Hodgkin lymphoma is one of the most common cancers in adolescents and young adults (AYAs), a population with distinct biological, clinical, and developmental characteristics. Yet care remains fragmented between pediatric and adult systems contributing to variability in treatment exposure and survivorship outcomes. We synthesized current evidence on AYA HL epidemiology, biology, treatment strategies, supportive care needs, long-term toxicity risk, and survivorship. AYAs have access to multiple efficacious treatment options with high cure rates, but long-term survivors face significant medical, psychosocial, and financial effects with notable risks for cardiopulmonary disease, secondary malignancies, fertility impairment, and unmet psychosocial needs. Harmonized pediatric-adult treatment frameworks, AYA-focused support, and developmentally tailored survivorship care are essential to improving outcomes for AYA HL survivors.
Particle therapy represents a cutting-edge modality in radiation oncology that offers potential advantages over conventional radiation therapy; however, its cost-effectiveness has not been established. We conducted a systematic search of several electronic databases to synthesize contemporary evidence on the cost-effectiveness of particle therapy. The methodological quality of the included studies was assessed, and reported outcomes on costs, health benefits, and incremental cost-effectiveness ratios (ICERs) were extracted. We identified 57 studies, which collectively reported 134 comparisons for particle therapies. In general, studies were of good quality, although better reporting of data sources and modeling assumptions is warranted. Included studies primarily evaluated the cost-effectiveness of proton therapy, used photon therapy as the comparator, utilized a Markov Cohort model, and used the payer's perspective. Findings were inconsistent, with the reported ICERs ranging from $55 to $1,066,266 per unit of benefit gained, with discrepancies across cancer sites and treatment modalities. Particle therapy is cost-effective for specific groups but may not be universally cost-effective. More research is warranted to identify subgroups for which particle therapy is cost-effective.
In this article, we review the development of accelerator and beam delivery technology for particle therapy. The working principles of accelerators, encompassing isochronous cyclotrons, synchrocyclotrons and synchrotrons, and recent advancements in other accelerator technology, are presented. For beam delivery technology, we focus on pencil beam scanning (PBS) for intensity modulated proton therapy (IMPT). In addition, we incorporate aspects of proton arc therapy, ultrahigh-dose rate FLASH therapy, and motion management for PBS beam delivery. Last, we have discussions on imaging guidance for particle therapy treatment delivery, upright patient positioning, and online adaptive therapy.
Hypofractionated particle therapy (HPT) is an evolving treatment paradigm in radiation oncology, offering enhanced therapeutic ratios through both biological and dosimetric advantages. Proton therapy leverages the Bragg peak phenomenon to reduce the integral dose to normal tissues, a benefit amplified by delivering larger doses per fraction. Carbon ion radiotherapy (CIRT) further augments this approach through high linear energy transfer (LET) and greater relative biological effectiveness (RBE), potentially overcoming radioresistance mechanisms. This review synthesizes updated clinical evidence for HPT, including proton and CIRT across various disease sites. Clinical trial data on efficacy and toxicity are reviewed, including comparisons with photon-based radiotherapy. The clinical outcomes observed thus far highlight the safety and efficacy of biologically intensified HPT regimens, underscoring the need for continued, well-designed phase II/III trials to define optimal indications and fractionation strategies.
Proton therapy requires accurate, reliable normal tissue complication probability (NTCP) models for treatment planning and evidence-based patient selection. This review examines 2 challenges in proton therapy: developing NTCP models that accurately reflect proton-specific toxicity and managing NTCP prediction uncertainty to ensure reliable clinical decision-making. Regarding model accuracy, photon-derived NTCP models work for some endpoints but fail for others when proton therapy exhibits distinct dose-response characteristics, indicating that the need for proton-specific models is endpoint-dependent. Clinical evidence that supports updating NTCP models by incorporating variable relative biological effectiveness is statistically weak due to interpatient heterogeneity and inconsistent findings. Despite ongoing efforts in improving NTCP prediction accuracy, the impact of prediction uncertainty on patient selection decisions has received limited attention. Further study is required to establish a robust, model-uncertainty-aware NTCP-guided patient selection framework for proton therapy that addresses both model accuracy and prediction confidence.
Particle therapy offers highly precise treatment, reducing damage of surrounding organs while delivering dose to the target areas. The improved therapeutic ratio is largely attributed to the Bragg curve, which demonstrates steep dose fall-off. Although historically pediatric tumors had the clearest benefit, the application of particle therapy has expanded to adult patients of all disease sites, including tumors of the head and neck, central nervous system, thorax, breast, gastrointestinal system, and genitourinary system. As emerging trials provide increasing evidence for the utilization of particle therapy, treatment is becoming more accessible. In addition, radiation technology continues to evolve, and techniques including intensity-modulated proton therapy and adaptive proton therapy are being implemented. We review the evolution of particle therapy, the current clinical evidence supporting its use, and practical considerations.
PURPOSE:Germline biomarker testing to assess inherited risk for developing malignancy has evolved quickly from testing for 1 or 2 genes from a few laboratories to ordering panels of 80 or more genes available from multiple laboratories. Many health professionals did not receive foundational information in training yet are expected to identify and manage care for individuals and families with germline risk. Errors in testing do occur and can have significant adverse consequences including missed opportunities for prevention and detection for the patient and family, unnecessary risk-reducing surgery, and even death. By better understanding these errors and underlying causes, as well as the potential negative consequences due to these errors, strategies can be developed to help prevent future harm to patients. METHODS:Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting system a literature review was completed to identify case reports of errors in germline testing for hereditary cancer. Ovid MEDLINE, Scopus, and EBSCOHOST CINAHL, were searched from January 2009 through February 2025. Reference lists were reviewed to identify additional case reports. Each case report was abstracted to identify error(s), consequence(s), and potential error(s) prevented. RESULTS:A total of 106 cases were identified from the search of the databases and 1 case using archival methods. Sixty-six (61%) cases described more than one error and 61 (44%) described more than one negative consequence. In 48 (45%) cases one or more additional errors were prevented when a genetics professional was consulted. The most common errors were misinterpretation of data, failure to take a full family history and review previous test results, not recognizing a syndrome, and selecting the wrong test or wrong laboratory for testing. Negative consequences included missed opportunities for prevention and detection for the patient and potentially other family members, one or more unnecessary risk-reducing surgeries in 10 patients, late detection of malignancy in 8 patients, and 7 patient deaths. DISCUSSION:Although germline testing seems to be a simple laboratory test, many errors occur that have avoidable adverse consequences for both the patient and family. Errors may occur because of a lack of foundational knowledge in comprehensive risk assessment and on how to order the best test in a laboratory capable of detecting a pathogenic variant as well as how to interpret germline testing results. Increasing the number of genetics professionals, implementing new delivery models, and increasing educational efforts in nongenetics professionals could prevent and decrease errors.
In children, decades of survivorship magnify the harms of irradiation to normal tissues. Proton therapy (PT) leverages the Bragg peak phenomenon to maintain dose to tumor volumes while reducing dose to surrounding structures. This results in disease control comparable to photons while lowering normal tissue dose and reducing subsequent late effects. The clearest advantages occur when fields are large or when critical organs abut the target volume. Here, we discuss the clinical physics and comparative dosimetry that drive benefit across pediatric indications. We also synthesize PT outcomes for pediatric malignancies and highlight organ-specific late effects where PT reduces the incidence or severity of toxicities. We close with a brief look at the future of particle therapy for pediatric malignancies.
Modern photon-based, intensity-modulated radiation therapy (IMRT) kills tumors but may also excessively damage normal tissues; the resultant morbidity can prompt treatment interruptions, worsen tumor control, and degrade quality of life. Charged particles (eg, protons, carbon ions) may be less toxic and more effective than IMRT because particles irradiate less surrounding normal tissues and are more biologically effective than IMRT. However, protons/carbon ions have physical drawbacks that can affect dose precision. Helium ions are being explored as an alternative type of charged-particle therapy because their biophysical characteristics are intermediate between those of protons and carbon ions, potentially improving treatment precision. However, systematic studies of helium ion radiotherapy (HeRT) are scarce. We review current knowledge of the biophysical effects of HeRT: its relative biological effectiveness (RBE) versus photons; its effects on gene mutation, DNA damage and repair, cell cycling, cell death, and radiosensitization; and early explorations of ultra-high dose rate HeRT.
FLASH radiotherapy is an emerging treatment modality characterized by the ultrahigh dose rate delivery of radiation, which has demonstrated the potential to significantly reduce normal tissue toxicity while maintaining tumor control. In cancers traditionally managed with radiotherapy, this approach could improve the therapeutic ratio by mitigating severe side effects associated with current techniques. The integration of particle therapy-such as protons or heavier ions-with FLASH dose rates offers unique physical and biological advantages, including enhanced normal tissue sparing and the possibility of safe dose escalation. Clinical implementation will require a deeper understanding of the mechanistic biological underpinnings of the FLASH effect, alongside advancements in beam delivery systems capable of achieving FLASH dose rates, rigorous quality assurance protocols, and adaptive strategies to accommodate anatomic changes during treatment. Ultimately, widespread clinical adoption will depend on prospective trials comparing FLASH particle therapy with established modalities, with endpoints focused on toxicity, disease control, and patient-reported quality of life.
This review summarizes contemporary management of Classic Hodgkin Lymphoma in special clinical situations, with a focus on integrating primary clinical trial and observational data to inform individualized treatment decisions. The emphasis is on practical, evidence-based recommendations rather than exhaustive coverage of all regimens.
Hodgkin lymphoma is one of the most common cancers in adolescents and young adults (AYAs), a population with distinct biological, clinical, and developmental characteristics. Yet care remains fragmented between pediatric and adult systems contributing to variability in treatment exposure and survivorship outcomes. We synthesized current evidence on AYA HL epidemiology, biology, treatment strategies, supportive care needs, long-term toxicity risk, and survivorship. AYAs have access to multiple efficacious treatment options with high cure rates, but long-term survivors face significant medical, psychosocial, and financial effects with notable risks for cardiopulmonary disease, secondary malignancies, fertility impairment, and unmet psychosocial needs. Harmonized pediatric-adult treatment frameworks, AYA-focused support, and developmentally tailored survivorship care are essential to improving outcomes for AYA HL survivors.
Before 1970, Hodgkin lymphoma (HL) was an often-fatal lymphoma treated with radiation and/or single-agent chemotherapy. In contrast, HL is now a largely curable disease treated with multiagent chemotherapy regimens. In the intervening half-century, the goal of HL treatment has evolved from improving cure rates to developing novel treatment paradigms that maintain historical efficacy while minimizing the short- and long-term side effects of intensive chemo- and radiation therapies. The development of PET-adapted escalation and de-escalation strategies has played a critical role in balancing the desired efficacy with toxicity. More recently, novel therapies including brentuximab vedotin and nivolumab have resulted in dramatic improvements in outcomes and a necessary reduction in toxicity in both pediatric and adult patients. Future efforts to improve short- and long-term toxicities through novel therapies and collaborative efforts between adult and pediatric groups will be essential as we seek to improve outcomes in patients with advanced-stage HL.
Radiation therapy (RT) has long been an important part of the history of curative treatment for Hodgkin Lymphoma since the pioneering work of Vera Peters, MD and Henry Kaplan, MD. The contemporary role of radiation therapy in the management of patients with early-stage favorable and unfavorable disease, advanced disease, and relapsed/refractory disease will be explored. Seminal clinical trials that highlight the critical role of RT in local control and progression-free survival will be reviewed. The interest in combined modality therapy (CMT) (combination of chemotherapy and RT) will be explored as well as the use of CMT with emphasis on cost effectiveness, age and sex, and risk profile including secondary malignancy and cardiac toxicity compared with chemotherapy alone. Contemporary radiation treatment volumes, techniques, and doses will be discussed as modern strategies to mitigate late toxicities while maintaining efficacy.
Management of relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) has evolved substantially with the integration of novel targeted and immune-based therapies. Agents such as brentuximab vedotin (BV) and immune checkpoint inhibitors (CPIs) have demonstrated high response rates in multiple settings and are increasingly used as therapeutic strategies for frontline, salvage, and multiply relapsed cHL. Consequently, the traditional roles of cytotoxic chemotherapy and stem cell transplantation are being redefined, with greater emphasis on disease biology and individualized risk-benefit assessment. Though data are continuing to evolve, it appears that the use of CPIs and BV can improve outcomes for patients with R/R disease, even as retreatment, and can lead to durable remissions. This review summarizes current management paradigms for R/R cHL and highlights emerging data regarding sequencing, retreatment, and the use of novel agents.
Combined modality therapy (CMT; chemotherapy with consolidative radiation) has led to excellent long-term outcomes in patients with early-stage Hodgkin lymphoma. However, despite high cure rates, CMT can lead to significant long-term toxicity in a typically young patient population; as a result, there has been a push in the field to develop novel treatment strategies that can maintain robust patient survival while minimizing the risk of treatment-related complications. This has been primarily explored by 2 mechanisms: first, the use of response-adapted treatments based on interim FDG-PET/CT; and second, the incorporation of novel therapies, including the CD30-directed antibody-drug conjugate brentuximab vedotin (BV) and immune checkpoint blockade. In this article, we provide a historical review of the management of early-stage HL and discuss ongoing studies that may change the standard of care for this disease.
Emerging treatment paradigms in classic Hodgkin lymphoma (cHL), which increasingly incorporate immunotherapy and response-adapted strategies, have increased the need for more accurate disease assessment tools. PET/CT remains the cornerstone for staging and response evaluation, but has limited sensitivity for low-volume residual disease, interobserver variability, and a high false-positive in the setting of immunotherapy. Baseline clinical scores and erythrocyte sedimentation rate (ESR) provide baseline prognostic information but offer little insight into tumor biology or treatment response. Further, tissue-based molecular profiling is constrained by the paucity of Hodgkin Reed-Sternberg (HRS) cells. We summarize emerging strategies, including total metabolic tumor volume (TMTV), serum thymus and activation-regulated chemokine (TARC), and circulating tumor DNA (ctDNA) for more accurate disease burden quantification, noninvasive genotyping, molecular subtyping, and minimal residual disease detection. Together, these tools have the potential to enable a multimodal approach to disease assessment, risk stratification, and response evaluation in cHL.
Older patients age >60 years with advanced-stage cHL have historically had poorer outcomes, attributed to comorbid conditions, performance status, and chemotherapy intolerance. The use of an anthracycline-based chemotherapy backbone has shown strong correlation with improved survival, and the intent of treatment remains curative even in the older population. Strategies to help mitigate treatment toxicity to allow for treatment continuation remain one of the greatest concerns in the treatment of older cHL patients. Avoidance of bleomycin, use of G-CSF in brentuximab vedotin (BV)-AVD, and the use of comprehensive geriatric assessments to assess fitness have allowed for more tailored therapy with improved outcomes in older cHL patients. In clinical practice, identification of comorbid conditions or functional deficits using a comprehensive geriatric assessment allows the provider to intervene earlier, modify risk factors, provider supportive care, and possibly modify therapy based on frailty index. Despite these advances, a standardized frontline treatment regimen has not been universally recognized, but recent advances with the use of targeted therapies such as BV or nivolumab have demonstrated improved outcomes. The recent subset analysis of older patients with advanced-stage cHL treated with N-AVD is the first to suggest an OS benefit in oHL patients, with an acceptable toxicity and tolerability profile. The S1826 study assessed patient-reported QOL measures longitudinally and found that older patients treated with BV-AVD experienced more self-reported neuropathy, diarrhea, and arthralgias/myalgias compared with those on N-AVD. The self-reported tolerability and physician-reported toxicity profile of the S1826 regimen with N-AVD supports the emerging use of N-AVD as frontline therapy in older patients with advanced-stage cHL. Further research is ongoing to tailor treatments for older patients with cHL.
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma subtype, representing a small fraction of Hodgkin lymphoma or an even smaller fraction of B-cell non-Hodgkin lymphoma, depending on the classification schema used. NLPHL is characterized by rare lymphocyte-predominant (LP) cells interspersed within a complex immunologic architecture. NLPHL immunoarchitecture has led to hypothesis-driven research suggesting the pathogenesis of NLPHL may be driven by aberrant immune responses to commensal microorganisms, including Moraxella catarrhalis and Rothia mucilaginosa. NLPHL commonly presents in younger adults with asymptomatic lymphadenopathy in early stages. Although late relapses are a well-known feature of this disease, the prognosis is outstanding, nearly mirroring the average life expectancy in Western populations. Management options must carefully weigh the benefits of treatment against the risks of long-term toxicities, including end-organ damage and secondary malignancies. Options utilizing least-toxic approaches include active surveillance, radiation therapy, and combination chemoimmunotherapy for higher-risk presentations. A recent prognostic score, the LP-IPS, derived from large multicenter datasets, may help personalize approaches for patients at higher risk of morbidity/mortality requiring therapy and identify lower-risk patients for active surveillance or low-toxicity approaches.
