Salvage Radiotherapy Research Articles

Impact of Salvage Versus Palliative Dose Bridging Radiation Therapy on Local Control and Overall Survival in Patients with DLBCL Receiving CD19 CAR T Cell Therapy.

In patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), radiation therapy (RT) can be used to "bridge" patients during the period of chimeric antigen receptor T cell (CAR T) manufacturing. Although RT has been shown to improve local control (LC) in patients who receive RT versus do not, it is unknown whether there is an optimal dose. This was a retrospective study of patients with DLBCL who received bridging RT and CAR T cell therapy between 8/2021 and 12/2022 at a single institution (IRB #202103122). Patient, disease, and treatment characteristics were abstracted. PET/CT and laboratory data were collected at various time points. RT data including dose, planning target volume (PTV), and body volume receiving 2Gy and 4 Gy were tested for associations with LC, overall survival (OS), cytokine release syndrome (CRS) and immune effect cell-associated neurotoxicity syndrome (ICANS). Statistical tests were performed using Python libraries. Twenty-two patients with DLBCL were included for analysis. The median patient age was 68 (range 35-82) and the median prior lines of failed therapies was two. All patients had successful apheresis and subsequent CAR T manufacturing. No patients died before CAR T infusion. All patients had a pre-radiation PET/CT scan that showed Deauville 5 disease. Patients with limited stage disease received salvage dose RT (EQD2∼40Gy, n = 8) while patients with advanced disease received palliative dose RT (n = 14). The median PTV volume was 1332 cm3. With a median follow-up of 156 days (IQR 63 - 252 days) from CAR T infusion, 10 patients had died and six progressed at an RT target. A higher salvage RT dose was not associated with LC at the day 30 PET or day 90 PET time points. In a Cox regression model, no independent variable, including RT dose, was significantly associated with LC or OS, but post-RT residual target SUV trended toward an association with OS (HR 6.2, 95% CI 0.9 - 471.0, p = 0.06). Post-RT LDH was associated with CRS grade (ρ = -0.39, p = 0.05). Other non-significant associative trends were noted between CRS grade and post-RT absolute lymphocyte count (ALC) (ρ = - 0.33, p = 0.09) and residual target SUV max (ρ = - 0.37, p = 0.08) and between ICANS grade and pre- to post-RT LDH change (ρ = -0.38, p = 0.06) and post-RT lymphocyte count (ρ = 0.36, p = 0.07). In an exploratory analysis of body volume receiving integral doses of 4Gy or 2Gy and pre- and post-RT ALC change, it appeared that higher integral dose did lead to larger decreases in ALC (ρ = -0.32, p = 0.15 and ρ = -0.3, p = 0.18, respectively). In this small series of patients with r/r DLBCL treated with bridging RT prior to CAR T therapy, RT dose was not associated with LC. However, higher post-RT target residual SUV was associated with worse OS. The impact of post-RT LDH on CRS and ICANS grades should be explored further.

Gastrointestinal Toxicity Following Proton and Photon Radiation for Prostate Cancer in Patients with Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) has been considered a relative contraindication for radiation for prostate cancer (PC) due to concern for gastrointestinal (GI) toxicity. Modern radiation planning techniques such as intensity modulated radiation therapy (IMRT) have resulted in a significant decrease in GI toxicity in the general PC population. Several published case series have suggested overall excellent outcomes using IMRT in PC patients with IBD. Proton therapy (PT) with improved dosimetric sparing of bowel and rectum may offer additional benefit, but to our knowledge, there is no published data assessing outcomes after PT in PC patients with IBD. We report our institutional experience treating PC patients with IBD with both PT and IMRT. We identified patients with an IBD diagnosis treated for PC at our institution from 2012-2022 with either IMRT or PT. Baseline clinical characteristics were captured, along with radiation parameters, including dose, fractionation, inclusion of pelvic nodes, and use of a rectal spacer. IBD specifics captured included type of IBD, use of IBD medication, and pre radiation colonoscopy findings when available. Early and late GI toxicities were captured via retrospective chart review and graded per the Common Terminology Criteria for Adverse Events (CTCAE) version 5. Eighteen patients with IBD were treated with RT for PC at our institution, including 10 with ulcerative colitis, 7 with Crohn's disease, and 1 with IBD NOS. Nine of these patients were treated with PT and 9 with IMRT. Most were treated with conventional fractionation (n = 14) and the rest with moderate hypofractionation. Fourteen received primary RT to an intact prostate, and the rest received salvage RT. In four patients, the pelvic nodes were also treated. Rectal spacers were used for 8 patients. Nine of the patients were on IBD medications, and of the 15 patients with records of pre-RT colonoscopy, only 1 demonstrated inflammatory findings, which were noted in the ileum. Median follow-up was 3.5 years (1-6) Acute grade (Gr)1 GI toxicity was seen in 6(33%) patients with diarrhea and proctitis. No patients developed acute Gr 2 GI toxicity, and 1 patient developed acute Gr 3 diarrhea and proctitis. This patient had asymptomatic Crohn's disease prior to IMRT, not on medication, and was treated to the prostate and pelvic nodes. Late Gr 1 GI toxicity was seen in 4 (22%) patients. Median time to late GI toxicity was 9.5 months. No patients developed late Gr 2 or higher GI toxicity. Modern radiation techniques including IMRT and PT are well tolerated in PC patients with well-controlled IBD. Larger studies with longer follow up would be helpful to further characterize these patients' outcomes. In the meantime, IMRT and PT should be considered as treatment options in patients with well-controlled IBD.

A Systematic Review and Network Meta-Analysis Assessing the Impact of Adding First Generation Non-Steroidal Anti-Androgens (NSAA) to LHRH Agonists (LHRHa) in Men Receiving Radiotherapy for Localized Prostate Cancer.

Randomized clinical trials consistently demonstrate that the addition of androgen deprivation therapy (ADT) to prostate radiation therapy improves overall survival (OS). However, there is substantial heterogeneity regarding the type of ADT: LHRHa alone, first generation NSAA alone (e.g., bicalutamide) or combination androgen blockade (CAB) with NSAA and LHRHa. There are no published randomized trials in localized disease that specifically compare the efficacy of NSAA to LHRHa, nor the utility of CAB over monotherapy ADT. We herein performed a systematic review and network meta-analysis to assess the impact of NSAA in relation to LHRHa in men receiving radiotherapy for localized prostate cancer. We performed a systematic literature search in PubMed to identify clinical trials of patients with localized prostate cancer for which ADT duration was the primary randomization variable. Both definitive and salvage radiation trials were included. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated from data extracted from published survival curves. A network meta-analysis was performed to compare OS by ADT regimens. We defined NSAA toxicity as early discontinuation of any ADT agent due to side effects given the inconsistent reporting of specific related toxicity. A meta-regression was performed to assess association with NSAA toxicity, adjusted for study year, patient age, T stage, Gleason score and total ADT duration. NSAA duration was assessed as a continuous variable. Of the 11 trials (8,169 patients) with OS data, the median duration of any ADT was 3 months (range 0-36 months) and the median duration of NSAA specifically was 3.5 months (range 0-24 months). There was no significant difference in OS between those treated with LHRHa (n = 369) vs. CAB (n = 4,792; HR 1.10, 95% CI 0.78-1.55). Among those receiving CAB, increased NSAA duration did not improve OS (versus 0 months; 1-6 months HR 1.41, 95% CI 0.94-2.13; 7-12 months HR 1.43, 95% CI 0.87-2.34) when controlling for total ADT duration. Of the 19 trials (15,067 patients) with toxicity data, patients on NSAA (n = 503) appeared more likely to discontinue treatment early compared to those receiving LHRHa (n = 902), though this was not statistically significant (odds ratio [OR] 4.20, 95% CI 0.16-109.19). A longer duration of NSAA did not adversely affect ADT compliance. Patients were more likely to discontinue ADT prematurely, regardless of type, if the planned duration was longer (OR 1.08, 95% CI 1.07-1.09). We did not detect an overall survival benefit to adding NSAA to LHRHa, and NSAA appeared less well tolerated than LHRHa in men receiving radiation therapy for localized prostate cancer. These data suggest that providers should consider LHRHa without the addition of a NSAA as optimal when clinically appropriate.

Radiation therapy as a bridging and salvage strategy in patients with relapsed or refractory multiple myeloma undergoing BCMA-targeted CAR T-cell therapy

Radiation therapy (RT) may play an important role prior to and following BCMA-targeted CAR T-cell therapy in multiple myeloma (MM). We report a series of 13 patients: 5 patients received bridging RT pre-CAR T, 4 patients received salvage RT post-CAR T failure, and 4 patients received both. There was no worsening of CAR-T- or RT-related toxicities. The RT in-field local control rate was 100%, with a median follow-up after each RT course of 7.3 months. RT as a bridging and salvage strategy is safe, feasible, and offers excellent local control in MM patients treated with CAR T-cell therapy.

Disease and Toxicity Outcomes after Salvage Radiotherapy (SRT) for Biochemically Recurrent Prostate Cancer (PC) for Patients Enrolled in a Phase II, Open Label Trial Investigating Neoadjuvant Chemohormonal Therapy Followed by Radical Prostatectomy (RP)

Men with metastatic hormone sensitive prostate cancer have improved progression free and overall survival (PFS/OS) when treated with docetaxel and androgen deprivation therapy (ADT). Our institution conducted a phase II trial (UW17009) investigating the addition of three cycles of neoadjuvant docetaxel and ADT to RP in men with high-risk prostate cancer. Here we report toxicity and freedom from biochemical recurrence (FFBCR) for patients treated with SRT following participation in this trial. Between January 17, 2018 and August 10, 2021, 28 patients enrolled on UW17009. Patients who had a recurrence and received SRT were identified. Toxicity was assessed using modified LENT (Late Effects of Normal Tissues)/RTOG (Radiation Therapy Oncology Group) criteria, and time to recurrence following SRT was determined for each patient. Additionally, the months of ADT received by each patient was recorded. FFBCR was then determined for this cohort using the method of Kaplan and Meier. Of 28 patients enrolled on UW17009, 20 (71%) had BCR after RP. Of these, 19 received SRT, representing 68% of the patients enrolled on the trial. The rates of acute grade 1 and grade 2 GU toxicity with SRT were 37% (7) and 53% (10), respectively. The rates of acute grade 1 and grade 2 GI toxicity with SRT were 32% (6) and 37% (7), respectively. On patient experienced a grade 4 genitourinary toxicity during SRT. There were no acute grade 3 or grade 5 toxicities. The rates of late grade 1 and grade 2 GU toxicity were 16% (3) and 11% (2), respectively. The rates of late grade 1 and grade 2 GI toxicity were 11% (2) and 5% (1), respectively. There was 1 (5%) late grade 3 GU toxicity. There were no late grade 3-5 GI toxicities, or late grade 4-5 GU toxicities. The average duration of ADT after prostatectomy was 15 months (range: 0-37 months). According to the method of Kaplan and Meier, mean FFBCR after SRT was 34.0 months at a median of 37.8 months. Median FFBCR had not yet been reached. At the time of analysis, 13 patients remained free from biochemical recurrence after SRT. Rates of biochemical recurrence and SRT following neoadjuvant docetaxel and ADT and then RP were consistent with historical data, as was the rate of successful SRT. Toxicities were also consistent with historical data, though there was notably one acute grade 4 GU toxicity.

Conditional Prostate Cancer-Specific Survival Probabilities in Recurrent Prostate Cancer Patients Receiving Radiation ± Antiandrogen Therapy: Secondary Analysis of a Randomized Clinical Trial

Salvage radiation therapy (SRT) and androgen-deprivation therapy (ADT) are routinely used in patients with elevated prostate-specific antigen (PSA) levels after radical prostatectomy (RP) for prostate cancer (PCa). Although prostate cancer-specific survival (PCSS) following SRT is useful when counseling patients at the time of treatment, the utility of this data from time of diagnosis diminishes over time. Conditional survival (CS) can provide more relevant estimates, especially given long-term PCa survivorship. The primary aim of this study was to analyze CS estimates for recurrent PCa patients undergoing SRT ± ADT. The secondary objective was to determine if factors prognostic of PCSS at diagnosis remain relevant in survivorship. We analyzed data from 760 post-RP patients enrolled in NRG/RTOG 9601 (1998-2003). Eligible patients included men who had undergone prior RP and had pT2/T3 disease without nodal involvement and detectable PSA levels of 0.2-4.0 ng/mL. Patients were randomly assigned to undergo SRT and receive either 24 mo of ADT or placebo. OS was calculated (Kaplan-Meier), cumulative incidence was used to estimate PCSS rates, and prognostic factors associated with PCSS were analyzed by multivariable Cox proportional hazards modeling (MVA). Patients were followed for a median of 13 y. The 5- and 10-y PCSS estimates from diagnosis were 98.52% and 92.7%, respectively. At 1- (n = 755), 3- (n = 727), 5- (n = 680), and 8-y (n = 602) survivorship, chances of PCSS at an additional 5-y were 97.41%, 95.29%, 93.76%, and 91.04%, respectively. On MVA at diagnosis, omission of ADT (HR 2.156, P = 0.0003), increasing age (HR 1.833, P = 0.03), Gleason score (GS) 7 (HR 2.356, P = 0.0057), and GS 8-10 (HR 4.841, P < 0.0001) were associated with PCa-specific mortality. For those who achieved survivorship at 1-, 3-, 5-, and 8-y, all variables remained prognostic of PCa-specific mortality on MVA. Conditional risk of death from PCa for patients treated with SRT increases over time. The initial risk of dying from PCa over a given period, however, is higher than if already having survived a portion of that period. ADT, younger age, and lower GS continue to confer a reduced risk of PCa-specific mortality for long-term survivors. This data can be used to inform survivorship care planning, giving patients more relevant prognostic information during continued surveillance after completion of treatment.

Radiotherapy for Postoperative Vaginal Recurrences of Cervical Cancer Patients: Analysis of Recurrent Causes and Prognosis

Vagina is the most common site of cervical cancer recurrence, and salvage radiotherapy (RT) is recommended owing to its effectiveness and tolerable adverse events. Several studies have focused on prognostic factors of RT treatment for postoperative recurrent cervical cancer patients. However, few researches identified different recurrent causes as a prognostic factor and studied the relationship between recurrent causes and survival. The aim of this study was to identify the recurrent causes affecting prognosis of vaginal recurrent patients treated with salvage RT. One hundred and twenty-six female patients with vaginal recurrent cervical cancer, treated with salvage RT between July 2011 and January 2020, were reviewed in this study. Among these patients, a combination of EBRT and BRT was delivered to 94 patients, EBRT alone was delivered to 20 patients. Causes of recurrence were distributed into five groups: (1) selection of surgical indication (n = 15): included ①surgery beyond indication (n = 8) and ②neoadjuvant therapy (n = 7);(2) Positive surgical margin (n = 18); (3) nonstandard RT (n = 20): include ④no RT, despite indications of postoperative RT (n = 15), and ⑤insufficient postoperative RT dose (n = 5); (4) with risk factors but no indication for RT according to the Sedlis criteria (n = 29): include ⑥non-squamous carcinoma (n = 7) and ⑦only one intermediate risk factor in Sedlis criteria (n = 22); (5) HPV infection (n = 44). Log-rank tests and Cox proportional hazards regression methods were used to identify prognostic factors. The median follow-up time of the 126 cervical cancer patients was 39.1 months with estimated 5-year OS, PFS and LC rates of 79%, 75% and 86%, respectively. In multivariate analysis, recurrence pattern (including endovaginal recurrence, paravaginal recurrence, invasion of surrounding organs and distant metastasis, p < 0.05) and causes of recurrence were independent prognostic factors for OS. Recurrence because of "(1) the selection of surgical indication" (p < 0.05) was associated with poor OS, while recurrence because of "(2) positive surgical margin" was associated with prolonged OS. Multivariate analysis also revealed that recurrence pattern, causes of recurrence (p < 0.05) and re-irradiation were independently factors for PFS. Majority of patients with recurrence causes of HPV infection (79.5%) and positive surgical margin (77.8%) experienced endovaginal recurrence. Patients with recurrence cause of selection of surgical indication had the highest proportion (26.7%) of recurrence with invasion of surrounding organs, and 53.3% experienced re-irradiation. The results this research suggest that salvage RT is an effective treatment for vaginal recurrences in postoperative patients with cervical cancer. Causes of recurrence was an independently factor for OS and PFS, and recurrence caused by selection of surgical indication was associated poor survival.

Adjuvant Radiotherapy in Atypical Meningioma: Are the Risks Worth the Benefit?

Adjuvant radiotherapy (RT) improves progression-free survival (PFS) in atypical meningiomas. Herein, we assess whether the treatment-related acute and long-term toxicity of upfront RT in atypical meningioma patients versus surveillance merits the PFS benefit. In our prior single institution retrospective study of 230 patients with resected intracranial atypical meningiomas between 2000-2015, adjuvant RT was associated with a significantly lower risk of progression/recurrence compared to surveillance (HR = 0.21 [95% CI 0.11-0.41]; p<0.01), with 36% of surveillance patients eventually requiring salvage RT. In the current study, the acute (≤6 months) and long term (>6 months) RT-related toxicities from the same patient cohort for those who received adjuvant RT (n = 51) were evaluated and compared to those who received salvage RT (n = 64) in the surveillance group. Additionally, overall treatment-related toxicity at time of last follow up was obtained for comparison between the adjuvant RT (n = 51) vs surveillance (n = 179) group. All toxicities were graded per CTCAE v5.0. Kaplan-Meier analysis was used to calculate the cumulative incidence of toxicities; Pearson's chi-squared and log-rank test were used for comparison. Adjuvant RT as compared to salvage RT was generally associated with greater RT-related toxicities both in the acute (90% vs 69%, p = 0.006) and long term (57% vs 33%, p = 0.010). While there was no significant difference in grade 3-4 acute toxicities, long term grade 3-4 toxicities (including headache, seizure, vision loss, neuromotor deficit, and neurocognitive deficit) were present in 14% of adjuvant vs 3% of salvage RT group (p = 0.035). Radionecrosis occurred in 18% of adjuvant RT vs 8% of salvage RT group (p = 0.11). Between adjuvant RT vs surveillance groups, any-treatment related toxicity at last follow up was greater with adjuvant RT (31% vs 15%; p = 0.006), with trend towards greater grade 3-4 toxicities (including headache, vision loss, neuromotor deficit, neurocognitive deficit, and cerebral edema) as well (8% vs 3%; p = 0.101). Cumulative incidence of treatment-related neuromotor deficit (any grade) was significantly greater in the adjuvant RT vs surveillance group with 14% vs 2% at 10 years (p = 0.004). There was no difference in rate of cerebrovascular accident between adjuvant RT (6%) vs surveillance (4%) groups (p = 0.83). Adjuvant RT for patients with atypical meningioma was associated with greater acute and long-term treatment toxicities. Potential RT-related toxicity and impact on quality-of-life should thus be carefully weighed against the tumor control benefit of RT in deciding the optimal use and timing of RT.

Impact of Testosterone Recovery on Clinical Outcomes of Patients Treated with Salvage Radiotherapy and Androgen Suppression: A Secondary Analysis of the NRG/RTOG 0534 Sport Phase 3 Trial

Testosterone (T) kinetics and its relationship with clinical outcomes has not been studied in trials using salvage radiotherapy and androgen deprivation therapy (ADT). We performed a secondary analysis of the NRG Oncology/RTOG 0534 SPPORT trial, which compared prostate bed radiotherapy (PBRT) (arm 1), PBRT + short-term androgen deprivation therapy (ADT) (arm 2), or PBRT + pelvic lymph node radiotherapy (PLNRT) + short-term ADT (arm 3). We assessed longitudinal serum T levels and the impact of testosterone recovery (TR) on clinical outcomes. ADT was given for 4-6 months in arms 2 and 3, starting 2 months prior to radiotherapy. The trial excluded patients with baseline T < 40% of the lower limit of normal. TR was defined in 3 ways: 1) return to non-castrate level (>50 ng/dL), 2) return to normal level (>300 ng/dL), and 3) return to baseline level. Time to TR was estimated using cumulative incidence and death without an event considered a competing risk. Unadjusted and adjusted hazard ratios and 95% confidence intervals (CIs) were calculated using Cox proportional hazards model. Freedom from progression (FFP) was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. A total of 1699 patients with T at baseline and at least 1 follow-up assessment were included. The median age was 64 years (IQR 59 - 69), 12.8% were black, 14.9% had diabetes, and 54.1% were former or current smokers. Median baseline T in arms 1, 2 and 3 was 320 ng/dL (IQR 239 - 424), 319 ng/dL (IQR 237 - 438) and 330 ng/dL (IQR 252 - 446), respectively. At 6 months, median T in arms 1, 2 and 3 was 290 ng/dL (IQR 210 - 390), 190.4 ng/dL (IQR 66 - 296) and 191 ng/dL (IQR 40.5 - 313). At 2 years, in arms 2 and 3, TR to non-castrate, normal and baseline levels were 95%, 55% and 23%, respectively. At 5 years, in arms 2 and 3, TR to non-castrate, normal and baseline levels were 98%, 73% and 42%, respectively. FFP was superior in arms 2 and 3 vs. arm 1 in patients with TR by all three definitions. In patients with recovered T to normal levels by 2 years (n = 904), the 5-year FFP rates were 71.8% (95% CI 66.9-76.6) in arm 1, 77.2% (72.1-82.2) in arm 2, and 86.3% (82.3-90.3) in arm 3 (arm 2 vs arm 1: HR 0.74, 95% CI 0.56-0.98, p = 0.034; arm 3 vs arm 1: HR 0.54, 95% CI 0.40-0.72, p<.0001). This work represents the largest study of T kinetics in patients treated with salvage radiation and ADT. Approximately half of patients did not normalize their T levels by 2 years. Our data validate an incremental and meaningful FFP benefit of adding short-term ADT and PLNRT to PBRT independent of T recovery.

Salvage Radiotherapy Improves Survival in Patients with Metastatic Liver Cancer after Immunotherapy Oligoprogression

Immune checkpoint inhibitors (ICIs) have ameliorated the survival outcome of liver cancer, a majority of patients receiving ICIs have eventually developed progression. Local therapy, especially radiotherapy (RT), is increasingly being considered in the setting of oligoprogression to delay the need to change systemic therapy. The aim of this study was to evaluate the efficacy and safety of RT as a salvage treatment in patients with oligoprogression after ICIs. This retrospective study was performed to evaluate the use of salvage radiotherapy in oligoprogressive metastatic liver cancer patients. Patients with metastatic liver cancer who had previous stability or response after ≥ 6 mo of ICIs were eligible if they developed progression of five of fewer metastases. Overall, 178 patients treated between August 2018 and March 2022 were included. The patients were followed for a median of 17.2 months. The overall response rate (ORR) and disease control rate (DCR) were 38.2% and 57.8%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 6.5 (95% CI:5.116-7.884) and 17.3 (95% CI:11.166-23.434) months. In multivariate analysis, factors associated with OS included tumor size, tumor number, and radiated tumor site (intrahepatic vs. extrahepatic). The most frequent AEs were fatigue, decreased appetite, rash, fever, and nausea. The above-mentioned AEs were reversible and manageable. Salvage radiotherapy has a potential activity and is tolerable for oligoprogression after ICIs with appropriate radiated tumor site and patient selection. A prospective randomized trial is ongoing to validate this finding (ChiCTR2200060664).

Definitive and Salvage Radiotherapy Compared to Other Modalities for Laryngeal Carcinoma in Situ

We sought to analyze survival endpoints for laryngeal carcinoma in situ (CIS) undergoing definitive radiotherapy (RT) compared to other modalities. Usingour prospectively maintained head and neck cancer database, we identified laryngeal CIS patients treated between 6/2001 and 12/2021. We excluded low-grade dysplasia, CIS with any synchronous invasive squamous cell carcinoma (SCC) within 3 months of the initial CIS biopsy and cases with inadequate follow up. Patients were offered either definitive RT, CO2/KTP laser ablation, photodynamic therapy (PDT) or any sort of therapeutic excision. After first line treatment, follow-up includes visits every 3-6 months with laryngoscopy and biopsies as appropriate. For recurrent CIS beyond 6 months of first line treatment, we reported salvage therapies received and long-term outcomes were reported. Using Kaplan-Meier curves and log-rank test we investigated recurrence free (RFS), progression to invasive SCC free (IFS) and overall (OS) survival across treatment groups. Patients managed with salvage RT were compared to first line RT recipients. Atotal of 85 CIS cases were included: median age 65 years (IQR: 55-74), 73 males (85%) and 70 white (82.4%). 86% had a history of smoking with median pack year of 38 (IQR: 20-55) and 66% had a history of alcohol use. CIS was glottic in most of the cases (90.6%: 66% unilateral, 21% bilateral & 13% involved commissure); with only 9.4% in the supraglottic region. RT was used in 49.4% (n = 42) after biopsy (55%) or surgery (45%) with median dose of 63 Gy/28 fractions, mainly by 3D conformal RT (76%). The remaining 50.6% (n = 43) got therapeutic excision alone (commonly microflap excision) (46.5%), CO2/KTP laser (32.6%) or PDT (20.9%). Demographics and clinicopathological details were non-different between RT and non-RT patients except for Charlson comorbidity index: median 2 (IQR 1-3) in non-RT vs 1 (IQR 0-2) in 1ry RT; p = 0.007. After a median follow-up of 4.8 years (IQR 3.5), 51.8% had recurrent disease, 21.2% progressed to invasive SCC and 9.4% had laryngectomies mainly for invasive SCC after RT. First line RT had improved 2-(83% vs 39%) and 5-(74% vs 22%) year RFS vs non-RT therapies (p<0.001). Nevertheless, 2- and 5-year IFS (89% vs 98% and 80% vs 79%) and OS (92% vs 93% and 81% vs 77%) were non-significant among both (p>0.05 for all). Among non-RT cases with CIS recurrences, 12/35 (34%) had salvage RT. Following RT, salvage RT patients had similar 2- and 5-year RFS (81% vs 83% and 81% vs 74%) and IFS (81% vs 89% and 81% vs 80%) compared to first line RT (p>0.05 for all). All cases with CIS recurrences were salvaged successfully with 100% living with no CIS at latest follow-up. Laryngeal CIS can be treated with a wide range of modalities including 1ry RT which has better recurrence free survival. Nevertheless, non-RT recurrent CIS can be salvaged successfully with many options including RT with equivalent long-term results.

CNS Control after First-Line Osimertinib in Patients with Metastatic EGFR-Mutant NSCLC

Although osimertinib (osi) has excellent intracranial activity in EGFR-mutant metastatic non-small cell lung cancer (NSCLC), there is no consensus regarding whether to continue osi for central nervous system (CNS) control with second-line chemotherapy (chemo) at the time of systemic progression. We aimed to compare CNS outcomes after first-line osi in patients receiving second-line chemo with or without continuation of osi. We retrospectively reviewed patients with EGFR-mutant NSCLC with brain metastases (BrM) at the time of initiating first-line osi who experienced progression and started second-line chemo. Cumulative incidence of local and distant CNS progression, and extracranial (EC) progression was calculated from time of second-line chemo initiation with death as a competing risk. Overall survival (OS) was analyzed using Kaplan-Meier. We included 52 patients with a median follow up of 9.6 months (range 0.4-36.4). Median OS and CNS progression-free survival (PFS) from the time of starting second-line chemo was 12.5 months (95% CI 8.1-16.9), and 5.3 months (95% CI 3.35-7.26), respectively. The 1-year cumulative incidence of local, distant CNS progression, any CNS progression, and EC progression was 14.4% (95% CI 4.5-24.2), 42.8% (95% CI 22.8-56.8), 42.8% (95% CI 22.8-56.8) and 66.8% (95% CI 53.5-80.2), respectively. After progression on first-line osi, 25 (48.1%) and 27 patients (51.9%) continued and discontinued osi, respectively. Patients who continued osi had significantly higher BrM burden than those who did not, with 17 (68%), 3 (12%), and 5 (20%) versus 26 (96%), 0, and 1 (3.7%) patient having <10 or >11 parenchymal brain lesions, or leptomeningeal disease (LMD) at the time of second line therapy, respectively (p<0.01). In those who continued osi vs those who did not, median OS (10.8 vs 12.5 months; p = 0.37), median intracranial PFS (5.3 vs 4.8 months; p = 0.99), 1-year cumulative incidence of local (8.4% versus 20 % p = 0.26), and 1-year distant CNS progression (24.8% vs 60%; p = 0.08) was not significantly different. CNS complications such as symptomatic, hospitalizations, and steroid initiation for CNS disease, and progression of LMD were not significantly different between the two groups. Eventually, 10 patients underwent salvage RT post first-line osi and median time to salvage RT was 7.8 months (range 2-9.4). Of patients who underwent salvage RT, 2 patients (20%) had continued osi with second-line chemo. Twelve patients (44.4%) who did not continue osi eventually re-started osi for progressive disease. Patients who continued osi had significantly higher BrM tumor burden. Despite these patients being at higher risk for CNS progression, time to CNS progression and incidence of CNS complications were not significantly different in the two cohorts. Patients who discontinued osi were more likely to undergo salvage RT. Continuation of osi may allow patients to defer salvage RT.

FORMULA-509: A Multicenter Randomized Trial of Post-Operative Salvage Radiotherapy (SRT) and 6 Months of GnRH Agonist with Either Bicalutamide or Abiraterone Acetate/Prednisone (AAP) and Apalutamide (Apa) Post-Radical Prostatectomy (RP)

FORMULA-509 was designed to evaluate whether adding six months of AAP and Apa to a GnRH Agonist could improve outcomes compared to six months of bicalutamide plus GnRH Agonist for patients with unfavorable features receiving SRT for a detectable PSA post-RP. FORMULA-509 is an investigator-initiated, multi-center, open-label, randomized trial. Patients had PSA ≥0.1 post-RP and one or more unfavorable features (Gleason 8-10, PSA >0.5, pT3/T4, pN1 or radiographic N1, PSA doubling time <10 months, negative margins, persistent PSA, gross local/regional disease, or Decipher High Risk). All patients received SRT plus 6 months of GnRH agonist and randomization was to concurrent bicalutamide 50 mg or AAP 1000 mg/5 mg + Apa 240 mg QD. Radiation to pelvic nodes was required for pN1 and optional for pN0. The primary endpoint was PSA progression-free survival (PFS) and secondary endpoint was metastasis-free survival (MFS) determined by conventional imaging. The study was powered to detect a HR of 0.50 for PFS and a HR of 0.30 for MFS, each with 80% power and one-sided type I error of 0.05. Stratification was by PSA at study entry (>0.5 vs.≤0.5) and pN0 vs pN1. Analyses within these subgroups were pre-planned and utilized two-sided p-values. Three hundred forty-five participants (332 evaluable) from 9 sites were randomized from 11/24/2017 to 3/25/2020 (172 bicalutamide, 173 AAP/Apa). Median follow-up was 34 (6-53) months; 29% were pN1 and 31% had PSA >0.5 ng/mL. The HR for PFS was 0.71 (90% CI 0.49-1.03), stratified one-sided log-rank p = 0.06 (3-year PFS was 68.5% bicalutamide vs 74.9% AAP/Apa). The HR for MFS was 0.57 (90% CI 0.33-1.01), stratified one-sided log rank p = 0.05 (3-year MFS was 87.2% bicalutamide vs 90.6% AAP/Apa). In a pre-planned analysis by stratification factors, AAP/Apa was significantly superior for patients with PSA >0.5 for PFS [HR 0.50, (95% CI 0.27-0.95), p = 0.03 (2-sided); 3-year PFS 46.8% bicalutamide vs. 67.2% AAP/Apa] and for MFS [HR 0.32 (95% CI 0.13-0.84), p = 0.02 (2-sided); 3-year MFS 66.1% bicalutamide vs. 84.3% AAP/Apa.] No statistically significant benefit was detected in pre-planned analyses of stratification subgroups defined by PSA≤0.5, pN0, or pN1. Adverse events were consistent with the known safety profiles of the agents being studied, with more rash and hypertension in the AAP/Apa arm. Although this primary analysis did not meet the pre-specified threshold for statistical significance, it does strongly suggest that the addition of AAP/Apa instead of bicalutamide to SRT+6 months of GnRH Agonist may improve PFS and MFS, particularly in the subgroup of patients with PSA>0.5 where a pre-planned subgroup analysis by stratification factors observed a statistically significant benefit for both PFS and MFS. (NCT03141671).

Association between Radiation Dose and Local Failure in Recurrent High-Risk Neuroblastoma

Historically, standard-of-care (SoC) for high-risk neuroblastoma recurrences is irradiation to 2160 cGy for gross or microscopic disease. Boosting gross disease to 3000-3600 cGy remains controversial. Prior reports have demonstrated worse local control with gross disease irradiated to <3000 cGy. We sought to evaluate whether higher radiation doses delivered to sites of recurrence affected local control. We identified seventy-five high-risk neuroblastoma patients aged 6 months to 26 years that completed definitive treatment between 2007 and 2021 at two large academic centers. Only patients with distant recurrences treated with radiotherapy were included for analysis. Treatments were stratified into 1800-2160 cGy or 3000-3600 cGy dose levels. Local failure after irradiation was defined as progression within the radiation field after salvage RT. The Fine-Gray competing risk model was used to identify cumulative incidence of local failure (CILF) after irradiation with competing risk of death. Thirteen patients experienced recurrence after completion of definitive treatment, representing 30 metastatic lesions. Thirteen lesions received 1800-2160 cGy and seventeen received 3000-3600 cGy. With a median follow-up of 42.0 months (IQR 30.8-60.8), local failure after irradiation occurred in 10% (3/30) of metastatic lesions. Median time to failure was 7 months. All three failures had been treated to 2160 cGy; two in the calvarium and one in the femur. There were no local failures among patients treated to 3000-3600 cGy. The 1-year and 2-year CILF for the low- versus high-dose levels were 15% versus 0% (p<0.01) and 25% versus 0% (p<0.01), respectively. Four of the 13 patients (31%) died at a median time of 12.5 months after first recurrence; all four had distant recurrences. Dose-escalated irradiation ≥3000 cGy was associated with improved local control in recurrent high-risk neuroblastoma; prospective study and validation is warranted.

DCE-MRI-Based Atlas for Prostate Bed Recurrence after Radical Prostatectomy: Consistency of CTV Delineation with the Available Contouring Guidelines

To create a magnetic resonance image (MRI)-based atlas of prostate bed recurrence for prostate cancer patients undergoing salvage radiotherapy (sRT) after radical prostatectomy and to evaluate the consistency of contouring guidelines for the prostatic fossa clinical target volume (PF-CTV) delineation. Patients with biochemical recurrence and prostate bed lesions at MRI before sRT were included. A reference patient was identified and the lesion(s) of each patient was mapped by a deformable co-registration among T2 weighted (T2w) images. The structure sets were combined to create a 3D recurrence incidence map, overlapped on T2w reference set, then transferred to the planning CT. The volume and the location of the lesions were extracted. On the reference CT, 5 PF-CTV contouring strategies were implemented: Radiation Therapy Oncology Group (RTOG); European Organization for Research and Treatment of Cancer (EORTC); Francophone Group of Urological Radiotherapy (GFRU); Faculty of Radiation Oncology Genito-urinary Group (FROGG) and Princess Margaret Hospital (PMH). Coverage was assessed after identifying the centroid of each lesion: if the centroid was included in the PF-CTV, the coverage was considered complete (fully covered-FC), otherwise uncovered (UC). The coverage was evaluated for each contouring strategy and compared with the chi-squared test; the strength of the correlation was assessed with the phi coefficient. A total of 112 patients with 124 recurrences were identified. The lesions were located at the vesicourethral anastomosis (VUA), around the bladder neck (BN) and beyond the bladder (RV) in 63, 36 and 25 cases. Regardless the contouring strategy, 89.1% of the lesions were FC. Coverage was higher (p<0.001) for BN (95.6%) over RV (83.2%) and VUA (73.7%) lesions. FC/UC rates were 66.1%/33.9%, 83.9%/16.1%, 89.5%/10.5%, 83.1%/16.9%, 87.1%/12.9% for EORTC, FROGG, GFRU, RTOG and PMH, respectively. At pair-wise comparison, the EORTC definition had lower coverage (p<0.001) and was poorly correlated to the other strategies (phi values ranging 0.385-0.540, p <0.001). Conversely, the correlations between the other definitions were >0.700, the highest between PMH-FROG (0.812, p<0.001). After selecting VUA lesions only (N = 63), the probability of FC was 60.3%, 74.6%, 82.5%, 71.4% and 79.4% for EORTC, FROGG, GFRU, RTOG and PMH, respectively. The EORTC definition performed poorly than GFRU (p = 0.006) and PMH (p = 0.020). When considering lesions above the VUA (N = 61), the performance improved (FC: 72.1%, 93.4%, 96.7%, 95.1% and 95.1% for EORTC, FROGG, GFRU, RTOG and PMH, respectively) but the EORTC was significantly less covering and its correlation with the others was ≤ 0.1. According to the criterium of coverage our data do not support the use of the EORTC definition. Here we provide an MRI-based atlas of prostatic bed recurrence that can optimize sRT contours.

Mapping the Anatomical Distribution of MRI-Identified Locoregional Recurrence following Robotic-Assisted Laparoscopic Prostatectomy for Prostate Adenocarcinoma

The pattern of locoregional recurrence specifically after robotic-assisted laparoscopic prostatectomy (RALP) for prostate adenocarcinoma is still unknown. In this study, we reviewed pelvic magnetic resonance images (MRI) after postoperative biochemical recurrence (BCR) and drew a map of locoregional recurrence to support evidence of determining the optimal target volume of salvage radiotherapy in a post-RALP BCR scenario. We have retrospectively searched 7,583 prostate adenocarcinoma patients who have received RALP in our institution between January 2010 and December 2021, and found a pool of highly selected patients with gross tumor recurrence confirmed by post-BCR pelvic MRIs and did not have other histories of malignancy. BCR was defined as the serum PSA more or equal to 0.2 ng/mL, or three consecutive increases. Patients with serum PSA nadir more or equal to 0.2 ng/mL on the 90th postoperative day (POD 90) were excluded to guarantee successful tumor removal. We have reviewed serum PSA levels using R codes, MRI and pathological reports using Excel, and descriptive statistics using SPSS 25. The gross lesions were contoured on the correlating MRIs using MIM Maestro 7.1. The RT structure DICOM files were merged into a map using MATLAB 2022b. In addition, we have conducted Fisher exacted test, Mann-Whitney U test, and logistic regression to identify risk factors for regional recurrence. A total of 173 patients were identified with locoregional recurrence from post-BCR pelvic MRIs, and 139 (80.3%) patients were in the high-risk group or very-high-risk group according to the NCCN guidelines: 57 (32.9%) patients with histological grade group 5, 50 (28.9%) patients with initial PSA over 20 ng/mL, 114 (65.9%) patients with extracapsular extension, 55 (31.8%) patients with seminal vesicle invasion, and 15 (9%) patients with pN1. The median follow-up was 4.7 (IQR 2.8-6.9) years for pelvic MRIs and 5.8 (IQR 4.0-8.6) years for serum PSA. The BCF survival was median of 10.7 (IQR 4.6-19.1) months, and the locoregional recurrence-free survival was median of 24.6 (IQR 9.7-49.4) months for this subgroup of patients. At first locoregional recurrence, 148 (85.5%) patients were local only, 20 (11.6%) patients were regional only, and 5 (2.9%) patients were both local and regional. Out of the 25 patients with regional recurrence, the incidence of gross tumor recurrence differed by nodal sites: 3 (12%) in perirectal space, 5 (20%) in internal iliac, 7 (28%) in obturator, 13 (52%) in external iliac, and 6 (24%) in common iliac lymph nodes. We have found 173 patients and were able to map reliable gross tumor recurrence sites after RALP and confirmed by pelvic MRIs following BCR. The map supports evidence of using the existing consensus pelvic clinical target volume of salvage radiotherapy, in a post-RALP BCR scenario.

Change in Therapeutic Approach after PET/TC PSMA-18F DCFPyL in Occult Biochemical Recurrence of Prostate Carcinoma with Low PSA Values

To analyze changes in therapeutic attitude after PET-PSMA. in patients with occult biochemical recurrence after primary treatment with low PSA values. Retrospective study of patients diagnosed with prostate carcinoma who after primary treatment with curative intent present biochemical recurrence with low PSA values (<2ng/ml) and negative imaging tests (ultrasound, CT-Scan, MRI, GGO and/or PET-Choline). The assessment was performed by two expert nuclear physicians. All patients underwent a study with 300-350MBq PSMA-18F DCFPyL PET/TC, and after a follow-up of no less than six months we assessed whether there were changes in therapeutic attitude directly related to the results of the test. The clinical/therapeutic evaluation was performed by expert radiation oncologists. Descriptive statistical analysis was performed. RoC curves (sensitivity vs. 1-specificity) and the corresponding areas under the curve were calculated to assess the predictive power of the study. PET-PSMA with complete follow-up was performed on 85 patients aged 48-78 years (mean age 69 years) with occult biochemical recurrence. Most patients were staged T2 (50.58%) - T3 (48.23%), cases N1 (10.58%), Gleason score ≥ 7 (96%) with mean PSA level 11.24 ng/ml at diagnosis. The mean nadir PSA values of 0.13 mg/dl following primary treatment with radical intent. In 48.2% of patients (41/85) had a positive PET-PSMA during follow-up, pre-study the median PSA levels were 0,62 ng/dl. There is a correlation between the PSA value and the ability to detect disease in the PET-PSMA study (AUC: 0,74). In 75% of patients with positive PET-PSMA (31/41) there were changes in the therapeutic approach. This proportion was significantly lower (25%) in those without pathological PET findings (11/44). In PET-PSMA-positive patients the therapeutic changes found were classified as indicating or changing the planning of salvage radiotherapy treatment and/or initiating systemic treatment with hormone therapy (median PSA levels after treatment changes were 0.08 ng/dl). In cases with negative PET-PSMA a watchful waiting attitude was adopted. PET-PSMA is a powerful diagnostic tool that conditions significant changes in the therapeutic approach in those patients with occult biochemical recurrence with low PSA, changing the treatment in 75% of the cases when the study is positive.

Quality of Life Results of Addition of Androgen Deprivation Therapy and Pelvic Lymph Node Treatment to Prostate Bed Salvage Radiotherapy: NRG Oncology/RTOG 0534 SPPORT

Report the quality of life (QOL) analysis of the SPPORT trial of men with a detectable prostate specific antigen (PSA) after prostatectomy for prostate cancer randomized to (Arm 1) salvage prostate bed radiotherapy (PBRT), (Arm 2) 4-6 months of short-term androgen deprivation therapy (STADT) + PBRT, and (Arm 3) pelvic lymph node radiotherapy (PLNRT) + STADT + PBRT. Primary analysis established a benefit of adding PLNRT and STADT to PBRT. There was higher short term but no statistically significant difference in long term adverse events with the exception of blood or bone marrow events. QOL endpoints were assessed at baseline, 6 weeks after RT start, 1 and 5 years, including Expanded Prostate Cancer Index Composite (EPIC) (bowel, urinary, sexual, and hormonal domains), Hopkins Symptom Checklist (HSCL-25) (depressive symptoms), and the EuroQol (EQ-5D) (health state weights used in quality adjusted life years (QALYs). In addition to statistical significance, differences in scores were assessed using 0.5 standard deviation (SD) as the criterion for clinical importance. Difference among arms was assessed using pairwise t-tests, Fisher's exact test, and mixed effects regression modeling. To control for multiplicity, the p-value required for statistical significance is p<0.025. Six hundred forty-four patients consented to QOL, about 210 on each arm. Baseline characteristics were not significantly different among arms: 81% were white and 54% <65 years. For EPIC, bowel domain scores decreased at 6 weeks post-RT then increased by years 1 and 5, although not to baseline levels. One clinically significant difference in bowel scores was Arm 3 vs. Arm 1 at 6 weeks. For the urinary domain, scores decreased at 6 weeks post-RT and remained below baseline at 1 and 5 years, but there were no significant differences among arms. For the sexual domain, there were statistically significant differences between arms at 6 weeks and 1 year with patients receiving STADT exhibiting poorer sexual QOL scores. By year 5 the differences were no longer significant. A similar pattern was seen for the hormonal domain. For HSCL-25, differences at 6 weeks were statistically but not clinically significant, and there were no significant differences at the later time points. Comparisons of QALYs for overall survival over an 8-year horizon showed no significant group differences, with a mean of about 7.8 in each arm. Regarding freedom from progression, QALY means were 5.7, 6.5, and 7.4 years for Arms 1, 2, and 3, respectively, with a significant difference between Arms 3 and 1 (p = <.001) favoring the more intensive treatment. While QOL generally declined among all arms at 6 weeks post RT, there were no clinically significant differences in QOL among arms at 5 years. QALYs for freedom from progression favored STADT + PLNRT + PBRT for salvage treatment of prostate cancer.

Salvage radiotherapy strategy and its prognostic significance for patients with locoregional recurrent cervical cancer after radical hysterectomy: a multicenter retrospective 10-year analysis

ObjectiveWe aimed to evaluate the clinical efficacy and prognostic significance of intensity-modulated radiotherapy (IMRT)-based salvage concurrent chemoradiotherapy (CCRT) for patients with locoregional recurrence cervical cancer after radical hysterectomy and evaluated two salvage radiotherapy modes—regional RT (involved-field RT combined with regional lymph nodes) and local RT (involved-field RT).MethodsPatients were enrolled retrospectively from January 2011 to January 2022 in three medical centers. Clinical outcomes were analyzed using the Kaplan–Meier method and a Cox proportional hazards model. Propensity score (PS) matching analysis was used to compare the two RT groups.ResultsThere were 72 patients underwent IMRT-based salvage CCRT. The 5-year overall survival and progression-free survival rates were 65.9% and 57.6%, respectively. Univariate analysis showed that patients with stump recurrence, a lower systemic inflammation response index (SIRI), only one metastatic lesion, and received regional RT had better prognosis than their counterparts. In multivariate analysis, recurrence site was the independent prognostic factor of OS, and SIRI was that of PFS. After PS matching, there were 15 patients each in the regional RT group and local RT group. The 5-year OS rate of regional RT group was better than that of local RT group (90.9 vs. 42.4, p = 0.021). However, there was no significant difference between them in terms of PFS rate (47.1 vs. 38.1, p = 0.195).ConclusionLocoregional recurrent cervical cancer treated with IMRT-based salvage therapy has a good prognosis. Recurrence site and SIRI were independent prognostic factors. Regional RT may be a better option for patients with locoregional recurrent.

The prognostic significance of a negative PSMA-PET scan prior to salvage radiotherapy following radical prostatectomy

AimThe optimal management for early recurrent prostate cancer following radical prostatectomy (RP) in patients with negative prostate-specific membrane antigen positron-emission tomography (PSMA-PET) scan is an ongoing subject of debate. The aim of this study was to evaluate the outcome of salvage radiotherapy (SRT) in patients with biochemical recurrence with negative PSMA PET finding.MethodsThis retrospective, multicenter (11 centers, 5 countries) analysis included patients who underwent SRT following biochemical recurrence (BR) of PC after RP without evidence of disease on PSMA-PET staging. Biochemical recurrence-free survival (bRFS), metastatic-free survival (MFS) and overall survival (OS) were assessed using Kaplan-Meier method. Multivariable Cox proportional hazards regression assessed predefined predictors of survival outcomes.ResultsThree hundred patients were included, 253 (84.3%) received SRT to the prostate bed only, 46 (15.3%) additional elective pelvic nodal irradiation, respectively. Only 41 patients (13.7%) received concomitant androgen deprivation therapy (ADT). Median follow-up after SRT was 33 months (IQR: 20–46 months). Three-year bRFS, MFS, and OS following SRT were 73.9%, 87.8%, and 99.1%, respectively. Three-year bRFS was 77.5% and 48.3% for patients with PSA levels before PSMA-PET ≤ 0.5 ng/ml and > 0.5 ng/ml, respectively. Using univariate analysis, the International Society of Urological Pathology (ISUP) grade > 2 (p = 0.006), metastatic pelvic lymph nodes at surgery (p = 0.032), seminal vesicle involvement (p < 0.001), pre-SRT PSA level of > 0.5 ng/ml (p = 0.004), and lack of concomitant ADT (p = 0.023) were significantly associated with worse bRFS. On multivariate Cox proportional hazards, seminal vesicle infiltration (p = 0.007), ISUP score >2 (p = 0.048), and pre SRT PSA level > 0.5 ng/ml (p = 0.013) remained significantly associated with worse bRFS.ConclusionFavorable bRFS after SRT in patients with BR and negative PSMA-PET following RP was achieved. These data support the usage of early SRT for patients with negative PSMA-PET findings.