 24 patients. Pulmonary fibrosis was the most frequent late toxicity in 15 (62.5%) patients.

Survival

Median follow-up was 9.4 (SE ± 20.5) months. The median overall survival was 13.9 months (95% CI: 10.1–17.6), the 2, 5, and 10 yearly survival were 33.1% (SE ± 0.043), 13% (SE ± 0.033), and 7% (SE ± 0.038), respectively [Figure 1].
Figure 1: Overall survival

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In univariate survival analysis of all factors [Table 3]; age (<, ≥60), gender, stage, nodal involvement, tumor location, presence of concurrent chemoradiotherapy, doses of radiation therapy (<, ≥50), PCI, platinum-based chemotherapy, non-platinum-based chemotherapy, sites of distant metastases, types of radiation therapy sources, treatment breaks were examined as a significant prognostic factors on survival. Age < 60 (0,044), presence of concurrent chemoradiotherapy (P = 0.01), doses of radiation therapy (<, ≥50) (P = 0.038) and radiation therapy with two-dimensional treatment through Linear accelerator (6–10 MV) (P = 0.00) were evaluated a statistically significant.
Table 3: Results of log-rank univariate analysis for overall survival

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In multivariate analysis, using Cox'proportional hazards model, age (<, ≥60), presence of surgery, tumor location, presence of concurrent chemotherapy, PCI, doses of radiation therapy (<, ≥50), and types of radiation therapy [2-D versus 3-D and/or intensity-modulated radiation therapy (IMRT)] were analyzed as a effective prognostic factor that could influence on survival. Among these factors, concurrent chemotherapy [HZ: 2.7 (%95 CI: (1.0–7.2)] (P = 0.037) and doses of radiation therapy (<, ≥50) [HZ: 1.4 (%95 CI: (1.0–2.2)] (P = 0.046) were statistically significant [Table 4].
Table 4: Results of multivariate analysis for overall survival by Cox proportional hazard model

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The median disease-free survival was 18 (SE ± 8.5) months and the 2- and 5-year survival rate were 48% and 26%, respectively [Figure 2]. With regard to multivariate anlaysis age (<, ≥60) [HZ: 2.2 (95% CI: (0.6–3.7)] (P = 0.011), doses of radiation therapy (<, ≥50) [HZ: 2.7 (95% CI: (1.0–7.2)] (P = 0.046), presence of surgery [HZ: 15.3 (95% CI: (1.5–152)] (P = 0.020), PCI [HZ: 2.3 (95% CI: (1.1–4.5)] (P = 0.014), and presence of concurrent chemoradiotherapy [HZ: 3.0 (95% CI: (1.3–6.8)] (P = 0.008) were important variable affecting disease-free survival [Table 5].
Figure 2: Disease-free survival

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Table 5: Results of multivariate analysis for disease-free survival by Cox proportional hazard model

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 > Discussion Top


Our analysis indicates that SCLC comprises approxiamtely (18%) of lung cancer.

Ramaswany et al., reported that the incidence of SCLC was 12.9% which are not similar to the results of our study. Over the past several decades, the proportion of SCLC among all lung cancer histologies had been decreasing.[10]

In the late 1960s, only multiagent chemotherapy has become the primary treatment for the SCLC. Nonetheless, a lot of recurrences began to develop in the previous disease area after chemotherapy. So the researchers reassessed the radiation therapy for LD-SCLC.[11],[12] They found that the addition of thoracic radiotherapy (TRT) to chemotherapy decreased the rate of intrathoracic failure. There were two metaanalysis about the role of TRT. In a meta-analysis by Pignon et al., the 3-year survival rate was reported as 14.3% with chemotherapy and thoracic radiation therapy and 8.9% with chemoterapy alone. As account of these results, in our clinic most of LD-SCLC patients (85.3%) administered to radiation therapy with chemotherapy protocol.[13],[14]

In Japan Clinical Oncology Group (JCOG) 9104, a phase trial by the Japan Clinical Oncology Group examined that whether a significance difference among the patients whom received concurrent or sequential chemoradiotherapy for patients LD-SCLC. EP regimen was applied to all patients. Despite the fact that patients in cocurrent arm had better 2-year or 3-year overall survival rates, these improvements were not statistically significant.[15] Several large studies have supported that concurrent chemotherapy or early radiotherapy in the schedule of chemotherapy. A recent meta-analysis of seven randomized trials concluded that radiotharapy which started within 30 days of the beginning of chemotherapy provided better 2-year and 5-year survival rates than radioterapy started > 30 days after chemotherapy (P = 0.002).[16]

In our study, only 9 of 129 (7%) patients received concurrent chemoradiotherapy. While two of them radiation therapy started 1 of cycle 3 of the chemotherapy regimen, one patient' radiotherapy treatment started 1 day of cycle 1 of chemotherapy regimen. Most of patients (76%) in the current study were treated with sequential chemoradiotherapy. The reason of using sequential arm in our hospital was because of patients who cannot tolerate concurrent chemoradiotherapy due to poor performance status and comorbid conditions. And also, they frequently had large tumor volume that causes an unacceptable dose to normal tissue. The median overall survival was 41.9 months (SE ± 7.6) and 2- and 5-year survival rate were 78% and 31%, respectively, in concurrent arm. Otherwise, the median overall survival was 13.9 months and 2- and 5-yearly survival were 33% and 13%, respectively in sequential arm. Even though sample size in concurrent arm was rather smaller, there was a significant difference compared two arms (P = 0.02).

At present, the optimal dose and fractionation scheme for TRT in SCLC is not clear. By virtue of several randomized trials, SCLC is considered highly radiosensitive, suggesting that higher doses of TRT may produce better survival rates. In the beginning of 1970s, the total TRT doses for LD-SCLC were 25–30 Gy; and in recent years, 60–70 Gy.[17] In 2003, Roof et al.,[18] reported that RT doses of 50 Gy or more doses could improve overall survival, local control and disease-free survival. In Cancer and Leukemia Group B (CALGB) and RTOG phase III study which was ongoing, comparing 45 Gy in 30 fractions twice daily, 70 Gy in 35 fractions daily, and 61.2 Gy in 34 fractions, 5 days/week for 16 days and then twice daily 5 days/week for 9 days. SCLC has a rapid proliferative rate; so investigators concentrated on hyperfractioned regimens against tumor repopulation.

With the aim of curative radiation therapy, patients received median dose 50 (SE ± 8) Gy. Thirteen of 129 LD-SCLC patients were treated in the palliative course as 30 Gy in 10 fractions. Our study shows that patients applied to radiation therapy 50 Gy and more had better overall survival rates compared with a dose of less than 50 Gy (P = 0.03). Besides these rates were consistent with the literature.

In the past, large treatment fields were required to encompass tumor volume and whole mediastinum. On the grounds of developing radiation therapy techniques to ensure better tumor coverage and apply to an agressive radiation therapy regimens with higher doses, the radiation therapy portals got smaller. In the 1980s, SWOG and CALGB researchers reported that using large fields including mediastinum prevented poorer survival.[19],[20] After 1990s, the investigaters supported that smaller target volumes did not change tumor control comparing larger volumes (irradiation with ENI) by their studies.[21],[22] And also, there was a growing concern about preinduction or postinduction volume. In another SWOG trial, patients were randomized to receive radiotherapy to either preinduction or postinduction volume after evaluating induction chemotherapy responses in 6 weeks. They showed that recurrence rates were 32% in the preinduction area and 28% postinduction area.[23] Owing the fact that there was not a significant diffrence, the larger volumes did not prefer anymore. Smaller radiation fields were also related to decreasing toxicities.

We could spare surrounding normal tissues of the lung, esophagus, heart, spinal cord, and bone marrow by using smaller radiation. We determined the most common radiation therapy (35%) toxicicity was esophagitis among 90 of 129 patients whose toxicity data were available. Thirty-two (91%) of them were in two-dimensional treatment through the Co 60 or Linear accelerator (6–10 MV) modality. In our study, we generally delineated target volumes according to preinduction volume in LD-SCLC. Before July 2011, we designed our volumes including preinduction gross tumor volume, involved lymph nodes, and elective lymph nodes. Treatment was planned by two-dimensional planning system and administered using the Co 60 and/or linear accelerator (6–10 MV) machine. After July 2011, ENİ was ommited and radiation therapy was administered using linear accelerator (6–18 MV) machine with three-dimensional planning system.

The incidence of brain metastases in SCLC is more than 50%.[24] It means that brain is one of the most frequent sites of metastases. Therefore, most of chemotherapeutic agents could not reach to the brain because of the nature blood–brain barrier; in 1970s, prophilactic cranial radiation therapy came into use. Several randomized trials investigated the contribution of prophilactic cranial irradiation following a response to initial therapy on survival and precaution of brain metastases. The study conducted by Gregor et al., demonstrated that PCI decreased brain metastases from 52% to 29%.[25] A meta-analysis on seven randomized trials revealed that PCI reduced the incidence of brain metastases comparing observation arm (59% vs 33%). In this analysis, while 85% of patients had a limited stage, 15% was extensive stage, and also a significant improve on survival in PCI arm (59% vs 33%). Radiation doses of PCI varied from 8 Gy in single fractions to 40 Gy in 20 fractions. In our study, when we compared patients to PCI and observation, we observed that PCI was not statistically effective on overall survival (P = 0.80), but it is statistically effective on disease-free survival (P = 0.002). Two types of radiothareapy schdule were used as 30 Gy in 15 fractions and 25 Gy in 10 fractions.[26]

Prophilactic Cranial İrradiation Overview Collaborative Group analyzed four different dose groups included 8 Gy, 24–25 Gy, 30 Gy, and 36–40 Gy. IAlthough no significant difference was found in survivalrates according to the total dose of irradiation, this meta-analysis suggested that the observed reduction in risk of brain metastases increased with total dose.[27] In addition to this, a more recent study concluded that higher doses arm had no greater benefit on incidence of brain metastases and had poorer 2-year overall survival rates in higher doses arm.[28]


 > Conclusion Top


This study strongly suggests that concurrent chemoradiotherapy is the mainstay in the treatment of LD-SCLC as the majority of the literature. With regard to survival probability, it seems surgery recommend for improved disease-free survival. LD-SCLC has prolonged overall survival due to combined with TRT and chemotherapy. PCI improves overall survival and disease-free survival and lessens the incidence of brain metastases. Some of the new technologies include improved computer-assisted treatment planning system, continuous imaging guidance, robotics, higher doses rates, and sterotactic treatments provide potentially treating the lung cancer more effectively. To evaluate the influence of these new technologies, there is a need for pilot randomized trials.

 
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Takada M, Fukuoka M, Kawahara M, Suguira T, Yokohama A, Yokota S, 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.  Back to cited text no. 15
    
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