Real-life study on the use of response adapted therapy in patients with Hodgkin Lymphoma: Results from a multicenter experience.

Few data are known regarding the use of interim positron emission tomography (iPET) after the first two cycles (iPET2) of chemotherapy in treatment-naïve classical Hodgkin lymphoma (cHL) in routine clinical practice, and about the real-life adoption of intensification strategies for iPET positive patients. We conducted a multicenter retrospective study on cHL to investigate the use of iPET in the real-life setting, its prognostic role and outcomes of patients early shifted to intensification. Six hundreds and forty-one patients were enrolled (62% had advanced stage). iPET2 was positive in 89 patients (14%) including 8.7% and 17% early and advanced stage patients, respectively (p = 0.003). Among iPET 2 positive cases treatment was immediately modified in 19 cases; in 14 cases treatment was modified after an additional positive iPET4. Overall 56 iPET2 positive patients never received intensified therapies. Most frequently used intensified therapy was autologous stem cell transplantation followed by BEACOPP. After a median follow-up of 72 months, the 5-year progression-free survival (PFS) was 82% with iPET2 positive patients showing a worse PFS compared with iPET2 negative cases: 31% versus 85%. Focusing on advanced stage patients with a positive iPET2, the 5-year PFS was 59% for patients shifted to intensified therapy at any time point versus 61% for patients who never received intensified therapy. Our study confirmed the higher curability of naïve cHL patients in a real-world setting, and the prognostic role of iPET2 in this setting. A poor adherence to response-adapted strategy which however did not translate into a difference in patient outcomes.

Intensified treatment of patients with early stage, unfavourable Hodgkin lymphoma: long-term follow-up of a randomised, international phase 3 trial of the German Hodgkin Study Group (GHSG HD14).

BACKGROUND: To improve the long-term tumour control in early, unfavourable Hodgkin Lymphoma, the German Hodgkin Study Group (GHSG) HD14 trial compared four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with an intensified chemotherapy regimen consisting of two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP) plus two cycles of ABVD. The final analysis of the trial showed a significant advantage in terms of freedom from treatment failure (difference 7·2% [95% CI 3·8-10·5] at 5 years) for patients who received two cycles of escalated BEACOPP and two cycles of ABVD. However, there was no difference in overall survival between the two groups. To evaluate long-term efficacy and toxicity of this strategy, we did a follow-up analysis. METHODS: Patients aged 18-60 years with performance status of 2 or less and primary diagnosis of early, unfavourable Hodgkin lymphoma (all histologies) were included in an international, randomised, open-label, phase 3 trial. Patients were randomly assigned to receive four cycles of ABVD (ABVD group) or two cycles of escalated BEACOPP and two cycles of ABVD (2 + 2 group), both groups also received 30 Gy involved field radiotherapy. The ABVD dosing regimen was doxorubicin 25 mg/m2 (days 1 and 15), bleomycin 10 mg/m2 (days 1 and 15), vinblastine 6 mg/m2 (days 1 and 15), and dacarbazine 375 mg/m2 (days 1 and 15), repeated on day 29. The escalated BEACOPP dosing regimen was cyclophosphamide 1250 mg/m2 (day 1), doxorubicin 35 mg/m2 (day 1), etoposide 200 mg/m2 (days 1-3), procarbazine 100 mg/m2 (days 1-7), prednisone 40 mg/m2 (days 1-14), vincristine 1·4 mg/m2 (day 8; maximum 2 mg), and bleomycin 10 mg/m2 (day 8), repeated on day 22. After closure of the ABVD group according to prespecified rules, patients were assigned to receive two cycles of escalated BEACOPP and two cycles of ABVD (non-randomised 2 + 2 group), which continued until the end of the predefined 5-year recruitment period. In this prespecified long-term follow-up analysis, we aimed to evaluate the secondary endpoints progression-free survival, overall survival, and long-term toxicity. To this end, we did a descriptive intention-to-treat analysis of all qualified HD14 patients and on the predefined subsets of randomised qualified HD14 patients and patients in the non-randomised 2 + 2 group. The trial was registered on the International Standard Randomised Controlled Trial database, 04761296. FINDINGS: Between Jan 28, 2003, and Dec 29, 2009, 1686 patients were randomly assigned to the ABVD group (847 [50·2%] patients) and the 2 + 2 group (839 [49·8%] patients). 370 additional patients were recruited to the non-randomised 2 + 2 group. 1550 (92%) randomly assigned patients (median observation time 112 months [IQR 80-132]) and 339 (92%) patients in the non-randomised 2 + 2 group (median observation time 74 months [58-100]) were included in the qualified analysis set. 10-year overall survival in the randomly assigned patients was 94·1% (95% CI 92·0-95·7) for the ABVD group and 94·1% (91·8-95·7) for the 2 + 2 group (HR 1·0 [95% CI 0·6-1·5]; p=0·88). 8-year overall survival in the non-randomised 2 + 2 group was 95·1% (95% CI 91·6-97·2). 10-year progression-free survival in the randomly assigned patients was 85·6% (95% CI 82·6-88·1) for the ABVD group and 91·2% (88·4-93·3) for the 2 + 2 group (HR 0·5% [95% CI 0·4-0·7]; p=0·0001), accounting for a significant difference of 5·6% (95% CI 1·9-9·2) favouring the 2 + 2 group (p=0·0001). In the non-randomised 2 + 2 group, 8-year progression-free survival was 94·5% (95% CI 91·1-96·6). Standardised incidence ratios of second primary malignancies were similar between the ABVD group (2·3 [95% CI 1·6-3·1]) and the 2 + 2 group (2·5 [1·8-3·4]; Gray's p=0·80). Standardised incidence ratio of second primary malignancies was 3·1 (95% CI 1·7-5·0) in the non-randomised 2 + 2 group. INTERPRETATION: This long-term analysis confirms superior tumour control in the 2 + 2 group compared with the ABVD group without translating into an overall survival difference. At longer follow-up, there is no difference regarding second primary malignancies between groups. In conclusion, the 2 + 2 regimen spares a significant number of patients from the burden of relapse and additional treatment without increased long-term toxicity. FUNDING: Deutsche Krebshilfe eV and Swiss Federal Government.

Advanced Hodgkin lymphoma in the East of England: a 10-year comparative analysis of outcomes for real-world patients treated with ABVD or escalated-BEACOPP, aged less than 60 years, compared with 5-year extended follow-up from the RATHL trial.

Treatment with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or escalated(e)-BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone) remains the international standard of care for advanced-stage classical Hodgkin lymphoma (HL). We performed a retrospective, multicentre analysis of 221 non-trial ("real-world") patients, aged 16-59 years, diagnosed with advanced-stage HL in the Anglia Cancer Network between 2004 and 2014, treated with ABVD or eBEACOPP, and compared outcomes with 1088 patients in the Response-Adjusted Therapy for Advanced Hodgkin Lymphoma (RATHL) trial, aged 18-59 years, with median follow-up of 87.0 and 69.5 months, respectively. Real-world ABVD patients (n=177) had highly similar 5-year progression-free survival (PFS) and overall survival (OS) compared with RATHL (PFS 79.2% vs 81.4%; OS 92.9% vs 95.2%), despite interim positron-emission tomography-computed tomography (PET/CT)-guided dose-escalation being predominantly restricted to trial patients. Real-world eBEACOPP patients (n=44) had superior PFS (95.5%) compared with real-world ABVD (HR 0.20, p=0.027) and RATHL (HR 0.21, p=0.015), and superior OS for higher-risk (international prognostic score ≥3 [IPS 3+]) patients compared with real-world IPS 3+ ABVD (100% vs 84.5%, p=0.045), but not IPS 3+ RATHL patients. Our data support a PFS, but not OS, advantage for patients with advanced-stage HL treated with eBEACOPP compared with ABVD and suggest higher-risk patients may benefit disproportionately from more intensive therapy. However, increased access to effective salvage therapies might minimise any OS benefit from reduced relapse rates after frontline therapy.

PET-guided omission of radiotherapy in early-stage unfavourable Hodgkin lymphoma (GHSG HD17): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Combined-modality treatment consisting of chemotherapy and consolidation radiotherapy is standard of care for patients with early-stage unfavourable Hodgkin lymphoma. However, the use of radiotherapy can have long-term sequelae, which is of particular concern, as Hodgkin lymphoma is frequently diagnosed in young adults with a median age of approximately 30 years. In the German Hodgkin Study Group HD17 trial, we investigated whether radiotherapy can be omitted without loss of efficacy in patients who have a complete metabolic response after receiving two cycles of escalated doses of etoposide, cyclophosphamide, and doxorubicin, and regular doses of bleomycin, vincristine, procarbazine, and prednisone (eBEACOPP) plus two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy (2 + 2). METHODS: In this multicentre, open-label, randomised, phase 3 trial, patients (aged 18-60 years) with newly diagnosed early-stage unfavourable Hodgkin lymphoma (all histologies) and an Eastern Cooperative Oncology Group performance status of 2 or less were enrolled at 224 hospitals and private practices in Germany, Switzerland, Austria, and the Netherlands. Patients were randomly assigned (1:1) to receive either standard combined-modality treatment, consisting of the 2 + 2 regimen (eBEACOPP consisted of 1250 mg/m2 intravenous cyclophosphamide on day 1, 35 mg/m2 intravenous doxorubicin on day 1, 200 mg/m2 intravenous etoposide on days 1-3, 100 mg/m2 oral procarbazine on days 1-7, 40 mg/m2 oral prednisone on days 1-14, 1·4 mg/m2 intravenous vincristine on day 8 [maximum dose of 2 mg per cycle], and 10 mg/m2 intravenous bleomycin on day 8; ABVD consisted of 25 mg/m2 intravenous doxorubicin, 10 mg/m2 intravenous bleomycin, 6 mg/m2 intravenous vinblastine, and 375 mg/m2 intravenous dacarbazine, all given on days 1 and 15) followed by 30 Gy involved-field radiotherapy (standard combined-modality treatment group) or PET4-guided treatment, consisting of the 2 + 2 regimen followed by 30 Gy of involved-node radiotherapy only in patients with positive PET at the end of four cycles of chemotherapy (PET4; PET4-guided treatment group). Randomisation was done centrally and used the minimisation method and seven stratification factors (centre, age, sex, clinical symptoms, disease localisation, albumin concentration, and bulky disease), and patients and investigators were masked to treatment allocation until central review of the PET4 examination had been completed. With the final analysis presented here, the primary objective was to show non-inferiority of the PET4-guided strategy in a per-protocol analysis of the primary endpoint of progression-free survival. We defined non-inferiority as an absolute difference of 8% in the 5-year progression-free survival estimates between the two groups. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01356680. FINDINGS: Between Jan 13, 2012, and March 21, 2017, we enrolled and randomly assigned 1100 patients to the standard combined-modality treatment group (n=548) or to the PET4-guided treatment group (n=552); two patients in each group were found ineligible after randomisation. At a median follow-up of 46·2 months (IQR 32·7-61·2), 5-year progression-free survival was 97·3% (95% CI 94·5-98·7) in the standard combined-modality treatment group and 95·1% (92·0-97·0) in the PET4-guided treatment group (hazard ratio 0·523 [95% CI 0·226-1·211]). The between-group difference was 2·2% (95% CI -0·9 to 5·3) and excluded the non-inferiority margin of 8%. The most common grade 3 or 4 acute haematological adverse events were leucopenia (436 [83%] of 528 patients in the standard combined-modality treatment group vs 443 [84%] of 529 patients in the PET4-guided treatment group) and thrombocytopenia (139 [26%] vs 176 [33%]), and the most frequent acute non-haematological toxic effects were infection (32 [6%] vs 40 [8%]) and nausea or vomiting (38 [7%] vs 29 [6%]). The most common acute radiotherapy-associated adverse events were dysphagia (26 [6%] in the standard combined-modality treatment group vs three [2%] in the PET4-guided treatment group) and mucositis (nine [2%] vs none). 229 serious adverse events were reported by 161 (29%) of 546 patients in the combined-modality treatment group, and 235 serious adverse events were reported by 164 (30%) of 550 patients in the PET4-guided treatment group. One suspected unexpected serious adverse reaction (infection) leading to death was reported in the PET4-guided treatment group. INTERPRETATION: PET4-negativity after treatment with 2 + 2 chemotherapy in patients with newly diagnosed early-stage unfavourable Hodgkin lymphoma allows omission of consolidation radiotherapy without a clinically relevant loss of efficacy. PET4-guided therapy could thereby reduce the proportion of patients at risk of the late effects of radiotherapy. FUNDING: Deutsche Krebshilfe.

One year of procarbazine lomustine and vincristine is poorly tolerated in low grade glioma: a real world experience in a national neuro-oncology centre.

BACKGROUND: Following optimal local therapy, adjuvant Procarbazine, Lomustine and Vincristine (PCV) improves overall survival (OS) in low-grade glioma (LGG). However, 1 year of PCV is associated with significant toxicities. In the pivotal RTOG 9802 randomised control trial, approximately half of the patients discontinued treatment after 6 months. As patients on clinical trials may be fitter, we aimed to further explore the tolerability of PCV chemotherapy in routine clinical practice. METHODS: We conducted a retrospective study between 2014 and 2018 at a National Neuro-Oncology centre. Patients who had received PCV during this time period were included. The primary objective was to assess tolerability of treatment. Secondary objectives included evaluation of treatment delays, dose modifications and toxicities. RESULTS: Overall, 41 patients were included, 24 (58%) were male and 21 (51%) aged ≥40 years. 38 (93%) underwent surgical resection and all patients received adjuvant radiotherapy prior to chemotherapy. The median number of cycles completed was 3,2,4 for procarbazine, lomustine and vincristine respectively. Only 4 (10%) completed all 6 cycles of PCV without dose modifications. There was a universal decline in dose intensity as cycles of chemotherapy progressed. Dose intensity for cycle 1 versus cycle 6 respectively: procarbazine (98% versus 46%), lomustine (94% versus 48%) and vincristine (93% versus 50%). Haematological toxicities were common. Six (14%) patients experienced Grade III-IV thrombocytopaenia and 13 (31%) experienced Grade III-IV neutropaenia. CONCLUSION: Toxicities are frequently observed with the PCV regimen in clinical practice. It might be preferable to adjust doses from the start of chemotherapy to improve tolerability or consider alternative chemotherapy, particularly in older patients with LGG.

Relapse After Early-Stage, Favorable Hodgkin Lymphoma: Disease Characteristics and Outcomes With Conventional or High-Dose Chemotherapy.

PURPOSE: We evaluated disease and treatment characteristics of patients with relapse after risk-adapted first-line treatment of early-stage, favorable, classic Hodgkin lymphoma (ES-HL). We compared second-line therapy with high-dose chemotherapy and autologous stem cell transplantation (ASCT) or conventional chemotherapy (CTx). METHODS: We analyzed patients with relapse after ES-HL treated within the German Hodgkin Study Group HD10+HD13 trials. We compared, by Cox proportional hazards regression, progression-free survival (PFS) after relapse (second PFS) treated with either ASCT or CTx and performed sensitivity analyses with overall survival (OS) from relapse and Kaplan-Meier statistics. RESULTS: A total of 174 patients' disease relapsed after treatment in the HD10 (n = 53) and HD13 (n = 121) trials. Relapse mostly occurred > 12 months after first diagnosis, predominantly with stage I-II disease. Of 172 patients with known second-line therapy, 85 received CTx (49%); 70, ASCT (41%); 11, radiotherapy only (6%); and 4, palliative single agent therapies (2%). CTx was predominantly bleomycin, etoposide, doxorubicin cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP [68%]), followed by the combination regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (19%), or other regimens (13%). Patients aged > 60 years at relapse had shorter second PFS (hazard ratio [HR], 3.0; P = .0029) and were mostly treated with CTx (n = 33 of 49; 67%) and rarely with ASCT (n = 8; 16%). After adjustment for age and a disadvantage of ASCT after the more historic HD10 trial, we did not observe a significant difference in the efficacy of CTx versus ASCT for second PFS (HR, 0.7; 95% CI, 0.3 to 1.6; P = .39). In patients in the HD13 trial who were aged ≤ 60 years, the 2-year, second PFS rate was 94.0% with CTx (95% CI, 85.7% to 100%) versus 83.3% with ASCT (95% CI, 71.8% to 94.8%). Additional sensitivity analyses including OS confirmed these observations. CONCLUSION: After contemporary treatment of ES-HL, relapse mostly occurred > 12 months after first diagnosis. Polychemotherapy regimens such as BEACOPP are frequently administered and may constitute a reasonable treatment option for selected patients with relapse after ES-HL.

Comprehensive Genomic Analysis in NRG Oncology/RTOG 9802: A Phase III Trial of Radiation Versus Radiation Plus Procarbazine, Lomustine (CCNU), and Vincristine in High-Risk Low-Grade Glioma.

PURPOSE: NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802. METHODS: IDH1/2 mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and MGMT promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates. RESULTS: Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37(35%) were IDH-mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; P = .003; HR, 0.13; P < .001) and OS (HR, 0.38; P = .013; HR, 0.21; P = .029) in the IDH-mutant/non-codeleted and IDH-mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the IDH-wild-type subgroup. CONCLUSION: This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with IDH-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.

Combined modality treatment: Outcome in patients with Hodgkin's lymphoma.

BACKGROUND: Hodgkin's lymphoma (HL) can be treated with combined modality treatment (CMT) to limit long-term toxicities in the early favorable stage. Early unfavorable and advanced stage HL is mainly treated with chemotherapy followed by radiation to the bulky site. This study examines the impact of CMT in early as well as advanced stage HL. MATERIALS AND METHODS: From 2001 to 2011, 125 patients with Stage I to IV HL were analyzed. Median age of the patients was 25 years (range 12-68 years). CMT, chemotherapy, and radiation alone were given to 51, 64, and 10 patients, respectively. Chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was given to 100 patients, 6 patients received ABVD-like regimen, and 9 patients received cyclophosphamide, vincristine, procarbazine, and prednisone regimen. Radiotherapy (RT) was given to 61 (49%) patients, involved field RT to 55 (90%), and extended-field RT to 6 (10%) patients, respectively. Median radiation dose was 30 Gy (18-40 Gy). RESULTS: All 25 patients with early-stage achieved complete response (CR) with CMT. At a median follow-up of 70 months (range 12-230 months), relapse was seen in two patients (1 local and 1 distant). Of 26 patients with advanced stage, 25 achieved a CR and 1 had stable disease with CMT. Relapse occurred in one patient (distant). In patients with early-stage treated with chemotherapy only ( n = 30, 24%), 9 patients had relapse (4 local and 5 distant) while in those with RT only ( n = 10, 8%), 4 developed distant relapse. In patients with advanced stage treated with chemotherapy only ( n = 34, 27%), 8 relapsed (5 local and distant, 3 distant only). Patients with relapse were salvaged with CMT ( n = 6), chemotherapy ( n = 15), or RT ( n = 3). Two patients have died. Five years' disease-free survival (DFS) in patients with early favorable stage, early unfavorable stage, and advanced stage was 91%, 82%, and 73%, respectively ( P = 0.026). DFS was significantly better with CMT than chemotherapy or radiation alone. Five years' overall survival (OS) was 93%, 92%, and 84%, respectively ( P = 0.139). Second malignancy occurred in 3 (2.4%) patients; carcinoma of the tongue, pseudomyxoma peritonei, and non-HL each, respectively. None of these patients had received prior radiation. CONCLUSION: CMT improved DFS in patients with HL. OS was similar in all patients irrespective of treatment combinations. The incidence of second malignancy was 2.4%.

ABVD vs BEACOPP escalated in advanced-stage Hodgkin's lymphoma: Results from a multicenter European study.

The optimal first-line treatment for advanced-stage Hodgkin's lymphoma (HL) is still a matter of debate. While ABVD is less toxic and as effective as other, more intensive chemotherapy regimens, escalated BEACOPP (BEACOPPesc) is superior to ABVD for initial disease control and prolonged time-to-relapse. However, this advantage is associated with higher rate of early and late toxicities. As most of these data have been accumulated from clinical trials, a retrospective analysis was conducted in a large database of patients treated outside clinical trials to investigate the advantages and disadvantages of these regimes in a real-world setting. From October 2009 to October 2018, 397 advanced-stage HL patients treated with either ABVD or BEACOPPesc were retrospectively assessed in 7 European cancer centers (2 Austrian and 5 Italian centers). Complete metabolic remission (CMR) by PET was achieved in 76% and 85% of patients in the ABVD and BEACOPPesc groups, respectively (p = .01). Severe adverse events occurred more frequently with BEACOPPesc than ABVD. At a median follow-up of 8 years, 9% of the patients who achieved CMR after BEACOPPesc relapsed compared to 16.6% in the ABVD group (p = .043). No statistical difference in progression free survival (PFS) was observed between the two cohorts overall (p = .11), but there was a trend towards a superior PFS in high-risk patients treated with BEACOPPesc (p = .074). Nevertheless, overall survival was similar between the two groups (p = .94). In conclusion, we confirm that ABVD is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control, the long-term outcome remains similar between the two regimens.

Adolescents and young adults with classical Hodgkin lymphoma in northern Tunisia: insights from an adult single-institutional study.

PURPOSE: The aim of this study was to extensively describe the epidemiological, clinical and therapeutic outcomes of adolescents and young adults (AYA) population with classical Hodgkin Lymphoma (cHL). Then, a comparison between AYAs and adults and between the subgroups of AYAs treated with the same adult protocol was accomplished to further inform on optimal therapy approach of choice for adolescent patients. MATERIAL AND METHODS: In this mono-centric, retrospective study, we reviewed the medical records. We analyzed 112 consecutive North Tunisian patients, including 66 AYAs (15 to 39 years) and 46 adults (≥40years) affected by cHL treated from 2000 to 2015 at Salah Azaiez Institute. Then, we performed a comparative analysis between AYA and 46 adult patients and a subgroup analysis between adolescents and young adults. All patients were treated according to the national protocol for HL, edited by the Tunisian Society of Hematology. The treatment included chemotherapy and involved-field radiotherapy (RT) at a dose of 20 or 30 Grays (Gy) for responders and 36Gy for non-responders. RESULTS: AYA patients presented with adverse features with nodular sclerosis subtype (p=3.88×10-02) and mediastinal mass involvement (p=9.40×10-04). At a median follow-up of 51 and 32 months for AYAs and adults, respectively, no statistical difference in terms of 3 and 5-years overall survival (OS) and event-free survival (EFS) was shown. Using the Kaplan-Meier method, in AYAs, the ABVD regimen has an impact on 3-years EFS (p=4.63×10-02). The 36Gy RT was associated with the best 3-years EFS (p=9.24×10-03). Besides, AYA patients with advanced-stage had the worst 3-years OS (76%) (p=2.41×10-02). Although the adolescents and young adults shared similar clinical presentation, we noted that the adolescent group had the worst 3-years EFS (48%), but the best 3-years OS (91%). We identified 15% of primary refractory patients and a rate of toxicity of 5.3% in AYA. CONCLUSION: The treatment approach used is well tolerated by adult patients. However, the AYA patients and particularly adolescent subgroup had more advanced disease at diagnosis and should be treated more intensively in dedicated units. RT dose<36Gy and ABVD chemotherapy were associated with lower EFS in this population.

Contemporary treatment options for a classical disease: Advanced Hodgkin lymphoma.

Advanced classical Hodgkin lymphoma (cHL) is a rare lymphoid disease characterized by the presence of Hodgkin and Reed-Sternberg (HRS) cells. Each year, cHL accounts for 0.5% of all new cancer diagnoses and about 80% are diagnosed with advanced stage disease. Given the significant improvement in cure rates, the focus of treatment has shifted towards minimization of acute and long-term toxicities. PET-adapted strategies have largely been adopted as standard of care in the United States in an attempt to balance toxicities with adequate lymphoma control. However, the appropriate upfront chemotherapy regimen (ABVD versus eBEACOPP) remains controversial.

Cost-effectiveness of first-line treatment options for patients with advanced-stage Hodgkin lymphoma: a modelling study.

BACKGROUND: Several strategies are available for the initial treatment of advanced-stage Hodgkin lymphoma, but the optimal strategy in terms of cost-effectiveness is unclear. The aim of this study was to compare the quality-adjusted effectiveness and costs of five modern treatment options for transplantation-eligible patients with newly diagnosed advanced-stage Hodgkin lymphoma. METHODS: A Markov decision-analytic model was developed using a 20-year time horizon. Five of the most common treatment approaches were selected based on clinical experience and expert opinion: (1) six cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD), including data from the HD2000 trial, Viviani and colleagues, and EORTC trial; (2) six cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP; from the HD15 trial or PET-adapted as in the HD18 trial, two initial cycles of BEACOPP followed by four additional cycles for patients with a positive PET and either two or four additional cycles of BEACOPP for patients with a negative PET); (3) PET-adapted escalation (as in the RATHL trial, two cycles of standard ABVD chemotherapy followed by an additional four cycles of ABVD or AVD in PET-negative patients and four cycles of BEACOPP in PET-positive patients); (4) six cycles of brentuximab vedotin, doxorubicin, vinblastine, dacarbazine (A-AVD) or ABVD as in the Echelon-1 trial; and (5) PET-adapted de-escalation (as in the AHL2011 trial, two cycles of BEACOPP followed by PET2 scan; PET-positive patients received two additional BEACOPP cycles and PET-negative patients received two cycles of ABVD; at PET4, PET-negative patients completed two further cycles of either ABVD or BEACOPP depending on what they received after PET2, and PET-positive patients received salvage therapy). Note that all uses of BEACOPP in these strategies were BEACOPPescalated. The randomised groups of interest from these studies comprised 4255 patients enrolled between April, 2000, and January, 2016. Baseline probability estimates and utilities were derived from the included trials in addition to a systematic review of published studies. A Canadian public health payer's perspective was considered (CAN$1=US$0·74) and adjusted for inflation for 2018. All costs and benefits were discounted by 1·5% per year because life-years now are more valuable than future potential life-years. FINDINGS: Probabilistic analyses (10 000 simulations) showed that, for a willingness-to-pay threshold of CAN$50 000, a PET-adapted de-escalation strategy based on AHL2011 was more cost-effective 87% of the time. This strategy had the highest number of life-years (14·6 years [95% CI 13·7-15·1]) and quality-adjusted life years (13·2 years [95% CI 10·2-14·4]), and the lowest direct costs ($53 129 [95% CI 31 914-94 446]) compared with the other treatment regimens. Sensitivity analyses showed that the model was robust to key variables, including probability of treatment-related mortality, relapse, frequency of secondary malignancy, death from secondary malignancy, and probability of infertility after BEACOPP. INTERPRETATION: Our results suggest that, when considering cost, effectiveness, and short and long-term toxicities, the preferred treatment strategy for patients with newly diagnosed advanced-stage Hodgkin lymphoma is the PET-adapted de-escalation regimen starting with BEACOPP and de-escalating to ABVD as appropriate. Although our findings do not provide an absolute best treatment approach for clinicians to follow for all patients, they can contribute to shared decision making between patients and treating physicians. FUNDING: None.

Five-year follow-up of SWOG S0816: limitations and values of a PET-adapted approach with stage III/IV Hodgkin lymphoma.

Patients with advanced-stage Hodgkin lymphoma (HL) demonstrated excellent 2-year progression-free survival (PFS) after receiving positron emission tomography (PET)-adapted therapy on SWOG S0816. Patients received 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Patients achieving complete response (CR) on PET scan following cycle 2 of ABVD (PET2) continued 4 additional cycles of ABVD. Patients not achieving CR on PET2 were switched to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for 6 cycles. After a median follow-up of 5.9 years, a subset of 331 eligible patients with central review of PET2 was analyzed. PET2 was negative in 82% and positive in 18%. For all patients, the estimated 5-year PFS and OS was 74% (95% confidence interval [CI], 69%-79%) and 94% (95% CI, 91%-96%), respectively. For PET2- and PET2+ patients, the 5-year PFS was 76% (95% CI, 70%-81%) and 66% (95% CI, 52%-76%), respectively. Seven (14%) and 6 (2%) patients reported second cancers after treatment with eBEACOPP and ABVD, respectively (P = .001). Long-term OS of HL patients treated on S0816 remains high. Nearly 25% of PET2- patients experienced relapse events, demonstrating limitations ABVD therapy and of the negative predictive value of PET2. In PET2+ patients who received eBEACOPP, PFS was favorable, but was associated with a high rate of second malignancies compared with historical controls. Our results emphasize the importance of long-term follow-up, and the need for more efficacious and less toxic therapeutic approaches for advanced-stage HL patients. This trial was registered at www.clinicaltrials.gov as #NCT00822120.

Protontherapy versus best photon for mediastinal Hodgkin lymphoma: Dosimetry comparison and treatment using ILROG guidelines.

The purpose of this work was reducing treatment-related toxicity for Hodgkin lymphomas using practical procedure inspired by the ILROG guidelines. Reporting the first case of localized Hodgkin lymphoma treated with protontherapy in France. A 24-year-old female with mediastinal, bulky, localized, mixed-cellularity, classic Hodgkin lymphoma required an involved-site radiation therapy after complete response following polychemotherapy. Three-dimensional conformal radiation therapy was not acceptable due to high doses to breasts, heart and lungs. We realized a four-dimensional computed tomography (CT) to evaluate target movements and another CT with gating and breath-hold technique. Delineation was performed on both CT using the initial fluorodeoxyglucose positron-emission tomography/CT. One dosimetric plan with rotational intensity-modulated radiation therapy with a helical Tomotherapy© was realized and compared to another one with conformational protontherapy. Ninety-five percent of the planning target volume was covered by 98 and 99% of the prescribed dose with protontherapy and helical Tomotherapy©. Protontherapy provided the best organ at risk protection. Lung and heart protections were better with protontherapy: lung mean dose (3.7Gy vs. 8.4Gy) and median dose (0.002Gy vs. 6.9Gy), heart mean dose (2.6Gy vs. 3.7Gy). Breast sparing was better for both breasts using protontherapy: right breast mean dose (2.4Gy vs. 4.4Gy) and left (1.9Gy vs. 4.6Gy). The biggest difference was seen with low doses, which were better with protontherapy: volume of lung receiving 5Gy was 17.5% vs. 54.2% with Helical Tomotherapy©. In view of these results, we decided to treat our patient with protontherapy using respiratory assessment. We delivered 30Gy (15 fractions) using protontherapy with one direct anterior field using pencil beam scanning and deep inspiration breath-hold technique. We observed only grade 1 skin erythema during treatment and no toxicity during early follow-up.