Low-grade Toxicity Research Articles

MT-Keyboard: A Bayesian Model-Assisted Interval Design to Account for Toxicity Grades and Types for Phase I Trials

Conventionally, dose finding trials are based on dose-limiting toxicity (DLT) that only captures the most severe toxicities, for example, treatment related grade 3 or higher toxicity according to the NCI Common Terminology Criteria for Adverse Events. However, this approach is often problematic for certain novel targeted therapies and immunotherapies, which may not induce DLT within a clinically active dose range and are often characterized by low grade toxicities. This important issue has been highlighted and discussed in the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forums, and is also an important consideration of the Project Optimus initiated by FDA to “reform the dose optimization and dose selection paradigm in oncology drug development.” In this article, we propose an easy-to-implement model-assisted Bayesian design, known as multiple toxicity keyboard (MT-Keyboard) design, to incorporate toxicity grades and types into dose finding. The MT-Keyboard design is able to accommodate binary, quasi-binary and continuous toxicity endpoints that are constructed to account for toxicity grades and types. We further extend the MT-Keyboard design, referred to as TITE-MT-Keyboard, to accommodate late-onset toxicity using the approximated likelihood approach. Simulation shows that the MT-Keyboard and TITE-MT-Keyboard designs have desirable operating characteristics, comparable to or better than some existing designs. A web-based software to implement the design will be freely available at www.trialdesign.org. Supplementary materials for this article are available online.

Abstract PO2-22-05: A prospective phase I-II study of hypofractionated accelerated breast and nodal intensity modulated radiation therapy delivered in the prone position

Abstract Background In patients with breast cancer, prone radiotherapy (RT) has been shown to reduce heart and lung dose. Routinely used for whole breast (WB) RT, its use to treat regional lymph nodes (LNs) is not widespread. Methods In this phase I-II study (NCT02308488) patients treated with lumpectomy or mastectomy with 1-5 pathologically involved LNs underwent WBRT or post-mastectomy RT plus regional nodal RT using IMRT to the supraclavicular and level III axillary LNs. The prescription was 40.5Gy in 15 daily 2.7Gy fractions with a daily concomitant 0.5Gy tumor bed boost. Patients who underwent sentinel LN biopsy (SLNB) alone (no axillary dissection) had the level I-II axilla included in the RT field. The primary endpoints were incidence of >grade 2 acute toxicity per CTCAE v 3.0 and dosimetric feasibility. The secondary endpoint was late toxicity. Clinical outcomes were local recurrence (LR), disease free survival (DFS), distant recurrence free survival (DRFS) and overall survival (OS). Coverage constraints included planning target volume [PTV] V48Gy ≥ 98%, PTV breast V40.5Gy ≥ 95% and PTV nodes V38.5Gy ≥ 95%. Normal tissue constraints included heart V5Gy < 5%, ipsilateral lung V10Gy < 20%, contralateral lung V5Gy < 15%, ipsilateral brachial plexus (BP) maximal dose (Dmax) < 42Gy, spinal cord Dmax ≤ 3 7.5Gy, thyroid contralateral lobe Dmax ≤ 15Gy, esophagus V30Gy < 50% and Dmax ≤ 40.5Gy. Results From 2011-2016, 97 patients with stage IB-IIA breast cancer were enrolled. 66 underwent lumpectomy and 31 underwent mastectomy. 16 had SLNB alone. There were no grade 3 acute toxicities meeting the primary toxicity endpoint. Common acute low-grade toxicities included fatigue (grade 1: 65 [66.3%]; grade 2: 7 [7.1%]), esophagitis (grade 1: 7 [7.1%]; grade 2: 10 [10.2%]), dermatitis (grade 1: 82 [83.7%]; grade 2: 7 [7.1%]). At median and maximum follow up of 8.02 (IQR: 3.31) and 13.3 years, respectively, there were 2 LRs (2.1%). 8-year DRFS, DFS and OS were 88.1% (95% CI 81.3%, 95.4%), 85.7% (95% CI 78.4%, 94.6%) and 90.5% (95% CI 84%, 97.6%), respectively. Clinician-rated cosmesis (n=64) was excellent/good in 67.2% of cases and fair/poor in 6.3%. Patient- rated cosmesis (n=47) was excellent/good in 91.5% and fair/poor in 8.5%, with patients rating themselves more favorably than their physicians (p=0.0014). The incidence of maximum grade 1, 2 and 3 late toxicities were 49 (62.8%), 15 (19.2%), and 3 (3.8%), respectively. This included 2 grade 3 asymmetries,1 grade 3 pigmentation change, and 1 grade 2 pneumonitis. There was no brachial plexopathy. Among the 28 patients who underwent reconstruction, 17 were implant-based and 11 were autologous. Of the implant-based, 9 underwent RT to the tissue expander and 8 to the permanent implant. 11/28 patients had long-term plastic surgery follow up. There were 3 hospitalizations with reoperation post-RT (1 unplanned revision, 1 implant removal for threatened exposure, and 1 excision of fat necrosis). There was 1 incident of wound infection/cellulitis. With regard to dosimetric constraints, 54.3% of plans (95% CI 43.6%, 64.8%) met all constraints. 92% (95% CI 83%, 97%), 98% (95% CI 93%, 100%) and 89% (95% CI 80%, 94%) met the PTV tumor V48Gy, PTV breast V40.5Gy, and PTV nodes V38.5Gy coverage constraints, respectively. Heart, contralateral lung, spinal cord, and esophagus constraints were met by all patients. 95% (95% CI 88.6%, 98.4%) met the ipsilateral lung V10Gy and 99% (95% CI 94%, 100%) met the thyroid contralateral lobe constraint. The BP constraint was met in 73% (95% CI 63.0%, 81.0%) of plans with a mean increase of 1.61 Gy (SD 1.96 Gy) over target. Conclusion Toxicity was low and outcomes were excellent in this prospective trial of hypofractionated regional nodal RT in the prone position. Dosimetric constraints were only met in 54% of plans with the nodal coverage and the BP constraint as the most frequently unmet. These constraints may need to be modified and/or techniques refined to optimize hypofractionated prone nodal RT. Citation Format: Juhi Purswani, Olivier Maisonet, Julie Xiao, Jose R Teruel, Christine Hitchen, Xiaochun Li, Judith D. Goldberg, Carmen A. Perez, Silvia C. Formenti, Naamit K. Gerber. A prospective phase I-II study of hypofractionated accelerated breast and nodal intensity modulated radiation therapy delivered in the prone position [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-22-05.

POTENTIAL IMPACT OF EXERCISE UPON SYMPTOM BURDEN IN ADOLESCENTS AND YOUNG ADULTS UNDERGOING CANCER TREATMENT

INTRODUCTION Adolescents and young adults (AYAs) experience vast symptom burden resulting from cancer treatment-related toxicities (TRTs). Evidence supports exercise to mitigate several TRTs in other cohorts, however evidence in AYAs is lacking. Conventional reporting of TRTs adopts a maximum grade approach failing to recognise the trajectory over time or lower grade toxicities. Alternatively, longitudinal analysis of toxicities over time (ToxT) may provide clinically meaningful summaries of this data. We evaluated the longitudinal impact of an exercise intervention on TRTs in AYAs undergoing cancer treatment. METHODS A prospective, randomised trial allocated participants to a 10-week exercise intervention (EG) or control group (CG) undergoing usual care. Detailed information on TRTs was collected throughout the intervention. All TRTs were graded per the Common Terminology Criteria for Adverse Events (CTCAE v5.0). RESULTS Forty-three (43) participants (63% male, mean age 21.1 years) were enrolled. When categorised to reflect the maximal worst grade experienced (Grade 0, Grade 1-2 and ≥Grade 3), the CG reported an increased incidence of severe fatigue (≥Grade 3) compared with the EG (p=0.05). No other differences between groups were evident (p>0.05). ToxT analysis of the four most common toxicities (fatigue, pain, nausea and mood disturbances) demonstrated no difference in the mean grade of each over time (p>0.05). Additionally, area under the curve (AUC) analysis revealed trends towards a higher magnitude of fatigue (mean AUC 12.5 vs 11.1 p=0.11) and mood disturbances (mean AUC 7.2 vs 5.7 p=0.28) over time in the CG. No differences were evident for pain and nausea between groups (p>0.05). CONCLUSION A 10-week exercise intervention reduces the severity of fatigue in AYAs undergoing treatment. While the ToxT approach provided insight into the toxicity profile, adequately powered studies are needed to better understand these differences within a homogeneous sample

The potential impact of exercise upon symptom burden in adolescents and young adults undergoing cancer treatment

PurposeAdolescents and young adults (AYAs) experience vast symptom burden resulting from cancer treatment-related toxicities (TRTs). Evidence supports integrated exercise to mitigate several TRTs in other cohorts; however, evidence in AYAs is lacking. Conventional reporting of TRTs adopts a maximum grade approach failing to recognise the trajectory over time, of persistent, or lower grade toxicities. Alternatively, longitudinal analysis of toxicities over time (ToxT) may provide clinically meaningful summaries of this data. We evaluated the longitudinal impact of an exercise intervention on TRTs in AYAs undergoing cancer treatment.MethodsA prospective, randomised trial allocated participants to a 10-week exercise intervention (EG) or control group (CG) undergoing usual care. Detailed information on TRTs was collected throughout the intervention. All TRTs were graded per the Common Terminology Criteria for Adverse Events (CTCAE v5.0).ResultsForty-three (43) participants (63% male, mean age 21.1 years) were enrolled. When categorised to reflect the maximal worst grade experienced (Grade 0, Grade 1–2 and ≥ Grade 3), the CG reported an increased incidence of severe fatigue (≥ Grade 3) compared with the EG (p = 0.05). No other differences between groups were evident (p > 0.05). ToxT analysis of the four most common toxicities (fatigue, pain, nausea and mood disturbances) demonstrated no difference in the mean grade of each over time (p > 0.05).ConclusionA 10-week exercise intervention reduces the severity of fatigue in AYAs undergoing treatment. While the ToxT approach provided insight into the toxicity profile, adequately powered studies are needed to better understand these differences within a homogenous sample.Trial registration(ACTRN12620000663954) 10th June 2020.

MC-Keyboard: A Practical Phase I Trial Design for Targeted Therapies and Immunotherapies Integrating Multiple-Grade Toxicities.

In targeted therapies and immunotherapies, the occurrence of low-grade (e.g., grade 1-2) toxicities (LGT) is common, while dose-limiting toxicities (DLT) are relatively rare. As a result, conventional phase I trial designs, solely based on DLTs and disregarding milder toxicities, are problematic when evaluating these novel therapies. Methods: To address this issue, we propose a novel phase I design called a multiple-constraint keyboard (MC-Keyboard) that integrates multiple toxicity constraints, accounting for both DLT and LGT, for precise dose escalation and de-escalation, and identification of the maximum tolerated dose (MTD). As a model-assisted design, an important feature of MC-Keyboard is that its dose-escalation or de-escalation rule can be pretabulated and incorporated into the trial protocol before the initiation of the trial, greatly simplifying its implementation. Results: The simulation study showed that the MC-Keyboard had high accuracy in identifying the MTD and is safer than some existing designs. Conclusion: The MC-Keyboard provides a novel, simple, and safe approach to assessing safety and identifying the MTD for targeted therapies and immunotherapies.

Safety of Total Skin Electron Therapy with Concurrent Systemic Therapy

Introduction: Mycosis fungoides has a long, waxing and waning course. Multimodality therapy is needed to control disease. Total skin electron beam therapy (TSE) is an effective means of controlling cutaneous disease, though response duration is limited necessitating incorporation of additional therapeutics. There are limited data informing the safety of systemic agents used concurrently with TSE. We characterize acute toxicities of patients undergoing TSE +/- concurrent or recent systemic therapy. Methods: We retrospectively analyzed 114 patients comprising a total of 121 consecutive courses of full body TSE from 2013-2023. Median follow up was 1.75 years from start of TSE. Toxicities occurring up to 3 months following radiation were recorded and graded per CTCAEv5 criteria when applicable; grade was characterized as low (grades 1-2) and high (3-4). Given conflating cutaneous symptoms prior to TSE, toxicities were further characterized as “new or worsened” (N/W) from baseline. Incidence of N/W toxicity was further categorized by class of systemic therapy: interferon, retinoic acid derivative, immunotherapy, systemic steroid, histone deacetylase inhibitor, folic analogue antimetabolite, and other. Recent systemic therapy included receipt of therapy within 1 and 3 months preceding TSE given multi-month half lives of some systemics. Results: During 75 courses, patients received systemic therapy concurrently with TSE (CS), and 46 had no concurrent systemic therapy (NCS). The majority of concurrent systemic therapies were interferons (49, 41%) and retinoic acid derivatives (32, 27%); “other” concurrent systemics included lenalidomide, imatinib, and ibrutinib. TSE dose included 36Gy (5%), 24Gy (6%), 12Gy (84%), and other (5%). Most patients had ECOG performance status 0-1 (88% overall). Patient characteristics were well balanced, excepting stage at TSE (stage III/IV CS 45.3% vs NCS 26.1%, p<0.05), though T stage and blood involvement were evenly distributed. At baseline among CS and NCS patients, 29% vs 30% had skin ulceration, 27% vs 35% had large cell transformation, and 12% vs 13% had concurrent infection, respectively (all p>0.05). Incidence of any N/W toxicity was 98.7% and 100% ( p>0.05)among CS and NCS patients, respectively (95% vs 94% low grade and 13% vs 26% high grade, both p>0.05). Prior to TSE, baseline rates of common symptoms among CS vs NCS courses were as follows: dermatitis 96% vs 94%, hyperpigmentation 28% vs 28%, edema 15% vs 24%, pruritus 97% vs 87%, and skin pain 32% vs 45%, respectively (all p>0.05). From start of TSE through 3 month follow up, the overall incidences of CS vs NCS N/W common toxicities included the following: N/W dermatitis 73% vs 83%, N/W hyperpigmentation 33% vs 37%, and N/W edema 21% vs 24% (all p>0.05). Twenty-five percent of CS patients experienced skin pain flare during TSE vs 13% NCS, and 20% of CS patients vs 11% NCS experienced pruritus flare (all p>0.05). At end of treatment, 59% of CS patients with baseline pruritus experienced improvement compared to 68% NCS, with 73% vs 70% experiencing improvement at 1-3 months in follow up (all p>0.05). One patient received a known concurrent radiosensitizer - methotrexate - and developed N/W grade 3 dermatitis (baseline grade 3), new grade 2 hyperpigmentation, worsened grade 1 anorexia, new grade 2 superficial soft tissue fibrosis, and pain flare. The median number of all reported N/W toxicities among systemic classes when given concurrently was low and well balanced. This persisted when the number of toxicities per class were assessed among systemics administered within 1 month preceding TSE, and within 3 months preceding TSE. Conclusions: Concurrent or recent receipt of systemic therapy can be safe among most commonly used concurrent agents that are not radiosensitizers. There was no notable increase in incidence of low or high grade toxicity, or median number of low or high grade toxicities recorded in CS vs NCS patients. Most patients experienced some acute toxicity, which is not unexpected given radiation to a tissue with high cell turnover, and the interplay of toxicity with expected disease response to TSE. High rates of baseline dermatitis and high rates of N/W dermatitis highlight this observation. Notably most systemic therapies included interferons and retinoic acid derivatives. Additional data is needed to better characterize the toxicity profile of other systemic therapies used concurrently with TSE.

Baseline neutrophil-lymphocyte ratio and platelet-lymphocyte ratio appear predictive of immune treatment related toxicity in hepatocellular carcinoma.

A well-recognized class effect of immune checkpoint inhibitors (ICI) is immune-related adverse events (IrAEs) ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI. Deaths are reported in < 5% of patients treated with ICI. There are, however, no reliable markers to predict the onset and severity of IrAEs. We tested the association between neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) at baseline with development of clinically significant IrAEs (grade ≥ 2) in hepatocellular carcinoma (HCC) patients treated with ICI. To test the association between NLR and PLR at baseline with development of clinically significant IrAEs (grade ≥ 2) in HCC patients treated with ICI. Data was extracted from an international database from a consortium of 11 tertiary-care referral centers. NLR = absolute neutrophil count/absolute lymphocyte count (ALC) and PLR = platelet count/ALC. Cutoff of 5 was used for NLR and 300 for PLR based on literature. We also tested the association between antibiotic and steroid exposure to IrAEs. Data was collected from 361 patients treated between 2016-2020 across the United States (67%), Asia (14%) and Europe (19%). Most patients received Nivolumab (n = 255, 71%). One hundred sixty-seven (46%) patients developed at least one IrAE, highest grade 1 in 80 (48%), grade ≥ 2 in 87 (52%) patients. In a univariable regression model PLR > 300 was significantly associated with a lower incidence of grade ≥ 2 IrAEs (OR = 0.40; P = 0.044). Similarly, a trend was observed between NLR > 5 and lower incidence of grade ≥ 2 IrAEs (OR = 0.58; P = 0.097). Multivariate analyses confirmed PLR > 300 as an independent predictive marker of grade ≥ 2 IrAEs (OR = 0.26; P = 0.011), in addition to treatment with programmed cell death ligand 1 (PD-1)/cytotoxic T lymphocyte-associated protein-4 (OR = 2.57; P = 0.037) and PD-1/tyrosine kinase inhibitor (OR = 3.39; P = 0.01) combinations. Antibiotic use was not associated with IrAE incidence (OR = 1.02; P = 0.954). Patients treated with steroids had a > 2-fold higher incidence of grade ≥ 2 IrAEs (OR = 2.74; P < 0.001), although 74% were prescribed steroids for the treatment of IrAEs. Given that high baseline NLR and PLR are associated with a decreased incidence of IrAEs, lower baseline NLR and PLR may be predictive biomarkers for the appearance of IrAEs in HCC treated with ICI. This finding is in keeping with several studies in solid tumors that have shown that baseline NLR and PLR appear predictive of IrAEs.

Fixed Duration Combination Therapy with Carfilzomib, Lenalidomide, and Dexamethasone Followed By Lenalidomide Maintenance Leads to High Rates of Sustained MRD Negativity in Patients with High-Risk Smoldering Multiple Myeloma: Long Term Follow up of an Investigator Initiated Phase 2 Trial

Background: Patients with high-risk smoldering multiple myeloma (HR-SMM) have a 5-year risk of progression to symptomatic multiple myeloma of approximately 75% and a median time to progression of less than 2 years (Lakshman et al., Blood Cancer J 2018) (Rajkumar et al., Blood 2015). We previously reported the primary results of our phase 2 trial of carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide maintenance (KRd-R) as prevention of symptomatic multiple myeloma in patients with HR-SMM (Kazandjian et al., JAMA Onc 2021). Herein, we present follow-up data after all patients have completed lenalidomide maintenance to evaluate the durability of responses off therapy. Methods: Patients with HR-SMM based on the Mayo Clinic, PETHEMA, and/or Rajkumar, Mateos, and Landgren criteria were eligible for enrollment in this single-center phase 2 investigator-initiated study. Patients received eight 28-day cycles (induction) of carfilzomib, 20/36 mg/m 2, with dexamethasone 20/10 (days 1,2, 8, 9, 15, 16) and lenalidomide 25 mg (days 1-21), followed by 2 years of maintenance therapy with lenalidomide 10 mg (days 1-21). The primary endpoint was the rate of minimum residual disease negative complete responses (MRD negative CR) at the end of induction as assessed by multicolor flow cytometry (MRD sensitivity 10 -5). Secondary objectives included progression to overt clinical multiple myeloma (end-organ damage or myeloma-defining event) or death (clinical PFS) and biochemical progression (PD) by IMWG criteria (biochemical PFS). Results: A total of54 patients were enrolled and started treatment between May 29, 2012 and July 23, 2020. Full patient demographics and baseline disease characteristics were previously reported. (Kazandjian et al., JAMA Onc 2021) At the data cut-off of July 17, 2023, the median follow-up time was 60.2 months (range: 33.7 - 127.8). As previously reported, 38 patients (70.4%) achieved MRD negative CR by the end of induction. The median duration of MRD negative CR was 57.4 months (95% CI: 44.6 - 97.2). To date, durability of MRD negative CR has been observed up to 120.6 months and 21 patients (39%) have remained MRD negative for over 2 years (95% CI: 25.9 - 53.1%). (Figure 1) All patients attained a PR or better and the median duration of response has still not been reached. At 60 months, 75.1% of patients maintained their response (95% CI: 59.9 - 85.2%). The median clinical PFS has also not been reached. Only 5 out of 54 (9.3%; 95% CI: 3.1-20.3%) patients have progressed to clinical multiple myeloma. At 60 months, 92.7% of patients were free from clinical progression (95% CI: 78.1 - 97.9%). The probability of being free of clinical progression at 100 months was 78.9% (95% CI: 51.9 - 91.8%). While the median biochemical PFS has not been reached, patients who were MRD negative by the end of induction had significantly less risk of having biochemical progression compared to patients who still had measurable disease at completion of induction (median biochemical PFS NR vs. 41.8 (HR 0.168 (95% CI: 0.060 - 0.474) (P value &amp;lt; 0.0001) (Figure 2). As previously reported, KRd-R was well tolerated, with no grade 4 non-hematologic adverse events and manageable low-grade toxicities. Discussion: Treatment of patients with HR-SMM with KRd-R has led to deep and durable remissions. At a median of 5 years of follow-up, this trial has yet to reach a median clinical PFS, indicating success in preventing serious end organ damage. However, it is still unclear if the beneficial outcomes seen in HR-SMM interventional studies are due to treatment of more susceptible disease or inherently less aggressive disease. An abstract evaluating the genomic profile of patients from this trial has been submitted to the meeting separately. Future prospective trials must capture and eventually select HR profiles based on validated genomic signatures. This study suggests that patients who achieve MRD negative remissions after induction therapy have prolonged biochemical PFS. However, further follow-up time is needed to fully understand the rates of clinical PFS and OS. To evaluate if additional treatment duration to achieve MRD negativity would be beneficial we have designed a trial using daratumumab, carfilzomib, and dexamethasone utilizing an adaptive treatment duration based on MRD status for patients with HR-SMM which is currently enrolling participants (NCT04933539).

Phase I-II Study of Prone Hypofractionated Accelerated Breast and Nodal Intensity Modulated Radiation Therapy

In patients (pts) with breast cancer, prone radiation therapy (RT) has been shown to reduce heart and lung dose which may decrease late toxicity. Routinely used for whole breast irradiation, its use to treat regional lymph nodes (LNs) is not widespread. In this phase I-II study, pts treated with partial mastectomy or mastectomy with 1-5 pathologically involved LNs underwent whole breast or post-mastectomy RT plus regional nodal irradiation using IMRT to the supraclavicular and level III axillary LNs. Pts who underwent sentinel LN biopsy (SLNB) alone (no axillary dissection) had the level I and II axillary LNs included in the RT field. 40.5Gy in 15 daily 2.7Gy fractions with daily concomitant 0.5Gy tumor bed boost was prescribed. Normal tissue dose constraints included heart V5Gy<5%, ipsilateral lung V10Gy<20%, contralateral lung V5Gy<15%, ipsilateral brachial plexus (BP) maximal dose (Dmax)<43Gy, spinal cord Dmax≤37.5Gy, spinal cord + 0.5cm Dmax<41Gy, thyroid contralateral lobe Dmax<16Gy, esophagus V30Gy<50% and Dmax≤40.5Gy. The primary endpoints were dosimetric feasibility and incidence of >grade 2 acute toxicity according to CTCAE, v3.0. The secondary endpoint was late toxicity. Exploratory outcomes were local recurrence, disease free survival (DFS), and overall survival (OS). Between January 2011 to December 2016, 97 pts with stage IB-IIA breast cancer were enrolled. 66 pts underwent partial mastectomy and 31 pts underwent mastectomy. 16 pts had SLNB alone. 33% (95% CI: 23.8%, 43.3%) met all protocol dose constraints. Heart, contralateral lung, spinal cord and esophagus V30Gy constraints were met by all pts. The ipsilateral lung constraint was met in 95% (95% CI: 88.6%, 98.4%) of plans with a mean V10Gy of 9.44% (SD: 6.08). The BP Dmax constraint was exceeded in 31.6% (95% CI: 22.4%, 41.9%) of plans with a mean increase of 2.86 Gy (SD: 7.92 Gy) over target. The esophageal Dmax<40.5Gy constraint was exceeded in 6 plans with an increase in 0.74 Gy (SD: 0.46 Gy) over target. There were no grade 3 acute toxicities meeting the primary toxicity endpoint. Common acute low-grade toxicities by pt included fatigue (grade 1: 54 [56%]; grade 2: 2 [2%]), esophagitis (grade 1: 8 [8%]; grade 2: 2 [2%]), dermatitis (grade 1: 81 [84%]; grade 2: 6 [6%]). At median and maximum follow up of 8.02 (IQR: 3.31) and 13.3 years, respectively, there were 2 local recurrences (2.1%). DFS and OS were 86.6% (95% CI: 78.2%, 92.7%) and 90.7% (95% CI: 83.1%, 95.7%), respectively. The incidence of pts with maximum grade 1, 2 and 3 late toxicities were 39 (40%), 14 (14%), and 2 (2%), respectively. The maximum grade late toxicities included 1 grade 3 retraction and 2 grade 3 asymmetries. There was no brachial plexopathy or pneumonitis. Patients treated with prone hypofractionated hybrid breast/chest wall tangents and IMRT to the regional LNs demonstrate excellent dosimetry to the heart, lungs and spinal cord, minimal acute and late toxicity and excellent clinical outcomes. PMID: 26723552.

Kidney Disease in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review

Kidney injury is a known late and potentially devastating complication of abdominal radiation therapy (RT) in pediatric patients. A comprehensive Pediatric Normal Tissue Effects in the Clinic review by the Genitourinary (GU) Task Force aimed to describe RT dose-volume relationships for GU dysfunction, including kidney, bladder, and hypertension, for pediatric malignancies. The effect of chemotherapy was also considered. We conducted a comprehensive PubMed search of peer-reviewed manuscripts published from 1990 to 2017 for investigations on RT-associated GU toxicities in children treated for cancer. We retrieved 3271 articles with 100 fulfilling criteria for full review, 24 with RT dose data and 13 adequate for modeling. Endpoints were heterogenous and grouped according to National Kidney Foundation: grade ≥1, grade ≥2, and grade ≥3. We modeled whole kidney exposure from total body irradiation (TBI) for hematopoietic stem cell transplant and whole abdominal irradiation (WAI) for patients with Wilms tumor. Partial kidney tolerance was modeled from a single publication from 2021 after the comprehensive review revealed no usable partial kidney data. Inadequate data existed for analysis of bladder RT-associated toxicities. The 13 reports with long-term GU outcomes suitable for modeling included 4 on WAI for Wilms tumor, 8 on TBI, and 1 for partial renal RT exposure. These reports evaluated a total of 1191 pediatric patients, including: WAI 86, TBI 666, and 439 partial kidney. The age range at the time of RT was 1 month to 18 years with medians of 2 to 11 years in the various reports. In our whole kidney analysis we were unable to include chemotherapy because of the heterogeneity of regimens and paucity of data. Age-specific toxicity data were also unavailable. Wilms studies occurred from 1968 to 2011 with mean follow-ups 8 to 15 years. TBI studies occurred from 1969 to 2004 with mean follow-ups of 4 months to 16 years. We modeled risk of dysfunction by RT dose and grade of toxicity. Normal tissue complication rates ≥5%, expressed as equivalent doses, 2 Gy/fx for whole kidney exposures occurred at 8.5, 10.2, and 14.5 Gy for National Kidney Foundation grades ≥1, ≥2, and ≥3, respectively. Conventional Wilms WAI of 10.5 Gy in 6 fx had risks of ≥grade 2 toxicity 4% and ≥grade 3 toxicity 1%. For fractionated 12 Gy TBI, those risks were 8% and <3%, respectively. Data did not support whole kidney modeling with chemotherapy. Partial kidney modeling from 439 survivors who received RT (median age, 7.3 years) demonstrated 5 or 10 Gy to 100% kidney gave a <5% risk of grades 3 to 5 toxicity with 1500 mg/m2 carboplatin or no chemo. With 480 mg/m2 cisplatin, a 3% risk of ≥grade 3 toxicity occurred without RT and a 5% risk when 26% kidney received ≥10 Gy. With 63 g/m2 of ifosfamide, a 5% risk of ≥grade 3 toxicity occurred with no RT, and a 10% toxicity risk occurred when 42% kidney received ≥10 Gy. In patients with Wilms tumor, the risk of toxicity from 10.5 Gy of WAI is low. For 12 Gy fractionated TBI with various mixtures of chemotherapy, the risk of severe toxicity is low, but low-grade toxicity is not uncommon. Partial kidney data are limited and toxicity is associated heavily with the use of nephrotoxic chemotherapeutic agents. Our efforts demonstrate the need for improved data gathering, systematic follow-up, and reporting in future clinical studies. Current radiation dose used for Wilms tumor and TBI appear to be safe; however, efforts in effective kidney-sparing TBI and WAI regimens may reduce the risks of renal injury without compromising cure.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Background: While oral targeted therapies (OTT) have transformed the care of patients (pts) with lymphoma, adherence, cost, and chronic low-grade toxicities with subsequent impact on health-related quality of life (HRQoL) remain challenging issues. There are limited data on HRQoL in older adults (OA), who tend to be more vulnerable to treatment-related adverse effects. We prospectively evaluated the role of geriatric assessment (GA) in predicting HRQoL and adherence in OA with lymphoma on OTT. Methods: Pts ≥70 years (yrs) with lymphoma, initiating or already on OTT were included. A GA was performed at baseline; pt, disease, and OTT characteristics were recorded. Pts were followed monthly for the first 3 months (mos), then every 3 mos for 1 year. QoL was measured at each visit using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 (EORTC QLQ-C30) and EORTC QLQ- chronic lymphocytic leukemia 16 (EORTC QLQ-CLL16) modules. The log QoL scores were modeled as a function of visit and mean scores at 12 months were compared to baseline using a linear mixed model. Results: We enrolled 50 pts. Median age was 77 yrs (70–93 yrs) with 88% pts having at least 1 geriatric syndrome (GS), including cognitive impairment (22%), depression (24%), polypharmacy (86%) and falls (16%); 50% pts had ≥2 GS; 50% having an impaired 4-meter gait speed (<1 m/s); 46% having an abnormal timed-up-and-go (TUG) time (>10s) and 86% had an adjusted CIRS-G score of ≥6. OTT included ibrutinib (54%), venetoclax (26%) and acalabrutinib (12%). At baseline, advancing age, activities of daily living (ADL) dependence, and instrumental activities of daily living (IADL) dependence were associated with inferior global health status, physical functioning, role functioning, and cognitive functioning scores. IADL dependence was also associated with worse social functioning and most symptoms scores. An abnormal TUG was associated with lower global health score (p = 0.002) and cognitive functioning (p = 0.003). At the end of 1 year, there was a statistically significant worsening of global health status (mean difference -8.4, p = 0.003) without any changes in other functional scales; however, it did not reach the predefined criterion for clinical relevance (absolute difference of >10, Figure 1). Only impaired baseline TUG was associated with significant worsening of global health status (-1.9 vs. -23.2, p = 0.048), physical (4.1 vs. -8.2, p = 0.031), role (1.3 vs. -18.5, p = 0.026) and social functioning (5.1 vs. -24.1, p = 0.016), and increasing fatigue scale (-11.5 vs. 20.4, p < 0.001) over 1 year. Other geriatric impairments did not impact changes in HRQoL over time. The research was funded by: Roswell Park Alliance Foundation Keywords: Cancer Health Disparities, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. P. Torka Consultant or advisory role: Genenetech, GenMab, Lilly USA, Seagen

Current management and new treatment strategies of chronic myeloid leukemia

The introduction of orally available tyrosine kinase inhibitors (TKI) into the treatment of chronic myeloid leukemia (CML) 25 years ago has substantially improved the clinical outcome of affected patients and resulted in a near-normal life expectancy in chronic phase (CP). Despite of a significant fraction of currently about one third of newly diagnosed CP patients eventually reaching treatment-free remission, the majority of patients still remain on life-long treatment with TKIs. Therefore, a profound knowledge of TKI-related side effects including an increased sensitivity for organ systems predominantly involved, grading, kinetics, duration and reversibility, class-effects versus compound-relatedness as well as a better understanding of how particularly long-lasting, chronic, sometimes formally low-grade toxicities can actually significantly impair patient's self-assessed quality of life is of utmost importance for an adequate patient/doctor relationship. Given that nowadays, severity and degree of preexisting comorbidities might predict long-term survival of individual patients more significantly than the underlying CML itself, it becomes most important to properly and thoroughly select the TKI of choice on this basis as well as on the individually required co-medications. Given the variety of 2nd, 3rd and now allosteric TKIs available for the molecular targeting of the disease-driving BCR-ABL oncogene in addition to the "class-defining" Imatinib, personalization of CML therapy should now be further extended towards a better appreciation of comorbidities and co-medications before selection of an individual's TKI treatment complemented by a long-term oriented, patient-centered management and prevention of (sometimes irreversible) TKI side effects.

Precision fluoropyrimidines dosing in a compound heterozygous variant carrier of the DPYD gene: a case report.

Fluoropyrimidines (FPs) form still nowadays the backbone of chemotherapic schemes in colorectal cancer (CRC). Inter-patient variability of the toxicity profile of FPs may be partially accounted for by variable expression of dihydropyrimidine dehydrogenase (DPD). DPD rate activity is genetically determined by its extremely polymorphic coding gene DPYD. In spite of pharmacogenetic guideline-directed-dosing of FPs based regimens treating carrier of multiple variants of DPYD gene remains still challenging. We present a case of a 48-year-old Caucasian man, compound heterozygous variant carrier of the DPYD gene (HapB3 and c.2194G>A) who had a diagnosis of adenocarcinoma of the left colon and was safely treated with a pharmacogenetic-guided 25% dose reduction of the standard CAP adjuvant treatment. Compound heterozygosis may have been responsible for an earlier over exposure to CAP resulting into low-grade toxicity with an anticipated median time to toxicity of the c.2194G>A variant to the 4th vs. 6th cycles. Some haplotypes of DPYD variants may have an advantage in terms of survival compared to wild-type patients. Our patient may also have benefitted from compound heterozygosis, as shown by no evidence of disease (NED) at 6-month follow-up. Pharmacogenetic-guided dosing of DPYD intermediate metabolizer compound heterozygous HapB3 and c.2194G>A variant carries should be managed by a multidisciplinary team with a dose reduction ranging from 25 to 50% to maintain effectiveness and close clinical monitoring for early detection of ADRs.

Stereotactic MR-Guided Adaptive Radiotherapy for Pancreatic Tumors: Updated Results of the Montpellier Prospective Registry Study.

Stereotactic MR-guided Adaptive RadioTherapy (SMART) is a novel process to treat pancreatic tumors. We present an update of the data from our prospective registry of SMART for pancreatic tumors. After the establishment of the SMART indication in a multidisciplinary board, we included all patients treated for pancreatic tumors. Primary endpoints were acute and late toxicities. Secondary endpoints were survival outcomes (local control, overall survival, distant metastasis free survival) and dosimetric advantages of adaptive process on targets volumes and OAR. We included seventy consecutive patients in our cohort between October 2019 and April 2022. The prescribed dose was 50 Gy in 5 consecutive fractions. No severe acute SMART related toxicity was noted. Acute and late Grade ≤ 2 gastro intestinal were low. Daily adaptation significantly improved PTV and GTV coverage as well as OAR sparing. With a median follow-up of 10.8 months since SMART completion, the median OS, 6-months OS, and 1-year OS were 20.9 months, 86.7% (95% CI: (75-93%), and 68.6% (95% CI: (53-80%), respectively, from SMART completion. Local control at 6 months, 1 year, and 2 years were, respectively, 96.8 % (95% CI: 88-99%), 86.5 (95% CI: 68-95%), and 80.7% (95% CI: 59-92%). There was no grade &gt; 2 late toxicities. Locally Advanced Pancreatic Cancers (LAPC) and Borderline Resectable Pancreatic Cancers (BRPC) patients (52 patients) had a median OS, 6-months OS, and 1-year OS from SMART completion of 15.2 months, 84.4% (95% CI: (70-92%)), and 60.5% (95% CI: (42-75%)), respectively. The median OS, 1-year OS, and 2-year OS from initiation of induction chemotherapy were 22.3 months, 91% (95% CI: (78-97%)), and 45.8% (95% CI: (27-63%)), respectively. Twenty patients underwent surgical resection (38.7 % of patients with initially LAPC) with negative margins (R0). To our knowledge, this is the largest series of SMART for pancreatic tumors. The treatment was well tolerated with only low-grade toxicities. Long-term OS and LC rates were achieved. SMART achieved high secondary resection rates in LAPC patients.

Complete Response of a Patient with Metastatic Medullary Thyroid Cancer With Liver and Bone Metastasis After Treatment With Selpercatinib

A phase 1-2 trial of selpercatinib showed durable efficacy with mainly low-grade toxicity in patients with medullary thyroid cancer (MTC) with and without previous treatment with cabozantinib or vandetanib. Complete response was observed in 5 of 55 previously treated and in 10 of 88 not previously treated patients. We report a 58-year-old patient with total thyroidectomy for a 3 cm Ret C634R positive MTC with 16 of 28 resected lymph nodes positive, largest deposit 2.1 cm. Metastatic MTC with several up to 6 mm large biopsy proven liver and a PETCT intensely enhancing 8 mm C6 bone metastasis were diagnosed 14 and 40 months after total thyroidectomy.

Radiation (RT)-Associated Kidney Injury in Pediatric Cancer Patients: Results from the Pediatric Normal Tissue Effects in the Clinical (PENTEC) Genitourinary (GU) Task Force

<h3>Purpose/Objective(s)</h3> RT-Associated kidney injury is a complication in children treated for cancer. Reported injury includes mildly elevated serum markers, decreased glomerular filtration rate, hypertension, abnormal renal imaging and rarely, renal failure. Through systematic review of available studies, The PENTEC GU task force aims to model the relationships between RT dose and chronic kidney disease (CKD). <h3>Materials/Methods</h3> We conducted a PubMed search of peer-reviewed reports from 1990-2017 evaluating pediatric CKD and RT. 2048 articles were retrieved with 98 fully reviewed. 19 contained whole kidney data for modeling but no article met criteria for partial kidney modeling. However, a 2021 investigation contained usable partial kidney data by Green et al. (JASN 2021). We used the National Kidney Foundation's (NKF) stages for CKD toxicity. Partial kidney dose was modeled from the odds radios (OR) reported in a St. Jude Lifetime Cohort Study (SJLCS) with coefficients in a logistic regression model calculated. The intercepts of the logistic regression models were obtained directly from the investigators. As only V5 and V10 were statistically significant in the SJLCS, we limited our partial kidney model to these doses. <h3>Results</h3> Normal Tissue Complication Rates ≥ 5%, expressed as EQD2 (equivalent doses, 2 Gy/fx) for whole kidney exposures occurred at 8.5, 10.2 and 14.5 Gy for NKF grades ³ 1, ³ 2, and ³ 3, respectively. Conventional Wilms whole abdominal RT (WAI) of 10.5 Gy in 6 fractions had risks of ³ grade 2 toxicity ∼ 4%, and ³ grade 3 toxicity ∼ 1%. For fractionated 12 Gy total body RT (TBI) those risks were 8%, and < 3%, respectively. Data did not support modeling with chemotherapy. Partial kidney modeling from 439 survivors of the SJLCS who received RT (median age 7.3 yrs) showed that 5 or 10 Gy RT to 100% kidney gave a <5% risk of grades 3-5 (severe) toxicity with 1500 mg/m2 carboplatin or no chemo. With 480 mg/m2 cisplatin, a 3% risk of severe toxicity occurred without RT, and a 5% risk when 26% kidney received ≥ 10 Gy. With 63 gm/m2 of ifosfamide, a 5% risk of severe toxicity occurred with no RT, and a 10% toxicity risk occurred when 42% kidney received ≥ 10 Gy. <h3>Conclusion</h3> In patients with Wilms, the risk of toxicity from 10.5 Gy of WAI is low. For 11-12 Gy fractionated TBI with various chemotherapies, the risk of severe toxicity is low but low-grade toxicity is not uncommon. In our partial kidney modeling of RT in the absence of chemo, or with only carboplatin, 10 Gy RT can be delivered to the entire kidney with a low risk of severe CKD. Cisplatin and ifosfamide, however, significantly increase the risk of CKD and decrease the tolerable RT dose. A better understanding of chemo effects, and dose-response-curves for regional renal injury will facilitate optimal use of tools such as IMRT and protons.

The effect of Mitomycin-C in neoadjuvant concurrent chemoradiotherapy for rectal cancer.

Neoadjuvant concurrent chemoradiotherapy (nCCRT) followed by total mesorectal excision has become the standard of care for advanced rectal cancer, but the most effective regimen of chemotherapeutic agents has not yet been determined. The purpose of this study is to determine the effect of Mitomycin-C (MMC) in nCCRT for rectal cancer. From 2000 to 2017, patients with rectal adenocarcinoma who received nCCRT followed by radical surgery were enrolled in our study. The patients were retrospectively separated into two groups according to nCCRT regimens (with or without MMC). Other factors related to cancer down-staging after nCCRT, disease-free survival (DFS) and overall survival (OS) were analyzed. One hundred ninety-five patients received radiotherapy (RT) + MMC + oral tegafur-uracil (UFUR), and 191 patients received RT + UFUR without MMC as neoadjuvant CCRT. Adding MMC might increase the down-staging rate (odds ratio [OR] = 1.520, p = 0.058), and down-staging had significant effect to improve OS (OR = 1.726, p = 0.002) and DFS (OR = 2.185, p < 0.001). The OS and DFS were improved in patients who received MMC, although this result did not reach a statistically significant difference. There was a higher incidence of low-grade toxicities in the MMC group, especially neutropenia, genitourinary side effects, and dermatological side effects ( p < 0.001). Adding MMC to the regimen of nCCRT for rectal adenocarcinoma is shown to increase tumor down-staging rate and improve disease-free and OS, although these benefits come at the cost of increased low-grade toxicities. Prospective randomized studies are needed to explore the role of MMC in nCCRT for rectal cancer.

Relationship between systemic inflammatory response markers and immune treatment related toxicity (IrAEs) in hepatocellular carcinoma (HCC).

e16204 Background: A well-recognized class effect of immune check point inhibitors (ICI) is IrAEs ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI. Treatment related deaths are reported in ̃5% of patients (pts) treated with ICI. There are, however, no reliable markers to predict the onset &amp; severity of IrAEs. We tested the association between neutrophil-lymphocyte ratio (NLR) &amp; platelet-lymphocyte ratio (PLR) at baseline with development of clinically significant IrAE (graded ≥2) in HCC pts treated with ICI. Methods: Data was extracted from a large international database from a consortium of 11 tertiary-care referral centers located in the USA, Europe &amp; Asia. NLR=Absolute neutrophil count/ Absolute lymphocyte count (ALC) &amp; PLR=Platelet count/ALC. A cutoff of 5 for was used NLR &amp; 300 for PLR based on literature. We also tested the association between antibiotic &amp; steroid exposure to IrAEs. Results: Clinical data was collected from 361 pts treated between 2016–2020 across the USA (66%), Asia (12%) &amp; Europe (22%) in this multinational database. Most pts received Nivolumab monotherapy (n=318, 74%). 167 (46%) pts developed at least one IrAE, highest grade 1 in 80 (48%), grade ≥2 in 87(52%) pts. Baseline characteristics did not differ significantly between the groups (Table). In a univariable regression model to predict grade ≥2 IrAEs, a PLR &gt;300 was associated with a lower incidence of clinically significant IrAEs (OR = 0.40; p=0.044). NLR &gt;5 was associated with a trend toward lower incidence of clinically significant IrAEs (OR = 0.58; p=0.097). Multivariate analyses confirmed PLR as independent predictive marker of grade ≥2 IrAEs (OR = 0.24; p=0.007). Antibiotics use was not associated with IrAE incidence (OR = 1.02; p=0.954). Steroid use was associated with a &gt;2-fold higher incidence of grade ≥2 IrAEs (OR = 2.74; p&lt;0.001), though it may be noted that 37% of pts received steroids for treatment of IrAEs. Conclusions: Lower NLR &amp; PLR may predict the appearance of IrAEs in HCC treated with ICI, although this conclusion warrants prospective validation. This finding is in keeping with several studies that showed improved survival in pts who develop of IrAEs &amp; have a lower NLR &amp; PLR.[Table: see text]

Metastasis-Directed Radiation Therapy with Consolidative Intent for Oligometastatic Urothelial Carcinoma: A Systematic Review and Meta-Analysis.

Simple SummaryPatients with oligometastatic urothelial carcinoma represent a challenging subset of subjects to manage. Herein we summarized evidence about the role of metastasis-directed radiation therapy in this clinical setting. Available preliminary evidence supports the role of metastasis-directed radiation therapy as a safe and efficacious option as it has the potential to facilitate local disease control and overall survival. However, in the absence of data from high-quality trials, definitive recommendations cannot be provided, and patients should be counseled on an individual basis.The management of patients with oligometastatic urothelial carcinoma (UC) represents an evolving field in uro-oncology, and the role of metastasis-directed therapies, including metastasectomy and metastasis-directed radiation therapy (MDRT), is gaining increasing attention. Herein, we summarize available evidence about the role of MDRT with consolidative intent in oligometastatic UC patients. A systematic review was performed in December 2021. Six studies involving 158 patients were identified. Most patients (n = 120, 90.2%) had a history of bladder cancer and the most frequent sites of metastases were lymph nodes (n= 61, 52.1%) followed by the lungs (n = 34, 29%). Overall, 144 metastases were treated with MDRT. Median follow-up ranged from 17.2 to 25 months. Local control rates ranged from 57% to 100%. Median Overall Survival (OS) ranged from 14.9 to 51.0 months and median progression-free survival ranged from 2.9 to 10.1 months. Rates of OS at one and two years ranged from 78.9% to 96% and from 26% to 63%, respectively. Treatment-related toxicity was recorded in few patients and in most cases a low-grade toxicity was evident. MDRT with consolidative intent represents a potential treatment option for selected patients with oligometastatic UC.

RTID-05. THE MULTI-ARM GLIOBLASTOMA AUSTRALASIA (MAGMA) TRIAL

Abstract BACKGROUND Survival outcomes for patients with newly diagnosed glioblastoma have not changed significantly since the introduction of concurrent temozolomide with post-surgical radiation followed by adjuvant temozolomide. METHODS Multi-Arm Glioblastoma Australasia (MAGMA) is a recently initiated phase III multi-arm, multi-centre randomized trial for patients with newly diagnosed glioblastoma, led by the Australian Cooperative Trials Group for Neuro-Oncology (COGNO), that will concurrently test multiple treatment questions. Initially, a partial factorial design will be implemented to compare the current standard of care with either or both of (1) neoadjuvant temozolomide and (2) aduvant temozolomide continued beyond six months until progression. MAGMA will transition to a multi-arm multi-stage (MAMS) design as additional tratment question are introduced. Treatment allocation to each question will be balanced (1:1) using minimisation over several stratification factors, including study site, age, IDH-mutation status, surgical extent and randomization to the prior treatment question(s). The primary outcome is overall survival. Secondary outcomes include progression-free survival (measured by mRANO), time to first non-temozolomide systemic treatment, clinically significant toxicity as measured by Grade 2/4 adverse events, and health-related quality of life measures. Parsimonious data collection and a streamlined assessment schedule have been incorporated to mitigate the burden of data collection (such as low grade toxicity from temozolomide), and to encourage participation in regional and rural settings. A consortium model has been adopted to foster neuro-oncology expertise and infrastructure and share academic credit and future design opportunities. PROGRESS Recruitment commenced in September 2020. To date, 60 patients have been recruited from an initial sample size target of 250 patients for each of these initial two treatment questions. Of these 60 patients, 45 have been randomized in Question 1 (neoadjuvant chemotherapy) whilst 50 randomized in Question 2 (prolonged adjuvant chemotherapy). To date, 14 of the 27 intended sites are open to recruitment.