Small cell lung cancer (SCLC) represents only small proportion of lung cancer but is an aggressive disease and unfortunately diagnosed already in advanced stage in majority of patients.1 In Slovenia 15.3% of lung cancer patients were diagnosed with SCLC in 2014, and majority had metastatic disease.
2 In recent years, percentage of patients with metastatic disease has slightly increased, but this might only be due to better staging with incorporation of PET/CT and brain MRI.3, 4
SCLC is highly chemo-sensitive disease and standard treatment for metastatic patients is platinum based chemotherapy (ChT), usually combined with etoposide or irinotecan.5, 6 Almost 75% of the patients have persisting intra-thoracic disease after treatment with ChT and addition of chest radiotherapy (RT) aimed to improve progression free survival (PFS) and overall survival (OS) in those patients.7 Prospective randomized CREST study suggested survival benefit of added thoracic RT in addition to PCI for ED-SCLC patients who respond to ChT; however, OS at 1-year, which was the primary endpoint of the study, was not significantly improved.8 Prospective RTOG 0937 study also failed to show 1-year survival benefit, though disease progression was delayed.9 On the other hand, some retrospective studies showed benefit of consolidation RT (cRT).10, 11, 12, 13 None of the prospective and only rare retrospective studies specifically researched the effect of radiation dose on survival.
In addition, selective patients might benefit from prophylactic cranial irradiation (PCI), which showed increase in overall survival if added to ED-SCLC after ChT.14 In spite of that, the median overall survival (mOS) of metastatic disease remains poor, ranging from 8 to13 months, with only 5% of patients being alive at 2 years.15 Recently, immunotherapy with atezolizumab or durvalumab added to ChT without chest irradiation has shown increased mOS in first line treatment of patients with metastatic SCLC, therefore in the future the role of radiotherapy would need to be reconsidered.16, 17
The aim of our study was to access if cRT improves survival of ED-SCLC patients treated in a routine clinical practice of tertiary single centre and to study the impact of cRT dose on survival. We also discuss whether the cRT still has the role in the treatment of ED SCLC in the era of immunotherapy.
We retrospectively reviewed medical records of consecutive patients with SCLC treated at the Institute of Oncology Ljubljana during the five year period, from January 2010 to December 2014. Median follow up was 65 months.
Not all metastatic SCLC patients were referred to our center for treatment; however, during the period studied, we were the only radiotherapy center in the country and all patients that needed irradiation, based on multidisciplinary tumor board decision, were treated at our institution. Only patients who had at least stable disease or regression of disease after chemotherapy were eligible for thoracic consolidation radiotherapy. The decision about the dose was at the discretion of radiation oncologist and based on the volume of the tumor and performance status of the patient since during the time period studied there was no uniform dose suggested in any of the guidelines.
Diagram in Figure 1 outlines the selection process. During 5 year period 704 consecutive patients with SCLC were treated at the Institute of oncology Ljubljana, 412 with extended disease and 292 with locally advanced disease. Among all ED-SCLC patients, 59 (14.3%) were treated with BSC, 67 (16.2%) patients with RT only, 113 (27.4%) with ChT only and 173 (41.9%) with combined ChT and RT. RT was either consolidation RT (cRT), delivered to 74 patients or any other type of RT which included urgent RT, partly concurrent ChT or RT that was prematurely closed due to any reason (99 patents).
The following parameters were recorded: demographic and clinical characteristics, date of diagnosis, TNM stage, treatment characteristics, including chemotherapy and radiation therapy details, metastatic locations and date of death or last follow up.
Of Majority (47.5%) of patients received all 6 planned cycles of chemotherapy, 66 patients (35.3%) received less than 4 cycles of ChT. Etoposide with platinum was the most frequent combination (83.8%), the rest received anthracycline based ChT. In the group with cRT were less patients who received 4 ChT cycles or less.
Radiotherapy with linear accelerators (photon beam 6-10MV), based on 3D CT-based conformal radiation therapy planning, started after ChT. There was no difference in frequency of patients who started before (29 patients) and after 4 weeks (25 patients) of ChT completion. Prophylactic cranial irradiation was delivered with two opposed lateral fields with the dose of 25 Gy in 10 fractions using 2D planning and 6MV photon beam energy.
The primary endpoints in this analysis were mOS, 1-year and 2-year OS of ED-SCLC patients treated with ChT only versus patients treated with ChT and cRT and those receiving higher
This survey was approved by Institutional Ethics Committee and Institutional Review Board in December 2017.
We performed two analysis. In our first analysis we included 187 patients, 113 patients treated with Cht only were compared to 74 patients treated with ChT and cRT. Different fractionation schemes were used for cRT. The doses in cRT were not uniform, therefore we divided them into 3 groups: below 30 Gy, 30–36 Gy and 45 Gy. Only 59 patients with doses above 30 Gy were included in our second analysis of dose comparison.
Baseline characteristics of 187 patients, divided to those with ChT only and those who also received cRT are presented in Table 1. The two groups were balanced regarding gender, age, T and N stage and metastatic locations. However, lower number of patients received 4 or less cycles of ChT and had 2 or more metastases present at diagnosis in ChT plus cRT group.
Patients’ characteristics: chemotherapy only
ChT only | ChT with cRT | p | ||
---|---|---|---|---|
n (%) | n (%) | |||
187 (100) | 113 (60.4) | 74 (39.6) | ||
Male | 126 (67.4) | 81 (71.1) | 45 (60.1) | 0.12 |
Female | 61 (32.6) | 32 (28.9) | 29 (39.9) | |
median (range) | 63 (42-80) | 61 (42-80) | 63 (47-80) | 0.24 |
< 65 | 122 (65.2) | 70 (61.9) | 52 (70.3) | |
> 65 | 65 (34.8) | 43 (38.1) | 22 (29.7) | |
< 4 | 66 (35.3) | 51 (47.2) | 15 (20) | |
> 4 | 113 (60.4) | 57 (52.8) | 56 (80) | |
0.23 | ||||
T1–2 | 32 (17.1) | 20(17.7) | 12 (16.2) | |
T3-4 | 122 (65.2) | 69 (61) | 53 (71.6) | |
Tx | 33 (17.7) | 24 (21.3) | 9 (12.2) | |
0.56 | ||||
N0–2 | 71 (38) | 40 (35.4) | 31(41.9) | |
N3 | 91(48.7) | 56 (49.6) | 35 (47.3) | |
Nx | 25 (13.3) | 17 (15) | 8 (10.8) | |
Brain | 44 (23.5) | 28 (24.8) | 16 (21.6) | 0.61 |
Liver | 86 (46) | 57 (50.4) | 29 (39.2) | 0.13 |
Bone | 42 (22.5) | 28 (24.8) | 14 (18.9) | 0.34 |
Adrenal gland | 38 (20.3) | 23 (20.4) | 15 (20.3) | 0.98 |
Other | 92 (49.2) | 62 (54.9) | 30 (40.5) | 0.06 |
1 | 105 (56.1) | 55 (48.7) | 50 (67.6) | |
> 2 | 82 (43.9) | 58 (51.3) | 24 (23.4) | |
Yes | 41 (21.9) | 20 (17.6) | 21 (28.4) | 0.08 |
no | 146 (78.1) | 93 (82.4) | 53 (71.6) |
* for 8 patients we were not able to retrieve the exact number of cycles from medical records, percentage of patient is calculated only for those with known number of cycles (179);
** some patients had more than 1 metastatic location, percentages are calculated as part of all patients in a group;
ChT = chemotherapy; cRT = consolidation radiotherapy; PCI = prophylactic cranial irradiation
Table 2 present baseline characteristics of 59 patients who received > 30 Gy cRT, comparing those with higher dose (45 Gy) cRT and lower dose (30–36 Gy). In summary, median age was 63 years, more than half were men. Majority of patients were younger than 65 years. Unfortunately, reliable PS could not be retrieved from medical records for half of the patients and more than 10% of patients had PS 2-3 before cRT. Non-significantly more patients had larger tumors (T3-4) and more extended lymph node disease (N3) in the group treated with lower dose RT. For more than 10% of patients with central tumors, the size of tumor (T) or nodal status could not be determined. Fifty-eight percent of patients had one metastatic site. The most frequent site of metastases were liver. Less than third of patients had PCI.
Patients’ characteristics: higher
All | 45 Gy | 30-36 Gy | p | |
---|---|---|---|---|
n (%) | n (%) | n (%) | ||
59 | 15 | 44 | ||
Male | 35 (60) | 6 (40) | 29 (65.9) | 0.078 |
Female | 24 (40) | 9 (60) | 15 (34.1) | |
median | 62 (42–76) | 60 (54–73) | 62 (42–76) | 0.12 |
< 65 | 42 (71.2) | 13 (68.7) | 29 ( 65.9) | |
> 65 | 17 (28.8) | 2 (13.3) | 15 (34.1) | |
< 4 | 12 (20.3) | 2 (13.3) | 10 (22.7) | 0.37 |
> 4 | 44 (74.6) | 13 (68.7) | 31 (70.5) | |
unknown | 3 (5.1) | 0 (0) | 3 (6.8) | |
0.66 | ||||
0-1 | 22 (37.3) | 5 (33.3) | 17 (38.6) | |
2–3 | 7 (11.8)) | 1 (6.67) | 6 (13.6) | |
unknown | 30 (50.9) | 9 (0.6) | 21 (47.8) | |
0.15 | ||||
T1–2 | 8 (13.6) | 4 (26.7) | 4 (9.1) | |
T3–4 | 42 (71.2) | 8 (53.3) | 34 (77.3) | |
Tx | 9 (15.3) | 3 (20) | 6 (13.6) | |
0.69 | ||||
N0–2 | 24 (40.7) | 7 (46.7) | 17 (38.6) | |
N3 | 29 (49.2) | 6 (40) | 23 (52.3) | |
Nx | 6 (10.1) | 2 (13.3) | 4 (9.1) | |
Brain | 14 (23.7) | 5 (33.3) | 9 (20.5) | 0.31 |
Liver | 27 (45.7) | 6 (40) | 21 (47.7) | 0.60 |
Bone | 13 (22) | 3 (30) | 10 ( 22.7) | 0.82 |
Adrenal gland | 15 (25.4) | 3 (30) | 12 (27.3) | 0.57 |
Other | 21 (35.6) | 3 (30) | 19 (43.2) | 0.10 |
1 | 34 (57.6) | 10 (66.7) | 24 (54.5) | 0.41 |
> 2 | 25 (42.4) | 5 (33.3) | 20 (45.4) | |
0.15 | ||||
< 4 weeks after ChT | 17 (53.1) | 6 (75) | 11 (45.9) | |
> 4 weeks after ChT | 15 (46.9) | 2 (25) | 13 (54.1) | |
Yes | 17 (28.8) | 5 (33.3) | 12 (27.3) | 0.65 |
* some patients had more than one metastatic site;
** for 31 missing patients no reliable data of the completion chemotherapy date could be retrieved from the medical records;
Ch =- chemotherapy; Gy = Gray; N = lymph nodes; PS = performance status; RT = radiotherapy; T = tumour
Median OS of patients who had either BSC or RT only was poor, 1.86 and 2.42 months, respectively. Patients who had any form of additional chest irradiation (173 patients) had significantly better mOS than 113 patients with ChT only (9.9m
Consolidation RT was delivered to 74 patients. Those patients had significantly longer mOS compared to 113 patients with ChT only as presented in Figure 2, 11.1 months (CI 10.1–12.0)
Univariate survival analysis (UVA) for patients with or without cRT included the following variables: cRT, gender, age, number of ChT cycles, T and N stage, metastatic location, number of metastatic locations and PCI. Presence of cRT, female gender, number of ChT cycles (4 or less and more than 4) and PCI were significant in univariate analysis and were tested in multivariate analysis (MVA) (Table 3). Except for gender, they were all independent predictors of better survival.
Univariate and multivariate analysis of overall survival for patients with cRT vs no cRT (n = 187)
p | Univariate analysis | p | Multivariate analysis | |
---|---|---|---|---|
HR (95% CI) | HR (95% CI) | |||
no | ||||
yes | ||||
0.68 | 1.03 (0.87–1.21) | |||
Male | ||||
Female | ||||
0.25 | 1.19 (0.88–1.62) | |||
> 65 | ||||
< 65 | ||||
< 4 | ||||
> 4 | ||||
0.98 | 1.00 (0.67–1.50) | |||
T1, 2 | ||||
T3, 4 | ||||
0.16 | 1.08 (0.96–1.22) | |||
N0-2 | ||||
N3 | ||||
Brain no/yes | 0.61 | 0.91 (0.64–1.29) | ||
Liver no/yes | 0.40 | 1.13 (0.84–1.52) | ||
Bone no/yes | 0.75 | 0.94 (0.67-1.33) | ||
Adrenal no/yes gland | 0.62 | 1.09 (0.76–1.57) | ||
Other no/yes | 0.18 | 1.21 (0.90–1.63) | ||
0.68 | 1.06 (0.79–1.42) | |||
1 | ||||
> 2 | ||||
No | ||||
Yes |
cRT = consolidation radiotherapy; N = lymph nodes; PCI = prophylactic cranial irradiation; T = tumour
In the group of 59 patients irradiated with cRT ≥ 30 Gy patients irradiated with 45 Gy had better mOS compared to patients irradiated with doses 30–36 Gy, 17.2 months
In the group of patients with cRT, we made another analysis. We included gender, age categories, PS before RT, RT dose, T and N stage, metastatic locations, number of ChT cycles, number of metastatic lesions, PCI and timing of RT in UVA. Statistically significant predictors of longer mOS were PCI irradiation and higher RT dose. Both were analyzed in MVA (Table 4) and remained independent predictors of improved survival. (PCI HR = 0.51, 95% CI 0.27–0.96; higher RT dose HR = 0.47, 95% CI 0.25–0.87).
Univariate and multivariate analysis of overall survival for higher
p | Univariate analysis | p | Multivariate analysis | |
---|---|---|---|---|
HR (95% CI) | HR (95% CI) | |||
45 Gy | ||||
30-36 Gy | ||||
0.17 | 1.4 (0.86–2.27) | |||
Male | ||||
Female | ||||
0.38 | 1.25 (0.75–2.09) | |||
> 65 | ||||
< 65 | ||||
0.089 | 1.94 (0.90–4.18) | |||
2–3 | ||||
0–1 | ||||
0.065 | 1.78 (0.96–3.31) | |||
< 4 | ||||
> 4 | ||||
0.34 | 0.72 (0.37–1.40) | |||
T1–2 | ||||
T3–4 | ||||
0.28 | 1.32 (0.79–2.20) | |||
N0–2 | ||||
N3 | ||||
Brain da/ne | 0.52 | 1.2 (0.68–2.11) | ||
Liver da/ne | 0.39 | 1.22 (0.76–1.92) | ||
Bone da/ne | 0.46 | 1.24 (0.70–2.21) | ||
Adrenal gland da/ne | 0.98 | 0.99 (0.59–1.67) | ||
Other | 0.84 | 0.95 (0.58–1.56) | ||
0.43 | 0.82 (0.51–1.33) | |||
1 | ||||
> 2 | ||||
0.71 | 1.13 (0.59–2.16) | |||
< 4 weeks after ChT | ||||
> 4 weeks after ChT | ||||
Yes | ||||
No |
ChT = chemotherapy; cRT = consolidation radiotherapy; N = lymph nodes; PS = performance status; RT = radiatiotherapy; T = tumour
Thoracic irradiation has never been considered such an important part of ED-SCLC treatment as chemotherapy. Since the pivotal study of Jeremic
Our analysis showed that cRT significantly improved mOS compared to patients who had ChT only, 11.1 months
How results of our study compares to others is presented in Table 5. In a retrospective study of 119 patients by Zhu
Trials of consolidation radiotherapy (cRT) in extended disease small cell lung cancer (ED-SCLC)
Author/Trial, reference | Publication year | Type of study | Patients -years enrolled | Number of patients | Patient selection | Thoracic irradiation dose scheme | mOS | 1-year OS | 2-year OS |
---|---|---|---|---|---|---|---|---|---|
Jeremic18 | 1999 | P | 1988–1993 | 109 | ED-SCLC with CR at metastatic sites and at least PR in thorax | 54 Gy in 36 fractions, BID | 17 m | 65% | 38% |
Slotman (CREST)8 | 2015 | P | 2009–2012 | 495 | ED-SCLC with any response to ChT | 30 Gy in 10 fractions | 8 m | 33% | 13% |
Gore (RTOG 0937)9 | 2017 | P | 2010–2016 | 97 | ED-SCLC (1-4 extracranial m., any response to ChT | 40 Gy in 15 fractions | 15.8 m | 50.8% | NR |
Zhu10 | 2011 | R | 2003–2006 | 119 | ED-SCLC | 40–60 Gy | 17 m P = | NR | 35% |
Giuliani12 | 2011 | R | 2005–2009 | 19 | ED-SCLC with metastatic minimal disease | 36–45 Gy | 14 m | 58% | 14% |
Yee11 | 2012 | R | 2008–2009 | 32 | ED-SCLC | 40 fractions Gy in 15 | 8.3 m | NR | NR |
Zhan13 (SEER database) | 2018 | R | 2010–2012 | 6812 | ED-SCLC from SEER database | Different, not reported | 9 m | NR | NR |
Stanic | 2020 | R | 2010–2014 | 187 | ED-SCLC | 30–45 Gy | 11.1 7.6 m m | 44% | 10% |
* group 1 CR/PR and RT
BID = twice daily; ChT = chemotherapy; CR = complete response; ED-SCLC = extended disease small cell lung cancer; m = months; mOS = median overall survival; NR-not reported; OS = overall survival; P = prospective; PR = partial response; R = retrospective
Three prospective randomized trials researched impact of RT on survival in ED SCLC.8, 9,18 Trial by Jeremic
Phase III EORTC study (CREST) included patents with PS 0–2 without brain and pleural metastases. Responders after 4–6 cycles of ChT and residual disease in the thorax were treated with irradiation of 30 Gy in 10 fractions.8 Contrary to our results, no benefit was shown for added RT after ChT regarding mOS, which reported to be 8 months in both groups and for 1-year OS (33% for ChT with cRT
More aggressive thoracic irradiation was given in RTOG 0937 trial with 45 Gy in 15 fractions.9 Reported median OS (15.8 months) was better than anticipated and much better than in CREST and our study. Unlike all other studies, they reported better mOS for ChT only group (15.8 months) than for ChT plus RT group (13.8 months), though the difference was not statistically significant. 1-year OS was similar, surprisingly higher for ChT only than for ChT plus cRT group (60.1%
Two meta-analyses were published. The first, published by Palma
We found that patients who had been irradiated with higher dose (45 Gy in 18 fractions) had better mOS compared to those who received lower doses 30–36 Gy (in 10–12 fractions), 17.2 months
Not many studies looked into dose difference for cRT. In retrospective study including 306 patients of whom 170 received cRT, those with higher RT dose (BED > 50 Gy) had longer 2y-OS, 32.3%
In CREST study, cRT dose used was 30 Gy in 10 fractions. The relative high intrathoracic failure rate of 42% indicated that this dose might be insufficient to eliminate all the residual disease. In additional analysis from CREST study, for patients with complete intrathoracic response no benefit of TRT was observed. They concluded that TRT should be offered to patients with a good or partial response after chemotherapy, but not to those without residual disease in the thorax. It appears that the greater the volume of the residual disease in the thorax is, the higher dose is needed to eliminate the tumor.
However, dose restrictions to the organs at risk and consequent toxicity limit the actual received dose.
Number of metastases was not predictive factor for survival in our analysis. Contrary to that, in recent retrospective publications it was shown that tumor burden of metastatic disease should be taken into account when treating ED SCLC patients, since those with ≥2 metastases had significantly worse outcome than those with only one metastasis.23, 24
No difference of timing was found in our survival analysis if RT started before or after 4 weeks after ChT completion. In RTOG 0937 trial and one retrospective Chinese study also no difference was found in survival for patients who received RT early or late.9, 25 On the contrary, meta-analysis for limited SCLC, showed that earlier or shorter RT brings 7.7% advantage in 5-year survival.26
In our study PCI was independent predictor of better survival, although only 21.9% of patients received one. Our previous publication, focused on impact of PCI on survival in patients with LD-SCLC, also showed that only low number of patients (6%) actually received PCI in routine clinical setting, nevertheless OS was improved with PCI.27 As our analysis is retrospective, this reflects real clinical situation. However, the reason why such a low number of patients actually received PCI is unclear. PCI as independent predictor of survival was reported also in retrospective study by Xu
Immunotherapy (IT) has been successfully incorporated into the treatment of metastatic non-small cell lung cancer (NSCLC) either as combination of ChT and IT or as mono-IT and lately also in stage III as consolidation treatment after concomitant chemoradiotherapy.30, 31, 32, 33, 34, 35, 36, 37, 38, 39
Recently, two randomized studies confirmed efficacy of IT also for the treatment in ED-SCLC. IMpower 133 study was the first to show improved OS in patients treated with atezolizumab combined with ChT (12.3 months) as compared to ChT plus placebo (10.3 months). 1-year OS rate was 51.7% in the atezolizumab group and 38.2% in the placebo group.16 Consolidation RT was not permitted, while patients could have PCI. The same criteria about cRT and PCI were also applied in CASPIAN study with durvalumab.17 Again, IT combination showed increased results, mOS in ChT-IT arm was 13 months and 10.3 months in ChT only arm and 1-year OS was 54%
Beside retrospective nature of our analysis we should acknowledge several other limitations of our research. The irradiation dose was not specified by the protocol or any other department regulation and the decision was under the discretion of treating physician. Larger tumors (T3-4, N3) were more frequently irradiated with lower dose, but this does not necessarily mean that larger tumors would not be feasible to the treatment with larger doses. Unfortunately, we were not able to retrieve reliable information about PS before RT in half of patients, reflecting real clinical practice. This would be valuable information as treatment decision in clinical practice is greatly influenced by PS and consequently might influence survival data. Due to the fact that not all patients were treated with ChT in our institution, PS before ChT could not be included in UVA and MVA. Also, the response to initial Cht as one of the main prognostic factors of cRT efficacy according to the published data, is missing, since not all the patients were treated at our institution. However, all the patients were discussed at the MTB before the treatment which at least partially reduces this shortcoming.
Our analysis has shown that cRT improved mOS as compared to ChT alone of the ED-SCLC patients treated at our institution. Consolidation RT, higher number of ChT cycles and profilactic cranial irradiation (PCI) were independent prognostic factors for better survival. For patients who received cRT, only higher doses and PCI had impact on survival regardless of number of ChT cycles received. Whether cRT and PCI will still be players in the era of immunotherapy is unknown and will be shown in further trials.