Re-re-irradiation for palliation: knowns, unknowns, and next steps.

With improving rates of survival among patients with metastatic malignancies, the request for palliative re-irradiation and re-re-irradiation continues to grow despite an absence of standardized guidelines. With only limited data regarding extra-cranial third-course palliative radiation, many radiation oncologists may feel uncomfortable proceeding with third-course irradiation of the same site. The review explores the available modern data regarding re-re-irradiation. A literature review identified four modern peer-reviewed studies investigating palliative, extra-cranial third-course irradiation with external beam radiation. These studies were retrospective, small, and heterogenous. While they reported comparable rates of pain palliation to first course irradiation and low rates of acute toxicity, interpretation is complicated by heterogeneous treatment parameters and insufficient reporting of cumulative dose equivalents and time intervals. With limited data available, it is critical to prioritize patient safety and quality of life in palliative radiotherapy. Patient selection should be meticulous, considering factors such as initial treatment response and predicted life expectancy. Conformal radiation techniques, strict immobilization, and daily image guidance should be employed to minimize toxicity to organs at risk (OARs). Long-term follow-up is essential for identifying and managing late toxicities effectively. Despite the scarcity of data, retrospective series suggest that extra-cranial third course irradiation can provide effective pain palliation comparable to first-course irradiation with tolerable rates of toxicity. However, careful consideration of patient prognosis and adherence to established principles of palliative radiotherapy are essential in decision-making. Further research and long-term follow-up are needed to refine treatment strategies and ensure safe and efficacious care delivery in this complex clinical scenario.

Thirty-day mortality as a metric for palliative radiotherapy in pediatric patients.

PURPOSE OF REVIEW: Thirty-day mortality (30DM) is an emerging consideration for determining whether terminally ill adult patients may benefit from palliative radiotherapy (RT). However, the efficacy and ethics of delivering palliative RT at the end of life (EOL) in children are seldom discussed and not well-established. RECENT FINDINGS: Palliative RT is perhaps underutilized among patients ≤21 years old with rates as low as 11%. While effective when delivered early, clinical benefit decreases when administered within the last 30 days of life. Pediatric 30DM rates vary widely between institutions (0.7-30%), highlighting the need for standardized practices. Accurate prognosis estimation remains challenging and prognostic models specific to palliative pediatric patients are limited. Discordance between provider and patient/parent perceptions of prognosis further complicates decision-making. SUMMARY: RT offers effective symptom control in pediatric patients when administered early. However, delivering RT within the last 30 days of life may provide limited clinical benefit and hinder optimal EOL planning and care. Early referral for palliative RT, preferably with fewer fractions (five or fewer), along with multidisciplinary supportive care, optimizes the likelihood of maintaining patients' quality of life. Prognosis estimation remains difficult, and improving patient and family understanding is crucial. Further research is needed to refine prognostic models and enhance patient-centered care.

Novel Postoperative Hypofractionated Accelerated Radiation Dose-Painting Approach for Soft Tissue Sarcoma.

Purpose: Hypofractionated radiation therapy (RT) offers benefits in the treatment of soft tissue sarcomas (STS), including exploitation of the lower α/ß, patient convenience, and cost. This study evaluates the acute toxicity of a hypofractionated accelerated RT dose-painting (HARD) approach for postoperative treatment of STS. Methods and Materials: This is a retrospective review of 53 consecutive patients with STS who underwent resection followed by postoperative RT. Standard postoperative RT dosing for R0/R1/gross disease with sequential boost (50 Gy + 14/16/20 Gy in 32-35 fractions) were replaced with dose-painting, which adapts dose based on risk of disease burden, to 50.4 and 63, 64.4, 70 Gy in 28 fractions, respectively. The first 10 patients were replanned with a sequential boost RT approach and dosimetric indices were compared. Time-to-event outcomes, including local control, regional control, distant control, and overall survival, were estimated with Kaplan-Meier analysis. Results: Median follow-up was 25.2 months. Most patients had high-grade (59%) STS of the extremity (63%) who underwent resection with either R1 (40%) or close (36%) margins. Four patients experienced grade 3 acute dermatitis which resolved by the 3-month follow-up visit. The 2-year local control, regional control, distant control, and overall survival were 100%, 92%, 68%, and 86%, respectively. Compared with the sequential boost plan, HARD had a significantly lower field size (total V50 Gy; P = .002), bone V50 (P = .031), and maximum skin dose (P = .008). Overall treatment time was decreased by 4 to 7 fractions, which translated to a decrease in estimated average treatment cost of $3056 (range, $2651-$4335; P < .001). Conclusions: In addition to benefits in cost, convenience, and improved biologic effect in STS, HARD regimen offers a safe treatment approach with dosimetric advantages compared with conventional sequential boost, which may translate to improved long-term toxicity.

International case series of metastasis to penis.

Objectives: To evaluate clinical characteristics associated with survival in patients with metastases to the penis. Methods: After approval by the IRB, records of collaborating centres in Leuven, London, Rostock, Amsterdam and Tampa were screened for men presenting with metastatic disease to penis. Multivariate logistic regression analyses were used to identify covariables associated with survival. We analysed clinical data on 34 patients. Results: Primary sites were most frequently prostate (n = 14, 41%) and bladder (n = 9, 26%). Twenty-eight of 34 (82%) presented with metachronous penile metastases, and 11 (32%) patients had penile metastases as the sole metastatic site. Penile metastatic locations were most frequently in the corpora (n = 18; 53%). Seven (21%) patients with penile metastases had priapism on presentation. Systemic therapy was frequent and variable (chemotherapy n = 12; immunotherapy n = 5; hormones n = 3). Local management included either surgery (n = 10) or RT (n = 8). Twelve- and 24-month overall survival rate were 67% and 35%, respectively. No clinical parameter including primary histology, synchronous or metachronous metastases or priapism showed statistical survival benefit or detriment. Conclusion: Metastasis to penis arises most frequently from pelvic primaries. Priapism does not appear to correlate with survival in this large, well-defined series.

Reirradiation of metastases of the central nervous system: part 1-brain metastasis.

Because of improved survival of cancer patients, more patients irradiated for brain metastases develop intracerebral recurrences requiring subsequent courses of radiotherapy. Five studies focused on reirradiation with whole-brain radiation therapy (WBRT) after initial WBRT for brain metastases. Following the second WBRT course, improvement of clinical symptoms was found in 31-68% of patients. Rates of neurotoxicity, such as encephalopathy or cognitive decline, were reported in two studies (1.4% and 32%). In another study, severe or unexpected adverse events were not observed. Survival following the second WBRT course was generally poor, with median survival times of 2.9-4.1 months. The survival prognosis of patients receiving two courses of WBRT can be estimated by a scoring tool considering five prognostic factors. Three studies investigated reirradiation with single-fraction stereotactic radiosurgery (SF-SRS) following primary WBRT. One-year local control rates were 74-91%, and median survival times ranged between 7.8 and 14 months. Rates of radiation necrosis (RN) after reirradiation were 0-6%. Seven studies were considered that investigated re-treatment with SF-SRS or fractionated stereotactic radiation therapy (FSRT) following initial SF-SRS or FSRT. One-year local control rates were 60-88%, and the median survival times ranged between 8.3 and 25 months. During follow-up after reirradiation, rates of overall (asymptomatic or symptomatic) RN ranged between 12.5% and 30.4%. Symptomatic RN occurred in 4.3% to 23.9% of cases (patients or lesions). The risk of RN associated with symptoms and/or requiring surgery or corticosteroids appears lower after reirradiation with FSRT when compared to SF-SRS. Other potential risk factors of RN include the volume of overlap of normal tissue receiving 12 Gy at the first course and 18 Gy at the second course of SF-SRS, maximum doses ≥40 Gy of the first or the second SF-SRS courses, V12 Gy >9 cm3 of the second course, initial treatment with SF-SRS, volume of normal brain receiving 5 Gy during reirradiation with FSRT, and systemic treatment. Cumulative EQD2 ≤100-120 Gy2 to brain, <100 Gy2 to brainstem, and <75 Gy2 to chiasm and optic nerves may be considered safe. Since most studies were retrospective in nature, prospective trials are required to better define safety and efficacy of reirradiation for recurrent or progressive brain metastases.

Reirradiation of metastases of the central nervous system: part 2-metastatic epidural spinal cord compression.

An increasing number of patients irradiated for metastatic epidural spinal cord compression (MESCC) experience an in-field recurrence and require a second course of radiotherapy. Reirradiation can be performed with conventional radiotherapy or highly-conformal techniques such as intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), and stereotactic body radiation therapy (SBRT). When using conventional radiotherapy, a cumulative biologically effective dose (BED) ≤120 calculated with an α/ß value of 2 Gy (Gy2) was not associated with radiation myelopathy in a retrospective study of 124 patients and is considered safe. In that study, conventional reirradiation led to improvements of motor deficits in 36% of patients and stopped further symptomatic progression in another 50% (overall response 86%). In four other studies, overall response rates were 82-89%. In addition to the cumulative BED or equivalent dose in 2 Gy fractions (EQD2), the interval between both radiotherapy courses <6 months and a BED per course ≥102 Gy2 (corresponding to an EQD2 ≥51 Gy2) were identified as risk factors for radiation myelopathy. Without these risk factors, a BED >120 Gy2 may be possible. Scoring tools have been developed that can assist physicians in estimating the risk of radiation myelopathy and selecting the appropriate dose-fractionation regimen of re-treatment. Reirradiation of MESCC may also be performed with highly-conformal radiotherapy. With IMRT or VMAT, rates of pain relief and improvement of neurologic symptoms of 60-93.5% and 42-73%, respectively, were achieved. One-year local control rates ranged between 55% and 88%. Rates of myelopathy or radiculopathy and vertebral compression fractures were 0% and 0-9.3%, respectively. With SBRT, rates of pain relief were 65-86%. Two studies reported improvements in neurologic symptoms of 0% and 82%, respectively. One-year local control rates were 74-83%. Rates of myelopathy or radiculopathy and vertebral compression fractures were 0-4.5% and 4.5-13.8%, respectively. For SBRT, a cumulative maximum EQD2 to thecal sac ≤70 Gy2, a maximum EQD2 of SBRT ≤25 Gy2, a ratio ≤0.5 of thecal sac maximum EQD2 of SBRT to maximum cumulative EQD2, and an interval between both courses ≥5 months were associated with a lower risk of myelopathy. Additional prospective trials are required to better define the options of reirradiation of MESCC.

Novel Definitive Hypofractionated Accelerated Radiation Dose-painting (HARD) for Unresected Soft Tissue Sarcomas.

Purpose: Soft tissue sarcomas (STS) are historically radioresistant, with surgery being an integral component of their treatment. With their low α/ß, STS may be more responsive to hypofractionated radiation therapy (RT), which is often limited by long-term toxicity risk to surrounding normal tissue. An isotoxic approach using a hypofractionated accelerated radiation dose-painting (HARD) regimen allows for dosing based on clinical risk while sparing adjacent organs at risk. Methods and Materials: We retrospectively identified patients from 2019 to 2022 with unresected STS who received HARD with dose-painting to high, intermediate, and low-risk regions of 3.0 Gy, 2.5 Gy, and 2.0 to 2.3 Gy, respectively, in 20 to 22 fractions. Clinical endpoints included local control, locoregional control, progression free survival, overall survival, and toxicity outcomes. Results: Twenty-seven consecutive patients were identified and had a median age of 68 years and tumor size of 7.0 cm (range, 1.2-21.0 cm). Tumors were most often high-grade (70%), stage IV (70%), located in the extremities (59%), and locally recurrent (52%). With a median follow-up of 33.4 months, there was a 3-year locoregional control rate of 100%. The 3-year overall and progression-free survival were 44.9% and 23.3%, respectively. There were 5 (19%) acute and 2 (7%) late grade 3 toxicities, and there were no grade 4 or 5 toxicities at any point. Conclusions: The HARD regimen is a safe method of dose-escalating STS, with durable 3-year locoregional control. This approach is a promising alternative for unresected STS, though further follow-up is required to determine long-term control and toxicity.