Thomas F. DeLaney

Purpose: To evaluate long-term outcomes and determine whether longitudinal plasma profiling provides biological insight into disease progression after proton hypofractionated ablative radiation therapy (HART) for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Patients and Methods: In this single-arm, multi-institutional phase II trial, 92 patients with localized unresectable HCC or ICC with Child-Pugh class A/B liver function received HART (up to 67.5 GyE in 15 fractions). Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Plasma samples were collected at baseline, days 1, 8, 15, and 1-month after treatment for exploratory correlative analyses. Results: Among evaluable patients (44 HCC, 39 ICC), median OS was 29.2 months (HCC) and 20.8 months (ICC), with 5-year OS rates of 25.9% and 12.3%, respectively. Median PFS was 13.8 months (HCC) and 8.4 months (ICC). In-field local failure occurred in 2 HCC (4.5%) and 7 ICC (17.9%) patients, whereas out-of-field intrahepatic/distant progression remained the predominant pattern of failure. No grade >3 treatment-related toxicities were observed. Exploratory plasma profiling identified distinct biological signatures associated with progression: HCC was characterized by markers of hypoxia, inflammation, vascular remodeling, stromal activation, and hepatic regeneration, whereas associations in ICC predominantly involved signatures of hypoxia and vascular remodeling. Conclusions: HART provides durable long-term in-field local control with minimal toxicity, but disease progression remains predominantly out-of-field intrahepatic/distant. Exploratory correlative analyses suggest that biological signatures reflecting vascular remodeling, hypoxia, inflammation, stromal activation, and hepatic reserve are associated with progression despite successful local therapy, informing future translational studies and combination strategies.

Opinion statement Soft tissue sarcomas (STS) are rare, aggressive, and heterogenous tumors, comprising approximately 1% of adult cancers with over 50 different subtypes. The mainstay of treatment for retroperitoneal sarcomas (RPS) includes surgical resection. The addition of radiation therapy (RT), either preoperatively or postoperatively, has been used to potentially decrease the risk of local recurrence. The recently published results from STRASS (EORTC-STBSG 62092-22092), which randomized patients to receive or not receive preoperative radiation, indicate no abdominal recurrence-free survival benefit (primary endpoint) nor overall survival benefit to date from the addition of preoperative RT prior to surgical resection in patients with RPS. Keeping in mind caveats of subgroup analyses, the data show a significant reduction in local recurrence with radiation therapy in resected patients and non-significant trends toward improved abdominal recurrence-free survival in all patients and improved local control and abdominal recurrence-free survival in patients with liposarcoma and low-grade sarcoma. Given the high rate of local failure with surgery alone, it is possible that higher RT dose and/or selective RT dose painting may improve outcomes. Prior to treatment, the authors encourage multidisciplinary review and discussion of management options at a sarcoma center for patients with RPS. Selective use of RT may be considered for patients at high risk of local recurrence.

Background and Objectives: Radiotherapy (RT) enables conservative surgery for soft tissue sarcoma (STS). RT can be delivered either pre‐operatively (PreRT) or postoperatively (PORT), yet in some patients, neither approach is fully satisfactory (e.g., urgent surgery or wound healing risk prevents PreRT, yet PORT alone cannot cover the entire surgical field). We hypothesized that, in such situations, low‐dose PreRT (LD‐PreRT) would decrease the risk of intraoperative tumor seeding and thus permit PORT to a reduced volume (covering the high‐risk tumor bed but not all surgically manipulated tissues).Methods: We identified a single‐institution retrospective cohort of 78 patients treated with LD‐PreRT (10–30 Gy), resection, and PORT between 1980 and 2018.Results: At a median follow‐up of 8.2 years, 8‐year overall survival (OS) was 65.9%, disease‐free survival (DFS) 50.5%, and local control (LC) 76.7%; in 45 patients with extremity/superficial trunk (E/ST) STS, 8‐year LC was 80.9%. Both before and after propensity score adjustment, there were no differences in OS, DFS, or LC between this cohort and a separate cohort of 394 STS (221 E/ST‐STS) patients treated with surgery and PORT alone.Conclusions: In patients for whom neither PreRT nor PORT alone is optimal, LD‐PreRT may prevent intraoperative tumor seeding and enable PORT to a reduced volume while preserving oncologic outcomes.

In this issue, Xiang and colleagues present data from the National Cancer Database comparing the number of second malignancies observed in adult and pediatric patients with 9 major cancer subtypes who received different radiation modalities. These are important findings because understanding the risk of late, radiation‐associated malignancies with different radiation modalities may help physicians reduce the risk of this devastating late treatment effect.

Background. Dedifferentiated chondrosarcomas (DDCSs) are highly malignant tumors with a dismal prognosis and present a significant challenge in clinical management. Methods. In an IRB approved retrospective protocol, we identified 72 patients with DDCS treated at our institution between 1993 and 2017 and reviewed clinicopathological characteristics, treatment modalities, and outcomes to analyze prognostic factors. Results. Femur (44.4%), pelvis (22.2%), and humerus (12.5%) were most commonly involved sites. Twenty-three patients (31.9%) presented with distant metastasis, and 3 (4.2%) of them also had regional lymph node involvement. The median overall survival (OS) was 13.9 months. On multivariate analysis, pathological fracture, larger tumor size, lymph node involvement, metastasis at diagnosis, extraosseous extension, and undifferentiated pleomorphic sarcoma component correlated with worse OS, whereas surgical resection and chemotherapy were associated with improved OS. For progression-free survival (PFS), pathological fracture and metastasis at diagnosis showed increased risk, while chemotherapy was associated with decreased risk. Among patients who received chemotherapy, doxorubicin and cisplatin were significantly associated with improved PFS but not OS. Among patients without metastasis at diagnosis, 17 (34.7%) developed local recurrence. Thirty-one (63.3%) developed distant metastases at a median interval of 18.1 months. On multivariate analysis, R1/R2 resection was related with local recurrence, while macroscopic dedifferentiated component was associated with distant metastasis. Conclusions. The prognosis of DDCS is poor. Complete resection remains a significant prognostic factor for local control. Chemotherapy with doxorubicin and cisplatin seems to have better PFS. More prognostic, multicenter trials are warranted to further explore the effectiveness of chemotherapy in selected DDCS patients.