Evidence-based clinical recommendations for hypofractionated radiotherapy: exploring efficacy and safety - Part 4: Liver and locally recurrent rectal cancer

1. Primary liver cancer

Liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related deaths worldwide [11]. HCC is the most common primary liver cancer, accounting for approximately 90% of cases, followed by intrahepatic cholangiocarcinoma (IHCC) and other primary liver cancers [12]. In the early stage of the disease, the mainstay of curative local therapy includes surgical resection, liver transplantation, and radiofrequency ablation (RFA). In the advanced stage, trans-arterial chemoembolization and/or systemic therapy are usually recommended [13,14]. However, these approaches are often limited due to tumor-related or patient-related factors, and their efficacies are often unsatisfactory [15]. In this context, radiotherapy has been increasingly utilized as an alternative treatment, or as part of a combination treatment for cure or palliation of primary liver cancer [16,17].

In the past, liver-directed radiotherapy was recognized as unsafe due to concerns about radiation-induced liver disease (RILD) or toxicity in the GI tract [18,19]. However, technical advances, including radiotherapy planning, and image-guided radiotherapy with respiratory motion control has led to safe and effective delivery of high-dose radiation [20]. Furthermore, the introduction of proton beam therapy has expanded the application of radiotherapy to primary liver cancer [21]. In particular, because HCC and IHCC require high-dose irradiation to achieve sufficient local control, this technical advance was critical for extending radiotherapy to the treatment of primary liver cancer [22]. Now, hypofractionated high-dose radiotherapy is a widely used regimen for the radiotherapy in primary liver cancer [23]. Nonetheless, high-dose liver-directed radiotherapy still raises concern about RILD and GI tract toxicity because patients with primary liver cancer tend to have underlying liver disease, poor liver function, and related gastroduodenopathy, which can be exacerbated by irradiation [24,25]. Therefore, the dose prescription depends on the tumor size, tumor location relative to the adjacent GI tract, underlying liver function, and estimated dose distribution in the normal liver parenchyma [2]. Hypofractionated regimens for HCC typically involve administration of 8–15 Gy per fraction over a course of 3–10 fractions [26]. Numerous prospective and retrospective studies employing this schedule have consistently shown an local control rate exceeding 90% across various research studies [26]. When determining the fraction size in radiotherapy for liver cancer, enhancement of the therapeutic ratio must be considered. This involves considering the dose–response of the tumor and the tolerance of OAR, to optimize the treatment parameters.

A clear dose–response relationship for guiding dose selection in HCC is controversial. Several studies have identified the relationship between local control rate and an equivalent dose in 2 Gy fractions (EQD₂). Lee et al. [27] reported a dose–response relationship, based on the EQD₂ with α/β ratio 10, in retrospective findings of radiotherapy in the caudate lobe. A local control rate of 100% has been observed with an EQD₂ >90 Gy. However, the correlation between higher doses and enhanced local control rates is controversial. Generally, excessively high doses may not always be necessary for small lesions [28,30]. Lee et al. [28]. reported the outcomes of ultra-hypofractionated radiotherapy with three fractions for HCC less than 3 cm showing that the local control was comparable between total doses of 45 Gy and 60 Gy. Furthermore Lee et al. [29] argued that the local control rates of hypofractionated radiotherapy for HCC were not associated with excessive dose above 100 Gy in biologically effective dose with α/β ratio 10 by reviewing the previous studies [30-34]. Further research is necessary to confirm the adequate dose regimen for optimal local control. In addition to considering the dose–response relationship of the tumor, the optimal dose regimen should take into account the baseline liver function. Decompensation of the liver frequently occurs following radiotherapy for HCC, particularly in cirrhotic patients or those with impaired liver function. Therefore, determining the optimal dose fractionation should be done while ensuring that the constraints of the normal liver, tailored to the Child-Pugh (CP) class, are met.

By summarizing the existing trials, a recent guideline from the American Society for Radiation Oncology (ASTRO) suggested hypofractionated radiotherapy doses and fractionation for HCC and IHCC, which are summarized in Table 1 [2]. Studies that primarily employed a 10-fraction hypofractionated schedule have mainly focused on the use of protons. Regarding proton beam therapy for primary HCC, the Proton Medical Research Center of the University of Tsukuba, Japan, has developed a dose regimen according to the location of primary tumor, relative to the porta hepatis and GI tract, which is also described in Table 1 [35].

Table 1.

Recommended hypofractionated radiotherapy regimen for HCC and IHCC

2. Metastatic liver cancer

Metastatic liver cancer accounts for the majority of liver cancer cases and its proportion is higher than that of primary liver cancer [36,37]. Liver exhibits the highest frequency of metastases, as compared with that in other organs, primarily due to the unique characteristics of its circulation system, known as the dual supply by the portal vein and hepatic artery, which increases the chance for metastatic cancer cells to be deposited [37,38]. Because the existence of liver metastasis reflects systemic dissemination of the disease, systemic therapies are the mainstay of treatment [39]. However, for hepatic oligometastasis (HOM), local treatment modalities, including surgical resection, radiotherapy, and RFA, are actively applied. Among those modalities, the evidence about the benefit of surgical resection for HOM, particularly that arising from colorectal cancer, is the strongest and this treatment tends to be prioritized [3,40]. However, because surgical resection is limited by the operability of patients and resectability of the tumor, surgical resection is feasible in only to a small portion of patients with HOM [41]. Therefore, alternative less-invasive therapeutic approaches, such as RFA and radiotherapy, are also considered for ablation of HOM. Although RFA also shows good local control rates for HOM, RFA is only feasible for tumors located in visible areas on ultrasonography, i.e., areas accessible by a probe, not proximal to the vessels, and with size of 2–3 cm or less [42,43]. Radiotherapy can be another option for patients with HOM whose disease is not amenable to surgical resection and RFA.

As the radiotherapy technique for HOM, hypofractionated radiotherapy, mainly with ultra-hypofractionation, is currently widely used. However, no standardized regimen of hypofractionated radiotherapy is available for HOM [3]. Several prospective studies have reported the outcomes of hypofractionated radiotherapy for HOM derived from various primary cancers. Those studies adopted diverse dose regimens. The selected prospective studies are summarized in Table 2 [44-51]. Due to the diversity of the studies, including the study population, tumor characteristics, and treatment regimens, the reported outcomes were also heterogeneous. However, some factors, including metastatic tumor size, burden of metastatic disease, control of extrahepatic metastasis, and prescribed dose, were significantly and consistently associated with the oncological outcomes in various studies [44-46]. These factors identify HOM candidates for whom high-dose hypofractionated radiotherapy are suitable. As with primary liver cancer, hypofractionated proton beam therapy can be an attractive option for HOM, because of its physical property of reducing the irradiated volume to the liver and enabling dose escalation. Some prospective studies have reported the outcomes of hypofractionated proton beam therapy for patients with HOM showing good oncological outcomes and minimal toxicities [47,48].

Table 2.

Selected prospective studies for stereotactic body radiotherapy or hypofractionated radiotherapy for liver metastasis

1. Clinical outcomes of SBRT re-irradiation for pelvic recurrence from colorectal cancer

Re-irradiation with SBRT has demonstrated promising results in the management of recurrent rectal cancer in the pelvic area. Several studies have investigated the efficacy and safety of re-irradiation with SBRT (Table 4). Kim et al. [65] conducted a study involving 23 patients with recurrent rectal cancer who were treated with SBRT, of whom five had previously received pelvic irradiation. SBRT was administered at a dose of 30–51 Gy in 3 fractions. The study reported 4-year OS and local control rates of 24.9% and 74.3%, respectively, with one case of grade 4 rectal perforation. In cases of presacral recurrence, radical surgery is seldom a viable option, due to the predominant detection of recurrence as a fixed mass invading the sacrum and/or pelvic wall. DeFoe et al. [66] evaluated the safety and efficacy of re-irradiation with SBRT in 14 patients with presacral recurrences of rectal cancer. The patients received re-irradiation with SBRT at doses of 36 Gy in three fractions or 12 Gy, 16 Gy, or 18 Gy in 1 fraction. The study reported 1-year and 2-year local control rates of 90.9% and 68.2%, respectively, with no grade 3 or 4 toxicities observed. The 1-year and 2-year OS rates were 90.0% and 78.8%, respectively. Notably, SBRT provided complete pain relief from recurrent lesions in 57.1% of patients. Dagoglu et al. [67] reported on the outcomes of re-irradiation with SBRT in 18 patients with pelvic recurrences from colorectal cancer. SBRT was administered at a dose of 25 Gy in 5 fractions. The study reported 1-year and 2-year local control rates of 100% and 93.7%, respectively, and 1-year and 2-year OS rates of 76.8% and 65.9%, respectively. However, the study also noted some grade 3 and 4 toxicities, including one case of small bowel perforation, one case of neuropathy, and one case of hydronephrosis resulting from ureteral fibrosis. These findings highlight the importance of careful patient selection and monitoring. Smith et al. [10] investigated SBRT re-irradiation for locally recurrent rectal cancer in 35 patients. SBRT was delivered at a dose of 30 Gy in 5 fractions. The study reported 1-year and 2-year local control rates of 84.9% and 69%, respectively, and 1-year and 2-year OS rates of 95.0% and 84.4%, respectively. Acute and late toxicities were minimal, with only one patient experiencing grade 3 pain. In addition, patient-reported quality of life scores improved after SBRT. In a multicenter retrospective analysis by Johnstone et al. [68], 69 patients treated with SBRT re-irradiation for locally recurrent rectal cancer were evaluated, making it the largest series of studies to date. The study reported a 2-year OS rate of 77.0% and a 2-year PFS rate of 28.0%. Although the cancer types were not limited to colorectal cancer, a systematic review conducted by Murray et al. [69], which analyzed 17 studies that investigated pelvic re-irradiation using SBRT, demonstrated that, out of a total of 205 patients, 13 patients experienced grade 3–4 toxicities. They also reported 1-year local control rates ranging from 51% to 100%.

Table 4.

Studies reporting outcomes of stereotactic body radiotherapy re-RT for recurrent colorectal cancer

Overall, these studies suggested that re-irradiation with SBRT can achieve favorable local control rates with acceptable toxicity profiles in patients with recurrent rectal cancer in the pelvic area. However, the number of reports is limited, and all reflect small retrospective studies. Therefore, further research, including prospective studies, is warranted to establish the role of SBRT as an alternative to surgery in this population and to optimize treatment techniques.

2. Considerations for dose prescription in SBRT pelvic re-irradiation

The optimal dose and fractionation of SBRT for pelvic re-irradiation have not been established and vary across the literature. The dose regimen of SBRT should be determined on an individual basis, considering the previous irradiation doses and constraints of the surrounding normal tissues. Currently, no clear consensus on the recommended dose constraints for normal pelvic organs in pelvic re-irradiation is available. Nevertheless, some studies have proposed principles for determining dose constraints during SBRT re-irradiation. Murray et al. [69] suggested applying traditional dose constraints cumulatively. This approach ensures that the sum of doses from the original treatment and re-irradiation does not exceed traditional tolerance limits. However, if these limits prevent the delivery of a meaningful target dose, a degree of repair could be assumed, influenced by the time to re-irradiation. For example, Robinson et al. [70] have proposed a fixed 15% per annum tissue recovery for acceptable OAR constraints. Therefore, the previous dose is converted to EQD₂, with a yearly reduction of 15%, which accounts for the cumulative dose. Then, the re-irradiation dose was determined based on the cumulative dose and their national consensus OAR constraints [53]. Using this process, they have proposed an isotoxic dose prescription in locally recurrent rectal cancer, where the dose is escalated until the maximum pre-defined OAR constraints are met. Furthermore, an international Delphi consensus for pelvic SBRT re-irradiation suggests that acceptable dose fractionation schedules for SBRT in the pelvis are 30–37.5 Gy in 5–6 fractions or 21–27 Gy in 3 fractions, with treatment delivered on alternate days [71]. In the consensus, the maximum cumulative dose in EQD₂ to 0.5 mL for each OAR is shown based on the first treatment of 45 Gy in 25 fractions (EQD₂, 43.2 Gy3). For example, based on the AAPM report of 101 dose constraints [52], the maximum cumulative doses for the bladder, small bowel, cauda equina/sacral plexus, and colon/rectum are 80 Gy, 70 Gy, 67 Gy, and 80 Gy, respectively, when assuming no recovery. Assuming a recovery of 25% after a time interval of at least 12 months following irradiation, the maximum cumulative doses are 91.4 Gy, 80.8 Gy, 77.9 Gy, and 91.4 Gy, respectively. Assuming a 50% recovery, the maximum cumulative doses are 102.2 Gy, 91.6 Gy, 88.6 Gy, and 102.2 Gy, respectively. This international Delphi consensus also suggested other dose constraints based on the published literature from Abusaris et al. [72], Smith et al. [10], and Paradis et al. [73].