Within the scope of this study, a group of 115 persons with 150 liver metastases was evaluated which received high-precision radiotherapy at the Department of Radiation Oncology, University Hospital Klinikum rechts der Isar, Technical University of Munich (TUM) from May 2004 to January 2020 as part of their treatment plan. This group is one of the largest cohorts analyzed in the literature to date concerning high-precision radiotherapy for liver metastases. We focused on survival parameters and therapy-associated toxicity. Looking at the results for the cohort, 6-, 12-, and 24-month survival rates of 87, 72, and 45% for OS and 7, 18, and 23% for the probability of metastatic recurrence were found. Metastases are a major problem in every oncological disease. The further the tumor spreads and the more organs and structures are affected, the worse the prognosis of the patient and the more limited and difficult the therapy management becomes. If, for example, metastatic penetration of the liver is found, the median survival of the patient is expected to be about 6 months, regardless of whether extrahepatic tumor localization exists [14].
To date, surgical removal of metastases in the liver area has proven to be the gold standard of therapy and the only potentially curative procedure in oligometastatic patients. Especially for isolated metastases, surgery is the therapy of choice. Depending on the organ, tumor spread, and patient’s condition, a distinction is made between open and laparoscopic variants, and between anatomical and non-anatomical resection [15]. However, surgery is a very invasive procedure and is only applicable in very few patients, especially in the case of liver metastases. Due to this, other ablative, local treatment methods are needed to offer an alternative therapy to patients who are not suitable for surgical excision. Various ablation methods, such as radiofrequency-, microwave-, and cryoablation, also play an important role in the treatment of metastases. However, these are also invasive and associated with more serious complications and side effects [5]. Stereotactic hypofractionated high-precision radiotherapy represents a non-invasive alternative therapy option and has developed into a promising method for the treatment of a wide variety of tumors and tumor metastases in recent years. Up to now, SBRT, FSRT and SRS have been widely used for the treatment of lung, prostate, and brain tumors and SBRT is now developing into a promising method also for the treatment of liver metastases [16].
The results of the cohort in this study are generally in good agreement with those of other studies, both in terms of OS and LC. Looking at the published LC rates, a broad range of 50–100% is reported [17,18,19,20,21]. Due to the frequent occurrence of competing events, no LC rate was determined, but the probability of local failure was estimated using a competing-risk analysis. LC of liver metastases after radiotherapy has already been associated with the amount of BED10 applied in some studies. Chang et al. reported an 18-month LC rate of 80% vs. 30% with application of a BED10 from ≥75 Gy and < 75 Gy [22]. Furthermore, Lanciano et al. published a 2-year LC rate of 75% was found with a BED10 of ≥100 Gy and 38% with a BED10 of < 100 Gy [23]. In this cohort of 115 patients, the association between higher BED10 and better LC was borderline significant (p = 0.055). In 8 out of 41 (19.5%) post-therapeutic progressive liver metastases, progress was recorded with an applied BED10 of ≥72 Gy. All other progressive liver metastases received BED10 < 72 Gy. Post-interventional toxicities are an important limiting factor for any new therapy. The advantage of hypofractionated stereotactic irradiation is extremely good tolerability. Due to the non-invasive, exact percutaneous application and the recess and thus sparing of surrounding healthy tissue, the therapy-associated side effects are very mild and easily treatable in most cases. Overall, the irradiation of liver metastases is very well tolerated [17,18,19,20,21]. The side effects are not very pronounced and CTCAE grade 3–4 toxicities occur in 1–10% of cases only [1]. Since the liver is a very radiation-sensitive organ, it is of great importance to preserve the surrounding healthy structures and to protect them from unnecessary radiation exposure, as this is associated with an increased risk of toxicities. In the past, radiation-induced liver disease (RILD) has played a major role as a side effect of conventional radiotherapy regimens, with patients having pre-existing liver dysfunction often being at the highest risk. In the case of liver metastases, the risk of developing RILD after radiotherapy is less than 1% according to the published results [1, 10].
Several different studies are also devoted to side effects in the bile ducts. According to Osmundson et al., the most common grade 3 toxicities are hepatobiliary stenoses and bile stasis. In their cohort, the effect of SBRT was investigated by irradiating various liver primary tumors and metastases. The results showed that, although grade 3 adverse events occurred in 18.8% of cases, irradiation of liver metastases was best tolerated and the least number of treatment-related complications occurred [24]. In the analyzed cohort of this study, we also found various hepatobiliary toxicities. In 6.1%, mild cholestasis was observed, in 3.5% a grade 3 biliary stenosis, in 1.7% a postradiogenic hepatitis, in 0.9% recurrent grade 2 cholangitis, and in 1.7% a grade 3 cholangitis. Both bile duct and gallbladder toxicities are considered to be rare after stereotactic radiotherapy. It is unclear which fractionation scheme is considered safe to prevent side effects in this area, but Eriguchi et al. declared a dose of 40 Gy in 5 fractions as safe for tumors in the liver hilum [25]. Similarly, the pathogenesis of stenosis of the bile ducts after radiotherapy is not yet fully understood. It is assumed that radiation-induced fibrosis causes occlusion or that interaction of systemic therapy, surgery and radiotherapy has an occlusive effect. In rare cases, gallbladder toxicities are described in the context of radioembolization with Yttrium-90, but not in SBRT [25]. This is also supported by the results of this study since no patient has experienced cholecystitis, gallbladder rupture, or other side effects. Other organs at risk near the liver are the stomach, the small and large intestine. These are the organs most frequently affected by therapy-associated side effects in every SBRT. The severity can range from mild nausea to severe gastrointestinal hemorrhages and perforations. In recent years, there have been isolated reports of patients with hemorrhagic gastritis and duodenal ulcers following radiation; however, as there are no uniform dose restrictions for intestinal organs at risk, extreme caution is advised when outlining the radiation plan. According to some studies, a cumulative dose of 30 Gy and a single dose of 10 Gy for duodenum and colon should not be exceeded to prevent severe toxicity [26, 27]. Further side effects of the therapy concern the skin in the irradiated area and the thoracic wall. SBRT of lung malignancies and breast cancer have already been reported to cause severe chest pain and pathological rib fractures [28]. In the group of patients in this study no pathologic fracture occurred in any of the patients, but there were isolated reports of chest and rib pain. Although the esophagus is one of the less affected organs at risk, there are also some cases of radiogenic side effects. According to Stephans et al., the occurrence of toxicities correlates with the application of a cumulative dose of more than 50 Gy while receiving systemic tumor therapy, often with VEGF-modulating drugs [29]. In this cohort, esophageal toxicities occurred in three patients. Two of them reported mild swallowing difficulties that did not require further treatment, but one patient developed grade 3 esophageal stenosis after stereotactic treatment. One of the other more serious complications following radiotherapy was a patient who developed a liver abscess in the radiation field. There is little information on this type of SBRT toxicity and there are almost no publications on this subject, as liver abscesses are more likely to occur during chemoembolization or radiofrequency ablation rather than SBRT [30, 31]. Nevertheless, there are a few isolated case reports that aim to draw attention to this side effect of radiotherapy, which should not be underestimated. In the cohort of Mahadevan et al. a grade 3 liver abscess occurred in one patient during SBRT of liver cholangiocellular carcinomas, and Macomber et al. also showed two cases of an abscess after liver radiation [32, 33]. The irradiated patient with liver abscess in the cohort of this study was rapidly discharged after surgical repair and systemic antibiotic treatment. The analysis and the available results indicate that stereotactic high-precision radiotherapy is a versatile, promising and above all, well-tolerable therapy option. However, there are some limitations of the study. Among them are the retrospective design of the analysis and the short follow-up period. Furthermore, the very heterogeneously applied irradiation regimes are also among the limiting factors, as there are no uniform recommendations regarding dose and fractionation. For this reason, it is advisable to continue to conduct larger-scale studies in this area to fully exploit the potential of this therapeutic method.
This work aimed to obtain a clearer picture of the therapeutic option of stereotactic high-precision irradiation and its field of application, as well as to evaluate the advantages and disadvantages for the patient in the best possible way.
