|Year : 2020 | Volume
| Issue : 4 | Page : 752-756
Can consolidative thoracic radiotherapy improve outcomes in extensive-disease small cell lung cancer after chemotherapy with complete/near-complete responders?
Esra Korkmaz Kirakli1, Hasan Yilmaz1, Cimen Akcay1, Berna Komurcuoglu2, Ufuk Yilmaz2
1 Department of Radiation Oncology, Dr. Suat Seren Chest Diseases and Surgery Training Hospital, Izmir, Turkey
2 Pulmonary Division, Dr. Suat Seren Chest Diseases and Surgery Training Hospital, Izmir, Turkey
|Date of Submission||10-Sep-2017|
|Date of Decision||06-Jan-2018|
|Date of Acceptance||26-Feb-2018|
|Date of Web Publication||26-Oct-2018|
Esra Korkmaz Kirakli
Department of Radiation Oncology, Dr. Suat Seren Chest Diseases and Surgery Training Hospital, Gaziler Cad, 35210 Yenisehir, Izmir
Source of Support: None, Conflict of Interest: None
Background: In extensive-disease-small cell lung cancer (ED-SCLC), the median survival is 8–10 months and 2-year survival is <5%. Primary tumor progression occurs in 90% of patients approximately within 1 year. The role of consolidative thoracic radiotherapy (C-TRT) for the postchemotherapy residue with the aim of improving local control (LC) and survival is currently of great interest. The objective of this study is to determine the effectiveness of C-TRT on LC, progression-free survival (PFS), and overall survival (OS) in ED-SCLC.
Materials and Methods: Medical records of patients diagnosed as SCLC between January 2010 and December 2015 were evaluated retrospectively. Patients who received C-TRT were identified. Pre- and post-chemotherapy radiological evaluations, radiotherapy schedules, relapse patterns, toxicity incidence, LC, PFS, and OS were analyzed.
Results: Among 552 SCLC patients, 26 ED-SCLC patients who underwent C-TRT were analyzed. Median follow-up was 7.5 months (range, 6.5–8.5 months). Nearly 50% of the patients had >4 metastatic lesions. Restaging was performed mostly by positron emission tomography/computed tomography and cranial magnetic resonance imaging. All patients had complete or near-complete response distantly. C-TRT was 10 × 300 cGy (n = 1), 23 × 200 cGy (n = 2), 25 × 200 cGy (n = 7), 30 × 200 cGy (n = 12), and 33 × 200 cGy (n = 4). There was no toxicity ≥ Grade 3. LC rate was 77%; there was no isolated local relapse. PFS was 3 months. Median survival was 13 months. The 1- and 2-year OS rates were 62% and 8%, respectively.
Conclusion: In ED-SCLC patients, C-TRT may prevent isolated local recurrence and may improve 1-year survival. This survival improvement might be the reflection of high intrathoracic control achieved in 77% of patients.
Keywords: Consolidation, extensive disease, small cell lung cancer, thoracic radiotherapy
|How to cite this article:|
Kirakli EK, Yilmaz H, Akcay C, Komurcuoglu B, Yilmaz U. Can consolidative thoracic radiotherapy improve outcomes in extensive-disease small cell lung cancer after chemotherapy with complete/near-complete responders?. J Can Res Ther 2020;16:752-6
|How to cite this URL:|
Kirakli EK, Yilmaz H, Akcay C, Komurcuoglu B, Yilmaz U. Can consolidative thoracic radiotherapy improve outcomes in extensive-disease small cell lung cancer after chemotherapy with complete/near-complete responders?. J Can Res Ther [serial online] 2020 [cited 2020 Sep 23];16:752-6. Available from: http://www.cancerjournal.net/text.asp?2020/16/4/752/244233
| > Introduction|| |
Small cell lung cancer (SCLC) accounts for 13% of all lung cancers and 70% of cases are extensive stage at the time of presentation. In the recent years, the prevalence of extensive disease-SCLC (ED-SCLC) has increased because of stage migration since computed tomography (CT), cranial magnetic resonance imaging (MRI), and positron emission tomography (PET/CT) have become routinely used for staging.,,
The standard treatment of ED-SCLC includes platinum-based chemotherapy (CXT), prophylactic cranial irradiation (PCI) in responding patients, and palliative radiotherapy (RT) in symptomatic cases., The primary lesion does not respond completely to CXT in 75%–90% of cases. Intrathoracic progression occurs in 90% of patients approximately within 1 year and is the main cause of morbidity., Unfortunately, treatment options are few and the success rate is very low following recurrence. Therefore, these patients and also patients with minimal disease burden (very limited ED-SCLC) diagnosed as a result of PET/CT evaluation in routine staging may benefit from aggressive effort during initial treatment, which is a therapeutic challenge.,
Although the role of PCI in ED-SCLC is clearly defined by Slotman et al., the role of consolidative thoracic RT (C-TRT) for the post-CXT residue with the aim of improving local control (LC) and survival is currently of great interest,, and has remained as an unresolved issue.,,,
There has been very limited data resulting in low level of evidence to recommend C-TRT to patients who do not need symptom palliation.,,,,,, Furthermore, it is very difficult to interpret the results in the literature to daily practice because of variability in terms of study designs, definition of ED-SCLC ranging from very limited to grossly metastatic as a result of different radiological evaluations, patients' characteristics, C-TRT target volumes, planning techniques, timing, dose, and fractionations.
Therefore, the present study aimed to determine the effectiveness of C-TRT on relapse patterns, LC, progression-free survival (PFS), and overall survival (OS) in ED-SCLC.
| > Materials and Methods|| |
Medical records of patients with a pathologically confirmed diagnosis of SCLC between January 2010 and December 2015 who had ED-SCLC (stage IV according to the American Joint Committee on Cancer 7th edition) were retrospectively reviewed. Patients who received C-TRT were evaluated in terms of the number and localization of metastatic lesions; response rates of both metastatic and primary lesions to CXT; restaging, dose, and timing of C-TRT treatment-related toxicity; time interval and localization of LR; distant relapse; and survival. Patients with limited disease (LD-SCLC) at the time of diagnosis that progressed to ED-SCLC during treatment, those that received radical TRT before CXT or TRT with palliative intent, and those with a nonsmall-cell component were excluded from the analysis.
TRT that was given to ED-SCLC patients who needed immediate symptom relief was defined as palliative. C-TRT group was defined as ED-SCLC patients who received TRT with a nonpalliative manner and who had complete/near-complete response (CR/NCR) at all distant metastatic sites and with any response at primary after CXT. All C-TRT and PCI plans were performed through three-dimensional-conformal RT (3D-CRT) technique. Gross tumor volume (GTV-tm) was based on post-CXT volume, whereas nodal volume (GTV-node) was based on pre-CXT volume. The clinical target volume (CTV) was calculated by adding a margin of 5 mm to GTV, and the planned target volume was calculated by adding a margin of 10 mm to CTV. Normal tissue dose constraints were pertained and corrections for tissue inhomogenities were performed. A LINAC-6MV (PRIMUS™ Linear Accelerator, Siemens® Medical Solutions, Inc., Concord CA, USA) device was used for treatment delivery.
Treatment-related toxicity was assessed according to CTCAE v. 4.0, (National Cancer Institute) whereas response was evaluated according to the RECIST criteria., PFS was considered as the time interval between the last day of C-TRT and date of first recurrence. Treatment period was considered as the time interval between the first day of CXT and the last day of C-TRT. Survival was considered as the time interval between diagnosis and death of any cause. Each patient was examined 1 month after RT and then once every 3 months. Necessary radiological analysis was performed according to patient's complaint(s). Statistical analysis was performed using IBM SPSS Statistics for Windows v. 21.0 (IBM Corp., Armonk, NY, USA). Continuous variables are shown as median (25th–75th percentile) and categorical variables are shown as n (%).
| > Results|| |
In total, 552 SCLC patients presented to the radiation oncology clinic during the study period. LD-SCLC patients (n = 130) were excluded. Among ED-SCLC patients, 166 (39.3%) received TRT at some point in their management; TRT was palliative in 140 (84.3%) and consolidative in 26 (15.7%) patients. The consolidative group was included for the analysis. The patients' clinical characteristics are shown in [Table 1].
Prior to C-TRT, the patients underwent a median six cycles of CXT (range, 5.75–6). Post-CXT restaging was performed by PET/CT in all but two (92.3%) patients and through cranial magnetic resonance imaging (MRI) in all but three (88.4%) patients. In four patients with brain metastases, CR was confirmed by cranial MRI. In all patients with metastases other than brain, there was CR/NCR. At primary, there was CR/NCR in 18 (69.2%) patients and partial response (PR) in 8 (30.8%) patients. Median follow-up was 7.5 (6.5–8.5) months.
Prior to CXT, five patients with bone metastases and four patients with brain metastases received palliative RT. The PET/CT fusion was used for C-TRT planning in 22 patients. The radiation field included post-CXT primer tumor volume and pre-CXT nodal volume. The C-TRT dose schedules are presented in [Table 1]. Based on patients' and physicians' choice, PCI was administered in 14/26 patients (53.8%) with 10 × 250 cGy dose schedule after C-TRT. None of the patients received CXT during C-TRT. The metastatic lesions which had radiographic residual disease after CXT but did not need palliation were not irradiated.
Median treatment period was 211 days (range, 78–235 days). All patients completed the scheduled C-TRT program. In total, 16 patients had interruption for median 1 day (0–2) during TRT. No delays were due to acute toxicity. Twelve patients developed acute Grade-2 esophagitis and three patients developed Grade-2 radiation pneumonitis, which completely resolved by symptomatic treatment.
Recurrence and survival
In total, three patients died without recurrence [Figure 1]. Localizations of first recurrences are shown in [Table 2]. In three patients, in-field local recurrence (LR) was the first site of recurrence, in whom systemic recurrence accompanied the local one. The rate of LR was 23%. There was no isolated LR. Median LR-free survival was 5 months.,,, Median PFS was 3 months (95% confidence interval [CI]: 2–4) and median OS was 13 months [95% CI: 10–16, [Figure 2]. The 1-year and 2-year OS rates were 62% and 8%, respectively.
| > Discussion|| |
In the present study, there was no isolated LR. In patients who relapsed locally, there was accompanying distant relapse also. The low LR rate in the current study is consistent with earlier reports,, even lower.,,
The incorporation of PET/CT findings in C-TRT planning (that might have discerned viable residual disease regions otherwise invisible by CT or X-ray) in most of the cases together with 3D-CRT in all patients and use of radical doses mostly might have played a role in this successful LC outcome. In the CREST study, thoracic CT was used for planning only in patients with high-volume tumors, both 2D and 3D planning were allowed, a dose of 10 × 300 cGy was used and LR was relatively higher (60%).,, Yee et al. used higher C-TRT doses, in-field LR was only 22%, which is very similar to our results.
In the present study, only 15.7% of ED-SCLC patients received C-TRT. There is only one report considering this issue; it was 9%. Such a low rate of C-TRT indication among ED-SCLC arises from strict inclusion criteria in the current study, in which patients were required to achieve either CR/NCR distantly and CR/NCR or PR primarily. The patients with response levels lower than these criteria did not receive C-TRT. Restaging before C-TRT was carried out by PET/CT and cranial MRI mostly. To the best of our knowledge, there is no study other than the present one that has used PET/CT and cranial MRI for re-staging in majority of the patients. Indeed, CREST study was criticized for using cranial scanning for re-staging in only 13% of asymptomatic patients which could have caused inclusion of patients with asymptomatic brain metastases., Furthermore, they carried out cranial scanning in only 46% of asymptomatic patients and chest CT was not mandatory at the time of diagnosis., Yee et al. declared that their patients did not undergo comprehensive pre- and post-CXT staging and they accepted that their study might have underestimated the benefit of C-TRT. Similarly, Van Houtte et al. proposed that full reevaluation post-CXT might have improved their results.
Uncertainty concerning the optimal dose schedule of C-TRT is notable in the present study, as in earlier studies.,,,, C-TRT was administered mostly with radical doses in the present cohort. Nevertheless, patient treatment compliance was good and the acute side effects were self-limited. In literature, the studies using high BED values reported relatively higher toxicity. Jeremic et al. administered 36 fractions of 54 Gy as 2 fractions/day and reported high bronchopulmonary (5%) and esophageal toxicity (20%) rates. Zhu reported that 66% of patients received ≥50 Gy, there was 1 Grade 3 and 1 Grade 5 radiation pneumonitis. In RTOG-0937, the BED value was relatively high (45 Gy in 15 fractions), but variations were permitted also. In the experimental arm, both C-TRT and consolidative RT to metastatic sites were administered in patients with oligometastases, but the study prematurely closed due to slow accrual and unanticipated toxicity in the first year through interim analysis.,,
The first randomized study considering C-TRT after cisplatin-based CXT was performed in 1999 by Jeremic. This single-center study reported the best survival rate to date (median: 17 months). The median survival in the present study is somehow lower than Jeremic's, but no other study has reported similar such long survival.,,, Although both the present study and Jeremic's have similar patient profile in terms of response rates to CXT, Jeremic included only favorable patients, namely those with Eastern Cooperative Oncology Group (ECOG) status 0–1, with oligometastasis and without brain metastasis., In the present study, however, only 80% of patients had ECOG 0–1, >50% of the patients had >4 metastatic lesions, and patients with brain metastases were also included which might have been the cause of observed survival difference. Although the effect of the overall treatment period on survival has not been investigated, shortening of the overall treatment period in Jeremic's study by hyperfractionation concurrently with daily low-dose CXT can be considered as another reason for survival difference. In the present study, patients did not receive concurrent CRT, which might have reduced the efficacy of treatment by prolonging overall treatment time and resulting in accelerated repopulation.,
Median 1-year survival in the present study is improved and in concordance with the 58% mentioned by Giuliani et al. and even higher than that reported in CREST study (33%) and by Yee et al. (32%)., Median PFS was 3 months, which is similar to that reported in the literature (4 months), suggesting that our results are representative., However, the 2-year survival rate was lower than that reported in earlier results (13%, 14%, and 38%).,, The inclusion of higher percentage of nonoligometastatic patients at the time of diagnosis, which is a well-known unfavorable prognostic factor, might be the reason because a review of the literature showed that patients included in these previous studies had only minimal metastatic burden.,,,, In addition, our 2-year survival results might have been better, if we hadused PCI systematically, preferred concurrent CRT, and excluded ECOG 2 patients and patients with brain metastases.
In the majority of our patients, first recurrence was in the form of distant metastasis as expected, and in line with literature, leading to decreased PFS. Low PFS, occurrence of first recurrence most commonly as in the form of distant metastasis, and low 2-year survival rates suggest that high metastatic burden at the time of diagnosis is of great importance again and clearly indicates the need for more effective systemic treatment.
The relatively better outcomes, in terms of LC and 1-year survival, might have been due to the use of C-TRT, in such a group that consisted of highly selected favorable subset of patients, with CR or NCR distantly known to be the patients with the best prognosis,,,, re-staging based primarily on PET/CT and cranial-MRI, RT planning with PET/CT fusion in majority of the patients, and use of relatively higher TRT doses.
The present study has the main limitations of being a single-center retrospective study and having relatively small number of patients available for analysis. Furthermore, these data are only applicable to very highly selected favorable subset patients who have good response to CXT in both distant and primary sites. As a local policy, since we have preferred to apply C-TRT in this selected patient subgroup in all the available cases, we could not be able to compare the impact of C-TRT to conventional treatment with CT and PCI alone. Furthermore, our data certainly are missing quality of life data, which is a main issue when considering TRT.
| > Conclusion|| |
Our results showed that in ED-SCLC patients, C-TRT may prevent isolated local recurrence and improve 1-year survival. This survival improvement might be the reflection of high intrathoracic control achieved in 77% of patients. Nevertheless, these positive results did not translate into improvement in 2-year survival, and distant failure remained a significant problem. This might indicate the importance of high metastatic burden at the time of diagnosis.
Identification of prognostic factors is required to determine which patients might benefit from C-TRT. In such a disease with limited prognosis, therapeutic ratio should be optimized without unfairly consuming the time of the patients while increasing dose, fractionation, and sites of radiation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A, et al.
Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: Analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 2006;24:4539-44.
Bradley JD, Dehdashti F, Mintun MA, Govindan R, Trinkaus K, Siegel BA, et al.
Positron emission tomography in limited-stage small-cell lung cancer: A prospective study. J Clin Oncol 2004;22:3248-54.
Niho S, Fujii H, Murakami K, Nagase S, Yoh K, Goto K, et al.
Detection of unsuspected distant metastases and/or regional nodes by FDG-PET [corrected] scan in apparent limited-disease small-cell lung cancer. Lung Cancer 2007;57:328-33.
Palma DA, Warner A, Louie AV, Senan S, Slotman B, Rodrigues GB, et al.
Thoracic radiotherapy for extensive stage small-cell lung cancer: A Meta-analysis. Clin Lung Cancer 2016;17:239-44.
Slotman BJ, van Tinteren H, Praag JO, Knegjens JL, El Sharouni SY, Hatton M, et al.
Use of thoracic radiotherapy for extensive stage small-cell lung cancer: A phase 3 randomised controlled trial. Lancet 2015;385:36-42.
Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton M, et al.
Prophylactic cranial irradiation in extensive small-cell lung cancer. N
Engl J Med 2007;357:664-72.
Giuliani ME, Atallah S, Sun A, Bezjak A, Le LW, Brade A, et al.
Clinical outcomes of extensive stage small cell lung carcinoma patients treated with consolidative thoracic radiotherapy. Clin Lung Cancer 2011;12:375-9.
Slotman BJ, van Tinteren H. Which patients with extensive stage small-cell lung cancer should and should not receive thoracic radiotherapy? Transl Lung Cancer Res 2015;4:292-4.
Singer L, Yom SS. Consolidative radiation therapy for extensive-stage small cell lung cancer. Transl Lung Cancer Res 2015;4:211-4.
Slotman BJ, Senan S. Radiotherapy in small-cell lung cancer: Lessons learned and future directions. Int J Radiat Oncol Biol Phys 2011;79:998-1003.
Zhu H, Zhou Z, Wang Y, Bi N, Feng Q, Li J, et al.
Thoracic radiation therapy improves the overall survival of patients with extensive-stage small cell lung cancer with distant metastasis. Cancer 2011;117:5423-31.
Jeremic B, Shibamoto Y, Nikolic N, Milicic B, Milisavljevic S, Dagovic A, et al.
Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: A randomized study. J Clin Oncol 1999;17:2092-9.
Yee D, Butts C, Reiman A, Joy A, Smylie M, Fenton D, et al.
Clinical trial of post-chemotherapy consolidation thoracic radiotherapy for extensive-stage small cell lung cancer. Radiother Oncol 2012;102:234-8.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.
New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.
De Ruysscher D, Pijls-Johannesma M, Bentzen SM, Minken A, Wanders R, Lutgens L, et al.
Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 2006;24:1057-63.
Jeremić B. Thoracic radiation therapy in extensive disease small cell lung cancer. Int J Radiat Oncol Biol Phys 2015;93:7-9.
Van Houtte P, Moretti L, Roelandts M. Is chest radiation now a classical practice for extensive small cell lung cancer? Transl Lung Cancer Res 2015;4:209-10.
van Loon J, Offermann C, Bosmans G, Wanders R, Dekker A, Borger J, et al.
18FDG-PET based radiation planning of mediastinal lymph nodes in limited disease small cell lung cancer changes radiotherapy fields: A planning study. Radiother Oncol 2008;87:49-54.
Spiegelman D, Maurer LH, Ware JH, Perry MC, Chahinian AP, Comis R, et al.
Prognostic factors in small-cell carcinoma of the lung: An analysis of 1,521 patients. J Clin Oncol 1989;7:344-54.
De Ruysscher D, Pijls-Johannesma M, Vansteenkiste J, Kester A, Rutten I, Lambin P, et al.
Systematic review and meta-analysis of randomised, controlled trials of the timing of chest radiotherapy in patients with limited-stage, small-cell lung cancer. Ann Oncol 2006;17:543-52.
van Loon J, Offermann C, Ollers M, van Elmpt W, Vegt E, Rahmy A, et al.
Early CT and FDG-metabolic tumour volume changes show a significant correlation with survival in stage I-III small cell lung cancer: A hypothesis generating study. Radiother Oncol 2011;99:172-5.
[Figure 1], [Figure 2]
[Table 1], [Table 2]