Hisashi Yamaguchi,Takahiro Kato,Michitaka Honda,Koichi Hamada,Ichiro Seto,Takuya Tominaga,Yoshiaki Takagawa,Kanako Takayama,Motohisa Suzuki,Yasuhiro Kikuchi,Yasushi Teranishi,Masao Murakami
Effectiveness of proton beam therapy for liver oligometastatic recurrence in patients with postoperative esophagus cancer
proton therapy,liver metastatic,esophagus cancer
Abstract There are several reports of hepatic resection for postoperative hepatic metastatic recurrence of esophageal cancer. However, it is unclear whether surgery is the best local treatment for liver metastases. Thus, this study aimed to retrospectively analyze proton beam therapy (PBT) for postoperative liver metastatic recurrence of esophageal cancer without extrahepatic lesions and examine outcomes and adverse events. This single-center historical cohort study selected patients who underwent PBT at our proton therapy center between 2012 and 2018. The patients were selected based on the following criteria: primary esophagus carcinoma was resection and metachronous liver oligometastasis recurrence without extrahepatic tumors and no more than three liver metastases. This study included seven males with a median age of 66 (range, 58–78) years, and 15 lesions were included in the study. The median tumor size was 22.6 (7–55.3) mm. The most frequent dose was 72.6 Gy relative biological effect (RBE)/22 fractions (fr) for four lesions and 64 Gy (RBE)/8 fr for four lesions. The median survival time was 35.5 (13.2–119.4) months. The 1-, 2- and 3-year overall survival (OS) rates were 100%, 57.1% and 42.9%, respectively. The median progression-free survival (PFS) time was 8.7 (1.2–44.1) months. The 1-, 2- and 3-year PFS rates were 28.6%. The 1-, 2- and 3-year local control (LC) rates were 100%. No grade ≥4 radiation-induced adverse events (AEs) were observed. We conclude that PBT can be considered an alternative to hepatic resection for recurrent liver metastases postoperative esophageal cancer.
Effectiveness of proton beam therapy for liver oligometastatic recurrence in patients with postoperative esophagus cancer

There are several reports of hepatic resection for postoperative hepatic metastatic recurrence of esophageal cancer. However, it is unclear whether surgery is the best local treatment for liver metastases. Thus, this study aimed to retrospectively analyze proton beam therapy (PBT) for postoperative liver metastatic recurrence of esophageal cancer without extrahepatic lesions and examine outcomes and adverse events. This single-center historical cohort study selected patients who underwent PBT at our proton therapy center between 2012 and 2018. The patients were selected based on the following criteria: primary esophagus carcinoma was resection and metachronous liver oligometastasis recurrence without extrahepatic tumors and no more than three liver metastases. This study included seven males with a median age of 66 (range, 58–78) years, and 15 lesions were included in the study. The median tumor size was 22.6 (7–55.3) mm. The most frequent dose was 72.6 Gy relative biological effect (RBE)/22 fractions (fr) for four lesions and 64 Gy (RBE)/8 fr for four lesions. The median survival time was 35.5 (13.2–119.4) months. The 1-, 2- and 3-year overall survival (OS) rates were 100%, 57.1% and 42.9%, respectively. The median progression-free survival (PFS) time was 8.7 (1.2–44.1) months. The 1-, 2- and 3-year PFS rates were 28.6%. The 1-, 2- and 3-year local control (LC) rates were 100%. No grade ≥4 radiation-induced adverse events (AEs) were observed. We conclude that PBT can be considered an alternative to hepatic resection for recurrent liver metastases postoperative esophageal cancer.

Metastatic recurrence is often experienced after esophageal cancer surgery. Ichida et al. [1] reported that of 296 cases of postoperative esophageal cancer patients, 138 (46.6%) cases had postoperative recurrence. Among those patients, 26 (8.8%) had liver metastases. Among patients with metastatic liver tumors, 17 (6.8%) had no extrahepatic lesions. Patients meeting indications for hepatic resection had even more stringent conditions. Nine patients (3%) had no extrahepatic lesions and two or fewer liver metastases, and six patients (2%) had performance status (PS) 0–1. Among those patients, one (0.34%) underwent radiofrequency ablation (RFA) and five (1.7%) underwent hepatic resection. The postoperative median survival time for the five patients who underwent hepatic resection was 13 months. Liu et al. [2] reported that among 69 patients with solitary liver metastases without extrahepatic lesions after esophageal cancer surgery, 26 (37.7%) underwent hepatic resection and 43 (62.3%) underwent non-resection and the 1- and 2-year overall survival (OS) of the hepatic resection group were 50.8 and 21.2%, respectively. The 1- and 2-year OS in the non-resection group were 31 and 7.1%, respectively, indicating a better prognosis in the liver resection group. Local treatment of postoperative liver metastatic recurrence of esophageal cancer may be advantageous in selected cases. It is unclear whether surgery is the best local treatment since postoperative patients with esophageal cancer may have poor PS and nutritional status, and liver resection may be too invasive. Recently, the Japanese Society for Radiation Oncology proposed ≤3 metastatic liver lesions, any type of primary tumors and no extrahepatic metastatic lesions, as indications for particle therapy, including proton beam therapy (PBT). Satisfactory results for liver metastases of gastric cancer have been reported. The 1- and 3-year OS were 100% and 69–78%, respectively; 1- and 3-year progression-free survival (PFS) were 60–100% and 40–43%, respectively; and 1- and 3-year local control (LC) were 89–100 and 78–85.7%, respectively [3, 4]. The largest number of cases was reported by Fukumitsu et al. [5] for PBT for metastatic liver tumors. Although the 5-year OS of PBT for 140 patients with liver metastases was 24%, only 3 (2%) included liver metastases from esophageal cancer. PBT results for postoperative liver metastases from esophageal cancer are unknown. There have been only two reports of PBT for liver metastases from gastric cancer [3, 4] and similarly of PBT for breast cancer [6, 7]. Factors contributing to the prognosis after PBT, and appropriate treatment indications are lacking. We retrospectively analyzed PBT for postoperative liver metastatic recurrence of esophageal cancer without extrahepatic lesions and examined the outcomes and adverse events (AEs). Factors affecting life expectancy were examined to determine appropriate indications.

This was a single-center retrospective cohort study. Cases with PBT performed at our proton therapy center (2012–2018) were selected from the database, with the following criteria: patients with primary esophagus carcinoma were resection and patients with metachronous liver oligometastasis recurrence without extrahepatic tumors and no more than three liver metastases.

The treatment plan was discussed and decided by surgeons, gastroenterologists, medical and radiation oncologists. The dose and fraction of PBT were determined by radiation oncologists and medical physicists according to tumor location and size. We modified the dose per fraction to 2–2.2 Gy (relative biological effect [RBE]) for the adjacent gastro-intestinal (GI) tract type, 3.2–3.8 Gy (RBE) for the adjacent hilar region type, and 8 Gy (RBE) for the hepatic periphery area away from the GI tract. Abdominal computed tomography (CT) was performed at 2-mm intervals with respiratory gating, with the patient in a supine position. Gross tumor volume (GTV) was defined as the volume of liver tumor determined using contrast-enhanced CT and magnetic resonance imaging (MRI) or positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-D-glucose integrated with CT before treatment. The clinical target volume (CTV) was the GTV, with a 5-mm margin in all directions. The planning target volume (PTV) was CTV plus 5-mm margins in all directions, plus 2-mm margins in the craniocaudal region, depending on the respiratory movements. The beam energy and spread-out Bragg peak were fine-tuned to the target volume such that the 90% isodose volume of the prescribed dose encompassed the PTV. Treatment was administered during the end-expiratory phase using a breathing gate. Respiration gating was controlled by checking body movement with a laser range finder. The dose constraints were: GI tract ≤50 Gy (RBE); if PTV overlapped, PBT planning was performed with priority given to organs at risk.

The primary endpoint was 2-year OS. The secondary endpoints were PFS, LC and AEs. OS was defined as the time from the date of PBT initiation to death from any cause; 1-, 2- and 3-year OS rates were determined. LC was defined as the date of the event when the response evaluation criteria in solid tumor evaluation resulted in progressive disease (PD) from PBT initiation; 1-, 2- and 3-year LC rates were determined. PFS was defined as the time from the date of PBT initiation to disease progression and death. If no mortality event was observed, the case was censored at the last survival observation, and any untraced survival was censored at the last survival confirmation. Events were defined as death owing to any cause, appearance of new lesions, tumor progression, or need for additional treatment for lesions with an inadequate PBT response. Progression included both PD on imaging and clinical exacerbations such as elevated tumor markers. If PD diagnosis was based on an imaging diagnosis, the event was defined as the ‘date of examination’ of the imaging test that led to the ‘confirmed diagnosis’ and not the date of examination of the ‘suspected exacerbation on imaging’; 1-, 2- and 3-year PFS rates were determined. We investigated medical records using the Common Terminology Criteria for Adverse Events version 5.0. During PBT, acute treatment-related toxicity was assessed and documented daily, and patients were evaluated weekly using blood tests. After completing PBT, patients were evaluated every 3 months via physical examination, blood tests, CT and/or MRI. Toxicities that occurred within 3 months after PBT were defined as acute, and those occurring after 3 months were considered late.

The OS, PFS and LC rates were calculated using the Kaplan–Meier method. Factors possibly related to OS, such as tumor size (for multiple lesions, the largest size), number of liver lesions, pathological diagnosis of primary site, duration of primary tumor resection to initiation of PBT, and the PFS time after PBT were investigated. The cut-off values were estimated using the receiver operating characteristic curve and area under the curve. The final cut-off value was selected as the point where ‘the sum of sensitivity and specificity was maximized.’ Univariate analysis was performed using the log-rank test. Statistical significance was P-values < 0.05. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R d4 (R Foundation for Statistical Computing, Vienna, Austria). EZR is a modified version of the R commander designed to add statistical functions commonly used in biostatistics [8].

Seven males with a median age of 66 (range, 58–78) years and 15 lesions were included. One of the seven cases was unresectable, and the remaining six cases were refused surgery and indicated PBT. Two cases had additional PBT performed for intrahepatic recurrence, two patients underwent additional PBT for one lesion and one patient underwent additional PBT for two lesions. The most frequent dose was 72.6 Gy (RBE)/22 fractions (fr) for four lesions and 64 Gy (RBE)/8 fr for four lesions. The median time to PBT from primary esophagus cancer surgery, lesion size, fraction size and BED10 were 23.2 (1.73–124.0) months, 22.6 (7–55.3) mm, 3.3 Gy (RBE)/fr (2–8 Gy (RBE)/fr) and 96.6 (77.8–115.2) Gy, respectively. Five patients (71.4%) received neoadjuvant chemotherapy comprising cisplatin and fluorouracil for primary esophagus cancers. Three patients (42.9%) received chemotherapy for liver metastasis, of whom one received cisplatin and fluorouracil, one received S-1 plus oxaliplatin (SOX) before ramucirumab/paclitaxel chemotherapy and the third received nivolumab before weekly paclitaxel. Another patient (14.3%) received chemotherapy with S-1 concurrent with PBT. Four patients received chemotherapy after PBT, of whom three received cisplatin and fluorouracil, and one received nivolumab. All these four patients started chemotherapy because they had new metastatic lesions. Thus, the three patients without new metastatic lesion did not experience adjuvant chemotherapy. These results are summarized in Tables 1 and 2.

The median follow-up period was 35 (13.2–119.4) months. As of December 2022, four patients had died and three patients were alive. Survival time for the three patients were 50.8, 57.2 and 119.4 months, respectively. There was one case of space-making surgery between the liver tumor and the stomach for a patient who arrived 119.4 months after PBT, without local recurrence. The 1-, 2- and 3-year OS rates were 100%, 57.1% and 42.9%, respectively, and the median survival time was 35.5 months, as shown in Fig. 1(a). Four patients had recurrences in their livers outside of the irradiated field, of whom two patients had three lesions re-irradiated with PBT. All reirradiations were performed safely without complications. Recurrence occurred in five patients. Four patients had intra hepatic new lesions out of the irradiated field and distant metastasis was observed in the distant lymph nodes in one patient. No patient had a local recurrence in the irradiated field. The median PFS was 8.7 months, with PFS rates shown in Fig. 1(b). The 1-, 2- and 3-year PFS rates were 28.6% for all. The LC rates are shown in Fig. 1(c), and the 1-, 2- and 3-year LC rates were 100% for all.

Tumor size (for multiple lesions, the largest size) and PFS time after PBT were the significant factor (both, P = 0.0143). The number of liver lesions (P = 0.404), pathological diagnosis of primary site (P = 0.771) and duration of primary tumor resection to initiation of PBT (P = 0.499) were not significantly related to the OS (Table 3).

No grade ≥4 radiation-induced AEs were observed although one patient had a grade 3 liver abscess. The patient's tumor size was 39.8 mm and it was treated with 76 Gy (RBE)/38 fr. Toward the end of PBT, the patient developed a fever and an abscess was diagnosed using a CT scan. The patient was implanted a fiducial gold marker, and the abscess was consistent with the puncture of the gold marker. We considered that the insertion technique of the gold marker may have had an effect. None of the patients experienced radiation-induced liver failure in the acute or late phase. The acute AE observed was a grade 1 radiation-induced dermatitis case, and the only late AE observed was a grade 1 radiation-induced rib fracture.

We retrospectively analyzed cases of PBT for hepatic oligometastases within three lesions of postoperative esophageal cancer without extra hepatic lesions. Although the number of cases in this study was very small, the OS rate showed that PBT was not inferior to the 1-, 2-year OS of liver resection in the largest previous report [2]. There were several case reports of one or two patients hepatic resection for postoperative liver metastatic recurrence of esophageal cancer [9–13]. Table 4 provides a summary of the outcomes of liver resection for postoperative hepatic metastatic recurrence of esophageal cancer, and the 1- and 2-year OS were 50.8–75% and 20–50%, respectively [1, 2, 14]. One report comparing conventional chemotherapy without resection and resection for liver metastases showed that the liver resection group was statistically better [2]. However, another report showed no statistically significant difference [1]. Thus, hepatic resection needs further study. Treatment options for metastatic liver tumors include high-precision radiation therapy such as stereotactic body radiotherapy (SBRT) and PBT. PBT has a physical property called the Bragg peak, which has less energy at the body surface and stops releasing energy at the tumor site. Therefore, the dose beyond the tumor is zero, and radiation exposure to the normal liver tissue is minimized. PBT can thus treat larger liver tumors than SBRT [15], and re-irradiation of PBT for additional heterochronous liver tumors can be safely performed [16]. This study found one grade 3 AE and we considered that the insertion technique of the gold marker may have had an effect. Currently, a marker-less irradiation technique has been developed [17], and we believe that the marker-related complications may be avoided. None of the patients experienced radiation-induced AEs in the acute or late phase. The number of patients overall (seven patients) and with AE (1 [14%] patient) was small, and this could have had a large impact. In prior report of PBT for liver metastasis, 0–1.5% of grades 3 or higher AEs were reported [3–7, 18, 19]. In prior reports of carbon ion beam therapy (CIBT), SBRT, RFA, transarterial chemoembolization (TACE), and surgery for liver metastasis, 0–6.9 [20, 21], 1.6% [22], 1.1–3.1% [23, 24], 0.0% [25] and 23% [2] of grade 3 or higher AEs were reported, respectively. High-precision radiation therapy such as SBRT and PBT could treat fewer AEs. However, there are very few reports regarding radiotherapy for postoperative liver metastatic recurrence of esophageal cancer. Even in reports of SBRT for metastatic liver tumors including various primary sites, there are no papers that clarity include esophageal cancer [22, 26–31]. Previous report of PBT for metastatic liver tumors of 133 cases included only three cases (2%) from esophageal cancer [5], furthermore 46 cases including only one patient (2%) from esophagus cancer [32]. There are only case reports on PBT and SBRT for postoperative liver metastatic recurrence of esophageal cancer, which are two reports of PBT [33, 34], and two reports including one in Japanese language of SBRT [35, 36]. There are two reports of PBT for liver metastatic recurrence of gastric cancer, which is more prevalent than esophageal cancer, and the number of cases is extremally small (seven and nine cases) [3, 4]. Previous report of PBT for other liver metastases were one report of colorectal cancer (41 cases) [19] and two of breast cancer (eight and 17 cases) [6, 7] and one of various primary cancers (46 cases) [18]. Previous reports of CIBT for metastatic liver tumors were only two reports on colorectal cancer (11 and 29 cases) [20, 21]. Other therapy options for metastatic liver tumors are RFA and TACE. Although there are only case reports on esophageal cancer, several reports on breast cancer [23–25, 37]. The outcomes of various treatment modalities for various liver metastases are summarized in Table 5. However, we believe that it should be described metastatic liver tumors separately by primary cancer, since the prognosis and response to local treatment differ depending on the primary cancer. In esophageal cancer, microscopic metastases may be present in recurrent liver metastases, even if they are single oligo-metastases on imaging studies and the invasiveness of surgery may weaken the patient's resistance and allow microscopic metastases to appear. Surgery delays the resumption of chemotherapy whereas PBT is less physically demanding and can be administered in combination with chemotherapy. Unlike surgery, chemotherapy can be administered without delay after PBT. According to CheckMate 577, a checkpoint inhibitor was investigated as an adjuvant therapy in patients with esophageal or gastroesophageal junction cancer, who were resected (R0) stage II or III esophageal or gastroesophageal junction cancer. A study reported that among the 532 patients who received nivolumab, the median disease-free survival was 22.4 months (95% confidence interval [CI], 16.6 to 34), as compared with 11.0 months (95% CI, 8.3 to 14.3) among the 262 patients who received placebo (hazard ratio for disease recurrence or death, 0.69; 96.4% CI, 0.56 to 0.86; P < 0.001) [38]. Therefore, it is suggested that even after complete resection, there is a risk of recurrence and the presence of microscopic tumors. There is a report that non-small cell lung cancer is prolonged twice by the median survival time in the immune checkpoint inhibitor (ICI) plus irradiation group compared with that in the ICI alone group [39] In Japan, the ICI is covered by public insurance for postoperative recurrence of esophageal cancer and is inexpensive, and many patients are using it. The ICI and PBT may be expected to have further synergistic effects on recurrent liver metastases. The univariate analysis results predicted a statistically significant worse life expectancy for larger tumors. However, the number of cases was small, multivariate analysis could not be performed, and no adjustment for confounding factors had been made, making it unreliable. There was no significant difference between single and multiple metastases, and the survival rate in this study of three or fewer lesion cases was good, suggesting that it is not necessarily true that only single metastasis is eligible for local treatment. Tumors located in both lobes of the liver could make hepatic resection difficult, but PBT allows irradiation without major problems, a benefit of PBT. This study had limitations. First, it was performed in a single institution, the sample size was small, with no control group; therefore, there may be selection bias. The 100% LC rates may be attributed to the short PFS and OS. Therefore, it should be noted that there are significant limitations in the evaluation of high LC in this study and readers should be careful in interpreting these results. Second, we treated patients referred from other hospitals using PBT. Thus, we do not know how many postoperative esophageal cancer patients are eligible for PBT for liver metastasis recurrence. Further, generalizations cannot be made. Recently, the Japanese Society for Radiation Oncology proposed ≤ 3 metastatic liver lesions and no extrahepatic metastatic lesions as indications for particle therapy, including PBT. A multicenter comparative study is thus required to further evaluate the effectiveness of PBT for liver oligometastatic recurrence in patients with postoperative esophagus cancer. Although this study included a small number of patients, PBT may be a feasible option and an alternative to other local treatment for recurrent liver metastases, in patients with postoperative esophageal cancer. Not only single liver metastasis but also multiple metastases suggest that hepatic metastases with no more than three and without extrahepatic lesions could be a good indication for PBT.