3.2 Survivals, tumor response, and toxicity
The median follow-up time after radiotherapy was 34 months (range, 9–86 months). The disease-free survival of primary treatment of patients (after diagnosis and initial treatment) was 19.5 months, and the mean time from the diagnosis of metastasis to radiotherapy was 6.3 months. As for the best tumor response, 16 lesions (28.1%) achieved complete response (CR) and 23 (40.4%) were partial response (PR), 15 lesions (26.3%) were stable disease (SD), and 3 lesions (5.3%) were PD. At the time of analysis, 11 patients remained alive, and 4 patients had no evidence of disease after follow-up of more than 55 months. The median OS and PFS for patients treated with radiotherapy were 30.0 months [95% confidence interval (95% CI) 21.3–38.7] and 11.0 months (95% CI 9.0–13.0), respectively (Fig. 1). One, 3, and 5 years’ LC rates were 63.2% (95% CI 50.66–75.74), 24.6% (95% CI 13.43–35.77), and 16.9% (95% CI 6.90–26.90), respectively.
Details for the toxicity within 3 months after treatment are summarized in Table 3. During follow-up, 1 patient experienced grade 2 transaminase elevation, 3 had grade 2 radiation pneumonitis with minor symptoms, and 3 patients with concurrent chemotherapy experienced grade 3 myelosuppression. Besides these, only moderate toxicities such as anorexia, fatigue, nausea, diarrhea, pain, and skin reaction were observed. There were no other severe toxicities above grade 3 or treatment-related deaths, and all patients tolerated the radiation treatment well.
3.3 Risk factors
Univariate and multivariate Cox regression analyses were performed to explore the factors associated with OS and the results are summarized in Table 4. In univariate analysis, all variables, such as age, gender, primary tumor site, number of metastasis lesions, previous local therapy, previous chemotherapy, concurrent chemotherapy, and later therapy after recurrence were not found to be significant prognostic factors of OS. However, in the multivariate analysis, number of metastasis lesions was demonstrated to be a prognostic factor and 2 metastatic lesions [hazard ratio (HR) 8.251; 95% CI 1.831–37.189; P = .006] or ≥3 metastatic lesions (HR 10.270; 95% CI 1.776–59.379; P = .009) were associated with poor survivals. Meanwhile, patients with metastatic lesions in both liver and lung were with better survival (P = .006).
In the present study, we retrospectively established a cohort to investigate the efficacy and safety of curative-intent radiotherapy in the treatment of patients with liver and/or lung oligometastases from CRC, and demonstrated that radiotherapy could achieve significant survival benefit in these patients. The median OS and PFS were 30.0 months (95% CI 21.3–38.7 months) and 11.0 months (95% CI 9.0–13.0 months) in patients with oligometastases. One, 3, and 5 years’ LC rates were 63.2% (95% CI 50.66–75.74), 24.6% (95% CI 13.43–35.77), and 16.9% (95% CI 6.90–26.90), respectively. On the contrary, most patients tolerated the radiotherapy well and there were no treatment-related deaths during our follow-up. Meanwhile, univariate Cox regression analysis did not find any significant prognostic factors of OS. However, number of metastasis lesions and simultaneous liver and lung metastases were demonstrated to be prognostic factors in the multivariate Cox regression analysis.
CRC represents one of the most commonly diagnosed cancer worldwide. At the time of diagnosis, CRC often presents with liver and/or lung oligometastatic disease, the survival of which was poor. In recent years, aggressive local treatments, which aim to ablate all metastatic lesions, are emerging as promising treatment strategy for oligometastatic tumors. Currently, resection of the oligometastatic lesions has been recommended as the standard treatment for CRC patients with oligometastases. However, surgical resection has shown survival benefit in only certain types of malignancies for a restricted selection of patients and potentially candidates for curative surgery are limited as the strict criteria for resection. Thus, nonsurgical treatments, such as radiotherapy, are increasingly being considered as therapeutic options for these patients. Takeda et al have investigated the effect of SBRT in patients with oligometastatic lung tumors from CRC and the 1-year and 2-year LC rates were 80% and 72%, respectively. Bae et al have evaluated the results of high-dose (≥45 Gy) SBRT for oligometastases from CRC. The median follow-up period from the SBRT date was 28 months (range, 6–65 months). The 3-year and 5-year LC rates were 64% and 57%, and the 3-year and 5-year OS rates were 60% and 38%, respectively. Filippi et al also got the similar results (OS rates at 1 and 2 years were 0.89 and 0.77 for SBRT). In 2015, a prospective study, which investigated the potential role of SBRT for the treatment of lung oligometastases from CRC, showed that OS rates at 1, 2, and 5 years were 84%, 73%, and 39%, respectively, and median OS was 46 months. PFS rates were 49% and 27% at 1 and 2 years, respectively. In our analysis, the median OS and PFS were 30.0 months and 11.0 months. LC rates at 1, 3, and 5 years were 63.2%, 24.6%, and 16.9%, respectively. Compared with these above studies, the survival results and LC rates in our analysis seem to be modest. It could be interpreted as follows: first, the performance status of patients in our study was worse than these studies. Forty percent of the patients were with ECOG PS score ≥1, while in other studies, most of the patients were with ECOOG PS score 0; besides, most of the patients in our study (95%) received at least 1 line of previous systemic chemotherapy, the prognosis of whom was predicted to be poor. Given these characteristics of the patients in our study, the survivals and LC rates in our study seemed to be acceptable.
In our study, there were 27 patients with solitary metastases and 13 patients with 30 oligometastatic lesions. Of these patients with oligometastatic lesions, 6 patients had 13 synchronous metastases and 7 patients had 17 metachronous metastases. In subgroup analysis, we investigated whether the metastatic status has an influence on the survival of these patients. We found that patients with metachronous metastases had longer OS (median, 41.0 months; 95% CI, 33.3–48.7) than patients with synchronous lesions (median, 17.0 months; 95% CI, 7.4–26.6, P = .001). However, there were no significant differences in PFS between the 2 groups, although PFS was longer for patients with metachronous metastases (11.0 vs 7.0 months, P = .272). Thus, patients with metachronous lesions might have better survival than those with synchronous lesions when treated with curative-intent radiotherapy.
The results of univariate Cox regression analysis on risk factors showed none of the analyzed factors, such as age, gender, primary tumor site, number of metastasis lesions, previous local therapy, previous chemotherapy, concurrent chemotherapy, and later therapy after recurrence, were significantly associated with OS. The results were similar to previously published study. However, in the multivariate Cox regression analysis, higher number of metastasis lesions was associated with worse OS than those with fewer number of metastatic lesions. Thus, number of metastasis lesions might be a potential prognostic factor affecting the survival of CRC patients with liver and/or lung lesion. Meanwhile, we also found metastatic lesions located in both liver and lung might have better survival (P = .006). It could be interpreted as most of these patients were with metachronous lesions. As was demonstrated above, patients with metachronous lesions might with better prognoses.
It is essential to address the limitations of this current study. To begin with, as data in our study were retrospectively collected from the medical records, prospective randomized control trials are required to further verify the role of radiotherapy in the treatment of oligometastases from CRC; second, the types and dose of radiotherapy were heterogeneous, and it may impair the reliability of our analysis; in addition, the sample size of our study was small and the study was performed in 1 medical center; studies with more samples need to be carried out.
In conclusion, the results of the retrospective study suggest that radiotherapy is a tolerable treatment for patients with liver and/or lung oligometastases from CRC. Curative-intent radiotherapy could improve the survivals and LC rates for these patients, especially in patients with metachronous oligometastatic disease. These findings provide a challenging alternative for patients who are not candidates for surgical resection and may play a major role in the future.
We wish to thank Dr Feng Wen, MD, for the revision of the English manuscript.
Conceptualization: Xiaofeng He, Qiu Li.
Data curation: Xiaofeng He, Zhiping Li, Xin Wang.
Formal analysis: Pengfei Zhang, Yali Shen.
Funding acquisition: Feng Bi, Yali Shen.
Investigation: Xiaofeng He, Feng Bi.
Methodology: Zhiping Li, Qiu Li.
Project administration: Feng Xu.
Resources: Xin Wang.
Software: Pengfei Zhang.
Supervision: Feng Xu, Meng Qiu.
Validation: Feng Xu, Meng Qiu.
Visualization: Qiu Li, Meng Qiu.
Writing - original draft: Xiaofeng He, Pengfei Zhang.
Writing - review & editing: Qiu Li, Meng Qiu.
Meng Qiu orcid: 0000-0003-3722-6938
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Keywords:Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
colorectal cancer; curative-intent; oligometastases; radiotherapy