Treatment Of Early-stage Hodgkin Lymphoma Research Articles

Toward a paradigm shift in prognostication and treatment of early-stage Hodgkin lymphoma.

Twenty years after the conceptual revolution that occurred in the millennium turnaround upon the introduction of PET/CT in lymphoma staging, restaging, and prognostication, a number of new parameters for PET reading have been proposed: (1) the shift from a qualitative to a semi-quantitative reading for PET reporting, (2) an international consensus on these novel interpretation keys, (3) a standardized and agreed procedure to measure the total metabolic tumour volume (TMTV), and (4) the proposition of new indexes to portray the tumour spread: (D-Max and Total Lesion Surface -TLS). These proved to be very powerful prognosticators, able to revolutionize the traditional Ann Arbor four-stage lymphoma staging. During the 17° Lugano meeting on lymphoma, one main question was asked to experts attending a closed workshop dedicated to new metrics for lymphoma diagnosis, staging, restaging, and prognostication: "Should the traditional 4-stage anatomic staging system be simplified to a more clinically relevant 2-stage system (e.g., limited vs. extensive disease)?" Early-stage HL is an example of how these new metrics could fit with this proposal.

Involved node radiation therapy in the combined modality treatment for early-stage Hodgkin lymphoma: Analysis of relapse location and long-term outcome

Background and purposeInvolved node radiation therapy (INRT) in the combined modality treatment for early-stage Hodgkin lymphoma (ESHL) has reduced the irradiated volume dramatically. Limiting the irradiated volume further based on initial disease bulk, 18F-fluoro-deoxy-glucose (FDG)-avidity, or residual computed tomography (CT) abnormality after chemotherapy seems attractive. In a cohort of patients treated with INRT a meticulous pattern-of-relapse analysis was performed to examine these options. Material and methodsPatients treated for ESHL in our institution from 2005 to 2014 who achieved complete remission with chemotherapy were included. Patient characteristics, treatment details and clinical outcome were registered. For relapsed patients, rigid co-registration of the positron emission tomography/computed tomography-scans from the time of diagnosis and at relapse was done to visually assess the relapse location relative to initial involvement and, if irradiated, the irradiated volume. Size and maximum Standardized Uptake Value of the initial node(s) with later relapse, and residual CT abnormalities after chemotherapy in those locations were measured. ResultsWe included 182 patients. Twelve (6.6%) patients relapsed, five in previously involved nodes (two irradiated, three not irradiated). Relapses did not occur preferentially in initially bulky disease, in lymph node(s) with the highest FDG-uptake, or in residual CT abnormalities after chemotherapy. ConclusionsModern treatment with brief chemotherapy and limited radiotherapy provides excellent long-term disease control in ESHL. Neither bulk, high FDG-uptake, nor residual CT abnormality after chemotherapy could predict initially involved lymph nodes with a high risk of relapse.

Chemotherapy or Combined Modality Therapy for Early-stage Hodgkin Lymphoma.

Optimizing treatment of early-stage Hodgkin lymphoma (HL) requires balancing cure with potential acute and late toxicities from treatment. We reviewed our institutional experience with chemotherapy alone (ChT) versus combined modality therapy (CMT). Patients with stage I-II classical HL in a complete response (CR) by functional imaging after chemotherapy were included. Progression-free survival (PFS) and overall survival (OS) were calculated and a multivariate analysis (MVA) was performed. A total of 136 patients with a CR to chemotherapy were identified. Consolidation radiation therapy (RT) was administered to 117 while 19 received no further therapy. PFS (5 years) was 97% with CMT and 84% with chemotherapy alone (p=0.02). Long-term (10 year) survival was no different (96 vs. 94%, p=0.8). On MVA, CMT improved PFS. Secondary malignancies were rare and no cardiac events were observed. Consolidation RT results in superior PFS in early-stage Hodgkin lymphoma with minimal added toxicity.

Treatment of Early-Stage Hodgkin Lymphoma: Are We Just Shifting Morbidities?

Treatment of Early-Stage Hodgkin Lymphoma: Are We Just Shifting Morbidities?

Current developments in the treatment of early-stage classical Hodgkin lymphoma.

After presenting the current treatment recommendations for early-stage Hodgkin lymphoma, we give an overview on recently published clinical trials in this setting. Furthermore, the potential influence of current trials on the treatment of early-stage Hodgkin lymphoma and integration of newly emerging drugs into treatment protocols will be discussed. Trials attempting treatment de-escalation and omission of radiotherapy on the basis of early interim PET-scans have been disappointing so far, but results of some large trials employing this strategy are still awaited. In contrast, a more defensive strategy of starting treatment with less aggressive doxorubicine, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy and intensifying treatment in early interim PET-positive patients has shown encouraging results. New drugs such as brentuximab vedotin and immune checkpoint inhibitors have shown promising results in relapsed and refractory Hodgkin lymphoma. Clinical trials of brentuximab vedotin in early-stage Hodgkin lymphoma have been initiated. Additionally, biomarker-based treatment de-escalation might be a possible route for future improvements. The challenge for future clinical research in early-stage Hodgkin lymphoma is to continue to cure the majority of patients with first-line treatment while reducing long-term toxicity. New strategies to achieve that goal are currently being developed and will further refine treatment of early-stage Hodgkin lymphoma.

ACR Appropriateness Criteria® Hodgkin Lymphoma-Unfavorable Clinical Stage I and II.

These guidelines review the historical evolution of treatment for early-stage Hodgkin lymphoma (HL) with current standards that rely on prognostic factors to risk stratify and direct current treatment schemes that includes differentiation of favorable and unfavorable presentations. The major clinical trials for unfavorable early-stage HL are reviewed. Patients in this heterogenous subgroup of classic HL are best managed with sequential chemotherapy and radiotherapy. The role of imaging response assessment as a means to modify therapy is a strategy under investigation. Tailoring the radiation treatment volume and radiation dose prescription along with selective use of modern conformal techniques is expected to help reduce long-term toxicities. Many patients are well served receiving involved-site radiotherapy to 30 Gy after appropriate systemic therapy intensity; but, there are nuances for which some variations in the chemotherapy and radiotherapy specifics are appropriately individualized. Following a discussion of the current evidence-based treatment algorithms, several different example cases are reviewed to help physicians make appropriate treatment decisions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Involved site radiation therapy for the treatment of early-stage Hodgkin lymphoma in adolescents and young adults.

Radiation therapy technology has permitted the development of new treatment planning techniques. Involved field, involved node, and involved site radiotherapy fields are discussed and compared. Indications for and implications of combined modality therapy are examined, particularly as pertinent to the adolescent and young adult population.

Chemotherapy only in early-stage Hodgkin lymphoma: more relapses but "same" (or possibly worse) survival--reconsidering the misguided trend to omit radiotherapy.

The standard treatment of early-stage Hodgkin lymphoma (ESHL) as recommended by most national guidelines is combined modality treatment (CMT) that includes a short course ABVD followed by a small field of low dose radiotherapy (RT). Recently a trend to treat patients with more chemotherapy alone has been promoted by some claiming that chemotherapy alone is good enough, and the overall survival is similar. These arguments need to be carefully examined, and the risk of more chemotherapy upfront and salvage considered. The suggestion that interim PET will identify patients that can have similar results with chemotherapy alone has recently been questioned by the results of both European and UK studies. It is the subject of this critical review.

The effect on esophagus after different radiotherapy techniques for early stage Hodgkin's lymphoma

Introduction. The cure rate of early stage Hodgkin's lymphoma (HL) is excellent; investigating the late effects of treatment is thus important. Esophageal toxicity is a known side effect in patients receiving radiotherapy (RT) to the mediastinum, although little is known of this in HL survivors. This study investigates the dose to the esophagus in the treatment of early stage HL using different RT techniques. Estimated risks of early esophagitis, esophageal stricture and cancer are compared between treatments. Material and methods. We included 46 patients ≥ 15 years with supradiaphragmatic, clinical stage I–II HL, who received chemotherapy followed by involved node RT (INRT) to 30.6 Gy at our institution. INRT was planned with three-dimensional conformal RT (3DCRT). For each patient a volumetric modulated arc therapy (VMAT), proton therapy (PT) and mantle field (MF) treatment plan was simulated. Mean, maximum and minimum dose to the esophagus were extracted from the treatment plans. Risk estimates were based on dose-response models from clinical series with long-term follow-up. Statistical analyses were performed with repeated measures ANOVA using Bonferroni corrections. Results. Mean dose to the esophagus was 16.4, 16.4, 14.7 and 34.2 Gy (p < 0.001) with 3DCRT, VMAT, PT and MF treatment, respectively. No differences were seen in the estimated risk of developing esophagitis, stricture or cancer with 3DCRT compared to VMAT (p = 1.000, p = 1.000, p = 0.356). PT performed significantly better with the lowest risk estimates on all parameters compared to the photon treatments, except compared to 3DCRT for stricture (p = 0.066). On all parameters the modern techniques were superior to MF treatment (p < 0.001). Conclusions. The estimated dose to the esophagus and the corresponding estimated risks of esophageal complications are decreased significantly with highly conformal RT compared to MF treatment. The number of patients presenting with late esophageal side effects will, thus, likely be minimal in the future.

Treatment for Early-Stage Hodgkin Lymphoma: Has Radiotherapy Had Its Day?

Treatment for Early-Stage Hodgkin Lymphoma: Has Radiotherapy Had Its Day?

A randomized trial of brief treatment of earlystage Hodgkin lymphoma: Is it effective?

Whether it is possible to reduce the intensity of treatment in early (stage I or II) Hodgkin lymphoma with a favorable prognosis remains unclear. Therefore, we conducted this randomized trial, comparing two treatment groups consisting of a combination chemotherapy regimen of two different intensities followed by involved-field radiation therapy at two different dose levels. Prospective, randomized, in patients referred to the Department Of Clinical Oncology And Nuclear Medicine. Ninety-eight patients with histologically proven early-stage Hodgkin lymphoma with a favorable prognosis were enrolled in this study between January 2008 and June 2010. They were randomly assigned in one of two treatment arms: arm I received four cycles of ABVD (adriamycin, belomycin, vinblastine, dacarbazine) followed by 30 Gy of involved-field radiation therapy; arm II received two cycles of ABVD followed by 20 Gy of involved-field radiation therapy. During the follow-up period, the 2-year relapse-free survival rates were 96% and 95% in arm I and arm II, respectively (P=.8), while the 2-year overall survival rates were 98% and 95% in arm I and arm II, respectively (P=.16). acute toxicity affected 54% of patients treated with four cycles of ABVD, who had grade III or IV toxicity, as compared with 30% of those receiving two cycles (P<.02). The rates of acute toxicity (grade III or IV) were also higher among patients treated with 30 Gy of involved-field radiation therapy than among those receiving 20 Gy (16% vs. 2.5%, P<.03) . In patients with early-stage Hodgkin lymphoma and a favorable prognosis, treatment with two cycles of aBVD followed by 20 Gy of involved-field radiation therapy was as effective as, and less toxic than, four cycles of ABVD followed by 30 Gy of involved-field radiation therapy.

Late Effects in the Era of Modern Therapy for Hodgkin Lymphoma

Extended-field and subtotal nodal radiation therapy (RT), developed in the 1960s, was the first reliably curative treatment for early-stage Hodgkin lymphoma (HL). However, the large volume of normal tissue irradiated resulted in significant delayed toxicity, including cardiac disease and second cancers (SCs). The 30-year cumulative incidence of heart disease among adult survivors receiving 40-45 Gy of extended-field or mantle RT is approximately 30%; the incidence of SCs is similar. Improving disease control while reducing the toxicity of treatment has been a major objective of HL trials for more than 2 decades. Contemporary involved-field RT (IFRT) reduces irradiated volumes and produces significant reductions in normal tissue dose compared with historic treatments. Recent data indicate that, compared with mantle RT, IFRT reduces the relative risk of breast cancer among young females receiving mediastinal RT by approximately 60% and also reduces cardiac dose. The recent transition to involved-node RT allows further reductions in normal tissue dose. Response-adapted therapy is being evaluated in clinical trials as a means of identifying those patients most likely to benefit from treatment reduction or intensification, enhanced screening will facilitate early intervention to reduce the clinical burden of late effects, and there is increasing interest in elucidating the genetic correlates of treatment toxicity.

Chemotherapy only for localized Hodgkin lymphoma

Radiation therapy (RT) alone and more recently in combination with chemotherapy (combined modality therapy; CMT) has been the cornerstone of curative treatment for early-stage Hodgkin lymphoma (HL) for over 40 years. Because of increasing awareness of the late morbidity and mortality associated with RT, recent treatment regimens have attempted to limit its use. Chemotherapy only has been demonstrated to be a treatment option for most patients with localized HL. Current clinical trials have targeted subgroups of such patients who may be at an increased risk of recurrence for the addition of limited RT to chemotherapy.

The Case for Chemotherapy Only for Localized Hodgkin Lymphoma

Although radiation therapy (RT) alone, and more recently in combination with chemotherapy, has been the cornerstone of curative treatment for early-stage Hodgkin lymphoma for >40 years, the late toxicities of this treatment are increasingly being recognized as causes of significant late morbidity and mortality. In recent years, the focus of treatment of early-stage Hodgkin lymphoma has been reductions in the doses and fields of RT and attempts to reduce the amount and the toxicity of chemotherapy. Another approach has been to treat with chemotherapy alone and to eliminate RT entirely unless it is absolutely necessary. This review summarizes the accumulating information on the late side effects of treatment of Hodgkin lymphoma, the results of trials with chemotherapy only, attempts to reduce the toxicity of chemotherapy, and the new role of positron emission tomography in treatment planning.

Doxorubicin, Vinblastine and Gemcitabine (AVG), a Novel Regimen Excluding Bleomycin for the Treatment of Early Stage Hodgkin Lymphoma (HL): Results of CALGB 50203.

The major challenge in treatment of early stage HL has been to achieve excellent treatment results while reducing short and long-term toxicities. Radiation therapy (RT) is a major cause of long-term toxicity. Doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) is the established standard chemotherapy regimen for HL. Treatment results in early stage HL with ABVD alone are similar to those with ABVD + RT. Bleomycin pulmonary toxicity is the major cause of short-term morbidity and mortality. Gemcitabine is one of the most active single agents for relapsed/refractory HL with response rates 39–43%, and promising results have been reported in CALGB 59804 in relapsed HL with gemcitabine, vinorelbine and liposomal doxorubicin (Ann Oncol 18: 1071–9, 2007). For these reasons, CALGB conducted a phase II trial of AVG for the initial treatment of stages I and II non-bulky HL. Treatment consisted of doxorubicin 25 mg/m2, vinblastine 6 mg/m2 and gemcitabine 800mg/m2 every 2 weeks for 12 treatments (6 cycles). By study design the dose of gemcitabine was decreased from 1000 mg/m2 to 800 mg/m2 because of at least grade 3 neutropenia in the first 5/6 patients. Growth factor support was permitted following a dose delay due to neutropenia. Responses were assessed according to the International Workshop criteria (JCO 17: 1244–53, 1999). Positron emission tomography (PET) was performed prior to treatment, after 2 and after 6 cycles of AVG. Results were centrally read by 2 independent reviewers and an adjudicator. PET results were not employed in remission assessment. The primary endpoint was complete response rate (CR) + CR/unconfirmed (u). Based on published results with ABVD, the null hypothesis was CR rate ≤ 85% vs. the alternative ≥ 92%. At least 88/98 patients had to achieve CR + CRu for AVG to be considered promising. 104 patients were enrolled, 5 never began treatment. Thus, 99 patients were assessable: median age 38 years (18–80), stages: 10 IA, 70 IIA, 19 IIB. 34/99 (34.3%) patients were ≥45 years of age. 91 patients completed 6 cycles of treatment. CR + CRu: 67/99 (67.7%) (95% CI; 58–77%), partial response (PR): 27/99 (27.3%), stable 4/99 (4%), not assessable 1/99 (1%). 17 patients have relapsed: 9 CR + CRu, 6 PR, 2 stable. Median followup for patients who did not relapse is 1.1 years (0.1 – 2.5). The estimated 1 and 2 year progression free survivals (95% CI) are 0.81 (0.70, 0.89) and 0.71 (0.54, 0.83). All patients are alive. Less than 10% of patients experienced grade 3 or 4 toxicities with the exception of leukopenia and neutropenia. Of the 93 patients who received the 800 mg/m2 dose of gemcitabine, 74% had grade 3 and 28% grade 4 neutropenia. The CR + CRu rates for AVG were lower and the early PFS was shorter than expected. Correlations of month 2 and month 6 PET results with response and PFS will be reported. [Display omitted]

Treatment of early-stage nonbulky Hodgkin lymphoma

Excellent results have been achieved in the treatment of early-stage Hodgkin lymphoma for more than 30 years with radiation therapy alone or the combined modalities of radiotherapy and chemotherapy. A major concern has been the long-term toxicity of treatment, most of which is attributable to radiotherapy. Recent trials that attempt to decrease acute and long-term toxicity are reviewed. To address the problem of late treatment morbidity, randomized trials of combined-modality therapy have been conducted demonstrating that the number of chemotherapy cycles and the extent and doses of radiotherapy can be reduced. Several studies, including three randomized trials of chemotherapy alone vs. combined-modality therapy, suggest that chemotherapy alone is a reasonable option for the treatment of nonbulky early-stage Hodgkin lymphoma. Positron emission tomography after one or two cycles of chemotherapy has been found to be highly predictive of treatment outcome for Hodgkin lymphoma. Combination chemotherapy alone including gemcitabine, a highly active drug with a favorable toxicity profile, with positron emission tomography early during treatment is under evaluation. Less toxic regimens with the aid of positron emission tomography may reduce the short-term and long-term toxicities of treatment of early-stage nonbulky Hodgkin lymphoma.