Hoppe, Bradford S.

PURPOSE Nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. METHODS Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. RESULTS We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). CONCLUSION In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

Abstract Immune checkpoint inhibitors (ICIs) have demonstrated remarkable response rates in relapsed or refractory Hodgkin lymphoma (HL). Still, most patients eventually progress. Patterns of progression after ICIs are not well described and are essential to defining the role of local therapies in combination with ICIs. We identified patients who received ICIs for HL between 2013 and 2022. Fludeoxyglucose-18 positron emission tomography (FDG-PET) before initiating ICI and at progression on/after ICI were reviewed, and areas of active HL were recorded. An exploratory analysis of treatable progression included patients with ≤5 sites of disease on pre-ICI FDG-PET and progression only at pre-ICI sites. Ninety patients were identified; 69 had complete records, and of these, 32 (52%) had relapsed at ICI initiation, 17 (25%) were refractory, and 16 (23%) received ICI as first-line therapy. Forty-five of 69 patients had ≤5 sites of disease (limited) on pre-ICI FDG-PET. Patients with &gt;5 sites of disease had a higher risk of progression, and every site of disease &gt;5 sites conferred an additional 1.2x higher chance of progression. At a median follow-up of 4.0 years, 41 of 69 patients had progressed on/after ICIs (cumulative incidence 66.4%), and of these, 22 of 41 patients progressed only at pre-ICI sites (cumulative incidence 39.4%). In an exploratory analysis, the cumulative incidence of a treatable progression among 45 patients with limited disease was 34%. The cumulative incidence of any progression among this cohort was 58.9%. More than one-third of patients with limited disease before ICIs experienced progression only at pre-ICI sites of disease. These patients could be candidates for radiation during or after ICIs.

Background: Chemotherapy in combination with radiotherapy (RT) is the standard for early-stage (ES) Hodgkin lymphoma (cHL). Despite high cure rates (12-year overall survival (OS) &gt;93%), there is room to improve short and long-term outcomes for children and adults with ES cHL. Incorporation of immunotherapy (IO) into front line treatment of ES cHL is an opportunity to both improve progression-free survival (PFS) and maintain OS, while minimizing long-term morbidity and mortality by reducing exposure to RT and high-dose chemotherapy. Study Design and Methods: HL leaders of the NCTN groups, expert HL researchers and physicians, and representatives from the Cancer Therapy Evaluation Program (CTEP) formed a working group in April 2020 with the goals of harmonizing treatment approaches for ES cHL across pediatric and adult patients and reaching consensus regarding the optimal study design for incorporating IO therapy into frontline treatment. Study champions identified from each of the North American cooperative groups [Children's Oncology Group (COG), SWOG, ECOG-ACRIN, Alliance, NRG] and experts in imaging, radiation oncology, lymphoma biology and patient-reported outcomes (PROs) were included. The resulting COG-led clinical trial, AHOD2131, represents the largest ES cHL trial in the history of North American cooperative groups and the first to enroll patients across the age continuum. AHOD2131 (NCT05675410; Figure) is a randomized, phase 3 trial enrolling patients ages 5 to 60 years with newly diagnosed, previously untreated stage I and II cHL and will investigate the addition of the CD30-antibody drug conjugate brentuximab vedotin (Bv) with PD-1 blockade (nivolumab) compared to standard chemotherapy +/- RT. Since the April 2023 activation, 97 North American sites have activated the trial, and 21 participants have enrolled. Target enrollment is 1875 patients over 5 years of accrual, for an estimated 1782 eligible and evaluable patients. The primary objective is to compare the 3-year PFS of patients with ES cHL treated through a response-adapted, superiority design with either standard therapy or with an IO approach (BV + nivolumab). All patients will be stratified as favorable or unfavorable based on disease risk features at enrollment. Based on initial response assessment by PET/CT (via central review) after 2 cycles of ABVD, patients were classified to PET2 positive (SER, defined as 5 Point Score 4 or 5, ~15% of patients) and PET negative (RER). Those who are PET positive will receive involved site RT (ISRT). The SER and RER patients will be randomized to standard chemotherapy vs. IO therapy respectively. In addition to the primary outcome of PFS, there are 11 secondary and 10 exploratory aims. The secondary aims focus on OS, PFS of subgroups, and event-free survival at 12 years, physician-reported treatment-related adverse event (AE) rates, patient-reported AE using pediatric and adult versions of Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and the capture of representation by self-report and the use of electronic PRO data collections. The exploratory aims include the assessment of imaging central review as compared to local institutional review and the use of convolutional neural networks through artificial-intelligence machine learning. The study will examine the effect of therapy on acute and long-term adverse effects including health-related quality of life (HRQoL) and OS for up to 12 years. The study will compare patient self-report and provider AE reports and evaluate the associations of self-reported race/ethnicity and social determinants of health (SDOH)and post-progression/post-relapse OS. AHOD2131 strengthens the effort between the North American cooperative groups to conduct collaborative clinical trials and aims to harmonize an improved standard of care for ES cHL across the age continuum.

Introduction Primary mediastinal large B-cell lymphoma (PMLBCL) is a rare and aggressive type of non-Hodgkin B-cell lymphoma, accounting for about 3% of all non-Hodgkin lymphomas. The role of radiation therapy following immunochemotherapy is controversial and lately there has been more studies suggesting there is less benefit of adding radiation therapy. Large-scale studies describing and evaluating the effect of radiation therapy on survival outcome are lacking. Materials and Methods The National Cancer Database (NCDB) was queried for patients diagnosed with PMLBCL between 2004 and 2019. All patients aged ³18 years diagnosed with PMLBCL were included. We excluded patients with unknown chemotherapy and radiation therapy status, or received radiation prior to chemotherapy, or received radiation 6 months after chemotherapy or lost to follow-up (unknown vital status of last contact). Kaplan-Meier and multivariate Cox regression were used in the analyses. Results The total cohort consisted of 1,899 patients with PMLBCL. Out of whom 1,177 (62%) were females, 1,560 (76%) were White non-Hispanic, 113 (6%) were White Hispanic and 205 (11%) were African Americans. Among patients with known disease stage, 1,164 (61%) had early-stage disease (stage I and II) and 351 (19%) had advanced stage disease (stage III and IV). 1,443 (76%) received chemotherapy only and 456 (24%) received chemotherapy followed by radiation therapy. The median age at diagnosis was 35 years (range 18-90), 1,215 (64%) were diagnosed at younger age (40 years or less). The median follow-up time was 60 months (95% CI 57-62), the median overall survival (OS) for the whole cohort was not reached, and the 5-year OS was 91%. The 5-year OS for early and advanced stage were 93% and 83%, respectively. In patients with early-stage disease, there was no statistically significant difference in the median OS between patients who received chemotherapy only (N=824) compared to patients who received chemotherapy followed by radiation therapy (N=340) (not reached in both groups, P=0.130) with 5-year OS of 92% and 93%, respectively. In patients with advanced stage disease, there was no statistically significant difference in the median OS between patients who received chemotherapy only (N=294) and patients who received chemotherapy followed by radiation therapy (N=57) (median OS not reached in both groups, P=0.067) with 5-year OS of 82% and 88%, respectively. On multivariate analysis, older age and Charlson-Deyo score ≥3 were associated with worse OS (HR 1.062 95% CI 1.047-1.078; P&lt;0.001 and HR 6.032 95% CI 1.853-19.634; P=0.003, respectively), early stage was associated with better OS (HR 0.508 95% CI 0.364-0.708; P&lt;0.001), whereas adding radiation to chemotherapy did not affect the OS (HR 0.713 95% CI 0.491-1.035; P=0.075). Over the years, there was a significant down trend in using radiation therapy (Figure 1). Using univariate and multivariate logistic regression analysis, we found early-stage disease was associated with increased use of radiation therapy after chemotherapy. Whereas patients who were treated at academic/research programs were less likely to receive radiation therapy (Table 1). Conclusion This large real-world analysis shows a practice change in PMLBCL treatment with a trend in omitting radiation therapy. In our analysis, we found that adding radiation therapy to systemic therapy did not affect the survival outcome in both early and advanced stage disease.

Background: cHL is one of the most curable forms of childhood cancer, but patients (pts) who have a SER to initial chemo are at high risk of relapse. The approaches currently used to treat pts with SER, such as dose intensification and radiotherapy (RT), can cause long-term toxicity.An unmet need remains to optimize treatment in pts with cHL and SER while minimizing long-term toxicity. The open-label, phase 2 KEYNOTE-667 study (NCT03407144) is being conducted to evaluate the efficacy and safety of pembro plus chemo in pediatric pts with cHL and SER to front-line chemo. Early analysis of pts in KEYNOTE-667 with high-risk cHL showed that pembro plus cyclophosphamide, vincristine, prednisone/prednisolone, and dacarbazine (COPDAC-28) consolidation had manageable safety and promising antitumor activity, with 66% of pts being spared RT. We present updated results for pts with high-risk cHL and SER. Methods: Pts eligible for the high-risk group were 3-25 y old and had newly diagnosed stage IIEB, IIIEA, IIIEB, IIIB, IVA, or IVB cHL, measurable disease per investigator assessment, and a Lansky Play-Performance Scale ≥50 (&lt;16 y old) or a Karnofsky score ≥50 (≥16 y old). All pts received 2 cycles of induction therapy with vincristine, etoposide, prednisone/prednisolone, and doxorubicin (OEPA). After induction, response was assessed by PET/MRI/CT (early response assessment). Pts with rapid early response received nonstudy therapy. Pts with SER (Deauville score, 4 or 5) received consolidation with pembro 2 mg/kg up to 200 mg IV Q3W (3-17 y) or 200 mg IV Q3W (18-25 y) plus 4 cycles of COPDAC-28. Response was then assessed by PET/CT/MRI (late response assessment [LRA]). Pts with PET positivity at LRA (Deauville score, 4 or 5) received involved-site RT (28.8 Gy) to late PET-positive residua plus maintenance pembro Q3W for up to 17 cycles; pts with PET negativity received maintenance pembro Q3W for up to 17 cycles without RT. The primary end point was ORR by BICR per Cheson 2007 IWG criteria in pts with SER, determined at any time after starting pembro and before start of new anticancer therapy. Secondary end points included PET negativity after consolidation, EFS, OS, and safety. Results: This analysis included 62 pts with high-risk cHL and SER to frontline OEPA. The median time from enrollment to data cutoff (March 1, 2023) was 16.8 mo (range, 2.3-36.4). At the data cutoff, 34 pts (55%) had completed consolidation and maintenance therapy, 23 (37%) were ongoing on treatment, and 5 (8%) had discontinued because of adverse events (AEs; n = 1), progressive disease (n = 2), or withdrawal by pt (n = 2). Median age was 14 y (range, 5-22), 30 pts (48%) were male, 29 (47%) had bulky disease, and 41 (66%) had Ann Arbor stage IV disease. Pts had received a median of 17 administrations of pembro (range, 1-17); the median time on pembro was 11.0 mo (range, &lt;0.1-11.8). Of 62 pts who received consolidation with pembro plus COPDAC-28, 53 (85%) had a LRA (9 are still in consolidation and have not reached the LRA time point), of whom 35 (66%) were PET negative by BICR (37 [70%] PET negative by investigator review). AEs regardless of causality that occurred during consolidation and maintenance were reported in 54 pts (87%), most commonly (≥15%) headache (n = 11; 18%), nausea (n = 11; 18%), cough (n = 10; 16%), COVID-19 (n = 10; 16%), and pyrexia (n = 10; 16%). Grade 3/4 AEs occurred in 21 pts (34%). 13 pts (21%) had a serious AE. No pts died because of AEs. Treatment-related AEs occurred in 38 pts (61%). Grade 3/4 treatment-related AEs occurred in 10 pts (16%). One pt (2%) discontinued treatment because of a treatment-related AE (grade 3 AST increased). Pembro-related AEs occurred in 23 (37%) pts; most commonly (≥5%) hypothyroidism (n = 4; 6%), nausea (n = 3; 5%), and ALT increased (n = 3; 5%). Three pts (5%) experienced grade 3/4 pembro-related AEs. One serious AE was related to pembro (abdominal pain). Six pts (10%) experienced immune-mediated AEs (hypothyroidism, n = 4 [2 grade 1, 2 grade 2]; colitis, n = 1 [grade 2]; pneumonitis, n = 1 [grade 2]). Conclusion: In this updated analysis, consolidation with pembro plus COPDAC-28 continued to have manageable safety and promising antitumor activity in pediatric pts with high-risk cHL and SER to front-line OEPA. Of pts with a LRA, 66% had a PET-negative response and were spared RT. These findings support the results of prior analyses and suggest that adding pembro to COPDAC-28 consolidation may augment responses in the high-risk cHL population.

Purpose The predominant pattern of relapse for patients with B-cell non-Hodgkin lymphoma (NHL) who undergo anti-CD19 Chimeric Antigen Receptor T-cell Therapy (CART) involves sites previously involved by NHL. Bridging radiotherapy (BRT) has shown to be an effective bridging treatment with excellent local control rates. Our previous work defined limited/oligometastatic lymphoma as disease involving &lt;5 sites. This study is the first to report on the role of BRT for patients with limited (&lt;5 involved sites) disease prior to CART. Methods Following Institutional Review Board approval, a retrospective review from 2018 to 2023 across 3 Mayo Clinic sites (Arizona, Florida, and Minnesota) was performed and identified 139 patients with relapsed/refractory (r/r) B-cell NHL without bone marrow involvement who received CART and had &lt;5 disease sites prior to leukapheresis. Ann Arbor staging was used to define the number of involved disease sites. An involved disease site included the Ann Arbor anatomical lymph node region(s) harboring the pathological lymph node(s) or any extranodal lesion. Bridging treatment (radiation and/or systemic therapy) was defined as treatment administered between leukapheresis and CART infusion. The primary endpoint was event-free survival (EFS),defined from CART infusion to any disease progression or initiation of post-CART consolidative/salvage therapy. Secondary endpoints included progression -free survival (PFS),defined from CART infusion to any disease progression, and overall survival (OS), defined from CART infusion to death. Results Prior to CART infusion, 44 (32%) patients received BRT and 95 (68%) did not. Bridging systemic therapy was given to 5 (11%) and 34 (36%) patients in the BRT and no BRT groups, respectively (p=0.003). The median number of involved disease sites prior to leukapheresis was 2 (range: 1-4). There was no significant difference in the baseline characteristics prior to CART infusion between the BRT and no BRT groups, except for extranodal involvement that was more common in the BRT group (Table 1). The median equivalent 2 Gy dose was 27 Gy (Interquartile range 23-34), and the most common BRT regimen was 20 Gy in 5 fractions. Among the 44 BRT patients, 34 received radiation to all visible PET-avid disease sites, and 10 received radiation to some but not all disease sites. The median follow-up was 20 months. The rate of grade ≥2 cytokine release syndrome was 41% in both groups (p=0.99). The rate of grade ≥2 immune effector cell-associated neurotoxicity syndrome was 21% and 37% in the BRT and no BRT groups, respectively (p=0.059). There were no observed grade ≥3 BRT-related toxicities. Objective response rate by PET 5 point scale was higher in the BRT group (93% versus 79%; p=0.036). Crude rates of progression were 30% in BRT and 55% in no BRT patients, with 9/13 (69%) and 43/52 (83%) patients relapsing in pre-existing sites of disease present prior to CART infusion in the BRT and no BRT group, respectively. Seven (16%) BRT patients relapsed in the radiation field. The 2-year EFS was 50% in the BRT group and 39% in the no BRT group (p=0.01). The 2-year PFS was 55% in the BRT group and 45% in the no BRT group (p=0.017). The 2-year OS was 55% in the BRT group and 62% in the no BRT group (p=0.7). Intriguingly, patients who received BRT to all visible PET-avid disease sites (n=34) had further improvement in 2-year EFS (67% vs 39%, p=0.003) and 2-year PFS (71% vs 46%, p=0.008) compared to no BRT or patients who received BRT to some but not all visible disease sites (n=105). Nine patients (2 in BRT and 7 in no BRT groups) received consolidative radiotherapy for day 30 residual disease with only one patient subsequently experiencing progression. Twenty-five patients (6 in BRT and 19 in no BRT groups) received salvage/palliative RT for post-CART relapsed disease. Thirty-seven (39%) patients in the no BRT group remained without disease progression and did not receive radiation in the bridging, consolidative or salvage/palliative setting. Conclusion Bridging radiotherapy prior to CART infusion for patients with limited (&lt;5 involved disease sites) r/r NHL appears to improve response rate, EFS, and PFS without causing significant toxicities. Approximately one third of patients who do not receive BRT will require subsequent post-CART radiation, and another third will remain free of radiation and disease progression.

Background: Pediatric patients (pts) with low-risk cHL achieve high cure rates with standard chemo. However, those with a SER to front-line chemo are at higher risk of relapse than pts with a rapid early response (RER). Current treatment options are also associated with long-term toxicities such as secondary malignancies, cardiovascular disease, and pulmonary and gonadal toxicity. Novel treatment approaches are needed to optimize outcomes while minimizing long-term toxicity. KEYNOTE-667 (NCT03407144) is an open-label, phase 2 study that included an analysis of safety and efficacy of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) induction in pediatric pts with low-risk cHL followed by consolidation with pembro plus AVD and involved-site radiotherapy (ISRT) and pembro maintenance in those with SER to front-line ABVD. We present an interim analysis of pts with low-risk cHL enrolled in this trial. Methods: Eligible pts were 3-25 y old and had newly diagnosed stage IA, IB, or IIA cHL without bulky disease, measurable disease per investigator assessment, and a Lansky Play-Performance Scale ≥50 (aged &lt;16 y) or a Karnofsky score of ≥50 (aged ≥16 y). Pts initially received 2 cycles of induction with ABVD. Response was then assessed by PET/MRI/CT (early response assessment). Pts with RER received nonstudy therapy per treating physician. Pts with SER (Deauville score [DS], 4 or 5) received consolidation with pembro 2 mg/kg up to 200 mg IV Q3W (3-17 y) or 200 mg IV Q3W (18-25 y) in combination with 2 cycles of AVD followed by a late response assessment (LRA) with PET/MRI/CT. All pts with a SER then received ISRT (21.6 Gy for pts with a complete PET response [DS, 1-3]; 30.6-36 Gy for pts with a partial PET response [DS, 4 or 5]) plus maintenance pembro Q3W for up to 17 cycles. Primary end point was ORR by blinded independent central review (BICR) per Cheson 2007 IWG criteria in pts with SER determined at any time after starting pembro and before start of new anticancer therapy. Secondary end points included rate of PET negativity after consolidation, EFS, OS, and safety. Results: 73 pts with low-risk cHL were enrolled, 9 of whom had SER to ABVD induction. 64 pts had a RER and received nonstudy treatment. At data cutoff (March 1, 2023), 2 of 9 pts (22%) with SER had completed consolidation and maintenance therapy, 5 (56%) were ongoing, and 2 (22%) had discontinued, both because of complete response. Median time from enrollment to data cutoff was 8.7 mo (range, 2.2-32.9). Median age was 16 y (range, 7-20), 5 pts (56%) were male, 2 (22%) had Ann Arbor stage I disease, and 7 (78%) had Ann Arbor stage II disease. Pts with SER had received a median of 8 doses of pembro (range, 1-17); median time on pembro was 4.8 mo (range, &lt;0.1-11.3). Of 9 pts who received consolidation therapy with pembro plus AVD, 6 (67%) had a LRA (3 are still in consolidation and have not reached the LRA timepoint), of whom 3 (50%) were PET negative by BICR (2 [33%] were PET negative by investigator review). Of 73 pts who received ABVD induction, 66 (90%) had an AE regardless of causality. 33 pts (45%) experienced grade 3/4 AEs, most commonly (≥10%) neutrophil count decreased (n = 19; 26%) and neutropenia (n = 9; 12.3%). One pt experienced grade 4 febrile neutropenia. Twelve pts (16%) had serious AEs. No pts discontinued treatment or died because of AEs. Treatment-related AEs due to ABVD induction occurred in 59 pts (81%), with grade 3/4 events in 31 (42%). Of the 9 pts with SER to ABVD induction who received consolidation and maintenance therapy, 7 (78%) experienced an AE regardless of causality. Two pts (22%) had grade 3/4 AEs. No serious AEs were reported during consolidation and maintenance therapy, and no pts discontinued treatment or died because of AEs. Treatment-related AEs occurred in 6 pts (67%) who received consolidation and maintenance therapy; with grade 3/4 events in 2 pts (22%). Six pts (67%) experienced AEs related to pembro; most commonly (≥3 pts) anemia, nausea, vomiting (n = 3 each [33%]). Two pts experienced grade 3/4 AEs related to pembro (vomiting, white blood cell count decreased). One pt (11%) experienced an immune-mediated AE (grade 2 hyperthyroidism). Conclusion: Early results from the low-risk cHL cohort of KEYNOTE-667 suggest that induction therapy with ABVD and consolidation with pembro plus AVD had a manageable safety profile. Among the relatively small number of pts with a SER to ABVD, 50% with a LRA had a PET-negative response by BICR and received a reduced dose of RT.

AbstractAnti‐CD19 chimeric antigen receptor T‐cell therapy (CART) has revolutionized the outcomes of relapsed and/or refractory B‐cell non‐Hodgkin lymphoma. However, CART is still limited by its availability, toxicity, and response durability. Not all patients make it to the CART infusion phase due to disease progression. Among those who receive CART, a significant number of patients experience life‐threatening cytokine release syndrome toxicity, and less than half maintain a durable response with the majority relapsing in pre‐existing sites of disease present pre‐CART. Radiation therapy stands as a promising peri‐CART and salvage treatment that can improve the outcomes of these patients. Evidence suggests that bridging radiotherapy prior to CART controls the disease during the manufacturing period, augments response rates and local control, cytoreduces/debulks the disease and decreases the severity of cytokine release syndrome, and may prolong disease‐free intervals and survival especially in patients with bulky disease. Consolidative radiotherapy for residual post‐CART disease alters the pattern of relapse and improves local recurrence‐free and progression‐free survivals. Salvage radiotherapy for relapsed post‐CART disease has favorable survival outcomes when delivered comprehensively for patients with limited relapsed disease and palliates symptoms for patients with diffuse relapsed disease. The biology of the disease during the peri‐CART period is poorly understood, and further studies investigating the optimal timing and dosing of radiation therapy (RT) are needed. In this review, we tackle the most significant challenges of CART, review and propose how RT can help mitigate these challenges, and provide The Mayo Clinic experts' approach on incorporating RT with CART.

Skull-base chordoma and chondrosarcoma are rare radioresistant tumors treated with surgical resection and/or radiotherapy. Because of the established dosimetric and biological benefits of heavy particle therapy, we performed a systematic and evidence-based review of the clinical outcomes of patients with skull-base chordoma and chondrosarcoma treated with carbon ion radiotherapy (CIRT). A literature review was performed using a MEDLINE search of all articles to date. We identified 227 studies as appropriate for review, and 24 were ultimately included. The published data illustrate that CIRT provides benchmark disease control outcomes for skull-base chordoma and chondrosarcoma, respectively, with acceptable toxicity. CIRT is an advanced treatment technique that may provide not only dosimetric benefits over conventional photon therapy but also biologic intensification to overcome mechanisms of radioresistance. Ongoing research is needed to define the magnitude of benefit, patient selection, and cost-effectiveness of CIRT compared to other forms of radiotherapy.