Late Toxicity Rates Research Articles

A pooled patient-reported outcomes analysis of moderately hypofractionated proton beam therapy and photon-based intensity modulated radiation therapy for low- or intermediate-risk prostate cancer.

We sought to characterize and compare late patient-reported outcomes (PROs) after moderately hypofractionated intensity modulated radiation therapy (IMRT) and proton beam therapy (PBT) for localized prostate cancer (PC). This multi-institutional analysis included low- or intermediate-risk group PC patients treated with moderately hypofractionated radiation to an intact prostate stratified by treatment modality: IMRT or PBT. The primary outcomes were prospectively collected patient-reported late gastrointestinal (GI) and genitourinary (GU) toxicity assessed by International Prostate Symptom Score (IPSS) and Expanded PC Index Composite (EPIC). Multivariable regression analysis (MVA) controlling for age, race, and risk group tested the effect of time, treatment, and their interaction. 287 IMRT and 485 PBT patients were included. Intermediate risk group (81.2 vs. 68.2%; p < 0.001) and median age at diagnosis (70 vs. 67 years; p < 0.001) were higher in the IMRT group. On MVA, there was no significant difference between modalities. PBT IPSS did not differ from IMRT IPSS at 12 months (odds ratio [OR], 1.19; p = 0.08) or 24 months (OR, 0.99; p = 0.94). PBT EPIC overall GI function at 12 months (OR, 3.68; p = 0.085) and 24 months (OR 2.78; p = 0.26) did not differ from IMRT EPIC overall GI function. At 24 months, urinary frequency was no different between PBT and IMRT groups (OR 0.35; p = 0.096). This multi-institutional analysis of low- or intermediate-risk PC treated with moderately hypofractionated PBT and IMRT demonstrated low rates of late patient-reported GI and GU toxicities. After covariate adjustment, late GI and GU PROs were not significantly different between PBT or IMRT cohorts.

Outcomes of definitive local therapy with intensity-modulated radiation therapy in elderly patients ≥70 years with HPV-associated oropharyngeal cancer.

The incidence of human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing among elderly (≥70 years) patients and the optimal treatment approach is not known. In this study, we aimed to determine disease and toxicity outcomes in an elderly HPV-OPSCC population primarily treated with a chemoradiation (CRT) approach.We identified 70 elderly HPV-OPSCC patients who were treated with either surgery, radiotherapy, or CRTbetween 2011 and 2021. Time-to-event analysis for overall survival (OS), progression-free survival (PFS), and local control (LC) were conducted using the Kaplan-Meier method. Univariate and multivariable cox regression models were used to estimate the hazard ratio associated with covariates.The median follow-up for our cohort was 43.9 months. Of the 70 elderly patients, 55 (78.6%) receive CRT and 15 (22.4%) received RT alone. Two patients underwent TORS resection. Of the 55 patients treated with CRT, the most common systemic agents were weekly carboplatin/taxol (n = 18), cetuximab (n = 17), and weekly cisplatin (n = 11). The 5-year OS, PFS, and LC were 57%, 52%, and 91%, respectively. On univariate analysis, Eastern Cooperative Oncology Group performance status and Charlson Comorbidity Index (CCI) were significant predictors of OS, while on multivariate analysis only CCI was a significant predictor of OS (p = 0.006). The rate of late peg tube dependency, osteoradionecrosis, and aspiration was 10%, 4%, and 4%, respectively.Definitive local therapy in elderly HPV-OPSCC patients is associated with excellent LC and a low rate of late toxicities. Prospective studies are needed to further stratify subgroups of elderly patients who may benefit from aggressive definitive local therapy.

Phase II Trial of Five-Fraction Accelerated Partial Breast Irradiation Using Noninvasive Image-Guided Breast Brachytherapy

NIBB has potential advantages over other APBI techniques by delivering highly conformal radiation with minimal collateral dose to the heart and lung compared with external beam techniques, but unlike other brachytherapy techniques NIBB is non-invasive. Previous data has shown encouraging outcomes using a 10-fraction regimen. To improve efficiency, convenience, and cost, reduction in the fraction number is desirable. Final results of a prospective phase II trial are reported. NIBB APBI was delivered using 28.5Gy in 5 fractions daily over 1 week. Patient eligibility criteria required: invasive carcinoma ≤2.0 cm or DCIS ≤3.0 cm, ER positive (if invasive), lymph node negative, LVI absent, and lumpectomy with margins negative by 2mm. The primary endpoint was grade ≥ 2 subcutaneous fibrosis/induration <30%. Secondary endpoints included any late toxicity, cosmetic outcome, and local control. 40 patients were treated with a median follow-up of 59.7 months. The mean age was 67 years (50-89 years) and tumor size was 1.0cm (0.3-2.0cm). 80% had invasive carcinoma. The mean breast separation with compression was 6.7cm (3.5-8.9cm). The 5-year actuarial local control was 96.6% and overall survival was 96.9%. Grade 2 and 3 late toxicities were 15% and 0%, respectively. The rate of grade 2 subcutaneous fibrosis/induration was 2.5% (+/-2.5%) meeting the study's primary endpoint. The most common late toxicity of any grade was skin telangiectasia; 22.5% grade 1 and 15% grade 2. Only breast separation was associated with telangiectasia risk, p=0.002. Overall cosmetic outcome was excellent, good, and fair/poor in 75%, 25%, and 0%, respectively. NIBB APBI delivered in 5 fractions results in a low rate of late toxicity and a high rate of good/excellent cosmetic outcomes. Telangiectasia risk can be minimized by keeping breast separation ≤7.0cm. The local failure rate was appropriately low. Further investigation of this technique is warranted.

Prognostic nutritional index and neutrophil-lymphocyte ratio predict toxicities and prognosis in patients with cervical cancer treated with curative radiochemotherapy

BackgroundThis study aimed to investigate the influence of immunonutritional factors on treatment-related toxicities and survival outcomes in patients with cervical cancer undergoing definitive radiochemotherapy. MethodsPatients with cervical cancer who received curative radiochemotherapy between 2016 and 2021 were retrospectively investigated. Pretreatment prognostic nutritional index (PNI), neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), and platelet-lymphocyte ratio (PLR) were measured. Survival outcomes, acute and late toxicities were evaluated. ResultsAmong the 138 patients, those with larger tumor diameters had significantly lower pre-treatment PNI (p = 0.005). Pre-treatment immunonutritional factors were predictive of clinical survival, whereas post-treatment factors did not correlate with prognosis. Patients with low pre-treatment PNI (<49.5) or high NLR (>2.4) had shorter progression-free survival (PFS, HR: 1.86, p = 0.045 for PNI; HR: 3.15, p = 0.002 for NLR) and overall survival (OS, HR: 1.80, p = 0.048 for PNI; HR: 3.83, p = 0.015 for NLR). High pre-treatment NLR was associated with an increased risk of acute diarrhea (p = 0.049) and late severe toxicities (p = 0.046). Combined analysis revealed that pre-treatment good nutritional status and low systemic inflammation were linked to longer PFS (p = 0.007) and OS (p = 0.002), and poor nutritional status and substantial systemic inflammation were associated with higher rates of late severe toxicities (p = 0.036), with higher prognostic value in advanced stage patients. ConclusionPretreatment immunonutritional measures serve as quantitative biomarkers for predicting survivals and treatment toxicities in patients with cervical cancer treated with definitive radiochemotherapy.

Radiotherapy combined with deep regional hyperthermia in elderly and frail patients with muscle-invasive bladder cancer: quality analysis of hyperthermia and impact on clinical results

Purpose: Radiotherapy (RT) in combination with deep regional hyperthermia (HT) after transurethral removal of bladder tumor (TURBT) can be offered to elderly and frail patients with muscle-invasive bladder cancer (MIBC). Methods: In total, 21 patients (mean age 84 years) with unifocal or multifocal MIBC received radiation to a dose of 48–50 Gy/16–20 fractions with weekly HT. The primary endpoint was the variation in temperature metrics, thermal dose expressed as cumulative equivalent minutes at 43 °C when the measured temperature is T90 (CEM43T90) and net power applied in target volume per each HT session. Secondary endpoints were three-year overall survival (OS), disease-free survival (DFS), local progression-free survival (LPFS) and toxicity. Results: The temperature metrics, CEM43T90, mean and maximum net power applied did not differ significantly among the HT sessions of the 21 patients. With a median follow-up of 65 months, 52% (95% CI 32–72%) of patients had died 3 years after treatment. The three-year DFS and LPFS rates were 62% (95%CI 41–79%) and 81% (95%CI 60–92%), respectively. The three-year bladder preservation rate was 100%. Three out of four patients with local failure received a thermal dose CEM43T90 below a median of 2.4 min. The rates of acute and late grade-3 toxicities were 10% and 14%, respectively. Conclusion: The reproducibility of HT parameters between sessions was high. A moderately high CEM43T90 (> 2.4 min) for each HT session seems to be preferable for local control. RT combined with HT is a promising organ-preservation therapy for elderly and frail MIBC patients.

Oncological Outcomes, Long-Term Toxicities, Quality of Life and Sexual Health after Pencil-Beam Scanning Proton Therapy in Patients with Low-Grade Glioma.

To assess oncological outcomes, toxicities, quality of life (QoL) and sexual health (SH) of low-grade glioma (LGG) patients treated with pencil-beam scanning proton therapy (PBS-PT). We retrospectively analyzed 89 patients with LGG (Neurofibromatosis type 1; n = 4 (4.5%) patients) treated with PBS-PT (median dose 54 Gy (RBE)) from 1999 to 2022 at our institution. QoL was prospectively assessed during PBS-PT and yearly during follow-up from 2015 to 2023, while a cross-sectional exploration of SH was conducted in 2023. Most LGGs (n = 58; 65.2%) were CNS WHO grade 2 and approximately half (n = 43; 48.3%) were located in the vicinity of the visual apparatus/thalamus. After a median follow-up of 50.2 months, 24 (27%) patients presented with treatment failures and most of these (n = 17/24; 70.8%) were salvaged. The 4-year overall survival was 89.1%. Only 2 (2.2%) and 1 (1.1%) patients presented with CTCAE grade 4 and 3 late radiation-induced toxicity, respectively. No grade 5 late adverse event was observed. The global health as a domain of QoL remained stable and comparable to the reference values during PBS-PT and for six years thereafter. Sexual satisfaction was comparable to the normative population. LGG patients treated with PBS-PT achieved excellent long-term survival and tumor control, with exceptionally low rates of high-grade late toxicity, and favorable QoL and SH.

Role of hypofractionated stereotactic radiotherapy for primary optic nerve sheath meningioma.

Optic nerve sheath meningiomas (ONSM) are rare tumors potentially causing visual deficits. This study aims to report the anatomic and visual outcomes of patients with primary ONSM treated with hypofractionated stereotactic radiotherapy (HF-SRT). Data of 36 patients treated with HF-SRT between 2008 and 2019 were retrospectively collected. The clinical target volume (CTV) was equal to the gross tumor volume and a 2 mm was added for the planning target volume. All responses other than progression were accepted as local control (LC). The VA grading was performed under 3 groups to provide an even distribution; 20/400 or worse, 20/40-20/400, and 20/40 or better. Median HF-SRT dose was 25 Gy and the median CTV was 1.94 cc. After a median of 106 months of follow-up, the tumor regressed in 23 (64%), was stable in 9 (25%), and progressed in 4 (11%) eyes. The overall rate of LC was 89% with 2-, 5-, 10-, and 15-year rate of 100%, 94%, 84%, and 84%, respectively. Treatment-related late toxicity rate was 11%. The VA was stable in 27 (75%) eyes, improved in 5 (14%) eyes, and worsened in 4 (11%) eyes, respectively, after HF-SRT. Female gender was the only independent predictor of an improved VA. Hypofractionated stereotactic radiotherapy is a safe and satisfactory treatment option for primary ONSM without severe toxicity. It may be advisable to commence treatment before an established visual deficit of 20/400 or worse occurs, to make the most of the functional benefit.

Toxicity Analysis of a Modified Prostate Bed CTV Based on PSMA-PET Patterns of Failure.

After radical prostatectomy (RP), about 20-50% of prostate cancer patients experience biochemical failure, and many can be cured with salvage radiotherapy (sRT). Adding androgen deprivation and pelvic lymph node (PLN) RT to sRT decreases risk of disease progression at the cost of increased toxicity. PSMA PET patterns of local failure after RP show failures outside the RTOG prostate bed CTV (RTOG_CTV) occurring postero-laterally and inferiorly, while in much of the covered bladder local failures are not seen. A modified CTV (m_CTV) encompassing all sites of observed local failures and less of the bladder would potentially reduce dose to the bladder but increase dose to rectum. Herein, we compared sRT plans using RTOG_CTV vs. m_CTV and assessed predicted genitourinary (GU) and gastrointestinal adverse events (AEs). Volumes for RTOG_CTV, m_CTV, PLN CTV, and OARs were retrospectively contoured on planning CT scans of 28 post-RP patients. Plans were generated for each RTOG_CTV and m_CTV. Doses to prostate bed PTV (CTV + 8mm expansion, 6mm posteriorly) and PLN CTV were 68 Gy and 52.7 Gy, respectively, all in in 34 fractions. Dose-volume histogram (DVH) data for bladder, rectum, and bowel of each plan were extracted. Normal Tissue Complication Probability (NTCP) curves were generated using Lyman-Kutcher-Burman model to predict risk of late G≥3 GU AEs, early GU urgency, leakage, frequency, nocturia, late GI bleed, and late G≥3 GI AEs. Data were compared using 2 sample t-test and Wilcox signed rank test. Correlation of bladder volume and differences in DVH and NTCP data between plans was assessed using Pearson coefficient. The m_CTV and RTOG_CTV had a median volume of 70.56cc (IQR 59.72-82.17cc) and 132.14cc (IQR 109.33-155.84cc), respectively. Use of m_CTVs resulted in mean absolute decrease of 20.22% and 17.94% in bladder V65 Gy and V40 Gy, respectively (p<0.01 for both), without differences in rectum V65 Gy (p = 0.44), rectum V40 Gy (p = 0.11), or bowel V45 Gy (p = 0.29). Per NTCP curves, m_CTV plans had mean absolute decrease of 24.89% in predicted late G≥3 GU AEs (p<0.01). For predicted early GU AEs, there were mean absolute decreases ranging from 4.85 to 10.21% (p<0.01 for all). Predicted late GI bleed (p = 0.98) and late G≥3 GI AEs (p = 0.99) were not significantly different between plans. When assessed as a continuous variable, smaller bladder volumes had strong correlation with more benefit from m_CTV in bladder V65 Gy (r = -0.71, p<0.01) and moderate correlation with less early GU AEs (r -0.59 to -0.56, p<0.01 for all). There was no correlation with bladder V40 Gy (p = 0.27) or late G≥3 GU AEs (p = 0.14). The m_CTV plans had significantly less dose to the bladder, no increased dose to the rectum and significantly lower predicted rates of early and late GU toxicity. Using a m_CTV encompassing observed local failures from PSMA PET could improve the therapeutic ratio for patients undergoing sRT. Further clinical validation is warranted.

SBRT in 3 Fractions for T1 Glottic Cancer

The purpose of this study was to report the results of a mature phase II study. This was a prospective study at a single institution that were enrolling patients with T1 glottic cancer. The true vocal cords (TVCs) were divided into thirds and the third(s) containing disease prescribed 36 Gy in 3 fractions. The portions of the TVCs next to the involved one were planned to receive 30 Gy in 3 fxs. The remaining parts of the TVCs as well the rest of the larynx was tentatively spared. SBRT was delivered by a LINAC-based approach using multiple arcs (VMAT). Toxicity was scored by CTCAE and late events were considered those occurring 3 months after SBRT. Voice quality was investigated by the voice handicap index (VHI) at regular intervals. A generalized linear mixed model was used to analyze longitudinal functional data and the actuarial approach was used to report late toxicity prevalence rates. The planned sample size, 75 patients, was calculated to reject the hypothesis of a 2-yr local control (LC) of 85% against the alternative hypothesis of 95%. The median follow-up time is 40 months (IQR: 31.5-47.3 months). Accrual was discontinued after 33 patients due to concerns on late toxicity rates on both the mucosa and the cartilages. Median age was 66 yrs (IQR: 60-71 yrs). T stage was as follows: T1a: 23 pts (69.7%); T1b: 10 pts (30.3%). Only two patients never smoked, while of the remaining ones, 13 (41.9%) kept smoking after SBRT despite appropriate counseling. At last, follow up, all patients are alive and without evidence of disease but one patient who died 21.3 months after SBRT for intercurrent causes. The observed local control rate of 100% allows to reject the null hypothesis because, according to the binomial distribution, the probability of not observing at least one recurrence out of the accrued 33 patients is <0.5% if a 2-yr LR ≤85% would be true. All but 5 patients developed transient confluent mucositis of the treated volume with a prevalence peak at 19 days after SBRT. Six patients (18.2%) developed soft tissue necrosis (N = 4) or cartilage necrosis (N = 2) after a median time of 14.9 months from SBRT (range: 9.1-24.5 months). The actuarial prevalence of any necrosis is 3.0%, 1.3% and 0.8% at 12, 24 and 36 months after SBRT, respectively, with a peak at 6.1% between 9.9 and 11.9 months. All 4 soft tissue events healed with conservative therapy after a median time of 2.5 months (range: 1-12.2 months). One patient with chondronecrosis refused total laryngectomy and is alive with persistent toxicity 22.9 months after its onset; the other patient underwent endoscopic removal of the necrotic arytenoid and he is alive without evidence of disease or further complications more than 2 years afterwards. Patient reported outcomes (VHI) will be presented as well. SBRT to 36/30 Gy in 3 fractions is highly effective in controlling T1 true vocal cord carcinoma, but necrosis, though mostly transient, is a concern. Based on the present results, a reduction in total doses is justified and a novel phase II study is ongoing.

Five-Fraction Stereotactic Radiation for Head and Neck Paragangliomas

Paragangliomas of the head and neck (HN) are benign, slow-growing neoplasms that are rarely functional. Treatment is often indicated for patients presenting with mass effect, cranial neuropathies, or pulsatile tinnitus. Radiotherapy, traditionally conventionally fractionated, is often used for primary, post-operative, and salvage therapy, given its excellent control rates and reduced risks to adjacent neurovascular structures. Stereotactic ablative radiation (SAbR) offers shorter treatment time, and modern techniques eliminate margins to improve organ-at-risk avoidance. SAbR may offer additional radiobiological sparing of normal structures over single-fraction SAbR. We aimed to evaluate tumor and symptom response, acute and late toxicity rates, and recurrence patterns in HN paraganglioma patients treated with 25 Gy in 5 fractions. Retrospective chart review collected baseline patient and tumor information, treatment and dosimetry details, acute and long-term toxicity grades (per the CTCAE v. 5.0), symptom and tumor response, and survival. Local control was defined as the absence of local enlargement (per RECIST v. 1.1) or marginal failure and was estimated using the Kaplan-Meier method. Between December 2009-March 2020, 39 patients received 25 Gy in 5 fractions to 43 HN paragangliomas, of which 17 were treated in 11 patients with hereditary paraganglioma-pheochromocytoma syndrome. Fifteen targets were post-operative recurrent or residual tumors. There were 27 jugulotympanic tumors, 4 jugular, 1 tympanic, 8 vagal, 5 carotid body, and 2 jugulotympanic or vagal. Median follow-up time was 3.3 years (range 0-11.4 years), and 21 targets had at least 4 years of follow-up. Tumor volume decreased by a median of 37%. Three-year local control was 100%. One patient, known to harbor an SDHD mutation, had 2 out-of-field recurrences within the post-operative bed at 7.1 years. Two patients experienced 2 marginal recurrences within the post-operative bed at 6.1 and 8.4 years: one had an SDHB mutation and developed metastatic disease, and the other did not have genetic testing. The most common grade 1-2 acute toxicities were headache and fatigue; the most common grade 1-2 late toxicities were dysphagia and otalgia. There were no grade >2 acute toxicities. A late grade 3 aspiration event was seen in 1 patient who presented with paralyzed vocal cord requiring multiple medialization laryngoplasties. Within 6 months of SAbR, 18% of symptoms or toxicities improved or resolved; 34% improved or resolved more than 6 months after SAbR. This is the largest series of HN paragangliomas treated with SAbR, detailing a 10-year experience with a 5-fraction regimen that is well-tolerated and achieves excellent local control. Post-SAbR recurrences occurred outside of the radiation field but within the post-operative bed, suggesting that some post-operative patients may benefit from expanded radiation volumes or close surveillance for salvage therapy.

Late Toxicity and Patient Satisfaction in Hypofractionated Post-Mastectomy Radiotherapy after Immediate-Autologous Reconstruction

Immediate autologous reconstruction (IAR) is increasingly being used in the context of breast cancer patients (BCP) treated with mastectomy with the need for subsequent radiotherapy treatment. Currently in clinical practice, despite the fact that conventional fractionated RT (CFRT) has been the standard schedule, hypofractionation schemes are becoming increasingly common. Although no results have been reported on tolerance, late toxicity and satisfaction with treatment in this setting. Our aim was to evaluate late side-effects and patient´s satisfaction receiving PMRT after IAR, comparing CFRT vs HFRT. Between June 2015 and February 2020, 47 patients received either CF or HF PMRT after IAR in a tertiary hospital. IAR was performed with latissimus dorsi (LD) or deep inferior epigastric perforator (DIEP) flaps at the time of mastectomy. The prescribed dose was 50 Gy over 25 fractions in the CF schedule and 40.05 Gy over 15 fractions in the HF schedule. The target volume to be treated was the reconstructed chest-wall and the axillary-supraclavicular nodes if indicated, using intensity-modulated radiotherapy treatment technique. Late toxicity was evaluated using CTCAE v.5.0 criteria, and patient´s global satisfaction was assessed using a self-evaluation questionnaire, in which patients answered a series of selected questions related to radiation therapy from the BREAST-Q questionnaire, from 1-5 points. Median age was 48 years (28-77) and median follow-up was 51 months (27-99). 25 patients received HFRT and 22 CFRT. Late side effects after PMRT and tolerance until 3 years with both schedules are shown in Table 1. No relationship was found between incidence of late side effects and RT fractionation. Mean patient´s satisfaction was 3.8 in the CFRT schedule and 4 in the HFRT schedule. According to our findings, HFRT after IAR in post-mastectomy setting seems to be safe and well tolerated, with no high rates of severe late toxicity and with a good level of satisfaction of the treated patients. Table 1. Three years side effects of CRFT and HFRT radiotherapy after mastectomy and immediate autologous reconstruction in 47 patients.

A Systematic Review and Meta-Analysis of Toxicity in Oropharyngeal Cancer Patients Treated with Proton Therapy

Proton radiotherapy (PRT) is an emerging treatment modality for patients with oropharyngeal cancer (OPC). Due to its dosimetric properties, PRT is hypothesized to be associated with lower rates of acute and late toxicity than photon intensity modulated radiotherapy (IMRT). Current evidence supporting PRT in this setting is limited to small, single institution reports. We sought to examine pooled rates of PRT toxicity from the current literature. A systematic review of PubMed, Embase, and Web of Science was performed. Articles published from 1980-2022 that contained >10 patients treated with definitive or adjuvant PRT for OPC were included. From these studies acute and late clinician rated adverse events (CRAEs) were extracted. The primary outcomes were the pooled rates of grade 3 or higher (G3+) acute CRAEs. The secondary outcomes were the pooled rates of late CRAEs. Pooled rates were estimated using random effects models for CRAEs that were reported in ≥3 studies and graded using Common Terminology Criteria for Adverse Events (CTCAE). In studies that reported both PRT and IMRT, a mixed effects log odds ratios (ORs) was used to compare risk of CRAE between modalities. A total of 8 studies (5 retrospective, 3 prospective) with 291 patients treated with PRT for OPC were identified. The majority of patients were men (90%) with HPV-associated disease (93%) treated with definitive intent (56%). Primary tumor was most frequently tonsil (55%); 58% had T1-2, and 60% had N2-3 disease (AJCC7). Estimated pooled rates of G3+ acute CRAEs were as follows: dermatitis: 22%, mucositis: 38%, xerostomia: 1.6%, dysphagia: 15%, and weight loss: 1.9%. Estimated pooled rates of G2+ acute CRAEs were as follows: dermatitis: 73%, xerostomia: 12%, weight loss: 14%, and dysgeusia: 29%. Rate of acute hospitalization was 10%. In terms of late toxicities of PRT, the pooled rate of G2+and G3+ xerostomia were 22.5% and 1.2%, respectfully, while the rates G2+ and G3+ dysphagia were 15.6% and 2.6%, respectfully. Among the included studies, 4 studies reported CRAEs from patients treated with IMRT. Due to inconsistent reporting of CRAEs, only use of feeding tube (FT) could be compared between treatment modalities. PRT was associated with significantly lower FT use in the acute setting compared to IMRT - 18% versus 28%, respectively (log OR -0.88, P<0.001). Long term FT use was not significantly different between PRT and IMRT - 1.4% versus 2.7%, respectively (log OR -0.95, P = 0.24). In the largest pooled analysis of PRT for OPC to date, PRT was associated with a 3-fold reduction of acute, but not late, FT use compared to IMRT. The pooled rates of other PBT CRAEs appear to be at least similar to, if not less than, those reported on IMRT trials treating similarly selected patients. Ultimately, heterogeneity in reporting PRT toxicity outcomes greatly reduces the interpretability of these data and limits proton-photon comparisons. Maximizing consistency of CRAE reporting in future studies is critical.

Outcomes of Stereotactic Body Radiation Therapy (SBRT) for Femur Oligometastases

Stereotactic body radiation therapy (SBRT) is increasingly used for oligometastatic bone disease, but there is limited data regarding the clinical outcomes of utilizing SBRT in treatment for femur metastases, which was excluded from SABR-COMET. We aimed to identify patient or treatment factors associated with clinical outcomes among patients treated with SBRT to femur metastases for oligometastatic disease control or re-irradiation. We identified 50 patients with 56 femur lesions consecutively treated with SBRT at a single institution May 2017-June 2022. The Kaplan-Meier method was used to characterize time-to-event endpoints and Cox proportional hazards models were performed to evaluate the associations between baseline factors and clinical outcomes. Local control was defined as the absence of regional tumor progression at treated area or need for surgical fixation post radiation. Most patients had ECOG 0-1 (90%), prostate (50%) or breast/lung (16%) cancer, and 1-3 lesions (100%), including 30 proximal and 5 distal. 55% of lesions received concurrent systemic therapy, including ADT (n = 18) or immunotherapy (n = 6). Median PTV volume was 54.7cc (range, 6.6 to 387cc). PTV V100(%) was 99% (range 71.5-100). Fractionation included 18-20 Gy/1F, 27-30 Gy/3F, 25-40 Gy/5F, and 50 Gy/10F. 43% of lesions had Mirel's score ≥ 7 and 91% of lesions did not have extraosseous bone extension on diagnostic CT and/or MRI. Acute toxicities included grade 1 fatigue (14.3%), pain flare (7.1%), and decreased blood counts (1.8%). Late toxicities included fracture (1.8%) at 1.5 years and 2 patients with radiation-induced osteonecrosis (3.6%) from dose of 40 Gy in 5F and 30 Gy in 5F (after prior 30 Gy/10F). One patient (n = 2%) required fixation post-radiation due to progression of disease or symptoms. With median follow up 19.4 months, 1 and 2-year rates of local control were 84% and 69%, progression-free survival were 55% and 27%, and overall survival were 91% and 74%. There was no significant association between patient or treatment characteristics and local control outcomes. Femur SBRT for oligometastatic disease control in well-selected patients was associated with good outcomes with minimal rates of acute and late toxicity. Further prospective study is warranted.

Meta-Analysis of Five Fraction Preoperative Radiotherapy for Soft Tissue Sarcoma

There is increasing interest in shorter courses of radiation therapy (RT) in the management of soft tissue sarcoma (STS). Studies investigating preoperative ultra-hypofractionated 5-fraction RT for STS are few and often limited to single institution experiences with less than 50 patients. We therefore performed a meta-analysis to determine the efficacy and safety of preoperative 5-fraction RT for STS based on currently published literature, with an analysis evaluating effects of dose delivered. This study level meta-analysis was conducted using Bayesian methods. Statistical estimation for risk of outcome rates were conducted by posterior mean and 95% highest posterior density (HPD) intervals. Studies with two-year local control (LC) and description of major wound complications (MWC) per the CAN-NCIC-SR2 study were included in this meta-analysis, and these served as the primary endpoints. Secondary endpoints included rates of acute and late toxicity. A total of ten studies were identified; seven met inclusion criteria (Kalbasi 2020, Kubicek 2021, Leite 2021, Spalek 2021, Gobo Silva 2021, Bedi 2022, Mayo 2022). Three studies (Kosela-Paterczyk 2014, Kosela-Paterczyk 2021, Potkrajcic 2021) did not include adequate information to accurately determine 2-year LC or MWC. Subgroup analyses were performed for ≥30 Gy vs <30 Gy as the EQD2 of 30 Gy in 5 fractions for an α/β of 3-4 is 50-54 Gy, equivalent to standard preoperative RT fractionation. A total of 208 patients were included from seven studies. Five studies used ≥30 Gy (n = 144) and 2 studies <30 Gy (n = 64). The median follow-up was 29 months (range: 21-57). Primary tumor location was lower extremity in 68%, upper extremity in 22%, and trunk in 10%. In studies with available information, most tumors were intermediate (27%, 46/169) or high grade (67%, 114/169) and 50% (79/158) were >10 cm. Two-year LC for the entire cohort was 96.9% (95% HPD: 0.9374-0.9889) and the rate of MWC was 30.6% (95% HPD: 0.2106-0.4149). Acute grade 2 and 3 dermatitis was seen in 12.7% and 2.2%, respectively. Late grade 2 toxicities included fibrosis (11.1%), stiffness (6.0%), and lymphedema (4.0%) and late grade 3 toxicities included fibrosis (1.8%) and stiffness (0.4%). Grade 4 toxicity was rare and included fibrosis (0.6%) and stiffness (0.6%). There was a trend toward improved LC with ≥ 30 Gy (95% HPD: 0.949-0.997 vs 0.838-0.986). There was no difference in MWC (95% HPD: 0.185-0.420 vs 0.172-0.553) or late toxicity between the two groups. Acute grade 3 dermatitis was seen less frequently with regimens <30 Gy (95% HPD: 0-0 vs 0.009-0.072), however rare overall. Preoperative 5-fraction RT for STS demonstrates excellent 2-year LC with MWC and toxicity similar to standard fractionation preoperative RT. Multi-institutional trials with a universal RT protocol and larger sample size are warranted to assess this novel treatment paradigm.

Acute and Late Toxicities in Patients with Collagen Vascular Disease Receiving Curative-Intent Intensity-Modulated Radiotherapy to the Head and Neck Region

Historically, collagen vascular disease (CVD) was considered at least a relative contraindication to radiotherapy (RT). However, more recent meta-analyses suggest that for patients with certain CVDs such as rheumatoid arthritis (RA), there may not be an increased risk for severe toxicities, while for patients with CVDs such as systemic lupus erythematosus (SLE), dermatomyositis (DM) and scleroderma, there may be as high as a 2- to 4-fold risk for severe toxicities compared to patients without CVD. There are also data to suggest that patients with head and neck cancer (HNC) and comorbid CVD are at especially high risk of severe toxicities from RT. This study evaluated the hypothesis that among patients with HNC treated with curative-intent intensity-modulated radiation therapy (IMRT), patients with SLE or DM were more likely to have had late grade ≥3 toxicity rates compared to patients with other CVDs. A total of 23 patients who had HNC with comorbid CVD and received IMRT between 2005-2022 were included. Acute (≤90 days after completion of RT) and late (>90 days) toxicities were retrospectively classified using CTCAE v5.0. Toxicity rates were compared across CVD groups using Chi-squared tests. Median follow-up was 56.3 months. The most common CVDs were RA (9 patients, 39%), SLE (4 patients, 17%), and DM (4 patients, 17%). Median total RT dose was 66 Gy (range: 48-70 Gy), in 1.8-2.4 Gy fractions. Nine (39%) patients received concurrent chemotherapy. 14 (61%) patients had mucosal squamous cell carcinoma (SCC), 3 (13%) had cutaneous SCC, 2 (9%) had nasal cavity/paranasal sinus tumors, 2 (9%) had salivary gland tumors, 1 (4%) had cutaneous melanoma, and 1 (4%) had mucosal melanoma. Eight (35%) patients experienced acute grade ≥3 toxicities, and 3 (13%) patients experienced late grade ≥3 toxicities (Table 1). No patients had grade≥4 toxicities. Patients with SLE or DM did not have significantly higher risk of late grade ≥3 toxicities compared to those with other CVDs (25% vs. 7%, p = 0.21). In this small sample size of patients with HNC and comorbid CVD, definitive or post-operative IMRT was associated with approximately 35% acute and 15% late severe toxicity rates. While SLE/DM were associated with >3-fold late grade ≥3 toxicities, this association needs to be confirmed with larger data sets.

Comparison of Estimated Late Toxicities between IMRT and IMPT when Treating Retroperitoneal Sarcoma Preoperatively with Ultra-Hypofractionation

While preoperative radiation did not improve abdominal recurrence-free survival for retroperitoneal sarcoma (RPS) in the randomized STRASS trial, it did reduce rates of local recurrence. The risk of radiation-associated toxicity is substantial, with 77% of irradiated patients experiencing grade ≥3 lymphopenia in STRASS. Thus, finding methods to mitigate the issues of delaying surgery and irradiating normal tissue may provide a path towards affording the benefits of radiation while limiting its downside. One potential solution involves the use of hypofractionation to limit delay from radiation initiation to surgery, and proton therapy to limit dose to surrounding organs at risk (OARs). We conducted a dosimetric comparison of preoperative ultra-hypofractionated intensity-modulated photon radiotherapy (IMRT) and proton therapy (IMPT) for RPS, comparing estimated rates of late toxicity using published normal tissue complication probability (NTCP) models. Volumetric modulated arc therapy IMRT and IMPT plans were generated on 10 RPS patients previously treated with preoperative radiation. The prescription was 25 Gy radiobiological equivalent (GyE) to the clinical target volume (CTV) and 30 GyE to the margin-at-risk, all in five fractions. Proton doses were calculated using a radiobiological effective dose of 1.1. NTCPs were calculated for each OAR as a function of equivalent uniform dose. The ΔNTCP (difference in absolute NTCP between IMRT and IMPT plans) for each of the toxicity domains was calculated. Student T-tests were used to compare differences in dosimetric and NTCP outcomes. CTV coverage was met for all IMRT and IMPT plans with >99% of CTVs receiving ≥100% of prescription doses. The following endpoints were significantly lower with IMPT than IMRT: mean doses to liver, bone, and all analyzed genitourinary and gastrointestinal OARs; bowel, kidney, and bone V5-V20; stomach V15; liver V5; maximum doses to stomach, spinal canal, and body; and whole-body integral dose. No OAR endpoint was significantly higher with IMPT. The average ΔNTCP for grade 3 bowel ulceration/perforation and renal toxicity was 1.9% (p = .037) and 43.0% (p = .023), respectively, favoring IMPT. Using a model-based selection threshold of any ΔNTCP >10%, 50% (n = 5) of patients would be eligible for IMPT. IMPT maintained target coverage while significantly reducing dose to adjacent OARs and integral dose compared to IMRT. This translated to significantly lower risks of estimated late gastrointestinal and renal toxicities with IMPT. Further investigation is warranted to validate these findings and potential clinical benefit in the management of RPS. A prospective trial treating RPS with preoperative ultra-hypofractionated IMPT at our institution is currently being pursued (NCT05302570).

Toxicity and Outcomes of Definitive Local Therapy in Elderly Patients with HPV-Associated Oropharyngeal Cancer

The incidence of human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) has increased in elderly patients. It is unclear if survival outcomes in elderly patients are similar to those seen in younger patients with HPV-OPSCC. In this study we evaluated disease outcomes and toxicity in an elderly HPV-OPSCC population treated with curative-intent treatment of radiotherapy with or without chemotherapy. We performed a retrospective study of elderly patients (≥70 years old) with HPV-OPSCC treated between 2011-2021 with radiation therapy (RT) with or without chemotherapy. Time to event analysis for overall survival (OS), local control, and progression free survival (PFS) were estimated using the Kaplan-Meier method. Univariate and multivariate Cox regression models were used to estimate the hazard ratio associated with the covariates. We identified 77 elderly HPV-OPSCC patients, of which 60 (78%) were treated with concurrent chemotherapy. Twenty (26%) received concurrent Carboplatin and Taxol, 16 (21%) received Cetuximab, 14 (18%) received Cisplatin,7 (9%) received Carboplatin alone, and 2 (2%) received immunotherapy (Pembrolizumab or Nivolumab). The majority of patients received a radiation dose of 69.96 Gy or 70 Gy (89%). Forty-seven patients (61%) were stage I, 11 (14%) were stage II, 16 (21%) were Stage III, and 3 (4%) had stage IV disease. 50 patients (64%) were former smokers, 27 (35%) were nonsmokers and 1 (1%) is a current smoker. 37 patients (48%) had a ≥10 pack year smoking history. The 5-year OS, LC, and PFS for the entire cohort was 61%, 94%, and 58%, respectively. On univariate analysis, ECOG performance status (HR 0.22, [CI 0.06-0.78], p = 0.019) and Charlson Comorbidity Index (CCI) (HR 1.33, [CI 1.06-1.69], p = 0.014) were significant predictors of OS. On multivariate analysis, only CCI (HR 1.34, [CI 1.02-1.77], p = 0.035) was a significant predictor of OS. The rate of long-term feeding tube dependency was 9%. Late toxicities include osteoradionecrosis in 4 patients (5%), aspiration in 3 patients (4%), and esophageal stricture in 2 patients (3%). Elderly HPV-OPSCC patients treated with definitive intent radiotherapy with or without chemotherapy have favorable disease outcomes with low rates of late toxicity. The Charlson-Comorbidity Index can identify a subset of patients who may have a prolonged OS, and therefore may benefit from more aggressive treatment.

IMRT in the treatment of locally advanced or inoperable NSCLC in the pre-durvalumab era: clinical outcomes and pattern of relapses, experience from the Oscar Lambret Center.

Intensity-modulated conformal radiotherapy (IMRT) has become the technique of choice for the treatment of locally advanced or inoperable non-small cell lung cancer (NSCLC). Nevertheless, this technique presents dosimetric uncertainties, particularly in treating moving targets such as pulmonary neoplasms. Moreover, it theoretically increases the risk of isolated nodal failure (INF) due to reduced incidental irradiation. The objective of this study was to evaluate the efficacy and safety of IMRT in patients with inoperable NSCLC and to describe the pattern of relapses. Patients with locally advanced NSCLC treated with radiotherapy and chemotherapy between 2015 and 2018 at the Oscar Lambret Center were retrospectively included in the study. Overall and progression-free survival were estimated using the Kaplan-Meier method. The cumulative incidence of the different components of relapse was estimated using the Kalbfleisch and Prentice method. Prognostic factors for relapse/death were investigated using the Cox model. A comparison with literature data was performed using a one-sample log-rank test. Seventy patients were included, and 65 patients (93%) had stage III disease. All the patients received chemotherapy, most frequently with cisplatin and navelbine. The dose received was 66 Gy administered in 33 fractions. The median follow-up and survival were 49.1 and 39.1 months, respectively. A total of 35 deaths and 43 relapses, including 29 with metastatic components, were reported. The overall survival rates at 1 and 2 years were 80.2% (95% confidence interval 68.3%-88.0%) and 67.2% (95% confidence interval 54.2%-77.3%), respectively. Locoregional relapse was observed in 14 patients, including two INF, one of which was located in the lymph node area adjacent to the clinical target volume. Median relapse-free survival was 15.2 months. No variable was statistically associated with the risk of relapse/death in multivariate analysis. Seven patients (10%) experienced grade 3 or higher toxicity. The use of IMRT for locally advanced or inoperable NSCLC led to favorable long-term clinical outcomes. The rate of locoregional relapse, particularly isolated lymph node failure, was low and comparable with that of the three-dimensional radiotherapy series, as was the rate of early and late toxicities.

Utilizing a novel hybrid brachytherapy technique FINITO (Freehand Interstitial Needles in addition to Tandem and Ovoid) for locally advanced cervical cancer

PURPOSEWe aimed to assess the clinical feasibility and advantages of using a novel hybrid brachytherapy technique by placing Freehand Interstitial Needles in addition to the Tandem and Ovoid applicator (FINITO) for the treatment of locally advanced cervical cancer (LAC). METHODS AND MATERIALSA retrospective analysis was performed on two cohorts of patients with LACC treated at our institution: 29 patients in the FINITO group and 17 patients in the control group using T&O only approach. Clinical outcomes of interest included local control (LC), progression-free survival (PFS), overall survival (OS), and rates of acute and late toxicities. Kaplan–Meier methodology was used to estimate OS, PFS, and LC. Wilcoxon signed-rank test was used to compare the median values for dosimetry parameters. A p-value of ≤ 0.05 was considered statistically significant. All statistical analyses were performed using RStudio. RESULTSAt a median of 2 years there was no difference in rates of OS, PFS or LC between the FINITO and the control group of patients. The 2-year OS, PFS, and LC for the FINITO group were 59% (95% CI 34%–100%), 58% (95% CI 38%–89%), and 84% (95% CI 69%–100%), respectively. Late toxicities were significantly lower in the FINITO group for both gastrointestinal and genitourinary symptoms (p = 0.001 and 0.01, respectively) as compared to the T&O group. CONCLUSIONBased on the equivalent LC rate and lower toxicity profile, our FINITO technique appears to be an excellent alternative to the standard intracavitary brachytherapy in patients with advanced disease, especially in resource-limited settings.

Definitive chemoradiation in vulvar squamous cell carcinoma: outcome and toxicity from an observational multicenter Italian study on vulvar cancer (OLDLADY 1.1)

BackgroundVulvar carcinoma is a rather uncommon gynecological malignancy affecting elderly women and the treatment of loco-regional advanced carcinoma of the vulva (LAVC) is a challenge for both gynecologic and radiation oncologists. Definitive chemoradiation (CRT) is the treatment of choice, but with disappointing results. In this multicenter study (OLDLADY-1.1), several institutions have combined their retrospective data on LAVC patients to produce a real-world dataset aimed at collecting data on efficacy and safety of CRT.MethodsThe primary study end-point was 2-year-local control (LC), secondary end-points were 2-year-metastasis free-survival (MFS), 2-year-overall survival (OS) and the rate and severity of acute and late toxicities. Participating centers were required to fill data sets including age, stage, histology, grading as well as technical/dosimetric details of CRT. Data about response, local and regional recurrence, acute and late toxicities, follow-up and outcome measures were also collected. The toxicity was a posteriori documented through the Common Terminology Criteria for Adverse Events version 5 scale.ResultsRetrospective analysis was performed on 65 patients with primary or recurrent LAVC treated at five different radiation oncology institutions covering 11-year time interval (February 2010–November 2021). Median age at diagnosis was 72 years (range 32–89). With a median follow-up of 19 months (range 1–114 months), 2-year actuarial LC, MFS and OS rate were 43.2%, 84.9% and 59.7%, respectively. In 29 patients (44%), CRT was temporarily stopped (median 5 days, range 1–53 days) due to toxicity. The treatment interruption was statistically significant at univariate analysis of factors predicting LC (p: 0.05) and OS rate (p: 0.011), and it was confirmed at the multivariate analysis for LC rate (p: 0.032). In terms of toxicity profile, no G4 event was recorded. Most adverse events were reported as grade 1 or 2. Only 14 acute G3 toxicities, all cutaneous, and 7 late G3 events (3 genitourinary, 3 cutaneous, and 1 vaginal stenosis) were recorded.ConclusionIn the context of CRT for LAVC, the present study reports encouraging results even if there is clearly room for further improvements, in terms of both treatment outcomes, toxicity and treatment interruption management.