DOI: https://doi.org/10.21203/rs.3.rs-35650/v1
Successful local therapy for oligometastases may lead to longer survival. The purpose of this multicenter retrospective study was to investigate the effectiveness of stereotactic body radiotherapy (SBRT) for pulmonary oligometastases and to investigate affecting factors for local control (LC).
The inclusion criteria was that SBRT for pulmonary oligometastases was the number of metastases was limited to 1 to 5, the primary lesion and other extrathoracic metastases were controlled before SBRT, and the biological effective dose (BED10) of SBRT was 75 Gy or more. The Cox proportional hazards model was used for analyses.
Data for 1378 patients with 1547 tumors from 68 institutions were analyzed. The median follow-up period was 24.2 months. One-year, 3-year and 5-year LC rates were 92.1%, 81.3% and 78.6%, respectively, and 1-year, 3-year and 5-year overall survival rates were 90.1%, 60.3% and 45.5%, respectively. Multivariate analysis for LC showed that increased maximum tumor diameter (p = 0.011), type A dose calculation algorithm (p = 0.005), shorter overall treatment time of SBRT (p = 0.035) and colorectal primary origin (p < 0.001 excluding esophagus origin) were significantly associated with lower LC rate. In survival analysis, local failure (p < 0.001), poorer performance status (1 vs. 0, p = 0.013; 2–3 vs. 0, p < 0.001), esophageal primary origin (vs. colorectal origin, p = 0.038), squamous cell carcinoma pathology of the primary lesion (vs. adenocarcinoma, p = 0.006) and increased maximum tumor diameter (p < 0.001) showed significant relationship with shorter survival.
LC of pulmonary oligometastases by SBRT showed a significant survival benefit compared to patients with local failure. Some important factors for achieving higher LC were revealed.
During the past few decades, increasing attention has been paid to the importance of control of the primary site in metastatic disease. Some prospective trials and many retrospective studies for metastatic disease have shown improvement in the survival of patients treated with surgery or radiotherapy for the primary lesion, though systemic therapy has been the standard treatment [1–5]. In addition, aside from the activity of the primary lesion, a few metastases known as oligometastases which might be a good candidate for metastasis-directed therapy have gradually been recognized [6]. The survival benefit of primary lesion control was revealed only in prostate cancer patients with low metastatic burden (probably oligometastatic state) [7]. Some phase 2 studies revealed that intensive local therapy for the primary lesion and for all known oligometastases improved the overall survival and disease-free survival of patients and results of a future phase 3 trial are awaited [8–10]. In any case, control of primary lesion is important in oligometastatic state, therefore, the classification of oligometastases according to the activity of the primary lesion is important when metastasis-directed therapy is to be performed. Oligometastases have been classified into oligo-recurrences and sync-oligometastases according to the activity of the primary lesion at the time of initial appearance of oligometastases and patients with oligo-recurrences had longer survival [11, 12]. Recently, an investigation to determine whether there is a survival difference between patients with pulmonary oligo-recurrences and patients with sync-oligometastases after control of the primary lesion was performed in Japan and it was shown that patients with oligo-recurrences had a survival advantage [13]. The next question is whether successful local therapy for pulmonary oligometastases leads to longer survival or not and what factors affected local control (LC). The aim of this study was to identify factors affecting LC and to determine the survival benefit of LC after stereotactic body radiotherapy (SBRT) for pulmonary oligometastases. LC was secondary endpoint and these were secondary endpoint analyses and exploratory survival analyses of this large survey.
The inclusion criteria were as follows: SBRT for pulmonary oligometastases was performed between January 2004 and June 2015, the number of metastasis was limited to 1 to 5 at the timing of emergence of the SBRT-targeted tumor, the primary lesion and other extrathoracic lesions were controlled before SBRT was performed, and the biological effective dose (BED10) of SBRT was 75 Gy or more and dose per fraction was 4 Gy or more. Combination treatment with SBRT and surgery for each lesion was allowed. The exclusion criterion was local recurrence of a thoracic primary tumor. The following formula was used for calculation of BED10: BED = nd [1 + d/(α/β)], where n is the number of fractions, d is dose per fraction and α/β ratio is 10 Gy for the tumors. Pulmonary oligometastasis was defined as the appearance of a solid tumor in the lung at the same time as or after treatment of the primary lesion. Local failure was defined as progression of the irradiated tumor, LC was defined as freedom from local failure, and locally controlled cohort was defined as freedom from any local failure of the irradiated tumor.
This study was a retrospective, multicenter study in Japan. This study was conducted in 68 institutions in Japan. All of the institutions were health insurance-covered medical institutions that covered all citizens in Japan. This study was approved by the ethical committee of a senior facility (Ethics Committee of Toho University Omori Medical Center, reference number: 27–148). Informed consent was waived due to the study design, but all participating institutions were guaranteed the chance to opt out of participation in this study by giving information of this study via the Internet or posters, and opt-out consent was obtained from all patients.
Statistical analyses were performed using EZR, version 1.37 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a modified version of R commander (R Foundation for Statistical Computing, Vienna, Austria) [14]. Time to event was calculated from the first day of SBRT to the day an event was confirmed. Cumulative LC and overall survival (OS) rates were calculated using the Kaplan-Meier method, and the 95% confidence interval (95% CI) was calculated using Greenwood's formula. The Cox proportional hazards model was adjusted for LC analyses, and variables with a p-value of < 0.200 in univariate analyses (UVA) were regarded as potential factors and were put in multivariate analysis (MVA) with a stepwise backward elimination/forward addition approach using the Akaike information criterion (AIC) to build the best MVA model. A p-value < 0.050 was defined as significant.
Analyses of pretreatment prognostic factors for OS (primary endpoint) were reported elsewhere [13]. Because local failure was observed factor after SBRT, further analysis of OS was performed in this study to determine the effect of LC on OS. First, LC was analyzed as a time-dependent covariate. Previously reported covariates selected by the stepwise approach without changing continuous variables into categorical variables were used: PS, primary lesions, pathology of primary lesion, oligometastatic state and maximum tumor diameter. Local status was forced into this multivariate model as a time-dependent covariate. Secondary, as sensitivity analyses, the landmark analysis method was also used [15–16]. Six months, 1 year, 2 years and 3 years were set as landmark times. All local failures after the landmark time and all deaths before that time were ignored. Then a log-rank test was performed to compare locally controlled and locally failed cohorts with a p-value of ≤ 0.012 denoting significance. Lung adverse events (AEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
A total of 1378 patients with 1547 tumors from 68 institutions were enrolled in this study. The baseline characteristics of the patients, primary tumors, oligometastatic tumors and SBRT are summarized in Table 1. Performance status (PS) and additional chemotherapy were judged at the timing of each SBRT if SBRT was performed asynchronously for two or more tumors. The dose calculation algorithm of type B was equivalent to Analytical Anisotropic Algorithm, type C was equivalent to Monte Carlo Algorithm and type A was an older generation algorithm such as Pencil Beam Convolution.
| Characteristic | Distribution | Number (%) |
|---|---|---|
| All tumors | 1547 | |
| Sex | Male | 994(64.2) |
| Female | 553(35.7) | |
| Age, years | Median, range, IQR | 72; 16–93; 63–78 |
| ECOG Performance Status | 0 | 841 (54.3) |
| 1 | 529 (34.1) | |
| 2 | 90 (5.8) | |
| 3 | 19 (1.2) | |
| Missing | 68 (4.3) | |
| Primary lesion sites | Lung | 451(29.1) |
| Colorectum | 391 (25.2) | |
| Head and Neck | 126 (8.1) | |
| Esophagus | 132 (8.5) | |
| Others | 447 (28.8) | |
| Pathology of primary lesion | Adenocarcinoma | 861 (55.6) |
| Squamous cell carcinoma | 396 (25.5) | |
| Sarcoma | 47 (3.0) | |
| Others | 168 (10.8) | |
| Missing | 75 (4.8) | |
| Control method of primary lesion | Surgery | 1222 (78.9) |
| Chemoradiation | 130 (8.4) | |
| Radiation (X-ray or particle) | 70 (4.5) | |
| Others | 44 (2.8) | |
| Missing | 85 (5.4) | |
| Disease-free interval, months | Median, range, IQR | 17.5; 0-423.9; 8.0-34.3 |
| Oligometastatic state | Oligo-recurrences | 1157 (74.7) |
| Sync-oligometastases | 133 (8.5) | |
| Unclassified | 133 (8.5) | |
| Missing | 124 (8.0) | |
| SBRT performed institution | Academic | 642(41.4) |
| Non-academic | 905 (58.5) | |
| Date SBRT was performed | 2004–2009 | 518 (33.4) |
| 2010–2015 | 1029 (66.5) | |
| Chemotherapy | Before SBRT | Yes, 591 (38.2) No, 945 (61.0) Missing, 11 (0.7) |
| Concurrent with SBRT | Yes, 34 (2.7) No, 1513 (97.8) | |
| After SBRT | Yes, 242 (15.6) No, 998 (64.5) Missing, 307 (19.8) | |
| Maximum tumor diameter, cm | Median, range, IQR | 1.5; 0.3–6.5; 1.0–2.0 |
| Number of oligometastases | 1 | 1036 (66.9) |
| 2–5 | 503 (32.5) | |
| Missing | 8 (0.5) | |
| Lung lobe involved with treated tumor | Right upper lobe | 293 (18.9) |
| Right middle lobe | 83 (5.3) | |
| Right lower lobe | 321 (20.7) | |
| Left upper lobe | 294 (19.0) | |
| Left lower lobe | 226 (14.6) | |
| Unknown lobe | Right lung, 12; Left lung, 7 | |
| Missing | 311 (20.1) | |
| Beams | Multiple static | 1145 (74.0) |
| Arc | 401 (25.9) | |
| Missing | 1 (0.0) | |
| X-ray energy | 4 MV only | 202 (13.0) |
| 6 MV only | 1179 (76.2) | |
| Others | 160 (10.3) | |
| Missing | 6 (0.3) | |
| Field coplanarity | Coplanar field | 1139 (73.6) |
| Non-coplanar field | 404 (26.1) | |
| Missing | 4 (0.2) | |
| Dose calculation algorithm | Type A | 541 (34.9) |
| Type B | 799 (51.6) | |
| Type C | 144 (9.3) | |
| Missing | 63 (4.0) | |
| Dose prescription | IC | 1103 (71.2) |
| D95 of PTV | 317 (20.4) | |
| Others | 127 (8.2) | |
| BED10 at isocenter, Gy10 | Median, range, IQR | 105.6; 75.0-289.5; 105.6-126.9 |
| OTT of SBRT, day | Median, range, IQR | 7; 3–81; 4–11 |
| Abbreviations: SBRT, stereotactic body radiotherapy; IQR, interquartile range; ECOG, Eastern Cooperative Oncology Group; IC, isocenter; D95 of PTV, dose covering 95% of planning target volume; BED, biological effective dose; OTT, overall treatment time. | ||
The median follow-up period for all patients was 24.2 months (range, 0.1-143.6 months; interquartile range [IQR], 13.7–42.7 months) and that for survivors was 26.9 months (range, 0.1-143.6 months; IQR, 14.7–49.4 months). Estimated 1-year, 3-year and 5-year LC rates were 92.1% (95% CI, 90.4–93.4%), 81.3% (95% CI, 78.8–83.6%) and 78.6% (95% CI, 75.6–81.2%), respectively (Fig. 1). Local failure of the irradiated tumor occurred in 222 tumors and the median interval from SBRT to local failure was 12.4 months (range, 2.9–98.6 months; IQR, 9.1–19.7 months). A total of 536 patients with 603 tumors died, and 10 deaths were caused by AEs of SBRT. Estimated 1-year, 3-year and 5-year OS rates were 90.1% (95% CI, 88.3–91.6%), 60.3% (95% CI, 57.1–63.3%) and 45.5% (95% CI, 41.8–49.1%), respectively (Fig. 1). The median survival period was 51.4 months (95% CI, 45.0-55.7 months). There were lung AEs reports from 1200 tumors in 1040 patients. Of those patients, 122 patients with 143 tumors (11.7%) had grade 2 or higher and 26 patients with 32 tumors (2.5%) had grade 3 or higher. Seven patients with 9 tumors had grade 5 of radiation pneumonitis and 3 patients with 4 tumors had grade 5 of hemoptysis.
The results of UVA for LC are shown in Supplementary Table 1, and the results of MVA for LC are shown in Table 2. Maximum tumor diameter (per 1-cm increase; hazard ratio [HR], 1.297; 95% CI, 1.059–1.588; p = 0.011), type B dose calculation algorithm (ref. type A; HR, 0.592; 95% CI, 0.410–0.856; p = 0.005), overall treatment time (OTT) of SBRT (per 10-day prolongation; HR, 0.610; 95% CI, 0.385–0.966; p = 0.035) and primary lesions were significantly associated with LC. In regard to primary lesions, the LC rate for oligometastases from colorectal cancer was significantly lower than LC rate for oligometastases from lung cancer (ref. colorectum; HR, 0.413; 95% CI, 0.274–0.622; p < 0.001), head and neck cancer (ref. colorectum; HR, 0.194; 95% CI, 0.077–0.489; p < 0.001) and other cancers excluding esophagus (ref. colorectum; HR, 0.337; 95% CI, 0.208–0.546; p < 0.001). Kaplan-Meier LC curves according to oligometastases from colorectal cancer and oligometastases from other cancers are shown in Fig. 2 (p < 0.001).
| Factors | Covariate | Local control | Overall survival | ||
|---|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | ||
| Local status | Controlled | - | - | reference | |
| Failed | - | - | 2.390 (1.839–3.106) | < 0.001 | |
| ECOG PS | 0 | - | - | reference | |
| 1 | - | - | 1.316 (1.059–1.635) | 0.013 | |
| 2–3 | - | - | 2.008 (1.405–2.869) | < 0.001 | |
| Primary lesion sites | Colorectum | reference | reference | ||
| Lung | 0.413 (0.274–0.622) | < 0.001 | 0.936 (0.685–1.280) | 0.681 | |
| H&N | 0.194 (0.077–0.489) | < 0.001 | 0.905 (0.556–1.474) | 0.690 | |
| Esophagus | 0.618 (0.306–1.248) | 0.179 | 1.650 (1.027–2.650) | 0.038 | |
| Others | 0.337 (0.208–0.546) | < 0.001 | 1.291 (0.916–1.818) | 0.143 | |
| Pathology of primary lesion | Adenoca. | - | - | reference | |
| SqCC | - | - | 1.525 (1.122–2.072) | 0.006 | |
| Others | - | - | 1.391 (0.988–1.960) | 0.058 | |
| Oligometastatic state | Oligo-rec | - | - | reference | |
| Sync-oligo | - | - | 1.391 (0.988–1.960) | 0.058 | |
| Unclassified | - | - | 1.246 (0.905–1.714) | 0.177 | |
| Chemotherapy concurrent with SBRT | Yes | 1.969 (0.859–4.513) | 0.109 | - | - |
| No | reference | - | - | ||
| Maximum tumor diameter | Per 1 cm | 1.297 (1.059–1.588) | 0.011 | 1.266 (1.131–1.417) | < 0.001 |
| Dose calculation algorithm | Type A | reference | - | - | |
| Type B | 0.592 (0.410–0.856) | 0.005 | - | - | |
| Type C | 0.732 (0.371–1.445) | 0.368 | - | - | |
| BED10 at isocenter | Per 10 Gy10 | 0.912 (0.828–1.006) | 0.065 | - | - |
| OTT of SBRT | Per 10 days | 0.610 (0.385–0.966) | 0.035 | - | - |
| Abbreviations: HR, hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; PS, performance status; H&N, head and neck; Adenoca., adenocarcinoma; SqCC, squamous cell carcinoma; Oligo-rec., oligo-recurrences; Sync-oligo, sync-oligometastases; SBRT, stereotactic body radiotherapy; BED, biological effective dose; OTT, overall treatment time. | |||||
In OS analyses, there were significant relationships of OS with local failed cohort (ref. local controlled cohort; HR, 2.390; 95% CI, 1.839–3.106; p < 0.001), PS of 1 (ref. PS of 0; HR, 1.316; 95% CI, 1.059–1.635; p = 0.013), PS of 2–3 (ref. PS 0; HR, 2.008; 95% CI, 1.405–2.869; p < 0.001), oligometastases from the esophagus (ref. colorectum; HR, 1.650; 95% CI, 1.027–2.650; p = 0.038), squamous cell carcinoma pathology of the primary lesion (ref. adenocarcinoma; HR, 1.525; 95% CI, 1.122–2.072; p = 0.006) and maximum oligometastatic tumor diameter (per 1-cm increase; HR, 1.266; 95% CI, 1.131–1.417; p < 0.001; Table 2). On the other hand, sync-oligometastases showed marginal significance (ref. oligo-recurrence, HR, 1.391; 95% CI, 0.988–1.960; p = 0.058). In landmark analyses, LC status of SBRT sites showed significant differences between the local controlled group and local failed group at all landmark time points (Fig. 3).
This study revealed the independent significance of OS benefit in a locally controlled cohort compared to that in a locally failed cohort by using SBRT for pulmonary oligometastases. In colorectal cancer, local failure of irradiated metastases have been reported to have correlation with worse OS [17]. Analyses of the large survey data in this study expanded the evidence into oligometastases from various primary cancer types. It will be certain that there is a situation in which metastasis-directed therapy works well, therefore, LC is important in that situation. The LC rate for patients who received SBRT for pulmonary metastases has been shown to be relatively high in prospective trials, but those results were not always obtained in a real world setting [18–20]. LC analyses in this study provide several key factors for successful LC by SBRT.
It is needed to be emphasized that SBRT consideration should be given to appropriate patients. In the present study, the inclusion criteria for patients included the criteria that the primary lesion and extrathoracic lesions needed to be controlled before SBRT and all pulmonary oligometastases were treated with local therapy. In a retrospective study in patients with synchronous oligometastatic (probably sync-oligometastases) epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer who were treated with an EGFR-tyrosine kinase inhibitor, OS improved only in patients who received local ablative therapy for the primary lesion and all oligometastatic lesions [21]. Then, the number of metastases and treatability of all lesions by local therapy will be important. In metastatic prostate cancer, survival benefit by definitive radiotherapy for primary lesion was seen only in low metastatic burden, and additional radiotherapy for all oligometastases showed retrospectively better castration-resistant prostate cancer-free survival than radiotherapy for only primary lesion [7, 22]. A recent consensus report proposed a maximum of five metastases and three organs as synchronous oligometastatic non-small cell lung cancer (probably sync-oligometastases) [23]. To work metastasis-directed therapy well, recent phase 2 trials required thoughtful eligibility criteria, treating primary lesion and all known oligometastases by local therapy [8–10, 24]. Appropriate selection of patients is important to obtain a benefit of SBRT.
The collaborative and detailed analyses of this study have also revealed some factors that affect LC. In MVA for LC showing that the primary site, maximum tumor diameter treated by SBRT and dose calculation algorithm were significant factors affecting LC confirmed previous findings [25–27]. Poor LC of metastatic lung tumors from the colorectum has been discussed because there were some reports of extremely low LC rates of colorectal metastases as well as reports of low LC rates of liver or bone metastases from the colorectum [27–32]. Interestingly, a German group reported that there was no significant difference in LC rates for colorectal metastasis and non-colorectal metastasis in the lung, but there was a significant difference in LC rates for those in the liver [20, 33]. In this study, a large crude difference of about 20% was found between LC rates for colorectal oligometastases and non-colorectal oligometastases were (Fig. 2). Analysis of SBRT for pulmonary oligometastases from colorectal cancer showed that dose escalation improved LC [34]. Consideration should be given to possible ways for improving LC of colorectal oligometastases. OTT of SBRT also showed a significant relationship with LC. OTT of SBRT would reflect the effect of reoxygenation, which has an influence on tumor radiosensitivity [35, 36]. SBRT sessions have often been performed on consecutive days in Japan. However an RTOG trial and another study required longer intervals in SBRT [23, 37]. Appropriate intervals each sessions such as 40 hours would contribute higher LC rate.
There are several limitations of this study. The retrospective nature of this study made all of the analyses subject to selection bias and confounding by indication. There was a considerable amount of missing data, SBRT methods varied from center to center, follow-up examinations were inconsistent, and there were unmeasured or uncontrolled factors. We could not investigate unlisted survey items such as a central lung tumor or not, patient’s comorbidities and dose–volume histogram analysis of the lung.
In conclusion, LC of pulmonary oligometastases by SBRT with a controlled primary lesion before SBRT had a survival benefit compared to the locally uncontrolled group and LC status showed the highest HR in multivariate analysis for OS. Therefore, LC is important and for achieving good LC, the use of a type A algorithm should be avoided and longer OTT of SBRT would contribute to higher LC rate, especially when treating large-size oligometastasis and colorectal oligometastasis.
LC, local control; SBRT, stereotactic body radiotherapy; BED, biological effective dose; OS, overall survival; CI, confidence interval; UVA, univariate analysis; MVA multivariate analysis; AIC, Akaike information criterion; AE, adverse event; PS, performance status; IQR, interquartile range; HR, hazard ratio; OTT, overall treatment time; EGFR, epidermal growth factor receptor
Ethics approval and consent to participate
This study was approved by the ethical committee of a senior facility (Ethics Committee of Toho University Omori Medical Center, reference number: 27-148). Informed consent was waived due to the study design.
Consent for publication
Not applicable.
Availability of data and materials
The datasets of this study are currently unavailable because it contains materials of unpublished manuscripts.
Competing interests
YN has received lecturer fees from Janssen Pharmaceutical K.K.
TY, MA, TS, KY, KY, HY, MO, YM, HO, KY, AN, KK, RO, AT and KJ declare no conflict of interest.
Funding
This study was supported by Grant-in-aid for research on radiation oncology of JASTRO 2015-2016.
Authors' contributions
Conception and design: YN and TY.
Provision of study patients: TY, YN, MA, TS, KY, KY, HY, MO, YM, HO, KY, AN, KK and RO.
Data analysis and interpretation: TY and KJ.
Manuscript draft: TY.
Manuscript editing and revision NY, MA, TS, KY, KY, HY, MO, YM, HO, KY, AN, KK, RO, AT and KJ.
Final approval of manuscript: All authors.
Acknowledgements
We acknowledge the collaboration of many radiation oncologists in Japan. We thank Drs. Akira Anbai, Gencho Kuga, Hajime Ikeda, Hideya Yamazaki, Hidekazu Tanaka, Hisashi Kaizu, Hiroki Kobayashi, Hisao Kakuhara, Ichiro Ogino, Imi Takanashi, Junichi Yokouchi, Kana Kobayashi, Katsuyuki Shirai, Keisuke Fujimoto, Kenji Nagata, Kentaro Yamamoto, Koda Ryuichi, Kosuke Amano, Koutaro Terashima, Masaaki Yamashina, Masayoshi Yamada, Michiko Imai, Miyako Myojin, Nanae Yamaguchi, Nobuhiko Yoshikawa, Nobuhisa Mabuchi, Osamu Suzuki, Saeko Hirota, Satoshi Itasaka, Seiji Kubota, Shigetoshi Shimamoto, Shinichi Ogawa, Shinya Takemoto, Shizuko Ohashi, Syuji Otsu, Takanori Fukuda, Takashi Sakamoto, Takashi Kawanaka, Takuya Yamazaki, Tetsuo Nonaka, Tetsuo Saito, Tetsuya Inoue, Toshiki Kawamura, Toshinori Soejima, Tomoyasu Kumano, Toru Sakayauchi, Tsunehiko Kan, Yasuhiro Dekura, Yasuo Matsumoto, Yoshiaki Okamoto, Yoshisuke Matsuoka, Yo Ushijima, Yuko Shirata, Yumi Sato, Yu Takada and Yutaka Naoi.