Clinical Intensity Modulated Proton Therapy for Hodgkin Lymphoma: Which Patients Benefit the Most?

PurposeRadiation therapy (RT) improves control of Hodgkin lymphoma (HL), but patients who undergo RT are at risk for late effects, including cardiovascular disease and second cancers, because of radiation doses to organs at risk (OARs). Proton therapy (PT) can reduce OAR doses compared with conventional photon RT. However, access to PT is currently limited, so referrals must be appropriately selective. We aimed to identify subgroups of patients with HL who could benefit the most dosimetrically from RT with PT based on the prechemotherapy disease characteristics.Methods and materialsNormal tissue radiation doses were calculated for 21 patients with HL who were treated with deep-inspiration breath-hold pencil-beam scanning (PBS) PT and compared with doses from 3-dimensional conformal (3D-CRT) and partial arc volumetric modulated (PartArc) photon RT. Prechemotherapy disease characteristics associated with significant dosimetric benefits from PBS compared with photon RT were identified.ResultsTreatment with PBS was well tolerated and provided with good local control. PBS provided dosimetric advantages for patients whose clinical treatment volume extended below the seventh thoracic level and for female patients with axillary disease. In addition, an increasing dosimetric benefit for some OARs was observed for increasing target volume. PBS significantly reduced the mean dose to the heart, breast, lungs, spinal cord, and esophagus. Dose homogeneity and conformity within the target volume were also superior with PBS, but some high-dose measures and hot spots were increased with PBS compared with partial arc volumetric modulated photon RT.ConclusionsPBS gives good target coverage and local control while providing reductions in radiation dose to OARs for individuals who receive RT for HL compared with advanced photon RT. Our findings highlight groups of patients who would be expected to gain more dosimetric benefit from PBS. These findings facilitate the selection of patients who should be considered a priority for PT.     

Pediatric hodgkin lymphoma: maximizing efficacy and minimizing toxicity

Historically, both adult and childhood Hodgkin lymphoma (HL) were treated with full-dose (35-45 Gy) extended-field radiation therapy (RT). Although this treatment was the first to produce reliable disease control, the resulting late toxicity led pediatric oncologists to pioneer the use of combined chemotherapy and low-dose (15-25 Gy) involved-field RT for all stages of HL. Currently, standard treatment of childhood HL is risk adapted; those with favorable risk disease typically receive 2 to 4 cycles of multi-agent chemotherapy with low-dose IFRT, whereas those with higher-risk disease receive more intensive chemotherapy before IFRT. This approach produces long-term survival rates >90% while limiting exposure to anthracyclines, alkylators, and radiation to normal tissues. In contrast to adult HL, IFRT remains an important component of the treatment of advanced-stage HL in pediatric patients. Current clinical trials for children with HL aim to further segregate patients into risk strata such that those who are highly curable can receive less toxic therapy, whereas high-risk patients can receive augmented therapy. Response-adapted therapy, in which overall treatment intensity is modified according to the initial response to chemotherapy, is emerging as a potential means of further reducing therapy for some while maintaining high cure rates. The challenge is to refine therapy in a rare disease in which long-time intervals are necessary to observe an adequate number of events (treatment failure or late effects) to answer judicious questions.     

国际淋巴瘤放射治疗协作组(ILROG)现代放射治疗靶区勾画及剂量指南——HL

放疗是HL最有效的LC治疗手段和重要的治疗组成部分。这些指南用来指导现代综合治疗条件下放疗在HL中的应用。结合现代影像的三维治疗计划和先进的治疗技术,能减少照射体积和照射剂量。最初使用的EF和IF技术,是基于淋巴结站的大体积治疗方式,目前已被仅以最初可检测到的淋巴结(和结外侵犯)范围为基础的有限的照射野所取代。这种照射技术基于增强CT、PET-CT、MRI或结合运用。ICRU定义了GTV、CTV、ITV和PTV概念。更新的治疗技术包括IMRT、呼吸门控、IGRT和4D图像应用,可以显著降低正常组织损伤风险且同时可达到对原发肿瘤控制的主要目的。能够获得理想治疗前影像患者,可以采用高度适形的受累淋巴结放疗(INRT)。受累部位放疗(ISRT)这个新概念作为标准的适形治疗方式被提出,通常在最佳的影像不可获得的情况下使用。越来越多证据表明过去应用的放疗剂量在综合治疗时代比疾病控制所需剂量高。现有数据支持在早期HL中应用INRT和更低放疗剂量。尽管INRT的应用尚未在正式的研究中得到验证,其应用比ISRT更加保守谨慎,原因为欠理想的影像信息和合适的靶区设计以达到可靠的肿瘤LC。目前使用更小照射野治疗的目标是减少治疗体积和剂量,同时维持治疗有效性并使急性和晚期并发症最小化。这篇综述是ILROG督导委员会关于HL放疗现代治疗手段的共识,概括了对HL在可以达到有效LC的同时减少治疗体积的新概念,即ISRT。     

霍奇金淋巴瘤现代治疗的远期不良反应

 源于20世纪60年代的扩大野和次全淋巴结区的放射治疗是第一个治愈早期霍奇金淋巴瘤的手段。但机体正常组织在接受大剂量照射后产生包括心脏疾病及二次肿瘤在内的许多远期不良反应,其中接受40～45 Gy的扩大野或斗篷野照射的患者30年内心脏疾病及二次肿瘤的累计发生率约30 %,因此改善预后与减少治疗的不良反应成为霍奇金淋巴瘤治疗的主要目标。目前受累野及受累淋巴结区的放射治疗均能减少照射的总剂量及正常组织的受照射量,同时效应依赖性治疗策略使患者在减量治疗或强化治疗中最大获益。加强远期不良反应的筛查有利于早期干预减少其临床后果,治疗不良反应相关的基因研究是目前研究的热点。     

Role of Radiation Therapy in the Treatment of Hodgkin Lymphoma

Radiation therapy has historically been the pillar of curative treatment for Hodgkin lymphoma (HL). With improved efficacy of systemic therapy and the ever-increasing recognition of treatment-related morbidity in long-term survivors, the role of radiotherapy has evolved significantly. Modern combined modality therapy (CMT) with multi-agent chemotherapy followed by involved site radiation therapy (ISRT) to initially involved sites of disease remains the gold standard for the majority of patients with HL. Reduction of long-term treatment-related toxicity has become the major driver in clinical trial design for early-stage HL while improved disease-specific survival remains the goal in patients with more advanced and unfavorable disease. This review will address the data supporting the use of radiotherapy in HL as well as specific methods for reducing late toxicity from radiotherapy.     

SOHO State of the Art Updates and Next Questions: Hodgkin Lymphoma

Until recently, advances in classic Hodgkin lymphoma (HL) treatment primarily consisted of minor modifications of highly effective decades-old chemotherapy and radiation approaches. In early-stage disease, excellent outcomes have been reported with fewer cycles of chemotherapy, lower doses, smaller radiation fields and in some circumstances, radiation elimination. In advanced-stage disease, maintaining the dose intensity of standard chemotherapy regimens has resulted in modest improvements in outcomes. During the past decade, the use of early interim positron emission tomography (PET) scans to escalate or de-escalate treatment has been the subject of intense investigation with the goal of maximizing efficacy and minimizing toxicity. Important updates from recent PET-directed trials include; elimination of bleomycin in patients with advanced-stage HL and negative interim PET findings, the benefit of therapy escalation in patients with unfavorable early-stage HL and positive interim PET findings, and the minimal benefit of consolidative radiotherapy in patients with unfavorable early-stage HL and negative interim PET findings. A more nuanced approach to consolidative radiotherapy is required for patients with favorable early-stage disease based on age, disease sites, secondary cancer risk, and cardiovascular disease. Brentuximab vedotin and nivolumab/pembrolizumab have provided promising new options with surprisingly high response rates and modest toxicity for patients with relapsed HL whose disease does not respond to standard treatments. Incorporating these agents into earlier therapy is an area of active investigation for all stages of HL. Although the overall prognosis for HL patients has seen incremental improvement, efforts to optimize treatment with more effective and less toxic approaches continue.     

Favorable early-stage Hodgkin lymphoma

The category of favorable early-stage Hodgkin lymphoma (HL) includes patients with Ann Arbor stages I or II disease with no bulky disease or B symptoms. The precise definition of favorable versus unfavorable early-stage disease may vary among American and European cooperative groups. The overall 10-year survival rate of patients with favorable early-stage HL exceeds 90%. Indeed, effective treatments for this group of patients have been available for more than 4 decades. However, treatment strategies have radically changed over the past 15 years and focus now on maintaining the high cure rate while reducing the risk of treatment-related long-term morbidity. The optimal treatment is still evolving, and more recently, reduction in the total amount of chemotherapy and in radiation field and dose has shown excellent results. Combined modality therapy is the preferred treatment for patients with classical favorable early-stage HL (nodular sclerosis or mixed cellularity histology). Patients with early-stage lymphocyte predominance HL are highly curable using involved-field radiation therapy (IFRT) alone and do not require chemotherapy. Classical favorable HL is also curable with radiotherapy alone or with chemotherapy alone, but larger fields and higher-dose radiation or longer chemotherapy is required compared with combined modality. The freedom from treatment failure rate is significantly better with a combination of short chemotherapy and IFRT than with either chemotherapy or radiotherapy alone. Although combined modality is the standard preferred treatment for favorable disease, radiation therapy alone or chemotherapy alone could be considered under special circumstances or as part of an investigational protocol.     

Consolidative proton therapy after chemotherapy for patients with Hodgkin lymphoma

BackgroundWe investigated early outcomes for patients receiving chemotherapy followed by consolidative proton therapy (PT) for the treatment of Hodgkin lymphoma (HL).Patients and methodsFrom June 2008 through August 2015, 138 patients with HL enrolled on either IRB-approved outcomes tracking protocols or registry studies received consolidative PT. Patients were excluded due to relapsed or refractory disease. Involved-site radiotherapy field designs were used for all patients. Pediatric patients received a median dose of 21 Gy(RBE) [range 15–36 Gy(RBE)]; adult patients received a median dose of 30.6 Gy(RBE) [range, 20–45 Gy(RBE)]. Patients receiving PT were young (median age, 20 years; range 6–57). Overall, 42% were pediatric (≤18 years) and 93% were under the age of 40 years. Thirty-eight percent of patients were male and 62% female. Stage distribution included 73% with I/II and 27% with III/IV disease. Patients predominantly had mediastinal involvement (96%) and bulky disease (57%), whereas 37% had B symptoms. The median follow-up was 32 months (range, 5–92 months).ResultsThe 3-year relapse-free survival rate was 92% for all patients; it was 96% for adults and 87% for pediatric patients (P = 0.18). When evaluated by positron emission tomography/computed tomography scan response at the end of chemotherapy, patients with a partial response had worse 3-year progression-free survival compared with other patients (78% versus 94%; P = 0.0034). No grade 3 radiation-related toxicities have occurred to date.ConclusionConsolidative PT following standard chemotherapy in HL is primarily used in young patients with mediastinal and bulky disease. Early relapse-free survival rates are similar to those reported with photon radiation treatment, and no early grade 3 toxicities have been observed. Continued follow-up to assess late effects is critical.     

Hodgkin lymphoma: A review and update on recent progress

Hodgkin lymphoma (HL) is a unique hematopoietic neoplasm characterized by cancerous Reed‐Sternberg cells in an inflammatory background. Patients are commonly diagnosed with HL in their 20s and 30s, and they present with supradiaphragmatic lymphadenopathy, often with systemic B symptoms. Even in advanced‐stage disease, HL is highly curable with combination chemotherapy, radiation, or combined‐modality treatment. Although the same doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapeutic regimen has been the mainstay of therapy over the last 30 years, risk‐adapted approaches have helped de‐escalate therapy in low‐risk patients while intensifying treatment for higher risk patients. Even patients who are not cured with initial therapy can often be salvaged with alternate chemotherapy combinations, the novel antibody‐drug conjugate brentuximab, or high‐dose autologous or allogeneic hematopoietic stem cell transplantation. The programmed death‐1 inhibitors nivolumab and pembrolizumab have both demonstrated high response rates and durable remissions in patients with relapsed/refractory HL. Alternate donor sources and reduced‐intensity conditioning have made allogeneic hematopoietic stem cell transplantation a viable option for more patients. Future research will look to integrate novel strategies into earlier lines of therapy to improve the HL cure rate and minimize long‐term treatment toxicities. CA Cancer J Clin 2018;68:116‐132 . © 2017 American Cancer Society .     

Estimated risk of cardiovascular disease and secondary cancers with modern highly conformal radiotherapy for early-stage mediastinal Hodgkin lymphoma

BackgroundHodgkin lymphoma (HL) survivors have an increased morbidity and mortality from secondary cancers and cardiovascular disease (CD). We evaluate doses with involved node radiotherapy (INRT) delivered as 3D conformal radiotherapy (3D CRT), volumetric modulated arc therapy (VMAT), or proton therapy (PT), compared with the extensive Mantle Field (MF).Patients and methodsFor 27 patients with early-stage, mediastinal HL, treated with chemotherapy and INRT delivered as 3D CRT (30 Gy), we simulated an MF (36 Gy), INRT-VMAT and INRT-PT (30 Gy). Dose to the heart, lungs, and breasts, estimated risks of CD, lung (LC) and breast cancer (BC), and corresponding life years lost (LYL) were compared.Results3D CRT, VMAT or PT significantly lower the dose to the heart, lungs and breasts and provide lower risk estimates compared with MF, but with substantial patient variability. The risk of CD is not significantly different for 3D CRT versus VMAT. The risk of LC and BC is highest with VMAT. For LYL, PT is the superior modern technique.ConclusionsIn early-stage, mediastinal HL modern radiotherapy provides superior results compared with MF. However, there is no single best radiotherapy technique for HL—the decision should be made at the individual patient level.     

Ependymoma: New Therapeutic Approaches Including Radiation and Chemotherapy

Summary Recent advances in neuroimaging, neurosurgery and radiation therapy have improved disease control and functional outcomes for children with ependymoma, including children under the age of 3 years. The rate of gross-total resection has been increased to 85% in some series and 3 year progression-free survival after radiation therapy as high as 75% has been reported along with significant reductions in neurologic, endocrine and cognitive deficits. Based on these advances and renewed interest in radiation therapy as a frontline treatment modality, attention has been refocused on disease control instead of radiotherapy avoidance. Future research in the treatment of this tumor, that afflicts fewer than 200 children in the US each year, will focus on molecular biology, clarifying risk factors for tumor control and late effects, and testing novel agents.     

Le rôle de la protonthérapie dans les cancers de l’oesophage

Because of the physical properties of proton beam radiation therapy (PT), which allows energy to be deposited at a specific depth with a rapid energy fall-off beyond that depth, PT has several theoretical advantages over photon radiation therapy for esophageal cancer (EC). Protons have the potential to reduce the dose to healthy tissue and to more safely allow treatment of tumors near critical organs, dose escalation, trimodal treatment, and re-irradiation. In recent years, larger multicenter retrospective studies have been published showing excellent survival rates, lower than expected toxicities and even better outcomes with PT than with photon radiotherapy even using IMRT or VMAT techniques. Although PT was associated with reduced toxicities, postoperative complications, and hospital stays compared to photon radiation therapy, these studies all had inherent biases in relation with patient selection for PT. These observations were recently confirmed by a randomized phase II study in locally advanced EC that showed significantly reduced toxicities with protons compared with IMRT. Currently, two randomized phase III trials (NRG-GI006 in the US and PROTECT in Europe) are being conducted to confirm whether protons could become the standard of care in locally advanced and resectable esophageal cancers.     

Advances in External Beam Radiation Therapy and Brachytherapy for Cervical Cancer

The standard of care for the definitive treatment of locoregionally advanced cervical cancer is external beam radiation therapy (EBRT) with concurrent chemotherapy followed by a brachytherapy boost. Historically, EBRT was delivered via a two-dimensional technique based primarily on bony landmarks. This gave way to three-dimensional conformal radiation therapy, which allows for dose calculation and adjustment based on individual tumour and patient anatomy. Further technological advances have established intensity-modulated radiation therapy (IMRT) as a standard treatment modality, given the ability to maintain tumoricidal doses to target volumes while reducing unwanted radiation dose to nearby critical structures, thereby reducing toxicity. Routine image guidance allows for increased confidence in patient alignment prior to treatment, and the ability to visualise the daily position of the targets and organs at risk has been instrumental in allowing safe reductions in treated volumes. Additional EBRT technologies, including proton therapy and stereotactic body radiation therapy, may further improve the therapeutic index. In the realm of brachytherapy, a shift from point-based dose planning to image-guided brachytherapy has been associated with improved local control and reduced toxicity, with additional refinement ongoing. Here we will discuss these advances, the supporting data and future directions.     

Conformal radiotherapy: tomotherapy]

Conformal radiation therapy allows the possibility of delivering high doses at the tumor volume whilst limiting the dose to the surrounding tissues and diminishing the secondary effects. With the example of the conformal radiation therapy used at the AZ VUB (3DCRT and tomotherapy), two treatment plans of a left ethmoid carcinoma will be evaluated and discussed in detail. The treatment of ethmoid cancer is technically difficult for both radiation therapy and surgery because of the anatomic constraints and patterns of local spread. A radiation therapy is scheduled to be delivered after surgical resection of the tumor. The treatment plan for the radiation therapy was calculated on a three-dimensional (3D) treatment planning system based on virtual simulation with a beam's eye view: George Sherouse's Gratis. An effort was made to make the plan as conformal and as homogeneous as possible to deliver a dose of 66 Gy in 33 fractions at the tumor bed with a maximum dose of 56 Gy to the right optic nerve and the chiasma. To establish the clinical utility and potential advantages of tomotherapy over 3DCRT for ethmoid carcinoma, the treatment of this patient was also planned with Peacock Plan. For both treatment plans the isodose distributions and cumulative dose volume histograms (CDVH) were computed. Superimposing the CDVHs yielded similar curves for the target and an obvious improvement for organs at risk such as the chiasma, brainstem and the left eye when applying tomotherapy. These results have also been reflected in the tumor control probabilities (equal for both plans) and the normal tissue complication probabilities (NTCP), yielded significant reductions in NTCP for tomotherapy. The probability of uncomplicated tumor control was 52.7% for tomotherapy against 38.3% for 3DCRT.     

Late effects of treatment for Hodgkin lymphoma

With advances in multimodality therapy, survival from Hodgkin lymphoma (HL) now exceeds 80%, resulting in a large cohort of survivors who are at risk for adverse long-term sequelae of therapy. This risk is complicated by possible endogenous predispositions to developing late effects, which relate to the patient's underlying susceptibility to HL. Finally, the impact of HL on the host can compromise organ function. This article reviews the possible dominant late effects for survivors of HL and strategies for monitoring and screening. As therapy for HL has changed and evolved, so has the spectrum of late effects. Mortality from HL has decreased, whereas delayed effects of therapy have increased. Refinements in therapy to decrease toxicity have occurred in response to the success in curing HL. Thus, modifications in therapeutic protocols using a risk-adapted strategy have reduced the use of alkylating agents, anthracyclines, and radiotherapy, which are associated with adverse long-term sequelae. The most clinically evident sequelae are those involving the endocrine and cardiovascular systems, and the most morbid are hematologic and solid second malignancies. Primary and secondary prevention strategies can be developed as knowledge of delayed effects of therapy increases.     

Importance of PET/CT Scan Use in Planning Radiation Therapy for Lymphoma

Background: Radiation therapy is a key part of the combined modality treatment for Hodgkin’s lymphoma(HL) and non-Hodgkin’s lymphoma (NHL), which can achieve locoregional control of disease. The 3D-conformalradiation oncology can be extended-field (EFRT), involved-field (IFRT) and involved node (INRT). Newtechniques have resulted in a smaller radiation field and lower dose for critical organs such as lung heart andbreast. Materials and Methods: In our research, we made a virtual simulation for one patient who was treatedin four different radiotherapeutic techniques: mantle field (MFRT), EFRT, IFRT and INRT. After delineatiionwe compared dose-volume histograms for each technique. The fusion of CT for planning radiotherapy withthe initial PET/CT was made using Softver Xio 4.6 in the Focal program. The dose for all four techniques was36Gy. Results: Our results support the use of PET/CT in radiation therapy planning. With IFRT and INRT,the burden on the organs at risk is less than with MFRT and EFRT. On the other hand, the dose distributionin the target volume is much better with the latter. Conclusions: The aim of modern radiotherapy of HL andNHL is to reduce the intensity of treatment and therefore PET/CT should be used to reduce and not increasethe amount of tissue receiving radiation.     

First spinal axis segment irradiation with spot-scanning proton beam delivered in the treatment of a lumbar primitive neuroectodermal tumour. Case report and review of the literature

Primary intraspinal primitive neuroectodermal tumour (PNET) is a rare tumour entity. The optimal therapeutic management is unclear but, in general, this tumour is treated with surgery followed by radiotherapy and chemotherapy. Proton beam radiation therapy (PT) offers superior dose distributional qualities compared with X- or gamma rays, as the dose deposition occurs in a modulated narrow zone called the Bragg peak. As a result, organs at risk are optimally speared. Here, we present a patient treated with the first spinal axis segment irradiation using spot-scanning PT with a single field, combined with conventional cranio-spinal axis radiotherapy after surgery and chemotherapy, and an extensive review of the literature outlining the clinical features and treatment modality of spinal PNET.     

Treatment of radiotherapy-induced fatigue through a nonpharmacological approach

BACKGROUND: Cancer-related fatigue (CRF) is a frequently occurring, burdensome side effect of radiation therapy that can result in detrimental effects to health-related quality of life (HRQL). The findings from a pilot study examining the efficacy of the complementary and alternative practice of Polarity Therapy (PT) in reducing CRF and improving HRQL are reported. METHODS: Fifteen women undergoing radiation therapy for breast cancer and experiencing fatigue were randomized to receive 1, 2, or no PT treatments. Treatments were given 1 week apart to the patients receiving 2 treatments. Fatigue and HRQL were assessed at baseline prior to PT, 3 days following the first PT treatment (week 1), and 3 days following the second PT treatment (week 2). RESULTS: There was a statistically significant improvement in both CRF and HRQL in the 10 patients who received a PT treatment compared to the 5 control patients at the week 1 assessment. In addition, there was a statistically significant difference among the 3 treatment groups in improvement in CRF at the week 2 assessment. This finding, coupled with a visual inspection of the means, supports the plausibility of a dose response concerning PT. CONCLUSION: Results from this pilot investigation suggest that PT may have a positive influence on CRF and HRQL in women undergoing radiation treatment for breast cancer. Randomized, controlled clinical trials with larger sample sizes are needed.     

Current status of intensity-modulated radiation therapy (IMRT)

External-beam radiation therapy has been one of the treatment options for prostate cancer. The dose response has been observed for a dose range of 64.8–81 Gy. The problem of external-beam RT for prostate cancer is that as the dose increases, adverse effects also increase. Three-dimensional conformal radiation therapy (3D-CRT) has enabled us to treat patients with up to 72–76 Gy to the prostate, with a relatively acceptable risk of late rectal bleeding. Recently, intensity-modulated radiation therapy (IMRT) has been shown to deliver a higher dose to the target with acceptable low rates of rectal and bladder complications. The most important things to keep in mind when using an IMRT technique are that there is a significant trade-off between coverage of the target, avoidance of adjacent critical structures, and the inhomogeneity of the dose within the target. Lastly, even with IMRT, it should be kept in mind that a “perfect” plan that creates completely homogeneous coverage of the target volume and zero or small dose to the adjacent organs at risk is not always obtained. Participating in many treatment planning sessions and arranging the beams and beam weights create the best approach to the best IMRT plan.     

Complications of pelvic radiation in patients treated for gynecologic malignancies

Radiation therapy is a critical treatment modality in the management of patients with gynecologic tumors. New highly conformal external‐beam and brachytherapy techniques have led to important reductions in recurrence and patient morbidity and mortality. However, patients who receive pelvic radiation for gynecologic malignancies may experience a unique constellation of toxicity because of the anatomic locations, combination with concurrent chemotherapy and/or surgery, as well as potential surgical interventions. Although side effects are often categorized into acute versus late toxicities, several late toxicities represent continuation and evolution of the same pathologic process. Comorbidities and radiation dose can significantly increase the risk of morbidity. Current understanding of the incidence of various morbidities in patients treated with current radiation techniques for gynecologic malignancies, the impact of chemotherapy and surgery, treatment options for those effects, and future areas of research are highlighted. Cancer 2014;120:3870–3883. © 2014 American Cancer Society.