Gy Involved Field Radiotherapy Research Articles

Doxorubicin, Vinblastine and Dacarbazine with or without Bleomycin for Older Patients with Early Stage Favorable Hodgkin Lymphoma: An Analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 Trials

IntroductionBleomycin is commonly omitted from the ABVD regimen (doxorubicine, vinblastine, dacarbazine and bleomycin) in older Hodgkin Lymphoma (HL) patients due to excessive toxicity, particularly bleomycin-induced lung toxicity (BLT). Very recently, however, the GHSG HD13 trial indicated that the omission of bleomycin from the ABVD regimen has a negative impact on efficacy (Behringer et al., EHA 2014). Given the high rate of BLT in older patients, the role of bleomycin in the ABVD regimen for this particular group of patients is still unclear. We therefore analyzed feasibility, toxicity and efficacy of ABVD or AVD in 287 older early stage favorable HL patients.MethodsAs described in detail previously elsewhere, HD10 and HD13 were prospective, randomized international multicenter trials including early stage favorable HL patients defined as stages I and II without any of the GHSG risk factors (Engert et al. NEJM 2010). For the present study, we focused on older HL patients (≥60 years), who were randomized to receive either 2 cycles ABVD (2 x ABVD) or AVD, in both cases followed by either 20 or 30 Gy involved-field radiotherapy (IF-RT). To estimate cumulative BLT, we also analyzed older HL patients who received 4 x ABVD followed by IF-RT in the HD10 trial.Results287 patients with a median age of 65 years (range 60-75) were included with an equal distribution of gender, IPS scores, histology and age between the treatment groups.Treatment consisted of 2 x ABVD in 137 patients (HD10 and HD13), 2 x AVD in 82 patients (HD13), and 4 x ABVD in 68 patients (HD10). Pulmonary function test (PFT) prior to therapy was available for 117 patients (HD13 only) showing impaired PF in 14 (26%) and 9 (15%) of the patients randomized to receive ABVD or AVD, respectively.Although patient numbers were too small to draw statistically sound conclusions, in our analysis, patients treated with AVD tended to receive higher relative dose intensity than patients treated with 2 x ABVD. Early termination of chemotherapy was only observed in 1 patient of each treatment arm.Overall, frequency of grade III-IV adverse events was similar for both patient groups. Respiratory adverse events were rare even in patients receiving 2 cycles of bleomycin (1 and 0 cases with 2 x ABVD and AVD, respectively). However, BLT occurred in 6 patients (9%) receiving 4 cycles ABVD and was lethal in half of the affected patients. PFTs or (chest x-ray) within two years after therapy were available for 80 HD13 patients and showed pathological results for 2 patients each out of 34 and 46 patients treated with 2 x ABVD or AVD, respectively.Regarding the efficacy, patient numbers were far too small for testing on (non-)inferiority of the AVD regimen as done in the HD13 trial. However, differences in PFS and OS were about the same magnitude as observed in the HD13 trial (Behringer et al., submitted), indicating that the effect of bleomycin on efficacy observed in this trial does also hold true for the subgroup of older patients.ConclusionIn this study of 219 older early stage favorable HL patients treated with 2 cycles of either ABVD or AVD, no significant effect of bleomycin on the incidence and severity of adverse events was detectable. In contrast, the additional 67 older patients receiving 4 x ABVD had more grade III/IV toxicity and a strikingly higher rate of BLT, indicating a cumulative toxicity of bleomycin in older HL patients. DisclosuresOff Label Use: Everolimus in relapsed or refractory Hodgkin Lymphoma. von Tresckow:Novartis: Honoraria, Research Funding; Takeda: Honoraria, Travel grants, Travel grants Other. Borchmann:Takeda: Honoraria, Research Funding, Travel grants Other.

Bulky Aggressive B-Cell Lymphoma: To Radiate or Not to Radiate—That Is the Question

Bulky Aggressive B-Cell Lymphoma: To Radiate or Not to Radiate—That Is the Question

Patterns of failure after involved field radiation therapy for pediatric and young adult Hodgkin lymphoma

Involved field radiation therapy (IFRT) is integral in curative therapy for Hodgkin lymphoma (HL), although primarily used in patients with intermediate/high-risk HL. We present failure patterns and clinical outcomes in a cohort of pediatric and young adult patients with HL treated with IFRT at the Johns Hopkins Hospital. Patients ≤40 years old with intermediate/high-risk HL who received chemotherapy and IFRT from 1997 to 2012 were included in this retrospective analysis. Patients were evaluated for failure patterns, overall survival (OS), and event-free survival (EFS) using Kaplan-Meier curves, descriptive statistics, and Cox proportional hazard regressions. We reviewed 74 patients (45 pediatric and 29 young adult) with a median follow-up of 4.4 years. The mean age at diagnosis was 21.4 years. Patients received a median of 29.75 Gy of IFRT (range 15-39.6 Gy). The majority of pediatric patients received ABVE-PC chemotherapy (n = 25) and <30 Gy of radiation (n = 33) while most young adults received ABVD chemotherapy (n = 24) and ≥30 Gy (n = 25). Estimated 5-year OS and EFS were 96% and 81%, respectively. Thirteen patients had recurrence; eight were pediatric. Distant relapse alone comprised 83% of failures in patients receiving ≥30 Gy. Of the seven patients who received <30 Gy and had recurrence, six had local failure as a component of their recurrence. Caucasian race (P = 0.02) and nodular sclerosing histology (P = 0.01) predicted for increased EFS. Late effects were minimal and all deaths (n = 4) were from HL. In this series, pediatric and young adult patients were treated with differing chemoradiation and had distinct recurrence patterns.

XVII. Radiotherapy in early stage Hodgkin lymphoma

The treatment of patients with Hodgkin lymphoma (HL) is one of the major success stories in oncology and 60–90% of patients are cured of their malignancy depending on clinical stage and risk factors. Radiotherapy was used to cure patients with HL as early as the 1940s, but more widespread successes came in the 1960s for early stage diseases I A and II A with the use of extended field radiotherapy (RT) techniques to include all nodal stations above the diaphragm such as the ‘mantle’ field [1]. Recurrence of disease outside the radiation field in some patients led to studies of adjuvant chemotherapy as part of a combined modality approach. These studies led to improved progression free survival (PFS) but no overall survival (OS) advantage was seen over RT alone because patients developing recurrent disease after RT were very efficiently salvaged by chemotherapy [2]. A sequential and thorough approach in large randomized trials exemplified by the German Hodgkin Study Group (GHSG) has led to substantial treatment reduction and established a standard of care based on minimal highly effective combined modality treatment (CMT). With a median follow-up of 7.5 years, 8-year results of the GHSG HD10 trial involving 1370 patients with early stage favourable HL showed that two cycles of chemotherapy regimen consisting of Adriamycin, Cyclophosphamide, Oncovin, Procarbazine, Prednisolone (ABVD) and 20Gy of involved field radiotherapy (IFRT) were as effective as four cycles ABVD and 30 Gy, produced less immediate toxicity and resulted in an OS of 95% and freedom from treatment failure and event-free survival of 86% [3]. For early stage unfavourable HL, moderate dose escalation using a chemotherapy regimen consisting of Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Oncovin, Procarbazine and Prednisone (BEACOPP) did not significantly improve outcome over four cycles of ABVD and 30 Gy IFRT, which the GHSG HD11 concluded remains the standard of care [4] Whilst efforts to improve a 5-year Failure From Treatment Failure (FFTF) of 85% and OS of 94.5% are ongoing in unfavourable disease, it will be difficult to improve the results of two cycles of ABVD and 20 Gy for the favourable

Hodgkin’s Lymphoma in Adults

With an incidence of 2 to 3 cases per 100 000 persons per year, Hodkgin's lymphoma (HL) is rare, but nonetheless one of the most common cancers in young adults. Improved treatment has made HL curable even in advanced stages, but controversy still surrounds a number of issues in patient care. Current research focuses on the avoidance of long-term adverse effects and secondary malignancies. We selectively searched MEDLINE, CENTRAL, and the Guideline International Network for publications about HL. Two experts independently screened the retrieved publications for pertinence and extracted data from potentially relevant meta-analyses, randomized controlled trials (RCTs), and cohort studies into evidence tables. 32 key questions were answered with 160 recommendations on the basis of evidence from 43 RCTs, 21 meta-analyses, and 119 cohort studies. Patients in an early stage of HL should be treated with two cycles of ABVD followed by involved-field radiotherapy (IF-RT) at a dose of 20 Gy (5-year overall survival [OS]: 94%). Patients in an intermediate (early unfavorable) stage should be treated with two cycles of BEACOPP escalated followed by two cycles of ABVD and 30 Gy IF-RT (5-year OS: 97.2%). Patients in an advanced stage should be treated with six cycles of BEACOPP escalated, and the decision whether this should be followed by consolidating radiotherapy (30 Gy) should be based on the findings of positron-emission tomography (radiate in case of PET-positive residual tumor; 5-year OS: 95.3%). Depending on the treatment regimen, there may be adverse effects including infection, leukopenia, anemia, thrombocytopenia, secondary neoplasia, and fertility disorders. Most questions in the treatment of HL can now be answered on the basis of sufficient evidence from the literature. This holds in particular for the potential benefit to be gained from PET, follow-up care, and lifestyle recommendations for patients.

Involved Nodal Radiotherapy vs. Involved Field Radiotherapy after Chemotherapy in the Treatment of Early Stage Hodgkin’s Lymphoma

Aim of work: This study is a prospective randomized trial aiming to investigate whether radiotherapy volume can be reduced without loss of efficacy from involved field radiotherapy (IFRT) to involved node radiotherapy (INRT) after four cycles of ABVD chemotherapy in the treatment of early stage Hodgkin’s lymphoma. Patients and Methods: Between September 2009 and January 2012, all patients with newly diagnosed early-stage favorable and unfavorable Hodgkin’s lymphoma attending to the Clinical Oncology department of Cairo University, faculty of medicine were enrolled into this study after a written consent was obtained from those cases enrolled. Patients were assigned to receive (ABVD) for four cycles followed by randomization for radiotherapy into two arms one arm of 30 Gy INRT +/– 6 Gy to residual disease or another arm of 30 Gy IFRT +/– 6 Gy to residual disease. Results: 35 patients were enrolled in this study: 16 patients in the INRT arm and 19 patients in the IFRT arm. The median observation time was 25 months. The overall survival for all eligible patients was 97% and freedom from treatment failure was 85.7%. Survival rates at the end of the study revealed no differences between INRT and IFRT arms. Also, in terms of complete remission post radiotherapy (14 versus 15), relapse (1 versus 4), and death (0 versus 1) respectively the outcome was similar in both arms. As regard acute and sub-acute toxicities no significant difference could be detected between both arms except that IFRT arm was associated with a higher incidence of radiation pneumonitis (4 versus 1 patient). Conclusion: Radiotherapy volume size reduction from IFRT to INRT after ABVD chemotherapy for four cycles produces similar results and less toxicity in patients with early-stage Hodgkin’s lymphoma especially in patients with mediastinal disease.

Interim positron emission tomography and clinical outcome in patients with early stage Hodgkin lymphoma treated with combined modality therapy

The aim of the study was to investigate whether interim positron emission tomography (iPET) is prognostic in a cohort of patients with early stage Hodgkin lymphoma (HL) homogeneously treated with 3–4 cycles of ABVD (adriamycin, bleomycin, vinblastine and dacarbazine) followed by 30 Gy involved field radiotherapy. Eighty patients were selected (stage I–IIA HL, availability of iPET, minimum follow-up of 12 months), and after central review, 70 were judged negative (iPET−: 87.5%) and 10 positive (iPET+: 12.5%). The two groups were then analyzed for response, progression-free survival (PFS) and overall survival (OS). Only one out of 70 iPET− patients relapsed, with 69 in continuous complete remission (CCR). All 10 iPET + patients achieved a complete response and maintained persistent CCR at follow-up. The 3-year PFS and OS were, respectively, 97% and 98.4% for iPET− and 100% and 100% for iPET+ (p = 0.63). iPET positivity does not seem to be a significant prognostic factor, and change in therapeutic strategy on the basis of iPET does not appear currently advisable outside clinical trials.

Comparing long-term toxicity and efficacy of combined modality treatment including extended- or involved-field radiotherapy in early-stage Hodgkin's lymphoma

To evaluate long-term toxicity and efficacy of a combined modality strategy including extended-field radiotherapy (EF-RT) or involved-field radiotherapy (IF-RT), the German Hodgkin Study Group carried out a follow-up analysis in patients with early unfavorable Hodgkin's lymphoma (HL). One thousand two hundred and four patients were randomized to four cycles of chemotherapy followed by either 30 Gy EF- or 30 Gy IF-RT (HD8 trial); 532 patients in each treatment arm were eligible. At 10 years, no arm differences were revealed with respect to freedom from treatment failure (FFTF) (79.8% versus 79.7%), progression-free survival (79.8% versus 80.0%), and overall survival (86.4% versus 87.3%). Non-inferiority of IF-RT was demonstrated for the primary end point FFTF (95% confidence interval for hazard ratio 0.72-1.25). Elderly patients had a poorer outcome when treated with EF-RT. So far, 15.0% of patients in arm A and 12.2% in arm B died, mostly due to secondary malignancies (5.3% versus 3.4%) or HL (3.2% versus 3.4%). After EF-RT, there were more secondary malignancies overall (58 versus 45), especially acute myeloid leukemias (11 versus 4). Radiotherapy intensity reduction to IF-RT does not result in poorer long-term outcome but is associated with less acute toxicity and might be associated with less secondary malignancies.

Management of HIV-Associated Hodgkin Lymphoma: How Far We Have Come

Although Hodgkin lymphoma (HL) is not considered an AIDSdefining malignancy, population-based studies have demonstrated an increased incidence of this disease in the setting of HIV infection. In a prospective cohort study of 11,112 individuals who were positive for HIV, with 71,687 patient-years of follow-up, the incidence of HL was 14 times higher than in the general population. In contrast to other HIV-associated malignancies that occur more commonly with severe immunocompromise, HL is associated with moderate immunologic impairment and the incidence actually seems to decline at CD4 lymphocyte counts of less than 200/ L. Although incidence rates for the AIDS-defining malignancies (Kaposi’s sarcoma, aggressive B-cell non-Hodgkin lymphoma [NHL]) have fallen, the incidence of HL may actually be increasing since the advent of combination antiretroviral therapy (cART), perhaps as a consequence of improvement in the level of immune function. However, the increased relative risk of HL is substantially lower than that observed for aggressive B-cell lymphoma. As a result of the small number of cases, studies investigating approaches to management of HIV-associated HL have been largely retrospective in design. For the more common AIDS-defining lymphomas, diffuse large B-cell lymphoma and Burkitt lymphoma, outcomes have improved dramatically in the 16 years since the introduction of active antiretroviral therapies, which have transformed HIV disease into a survivable chronic illness. Prospective studies in the pre-cART era demonstrated 2-year overall survival (OS) in the 10% to 20% range with complete remission (CR) rates of 35% to 50%, far inferior to those observed in non-HIV–associated lymphomas. Prognosis at that time was largely dependent on the severity of immunosuppression rather than on features of the lymphoma. This experience changed with the advent of cART such that now treatment outcomes using standard regimens such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone or dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab approach those observed in the non-HIV–infected population, with CR rates of 65% to 77% and 2-year OS rates of more than 60%. The International Prognostic Index (IPI) score seems to be a significant prognostic factor in patients treated with chemotherapy and concurrent cART. On the basis of the age-adjusted IPI score, the survival of patients in one trial using rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone was similar to that achieved by patients with aggressive lymphomas who were not infected with HIV. HL in the HIV-seropositive population is more likely to have mixed cellularity or lymphocyte-depleted histology and is almost always Epstein-Barr virus–associated. The majority of patients present with advanced-stage disease. Before the introduction of cART, treatment outcomes for HIV-HL were poor. In an Italian retrospective study of 114 patients with HIV-associated HL who received various standard chemotherapeutic regimens, the median OS was 15 months. Sixty percent died, 35% of those from opportunistic infection, 33% from HL, and 12% from both. As has been the case for aggressive B-cell lymphomas in patients with HIV infection, small retrospective and prospective studies have suggested improvement in outcome with the advent of cART. A retrospective study of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with cART in 62 patients with advanced-stage HIVassociated HL demonstrated a CR rate of 87% and 5-year OS of 76%. A prospective trial reported a CR rate of 81% and 2-year OS of 51% in 59 patients treated with the Stanford V regimen (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone) administered with antiretroviral therapy. The fact that only 10% of these patients received radiotherapy suggests that the regimen was either not delivered as designed or that the inclusion of patients with early-stage and low-bulk disease (factors associated with inferior outcome with this regimen) resulted in relatively disappointing outcomes. In the article that accompanies this editorial, the German HIV-Related Lymphoma Study Group presents data from the largest prospective trial ever conducted in patients with HIV-associated HL. In this study, 112 patients were allocated to treatment on the basis of stage and risk category. Those with early-stage favorable disease (IA/B or IIA/B) received two to four cycles of ABVD plus 30 Gy of involved-field radiotherapy. Patients with early-stage unfavorable disease received four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) at baseline or four cycles of ABVD followed by 30 Gy of involved-field radiotherapy if disease was 5 cm or residual disease was 2 cm. Those with advanced disease received eight cycles of BEACOPP with or without radiotherapy to sites 2.5 cm. Patients with advanced HIV disease, including Eastern Cooperative Oncology Group performance score 2, received ABVD. There were five toxic deaths: 4% with early favorable, 0% with early unfavorable, and 7% with advanced disease. CR rates were 96%, 100%, and 86% for these three groups, respectively, and 2-year PFS JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 33 NOVEMBER 2

Stanford V chemotherapy and involved field radiotherapy for children and adolescents with unfavorable risk Hodgkin lymphoma: Results of a multi-institutional prospective clinical trial.

9502 Background: To evaluate the efficacy of 12 weeks of Stanford V chemotherapy (prednisone, vinblastine, doxorubicine, nitrogen mustard, etoposide, vincristine, and bleomycin) without routine growth factor support plus response-adapted low-dose, involved-field radiotherapy (IFRT) in children and adolescents with unfavorable risk Hodgkin lymphoma (HL). Methods: Multi-institutional (St. Jude Children’s Research Hospital, Stanford University, Children’s Hospital Boston, Massachusetts General Hospital and Maine Children’s Hospital) clinical trial. One hundred forty-one patients with clinical stages IIB (n=43), IIIB (n=19), IVA (n=27), and IVB (n=52) HL were treated with 12 weeks of Stanford V chemotherapy and low dose IFRT between June 2002 and May 2011. Involved nodal sites in complete remission (CR, defined as &gt; 75% shrinkage of the original tumor and PET negative) after 8 weeks of Stanford V received 15 Gy IFRT; those sites that achieved only partial response received 25.5 Gy IFRT after completion of all 12 weeks of chemotherapy. Results: With a median follow-up of 4.6 years, the 3-year overall and event-free survival (EFS) are 97% (SE=2%) and 79% (SE=4%) respectively. There was no significant difference in EFS by stage (IIB vs. IIIB vs. IV; P=0.84). Ten patients developed progessive disease and 18 relapsed, while 5 have died (1 after relapse in an accident and 4 of refractory disease). Most common toxicities were grade 3 hematologic with 234 episodes of neutropenia in 101 patients (72%) and 85 episodes of anemia in 52 patients (37%); Fever and neutropenia occurred 13 times in 12 patients (9%). Conclusions: Risk-adapted, combined-modality therapy using 12 weeks of Stanford V chemotherapy plus IFRT is well tolerated in this population with manageable acute toxicities. Overall survival is comparable to other more intense chemotherapy regimens. Future high-risk front line therapies may consider a Stanford V backbone with targeted intensification and further tailoring of radiation therapy.

Dose-Intensification in Early Unfavorable Hodgkin's Lymphoma: Final Analysis of the German Hodgkin Study Group HD14 Trial

In patients with early unfavorable Hodgkin's lymphoma (HL), combined modality treatment with four cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) and 30 Gy involved-field radiotherapy (IFRT) results in long-term tumor control of approximately 80%. We aimed to improve these results using more intensive chemotherapy. Patients with newly diagnosed early unfavorable HL were randomly assigned to either four cycles of ABVD or an intensified treatment consisting of two cycles of escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by two cycles of ABVD (2 + 2). Chemotherapy was followed by 30 Gy IFRT in both arms. The primary end point was freedom from treatment failure (FFTF); secondary end points included progression-free survival (PFS) and treatment-related toxicity. With a total of 1,528 qualified patients included, the 2 + 2 regimen demonstrated superior FFTF compared with four cycles of ABVD (P < .001; hazard ratio, 0.44; 95% CI, 0.30 to 0.66), with a difference of 7.2% at 5 years (95% CI, 3.8 to 10.5). The difference in 5-year PFS was 6.2% (95% CI, 3.0% to 9.5%). There was more acute toxicity associated with 2 + 2 than with ABVD, but there were no overall differences in treatment-related mortality or secondary malignancies. Intensified chemotherapy with two cycles of BEACOPP escalated followed by two cycles of ABVD followed by IFRT significantly improves tumor control in patients with early unfavorable HL.

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.

Hypofractionated Radiotherapy and Stereotactic Boost with Concurrent and Adjuvant Temozolamide for Glioblastoma in Good Performance Status Elderly Patients – Early Results of a Phase II Trial

Glioblastoma Multiforme (GBM) is an aggressive primary brain neoplasm with dismal prognosis. Based on successful phase III trials, 60 Gy involved-field radiotherapy in 30 fractions over 6 weeks [Standard radiation therapy (RT)] with concurrent and adjuvant temozolomide is currently the standard of care. In this disease, age and Karnofsky Performance Status (KPS) are the most important prognostic factors. For elderly patients, clinical trials comparing standard RT with radiotherapy abbreviated to 40 Gy in 15 fractions over 3 weeks demonstrated similar outcomes, indicating shortened radiotherapy may be an appropriate option for elderly patients. However, these trials did not include temozolomide chemotherapy, and included patients with poor KPS, possibly obscuring benefits of more aggressive treatment for some elderly patients. We conducted a prospective Phase II trial to examine the efficacy of a hypofractionated radiation course followed by a stereotactic boost with concurrent and adjuvant temozolomide chemotherapy in elderly patients with good performance status. In this study, patients 65 years and older with a KPS > 70 and histologically confirmed GBM received 40 Gy in 15 fractions with 3D conformal technique followed by a 1–3 fraction stereotactic boost to the enhancing tumor. All patients also received concurrent and adjuvant temozolomide. Patients were evaluated 1 month post-treatment and every 2 months thereafter. Between 2007 and 2010, 20 patients (9 males and 11 females) were enrolled in this study. The median age was 75.4 years (range 65–87 years). At a median follow-up of 11 months (range 7–32 months), 12 patients progressed and 5 are alive. The median progression free survival was 11 months and the median overall survival was 13 months. There was no additional toxicity. These results indicate that elderly patients with good KPS can achieve outcomes comparable to the current standard of care using an abbreviated radiotherapy course, radiosurgery boost, and temozolomide.

Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

D. A. Eichenauer1, A. Engert1, M. Andre2, M. Federico3, T. Illidge4, M. Hutchings5, & M. Ladetto6 on behalf of the ESMO Guidelines Working Group* First Department of Internal Medicine, University Hospital Cologne and German Hodgkin Study Group (GHSG), Cologne, Germany; CHU Dinant-Godinne, UCL Namur, Yvoir, Belgium; Department of Oncology, Hematology and Respiratory Diseases, University of Modena and Reggio Emilia, Modena, Italy; Institute of Cancer Sciences, University of Manchester, Manchester, UK; Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Divisione di Ematologia, Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy

Results of a prospective clinical trial for VAMP alone without irradiation for pediatric favorable, early-stage Hodgkin lymphoma patients who achieve an early complete response.

9503 Background: To evaluate the efficacy of 4 cycles of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) alone in patients with early-stage, favorable Hodgkin lymphoma (HL) who achieve a complete response after 2 cycles of VAMP. Methods: Multi-institutional phase II trial. Eighty-eight patients with clinical stages I and II, favorable risk (< 3 nodal sites, no B symptoms, no mediastinal bulk and no extranodal extension) HL were treated with four cycles of VAMP chemotherapy with or without involved field radiotherapy (IFRT). Patients who achieved a complete response (CR) (n=46) after 2 cycles of VAMP received no IFRT and those who achieved less than CR (n=42) were given 25.5 Gy IFRT, one patient progressed prior to starting IFRT and another withdrew consent to be treated elsewhere. Results: With a median follow-up of 5.4 years, the 5-year overall survival and event-free survival (EFS) for the whole cohort are 100% and 88% (SE=4.6%) respectively; the EFS for patients who did not get IFRT is 89% (SE=6.5%). IFRT was not a predictor of EFS (P=0.98). Ten patients relapsed and one had progressive disease. One of the irradiated patients developed recurrence as diffuse large B-cell lymphoma. All 5 non-irradiated patients who relapsed were salvaged with intense multi-agent chemotherapy and IFRT without autologous stem cell transplant. No second malignancies have been observed. Therapy was well tolerated with 8 grade 3/4 infections in 6 patients. Neither gender, histology, nor stage were significant predictors of outcome. Conclusions: Risk-adapted, combined-modality therapy using only four cycles of VAMP chemotherapy without radiation for patients achieving a complete response after 2 cycles of VAMP is highly effective and without significant side effects. These results indicate that selected pediatric patients with stages I and II favorable HL can be cured with limited therapy without alkylating agent, bleomycin, etoposide, or radiation therapy. Non-irradiated relapsed patients can be easily salvaged without high dose chemotherapy.

A Phase III Study for the Treatment of Children and Adolescents with Newly Diagnosed Low Risk Hodgkin Lymphoma (HL)

AbstractAbstract 767 Introduction:Optimal therapy for favorable risk HL in children and adolescents continues to evolve. Although the great majority of children will be cured, the potential for long-term adverse sequelae of treatment remains significant. Current regimens seek to define less toxic approaches that effectively treat low risk HL patients. The Children's Oncology Group (COG) HL studies have focused on the use of a response based paradigm for reduction of therapy. Methods:COG protocol AHOD0431 was a single arm study designed to investigate: 1) the rate at which three cycles of doxorubicin, vincristine, prednisone and cyclophosphamide (AVPC) induces complete response (CR), 2) whether achieving CR after 3 cycles of chemotherapy alone allows elimination of involved-field radiation therapy (IFRT), while maintaining excellent disease control and 3) whether very early response as measured by [18F]–fluorodeoxyglucose-positron emission tomography (FDG-PET) after the first course of chemotherapy is predictive of outcome. Eligibility requirements were: ages 0–21 years with newly diagnosed Stages IA and IIA HL without bulk and without lymphocyte predominance (LP) histology. All subject received chemotherapy. Patients who achieved a CR after 3 cycles of AVPC received no further therapy. Those with a partial response (PR) received 21 Gy IFRT. CR was defined as at least 80% reduction in the size of each of the nodal masses, or return to normal size, and negative findings on FDG-PET or Gallium scanning. Imaging studies were centrally reviewed. Results:287 subjects were enrolled between February, 2006 and December, 2008. 9 subjects were subsequently found to be ineligible, and an additional 3 were inevaluable for 3-cycle response. The CR rate after 3-cycles of AVPC was 63.6%, lower than the goal rate of 80%. However, event free survival (EFS) for the entire cohort at 2 years was 84%, and overall survival (OS) was 100%. Analysis by CR vs. PR status after 3 cycles of chemotherapy showed a 2 yr EFS of 80% for those achieving CR after 3 cycles of AVPC (no IFRT) vs. 88% for those achieving PR and therefore receiving IFRT (p=0.11). 227 subjects had evaluable FDG-PET results after one cycle of chemotherapy (PET1). Among subjects who achieved a CR (no IFRT) the 2 year EFS for PET1 positive/equivocal vs. negative was 65% vs. 87% (p=0.005). Among subjects who achieved a PR after 3 cycles of chemotherapy and received IFRT per protocol, 2 year EFS for PET1 positive/equivocal vs. negative was 82% vs. 96% (p=0.047). In December, 2008 the Study Committee recommended IFRT for all CR patients who were PET1 positive or PET1 status unknown, and were within one year of completing chemotherapy. 12 subjects received IFRT based on this recommendation, and all remain in CR. At a median f/u of 25 months, 46% of the entire cohort remain in CR without receiving any radiation therapy. Conclusions:Low risk HL in pediatric and adolescents is well recognized to be a highly curable malignancy, however late toxicities of therapy are frequent and may be life threatening or substantially affect quality of life. Nearly half of our patients have not received radiation therapy on this protocol. These outcomes are similar to other published pediatric regimens for low risk HL (excluding LP histology), even those that incorporated radiation therapy for all or most patients. The OS of 100% suggests that those who did recur after limited therapy were quite salvageable, many without aggressive salvage regimens or stem cell transplant. CR status after 9 weeks of chemotherapy may not optimally identify patients in whom IFRT can be avoided. Very early response, as measured by FDG-PET after 3 weeks of therapy, had significant prognostic implications in both CR and PR subjects, suggesting that this assessment may have a role in identifying a cohort of patients for whom limited volume/low dose RT remains an important component of therapy. Alternatively, AVPC may require intensification to optimize EFS while limiting need for IFRT. The role of a limited intensity chemotherapy regimen with low-dose IFRT for those subjects that experience localized recurrence after chemotherapy alone is the subject of an ongoing investigation. Disclosures:No relevant conflicts of interest to declare.

AHOD0031: A Phase III Study of Dose-Intensive Therapy for Intermediate Risk Hodgkin Lymphoma: A Report From the Children's Oncology Group

AbstractAbstract 766The challenge in treating children with Hodgkin lymphoma (HL) is to continue progress in its curability while diminishing the risk for toxic events that compromise quality of life and survival. This therapeutic Phase III trial for patients with intermediate risk HL was designed to meet these tandem goals. Methods:Eligible patients had clinical stage I-IIA with bulk, I-IIAE, I-II B, IIIA-IVA with or without bulk. All patients initially received 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC), at which point a response evaluation was performed. Rapid early (RER) versus slow early responder (SER) status was defined by CT imaging. All SER patients were randomized at the end of 2 cycles to an additional two cycles of ABVE-PC vs. 2 cycles of dexamethasone, etoposide, cisplatin and cytarabine (DECA) followed by 2 additional cycles of ABVE-PC. All SER patients received 21 Gy involved field radiotherapy (IFRT) following completion of chemotherapy. RER patients received 2 additional cycles of ABVE-PC followed by response evaluation by both CT and functional imaging (Gallium scintigraphy or FDG-PET). RER with complete responder (CR) status (RER/CR) patients were randomized to involved field radiotherapy (IFRT) or no further therapy. RER/non-CR patients were non-randomly assigned to IFRT. Tables 1 shows patient characteristics. Results:Among 1712 eligible patients, the event-free survival (EFS) at 3 years was 85.6% (95% confidence interval [CI] 83.6 – 87.3%) for all patients, 87.1% (95% CI 84.9 – 89.0%) for RER patients vs. 77.8% (95% CI 72.0 – 82.5%) for SER patients (p=0.0001). Overall survival (OS) at 3 years was 98.2% (95% CI 97.3–98.8%) for all patients and differed between RER (98.7%) and SER patients (96.9%) (p=0.02). IFRT following 4 cycles of ABVE-PC did not appreciably improve outcome for RER/CR patients: 3-year EFS was 87.9% (95% CI 83.3–91.4%) for patients randomized to receive IFRT vs. 85.4% (95% CI 80.8–89.0%) for those randomized to no IFRT (p = 0.07). For SER patients randomized to DECA, 3-year EFS was 80.2% (95% CI 71.9–86.2%), and did not differ statistically from those who were randomized to no DECA, where the 3-year EFS was 75.6% (95% CI 67.1–82.2%).We conducted a secondary analysis of the data based on the FDG-PET response after two cycles of ABVE-PC. Among RER/CR patients, the 3-year EFS for those who were FDG-PET negative at the end of two cycles (PET2-) did not differ between those randomized to IFRT and no further therapy (86.1% vs. 86.5%). Among RER/CR patients who were FDG-PET positive or equivocal at the end of two cycles (PET+), there was no significant, but a slightly larger difference in 3-year EFS (82.5% for IFRT and 79.6% for no IFRT). Among SER patients who were PET2-, those randomized to no DECA had slightly better 3-year EFS (89.3%) compared to those randomized to DECA (86.9%), although the differences were not statistically significant. Among SER PET2+ patients, 3-year EFS was 75.1% for those treated with DECA compared with 57.4% for those treated without DECA (p=.08). Conclusions:Early response to chemotherapy is important in the optimization of subsequent treatment intensity in patients with HL. We have found that patients with RER followed by CR, particularly those who were PET2-, may not benefit from 21Gy IFRT. In addition, CT and PET both play an important role in defining response and titration of therapy. Augmentation with DECA did not improve the overall EFS for SER (which remained inferior to outcome for RER), but there was a trend toward improved outcome with DECA in SER patients who were PET2+. Alternative augmentation regimens may prove more effective than DECA; an ongoing COG trial is evaluating this hypothesis. Further analyses of the AHOD0031 cohort are being performed to assess the simultaneous contribution of disease and treatment factors to the role of early response to chemotherapy and subsequent titration of therapy with IFRT or additional chemotherapy.Table 1:Characteristics of the CohortMale908Female804Mean Age (yrs)14.6Median Age (yrs) (Range)15.2 (1.9, 21.9)IA bulk82IIA bulk614IAE, IIAE28IB16IIB363IIIA353IVA256RER1274RER/CR716RER/<CR524SER299Other139 Disclosures:No relevant conflicts of interest to declare.

Reduced Treatment Intensity in Patients with Early-Stage Hodgkin's Lymphoma

Whether it is possible to reduce the intensity of treatment in early (stage I or II) Hodgkin's lymphoma with a favorable prognosis remains unclear. We therefore conducted a multicenter, randomized trial comparing four treatment groups consisting of a combination chemotherapy regimen of two different intensities followed by involved-field radiation therapy at two different dose levels. We randomly assigned 1370 patients with newly diagnosed early-stage Hodgkin's lymphoma with a favorable prognosis to one of four treatment groups: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of radiation therapy (group 1), four cycles of ABVD followed by 20 Gy of radiation therapy (group 2), two cycles of ABVD followed by 30 Gy of radiation therapy (group 3), or two cycles of ABVD followed by 20 Gy of radiation therapy (group 4). The primary end point was freedom from treatment failure; secondary end points included efficacy and toxicity of treatment. The two chemotherapy regimens did not differ significantly with respect to freedom from treatment failure (P=0.39) or overall survival (P=0.61). At 5 years, the rates of freedom from treatment failure were 93.0% (95% confidence interval [CI], 90.5 to 94.8) with the four-cycle ABVD regimen and 91.1% (95% CI, 88.3 to 93.2) with the two-cycle regimen. When the effects of 20-Gy and 30-Gy doses of radiation therapy were compared, there were also no significant differences in freedom from treatment failure (P=1.00) or overall survival (P=0.61). Adverse events and acute toxic effects of treatment were most common in the patients who received four cycles of ABVD and 30 Gy of radiation therapy (group 1). In patients with early-stage Hodgkin's lymphoma and a favorable prognosis, treatment with two cycles of ABVD followed by 20 Gy of involved-field radiation therapy is as effective as, and less toxic than, four cycles of ABVD followed by 30 Gy of involved-field radiation therapy. Long-term effects of these treatments have not yet been fully assessed. (Funded by the Deutsche Krebshilfe and the Swiss Federal Government; ClinicalTrials.gov number, NCT00265018.)

Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Second Malignant Neoplasms in Survivors of Pediatric Hodgkin's Lymphoma Treated With Low-Dose Radiation and Chemotherapy

Survivors of childhood Hodgkin's lymphoma (HL) are at risk for second malignant neoplasms (SMNs). It is theorized that this risk may be attenuated in patients treated with lower doses of radiation. We report the first long-term outcomes of a cohort of pediatric survivors of HL treated with chemotherapy and low-dose radiation. Pediatric patients with HL (n = 112) treated at Stanford from 1970 to 1990 on two combined modality treatment protocols were identified. Treatment included six cycles of chemotherapy with 15 to 25.5 Gy involved-field radiation with optional 10 Gy boosts to bulky sites. Follow-up through September 1, 2007, was obtained from retrospective chart review and patient questionnaires. One hundred ten children completed HL therapy; median follow-up was 20.6 years. Eighteen patients developed one or more SMNs, including four leukemias, five thyroid carcinomas, six breast carcinomas, and four sarcomas. Cumulative incidence of first SMN was 17% (95% CI, 10.5 to 26.7) at 20 years after HL diagnosis. The standard incidence ratio for any SMN was 22.9 (95% CI, 14.2 to 35) with an absolute excess risk of 93.7 cases per 10,000 person-years. All four secondary leukemias were fatal. For those with second solid tumors, the mean (+/- SE) 5-year disease-free and overall survival were 76% +/- 12% and 85% +/- 10% with median follow-up 5 years from SMN diagnosis. Despite treatment with low-dose radiation, children treated for HL remain at significant risk for SMN. Sarcomas, breast and thyroid carcinomas occurred with similar frequency and latency as found in studies of children with HL who received high-dose radiation.