Advanced-stage Hodgkin Lymphoma Research Articles

HD12 Randomised Trial Comparing 8 Dose-Escalated Cycles of BEACOPP with 4 Escalated and 4 Baseline Cycles in Patients with Advanced Stage Hodgkin Lymphoma (HL): An Analysis of the German Hodgkin Lymphoma Study Group (GHSG), University of Cologne, D-50924 Cologne, Germany.

The preceding trial HD9 had shown a significant superiority for escalated BEACOPP (EB) for failure-free survival (FFTF) and overall survival (OS) over COPP/ABVD or baseline BEACOPP (BB) (each 8 cycles). HD12 aimed to de-escalate chemotherapy by comparing 8 cycles EB with 4 cycles EB plus 4 cycles BB, with or without consolidatory 30 Gy radiation (RT) to initial bulky and residual disease. A total of 1661 patients aged 16–65 with HL in stage IIB (large mediastinal mass and/or E-lesions) or stage III-IV were randomised from 9/1999-1/2003 according to a factorial design between: 8EB + RT, 8EB no RT, 4EB+4BB + RT, 4EB+4BB no RT. A central diagnostic panel reviewed CT images after completion of chemotherapy independent of randomisation arm, and prescribed RT in selected cases. In the fifth analysis of HD12 (5/2006), 94% of all 1593 eligible randomised patients were evaluable, including 1498 for the chemotherapy comparison and 1449 for the radiotherapy comparison. Patient characteristics were very similar for all 4 arms. Radiation was given in arms with planned RT in 65%, in arms with no planned RT in 10%. 93% of all patients reached a complete remission, 2.2% suffered early progression, 4.6% relapsed and 8.2% died with a median folllow-up time of 48 months. Death due to acute toxicity was 3.2% (sepsis, cardiac, pulmonary, infection), with 21 such deaths in the 8EB arms and 27 in the 4EB+4BB arms. Secondary neoplasias were observed in 55 patients (3.7%): 14 AML/MDS, 12 NHL and 29 solid tumors/others. Four-year Kaplan-Meier estimates for arm pairs according to the factorial design were:4 year rates, %(95% CI)8EB vs. 4EB+4BBwith RT vs. without RTFFTF88(86–91) 86(83–89)91(89–93) 88(86–91)OS93(91–95) 91(89–93)No significant differences were observed when comparing treatments according to the sequential analysis plan (N.B. 10% received RT in arms ‘without RT'). The final analysis, scheduled when 80% of patients have 5 years follow-up, must be awaited before final conclusions can be drawn.

Advanced Stage Hodgkin Lymphoma: The Predictive Value on Treatment Outcome of Early FDG-PET Scan Is Independent of and Superior to IPS Score.

Background: FDG-PET scan performed early during chemotherapy (CT) is a powerful prognostic tool in lymphoma management. This study aimed to compare the predictive value on treatment outcome of the International Prognostic Score (IPS) with that of FDG-PET scan performed after two courses of standard CT in untreated advanced stage (AS) HL patients.Patients: From December 2001, 202 new AS HL patients were consecutively admitted to 11 Italian and 3 Danish hematological centers, on behalf of Intergruppo Italiano Linfomi and Danish Lymphoma Cooperative Group. The mean age was 35.5 years (14–79), the male/female ratio 105/97; AS (IIB–IVB) was present in 153, and unfavorable stage IIA (> 3 nodal sites involved or sub-diaphragmatic presentation or bulky disease or ESR > 40) in 49. Bulky and extranodal disease was recorded in 71 and 58 patients, respectively. All patients had FDG-PET at baseline (PET-0) and after 2 courses of CT (PET-2). 192 patients were treated with ABVD, 8 with ABVD-like CT, 2 with BEACOPP. 102 patients received consolidation radiotherapy after CT. All patients were given the therapy programmed at baseline, except in case of overt progression.Results: The mean time from the diagnosis to latest follow-up was 796 days (range 91–1716). 164 patients attained CR while 38 were chemoresistant: 34 showed disease progression during CT and 4 showed early relapse (within 6 months) after CR entry: (+28 – +178 days). 4 out of the 164 pts attaining CR relapsed later than 6 months. In univariate analyses, both PET-2 (p<0.0001) and IPS (p<0.001) were significantly associated with a higher probability of treatment failure. However, in a multivariate analysis only PET-2 was independently predictive of relapse/progression probability (51.0; 95 % C.I. 20.9 – 124.2). The sensitivity of PET-2 for treatment failure was 85%, the specificity 96% and the overall accuracy 94%. The 2-y FFS probability for PET-2 negative and for PET-2 positive patients were 96% and 14%, respectively (log Rank test, p<0.0001; Fig. 1).Conclusions: so far, FDG-PET after two cycles of CT is the most powerful tool available for predicting treatment outcome in AS HL. [Display omitted]

Female Gonadal Toxicities after Treatment of Primary Hodgkin Lymphoma (HL). Analysis of the LENT-SOMA Questionnaire Registered in the Database of the German Hodgkin Study Group (GHSG).

Introduction:As a consequence of the impressive long-term remission rates in Hodgkin Lymphoma (HL), the reduction of treatment-related complications is becoming increasingly important. The most important treatment-related toxicities are secondary malignancies, infertility, pulmonary, cardiac, and thyroid dysfunction. Here, we report results of the prospectively planned LENT-SOMA questionnaire to determine female gonadal toxicities in women successfully treated for HL.Patients and methods:Between 1998 and 2002, the GHSG has conducted the fourth generation of clinical trials for the treatment of early, intermediate and advanced stage HL (HD 10–12) involving a total of approximately 4000 evaluable patients. The LENT-SOMA questionnaire was sent out to the participating centers 2, 5 and 10 years after a patient's randomisation to evaluate cardiac, pulmonary, and gonadal dysfunction after HL treatment. To focus on female gonadal toxicities, questions referred to the menstrual cycle, infertility, and osteoporosis.Results:Overall, approximately 1.900 (50%) LENT-SOMA questionnaire after 2 years were identified. A total of 568 questionnaire were evaluable for the question of menstrual cycle after therapy. Amenorrhea was most frequent in women with advanced stage after treatment with 8 cycles of escalated BEACOPP compared to treatment consisting of 4 cycles of escalated BEACOPP plus 4 cycles of BEACOPP baseline (45% vs. 19%, p<0.0001). A regular cycle was most commonly reported in women treated with two or four cycles of ABVD (98.8% and 95.9%). The frequency of gonadal dysfunction will be evaluated according to treatment modality (chemotherapy, chemo- and radiotherapy) and it will be analysed with respect to age.Conclusion:Female gonadal toxicities after HL treatment include amenorrhea, infertility and osteoporosis. The first analysis of the LENT-SOMA questionnaire focussing on female gonadal dysfunction will be presented.

Response-Based Chemotherapy and Involved Field Radiation for Intermediate Stage Hodgkin Disease. A GISL/NHLSG Trial.

Background.Most of the patients with advanced stage Hodgkin lymphoma can be cured with a standard course of six cycle of ABVD chemotherapy plus involved field (IF)radiotherapy. Patients with less advanced stage or with a more responsive disease could possibly achieve a cure with a shorter course of chemotherapy. In 1992, in the pre-PET era, the GISL addressed the issue of the proper number of chemotherapy cycles planning a response-oriented, ABVD-based study for intermediate-stage Hodgkin's lymphoma patients.Patients and Methods.From January 1992 to December 2002, 218 patients younger than 70 were enrolled. Eligible patients had histologically confirmed and clinically staged Hodgkin's disease. Patients with unfavourable disease included those with Ann Arbor I-III plus at least one among the following: B-symptoms, bulky tumor or extranodal localization. The required clinical staging evaluation included: history and physical examination; CBC count with differential, erythrocyte sedimentation rate, and routine renal and hepatic chemistries; chest radiograph, cervical, thoracic and abdominal computed tomography (CT) scan with contrast. Treatment Plan. Treatment included a first step of three ABVD cycles followed by an “early” restaging. Those patients in CR or CRu after 3 cycles were planned to receive one additional ABVD cycle while patients in PR were planned to receive 3 additional ABVD cycles. IF radiotherapy was recommended at the end of ABVD courses on sites involved at diagnosis.Results:The median age was 30 years (15–68) with an M/F ratio of 0.7. Nodular sclerosis accounted for 75% of the diagnoses. Seventy-eight percent of cases were in stage II, 7% stage I and 15% stage III; B-symptoms, bulky tumor and ESR>30 were recorded, respectively in 15%, 20%, 25%, and 80% of cases. Of the 206 evaluable cases, 34% of patients were in CR at early restaging, 11 in CRu and 47% in PR; four patients did not respond, and four were early drop-outs. Overall 57% of patients received 4 ABVD cycles, 47% six cycles, and 85% received the planned IF-RT. The CR-CRu rate was 72% at the end of chemotherapy and increased to 93% after the radiotherapy. First events included: 18 relapses, 14 less-than-CRs or progressive diseases and two deaths in CR. Of the 34 patients with recurrent or progressive disease, 12 subsequently died, the others were in second or third remission. With a median follow-up of 60 months (24–162), five-year OS and EFS (median-standard error) are 96.7%-2.7% and 83.8%-3.6%, respectively. Early responders who received four ABVD cycles had an excellent outcome with similar EFS (90% vs 84%) and better OS (100% vs 91% p=0.003) compared to the late responders.Conclusions.A response oriented chemotherapy program is feasible and safe in intermediate stage Hodgkin's lymphoma patients. Overall, with a flexible number of ABVD the OS and EFS of the present series nicely match those expected for this setting of patients. Early clinical restaging identifies cases who have an excellent outcome even with a shortened ABVD course.

Long-term results and competing risk analysis of the H89 trial in patients with advanced-stage Hodgkin lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte (GELA)

AbstractFrom 1989 to 1996, 533 eligible patients with stage IIIB/IV Hodgkin lymphoma (HL) were randomly assigned to receive 6 cycles of hybrid MOPP/ABV (mechlorethamine, vincristine, procarbazine, prednisone/Adriamycin [doxorubicin], bleomycin, vinblastine; n = 266) or ABVPP (doxorubicin, bleomycin, vinblastine, procarbazine, prednisone; n = 267). Patients in complete remission (CR) or partial response of at least 75% after 6 cycles received 2 cycles of consolidation chemotherapy (CT) (n = 208) or subtotal nodal irradiation (RT) (n = 210). A better survival probability was observed after ABVPP alone: the 10-year overall survival (OS) estimates were 90% for ABVPP×8, 78% for MOPP/ABV×8, 82% for MOPP/ABV with RT, and 77% for ABVPP×6 with RT (P = .03); and the 10-year disease-free survival (DFS) estimates were 70%, 76%, 79%, and 76%, respectively (P = .09). The 10-year DFS estimates for patients treated with consolidation CT or RT were 73% and 78% (P = .07), and OS estimates were 84% and 79%, respectively (P = .29). These results showed that RT was not superior to consolidation CT after a doxorubicin-induced CR in patients with advanced HL. An analysis of competing risks identified age more than 45 years as a significant risk factor for death, relapse, and second cancers. Prospective evaluation of late adverse events may improve the management of patients with HL.

First-line treatment of Hodgkin’s lymphoma

Substantial clinical progress over the last decades has made Hodgkin's lymphoma into one of the most curable human cancers in adults. About 80% of patients in all stages and of all histologic subtypes experience long-term disease-free survival. Modern treatment strategies aim to improve chemotherapy and radiotherapy, while minimizing therapy-related toxicities. Ongoing trials investigate a reduction of chemotherapy doses or cycles and the application of lower radiation doses and smaller radiation field sizes. For patients with a specific high-risk profile, novel approaches with more intense drug combinations are currently being investigated in clinical trials. This review discusses recent approaches to the first-line treatment of early-favorable, early-unfavorable, and advanced-stage Hodgkin's lymphoma.

Management of Advanced Stage Hodgkin Lymphoma

Although advanced Hodgkin lymphoma is highly curable, balancing the high cure rate with long-term toxicity is challenging. ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine) is the standard chemotherapy regimen, producing a high cure rate with acceptable toxicity. Stanford V and BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) are new regimens with encouraging results and are undergoing randomized clinical trials. The International Prognostic Score provides a clinical tool that may help identify patients with high-risk disease who may require a more aggressive regimen. Consolidative radiation's role in managing advanced Hodgkin lymphoma is still controversial, but it is most accepted for bulky or residual disease or after brief chemotherapy. The development and integration of newer imaging tools, such as fluorodeoxyglucose-positron emission tomography imaging, may allow a more precise evaluation of disease and help define which patients might benefit from consolidative treatment.

Could BEACOPP Be the New Standard for the Treatment of Advanced Hodgkin's Lymphoma (HL)?

In 1992, the German Hodgkin Study Group (GHSG) developed the BEACOPP regimen for further improving the outcome of patients with advanced Hodgkin's lymphoma (HL). Since then, BEACOPP has been introduced in 3 different prospective randomized clinical trials of the GHSG to find an equilibrium between maximal efficacy and least toxicity with the BEACOPP principle for the treatment of advanced stage HL. In the HD9 trial of the GHSG, with 1,186 patients, after a median observation time (mot) of 7 years, the rates for freedom from treatment failure (FFTF) are 85 percent, and for overall survival (OS) 90 percent for dose-escalated BEACOPP, and for COPP/ABVD (C/ABVD comparable to ABVD) the rate for FFTF is 67 percent, and for OS it is 79 percent. These superior BEACOPP results are obtained inspite of a higher rate of secondary AML/MDS in the esc. BEACOPP arm. The number of toxic deaths during treatment, however, was lower for esc. BEACOPP (1.6 percent) than for C/ABVD (1.8 percent). The majority of patients were treated in outpatient setting, in a multicenter study with more than 400 centers, including 120 private doctors, in Germany and 9 other European countries. The reduce acute and longterm toxicity, the GHSG started in the consecutive studies HD12 and HD15 for advanced stage HL to de-escalate BEACOPP by reducing the number of escalated BEACOPP cycles and by applying the baseline-dose BEACOPP, a time-dense regimen, called BEACOPP-14. The excellent results obtained with the BEACOPP principle challenge the seemingly global consensus that ABVD is the gold standard treatment strategy for advanced stage HL.

Could BEACOPP Be the New Standard for the Treatment of Advanced Hodgkin's Lymphoma?

In 1992, the German Hodgkin Study Group (GHSG) developed the BEACOPP regimen for further improving the outcome of patients with advanced Hodgkin's lymphoma (HL). Since then, BEACOPP has been introduced in 3 different prospective randomized clinical trials of the GHSG to find an equilibrium between maximal efficacy and least toxicity with the BEACOPP principle for the treatment of advanced stage HL. In the HD9 trial of the GHSG, with 1,186 patients, after a median observation time of 7 years, the rates for FFTF are 85 percent and for overall survival 90 percent for dose-escalated BEACOPP, and for COPP/ABVD (C/ABVD comparable to ABVD) the rate for FFTF is 67 percent and for overall survival it is 79 percent. These superior BEACOPP results are obtained inspite of a higher rate of secondary AML/MDS in the escalated BEACOPP arm. The number of toxic deaths during treatment, however, was lower for escalated BEACOPP (1.6 percent) than for C/ABVD (1.8 percent). The majority of patients were treated in an outpatient setting, in a multicenter study with more than 400 centers, including 120 private doctors, located in Germany and 9 other European countries. To reduce acute and long-term toxicity, the GHSG started in the consecutive studies HD12 and HD15 for advanced stage HL to de-escalate BEACOPP by reducing the number of escalated BEACOPP cycles and by applying the baseline dose BEACOPP, a time dense regimen, called BEACOPP-14. The excellent results obtained with the BEACOPP principle challenge the seemingly global consensus that ABVD is the gold standard treatment strategy for advanced stage HL.

Multicentre phase II study of the baseline BEACOPP regimen for patients with advanced-stage Hodgkin's lymphoma

A German Hodgkin's lymphoma (HL) study group designed the BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) regimen. In the BEACOPP regimen, treatment intervals were shortened and the dose-intensity was increased compared with those in the ABVD regimen (doxorubicin, bleomycin, vinblastine and darcarbacine), resulting in a long-term disease-free survival rate of approximately 75 – 80%. In the present study, we evaluated the safety and efficacy of the BEACOPP regimen. Between April 2001 and February 2004, 20 patients with HL of stage IIB or higher who had received no previous treatment were enrolled. The patients were aged 17 – 69 years (median 22 years). The histologic types were mixed cellularity in four cases and nodular sclerosis in 16 cases. The stages were stage IIB in four cases, stage III in 12 cases, and stage IV in four cases. Nineteen (95%) of the 20 patients achieved complete remission. The 3-year survival rate was 100% and the 3-year progression-free survival rate was 89.7%. Adverse drug reactions were grade 4 neutropenia in 12 patients, grade 3 – 4 thrombocytopenia in seven patients, and grade 3 or higher non-hematologic toxicities in two patients (stomatitis in one patient and ALT/AST elevation in one patient). The BEACOPP regimen for advanced-stage HL showed an excellent complete remission rate and high efficacy even in stage III/IV patients. However, a long-term risk of the BEACOPP regimen is the development of secondary leukemia or myelodysplastic syndrome. Therefore, long-term follow-up of these patients, including monitoring for toxicities, is necessary.

Cardiac Toxicities after Treatment of Primary Hodgkin's Lymphoma (HL). Analysis of the LENT-SOMA Questionnaire Registered in the Database of the German Hodgkin Study Group (GHSG).

Introduction:As a consequence of the impressive long-term remission rates in Hodgkin's Lymphoma (HL), the reduction of treatment-related complications is becoming increasingly important. The most important treatment-related toxicities are secondary malignancies, infertility, pulmonary, thyroid and cardiac dysfunction. Here, we report results of the prospectively planned LENT-SOMA questionnaire to determine cardiac toxicities in patients successfully treated for HL.Patients and methods:Between 1998 and 2002, the GHSG conducted the fourth generation of clinical trials for the treatment of early, intermediate and advanced stage HL (HD 10–12) involving a total of approximately 4000 evaluable patients. The LENT-SOMA questionnaire was sent out to the participating centers 2, 5 and 10 years after randomisation of participating patients to evaluate cardiac, pulmonary, and gonadal dysfunction after HL treatment. To focus on cardiac toxicities, questions referred to cardiac risk factors, subjective and objective cardiac dysfunction, cardiac intervention and therapy.Results:Overall, approximately 1.900 (50%) LENT-SOMA questionnaires after 2 years and 10% LENT-SOMA questionnaires after 5 years were identified. Among all documented toxicities, oedema were most frequently reported, followed by arrythmia, cardiac failure, myocardial ischaemia, cardiomegaly, and pericardial dysfunction. The frequency of cardiac dysfunction will be evaluated according to treatment modality (chemotherapy, chemo- and radiotherapy) and it will be analysed with respect to age, gender, and cardiac risk factors. Furthermore, the amount of patients suffering from more cardiac toxicities and the probability of recovery, once a cardiac dysfunction has been detected, will be presented.Conclusion:Cardiac toxicities after HL treatment include oedema, cardiac failure, myocardial ischaemia, cardiomegaly, arrythmia, and pericardial dysfunction. The first analysis of the LENT-SOMA questionnaire focussing on cardiac dysfunction will be presented.

Mortality during Treatment of Patients with Advanced Hodgkin's Lymphoma Undergoing Dose Escalated BEACOPP Chemotherapy: An Analysis of the German Hodgkin Study Group (GHSG).

Introduction: Due to substantial clinical progress over the past decades, the outcome of patients with Hodgkin's Lymphoma (HL) has improved with a long-term disease free survival of nearly 80%. Even patients with advanced-stage HL show a five year freedom from treatment failure (FFTF) of 87% and overall survival (OS) of 91% when treated with 8 cycles of BEACOPPescalated (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbacine, prednisone). However, BEACOPPescalated has been associated with some acute and long-term treatment related mortality (TRM). We thus analysed the incidence, clinical features and risk factors for TRM of patients treated with BEACOPPescalated in the HD12 multicenter trial of the GHSG performed between 1998 and 2002. The HD12 was conducted for advanced HL patients (Stage IIB with large mediastinal mass and/or extranodal involvement, stage III/IV). All patients received 8 cycles of chemotherapy either 8x BEACOPPescalated (Arm A/B) or 4xBEACOPPescalated + 4xBEACOPPbaseline (Arm C/D) +/− 30Gy radiation on bulk and residual tumor.Results: In this study, 43 patients (3.1%) from a total of 1392 included died from TRM. 5 patients were excluded from this analysis because of various reasons (change of fist-line therapy due to toxicity, TRM in BEACOPPbaseline) 38 patients were eligible for this analysis. 30 patients (79%) had infectious complications, 6 (16%) cardiac events such as arrhythmia or heart failure, 1 patient died due to bleomycin-related toxicity and 1 case remained unclear. 25 patients (66%) were older than 50 years in contrast to the whole HD12 study population with only 17% of patients being older than 50. There was no statistical difference between those cases with treatment related mortality and the whole study population in terms of other clinical risk factors such as gender, B-symptoms, extranodal involvement, stage of disease, large mediastinal mass or elevated ESR. There was also no difference between the 4 study arms. Most events occurred during the first 4 courses of BEACOPPescalated (79%) with the majority during the first cycle (n = 12; 32%). 23/26 (89%) of patients who died during cycles 2 – 8 had prior WHO grade III/IV leucopenia or infection.Conclusion: Patient age and toxicity in previous cycles are the most obvious risk factors for TRM in patients with advanced HL undergoing BEACOPPescalated chemotherapy. In the HD12 study, the use of G-CSF was mandatory and most patients received their treatment on an outpatient basis. Thus, possible measures to reduce toxicity with this treatment include the prophylactic use of antibiotics as well as treating those with risk factors at least for the first course as inpatients.

Secondary Amenorrhea After Hodgkin’s Lymphoma Is Influenced by Age at Treatment, Stage of Disease, Chemotherapy Regimen, and the Use of Oral Contraceptives During Therapy: A Report From the German Hodgkin’s Lymphoma Study Group

Long-term survivors of successfully treated Hodgkin's lymphoma (HL) are at risk for late complications. Among these, infertility for female patients is of major importance. The subject of this analysis is to evaluate the menstrual status after HL therapy. From 1994 to 1998, the German Hodgkin's Lymphoma Study Group conducted clinical trials for early-, intermediate-, and advanced-stage HL (trials HD7 to HD9) involving a total of 3,186 patients. A survey was carried out to evaluate the menstrual status after therapy. The following factors were assessed concerning their influence on amenorrhea: age, treatment, stage, and the use of oral contraceptives during chemotherapy. A total of 405 women aged younger than 40 years answered the study questions. After a median follow-up of 3.2 years, 51.4% of the women receiving eight cycles of dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) had continuous amenorrhea. Amenorrhea was significantly more frequent after dose-escalated BEACOPP compared with doxorubicin, bleomycin, vinblastine, and dacarbazine; cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine; or standard BEACOPP (P = .0066). Amenorrhea after therapy was most pronounced in women with advanced-stage HL (P < .0001), in women older than 30 years at treatment (P = .0065), and in women who did not take oral contraceptives during chemotherapy (P = .0002). Most women who are treated for advanced-stage HL experience amenorrhea after therapy. Amenorrhea is significantly more frequent in women with advanced-stage HL receiving eight cycles of dose-escalated BEACOPP and in women older than 30 years at first treatment. Furthermore, the data show a statistical association between the use of oral contraceptives and return of menstrual cycle, which is subject to further investigation.

ABVD Versus Modified Stanford V Versus MOPPEBVCAD With Optional and Limited Radiotherapy in Intermediate- and Advanced-Stage Hodgkin's Lymphoma: Final Results of a Multicenter Randomized Trial by the Intergruppo Italiano Linfomi

In this multicenter, prospective, randomized clinical trial on advanced Hodgkin's lymphoma (HL), the efficacy and toxicity of two chemotherapy regimens, doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone (Stanford V) and mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine (MOPPEBVCAD), were compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as standard therapy to select which regimen would best support a reduced radiotherapy program, which was limited to < or = two sites of either previous bulky or partially remitting disease (a modification of the original Stanford program). Three hundred fifty-five patients with stage IIB, III, or IV HL were randomly assigned. Three hundred thirty-four patients were assessable for the study and received six cycles of ABVD (n = 122), three cycles of Stanford V (n = 107), or six cycles of MOPPEBVCAD (n = 106); radiotherapy was administered to 76, 71, and 50 patients in these three arms, respectively. The complete response rates for ABVD, Stanford V, and MOPPEBVCAD were 89%, 76% and 94%, respectively; 5-year failure-free survival (FFS) and progression-free survival rates were 78%, 54%, 81% and 85%, 73%, and 94%, respectively (P < .01 for comparison of Stanford V with the other two regimens). Corresponding 5-year overall survival rates were 90%, 82%, and 89% for ABVD, Stanford V, and MOPPEBVCAD, respectively. Stanford V was more myelotoxic than ABVD but less myelotoxic than MOPPEBVCAD, which had larger reductions in the prescribed drug doses. When associated with conditioned and limited (not adjuvant) radiotherapy, ABVD and MOPPEBVCAD were superior to Stanford V chemotherapy in terms of response rate and FFS and progression-free survival. Patients were irradiated less often after MOPPEBVCAD, but this regimen was more toxic. ABVD is still the best choice when it is combined with optional, limited irradiation.

Quality control of involved-field radiotherapy in patients with advanced Hodgkin’s lymphoma (EORTC 20884)

To evaluate the impact of the quality of involved-field radiotherapy (IFRT) on clinical outcome in patients with advanced Hodgkin's lymphoma (HL) in complete remission (CR) after six to eight cycles of mechlorethamine, vincristine, procarbazine, prednisone-doxorubicin, bleomycin, and vinblastine (MOPP-ABV) chemotherapy. A retrospective review of clinical and radiologic data, radiation charts, simulator films, and megavoltage (MV) photographs was performed. IFRT consisted of 24 Gy to all initially involved nodal areas and 16-24 Gy to all initially involved extranodal sites. Major violations were defined as no or only partial irradiation of an originally involved area, or a total dose <90% of the prescribed dose. Of the 739 patients who were enrolled in the trial between 1989 and 2000, 57% achieved a CR; 152 of 172 patients randomized to IFRT actually received radiotherapy; and in 135 patients, quality control was performed. The overall major violation rate was 47%, predominantly concerning target volumes. The total dose was correct in 81% of the patients. After a median follow-up of 6.5 years, there was no difference in cumulative failure rate between patients with or without major violations. There was no relationship between incidence or site of relapse and major protocol violations. In advanced-stage HL patients in complete remission after six to eight cycles of MOPP-ABV, the outcome was not influenced by violation of the radiotherapy protocol.

Radiotherapy in Advanced-Stage Hodgkin's Lymphoma

Radiotherapy in Advanced-Stage Hodgkin's Lymphoma

Prognostic Factors in Localized Hodgkin's Lymphoma: How To Define Intermediate/Unfavourable Disease?.

Actually, the prognosis of localized Hodgkin's lymphoma (HL) patients may be assessed by different scoring systems. Although many similar characteristics have been identified, these scoring systems are not easy to relate to advanced stage HL. The aim of the present study was to refine the assessment of risk using the published scoring systems and to construct a statistical model for predicting risk of death. We report here the results of the EORTC, GHSG and Canadian-ECOG scoring systems obtained in 1156 patients for whom hematological data were available among the 1390 patients with localized HL prospectively treated within GELA centres in H8 (518 pts) and H9 (638 pts) trials. The International prognostic score (IPS) was available only for the H9 subset. All patients have been treated with radio-chemotherapy of different intensity or duration according to their prognostic factors. Median age was 30 yr [14–69] and age≥45yr.: 18%, female 50%; stage 1: 25%; stage 2: 75%; B symptoms with elevated ESR: 40%; number of nodal sites 1–2: 52%; ≥3: 48%; extra nodal involvement: 8%, bulky mediastinum> 0.35, 28%; elevated ESR> 50:33%; Hb< 10.5 g/dl: 7%; Lymphocytes < 600/μl: 6%; WBC > 15000/μl:11 %; albumin< 40g/l: 37%. With the EORTC scoring system 36% of patients had favourable HL, with GHSG 35% and with Canadian-ECOG 38%. The IPS was 0 in 19% and 1 in 45%. With a median follow up of 42 months, 54 patients died. Survival curves according to the different scoring systems significantly discriminated favourable and unfavourable patients outcomes (5 yrs OS 95% vs 92%, p=0.01). By multivariate Cox analysis, age > 45yr (RR=2.0), sex male (RR=2.5), haemoglobin <10.5g/dl (RR=2.3), lymphocytes < 600/μL (RR=3.6), B symptoms with elevated ESR (RR=3.6), extra nodal sites (RR=1.2) retained a significant prognostic value. The 5 yrs OS was 99%, 98%, 92%, 82%, 73% for patients with 0,1, 2, 3, 4–5 factors respectively (p< 0.0001, see figure). 10% of the patients had 3–5 factors. The covariates selection was validated by the bootstrap method. The introduction of albumin< 40g/l in the H9 subset population did not bring more significant information. In conclusion, these factors are similar with those described in the IPS when stages 3–4 are replaced by extra nodal (E) localization. They should be validated in other prospective trials because such a scoring system could unify the assessment of the prognosis for HL patients and facilitate the treatment choice. [Display omitted]

461 oral Quality control of involved-field radiotherapy in patients with advanced stage Hodgkin's lymphoma (HL) enrolled on the EORTC trial 20884

461 oral Quality control of involved-field radiotherapy in patients with advanced stage Hodgkin's lymphoma (HL) enrolled on the EORTC trial 20884

ABVD vs. STANFORD V (SV) vs. MOPP-EBV-CAD (MEC) in advanced Hodgkin's lymphoma. Final results of the IIL HD9601 randomized trial

6507 Background: About 30% of patients with advanced Hodgkin's lymphoma (HL) do not respond to initial therapy with ABVD or relapse. Recently SV and MEC were reported with higher cure rates. To test the superiority of SV and MEC over ABVD the Intergruppo Italiano Linfomi (IIL) conducted a three arms multicentric randomized trial. Methods: Patients with advanced stage HL (IIB-IV) and no previous treatment were randomised to receive 6 courses of ABVD or 6 courses of MEC or 12 weeks of SV. At the end of chemotherapy radiotherapy was delivered to residual masses or to the sites of previous bulky disease. The principal end point of the study was failure free survival (FFS): complete response (CR) rate, Freedom From Progression (FFP) and Overall Survival (OS) were secondary end-points of the study. Results: From January 1996 to April 2000, 355 pts were randomized; 23 cases were excluded due to missing data (22) or to revised histology (1). Finally 332 (94%) patients were assessed for response and survival. Baseline characteristics were well balanced among the three groups. Radiotherapy was delivered to 64%, 45% and 66% of patients treated with ABVD, MEC or SV, respectively. At the end of the therapy a CR was achieved by 88% of pts treated with ABVD, 94% with MEC and 72% with SV (P < 0.01). After a median follow-up of 56 months (60 months for alive pts), the 5-year FFS was 83%, 85% and 67% for ABVD, MEC and SV respectively (p<0.01); 5-year OS was 90%, 90% and 83% (p=ns) for ABVD, MEC and SV respectively. In addition 5-yrs FFP was 86% for ABVD, 93% for MEC and 76% for SV (p<0.01). Hematological toxicity was higher for MEC than for the other two regimens; grade III-IV leukopenia: 13% vs. 51% vs. 30% (p<0.01). Grade III-IV infections: 1% vs. 14% vs. 0% (p<0.01). Other extra-hematological toxicities were comparable in the three arms. At the time of present analysis, 2 pts per each arm died due to second cancer. Conclusions: The results of the HD9601 trial show an advantage of ABVD and MEC over SV in terms of response, FFS and FFP. No significant financial relationships to disclose.

ABVD vs. STANFORD V (SV) vs. MOPP-EBV-CAD (MEC) in advanced Hodgkin's lymphoma. Final results of the IIL HD9601 randomized trial

6507 Background: About 30% of patients with advanced Hodgkin's lymphoma (HL) do not respond to initial therapy with ABVD or relapse. Recently SV and MEC were reported with higher cure rates. To test the superiority of SV and MEC over ABVD the Intergruppo Italiano Linfomi (IIL) conducted a three arms multicentric randomized trial. Methods: Patients with advanced stage HL (IIB-IV) and no previous treatment were randomised to receive 6 courses of ABVD or 6 courses of MEC or 12 weeks of SV. At the end of chemotherapy radiotherapy was delivered to residual masses or to the sites of previous bulky disease. The principal end point of the study was failure free survival (FFS): complete response (CR) rate, Freedom From Progression (FFP) and Overall Survival (OS) were secondary end-points of the study. Results: From January 1996 to April 2000, 355 pts were randomized; 23 cases were excluded due to missing data (22) or to revised histology (1). Finally 332 (94%) patients were assessed for response and survival. Baseline characteristics were well balanced among the three groups. Radiotherapy was delivered to 64%, 45% and 66% of patients treated with ABVD, MEC or SV, respectively. At the end of the therapy a CR was achieved by 88% of pts treated with ABVD, 94% with MEC and 72% with SV (P < 0.01). After a median follow-up of 56 months (60 months for alive pts), the 5-year FFS was 83%, 85% and 67% for ABVD, MEC and SV respectively (p<0.01); 5-year OS was 90%, 90% and 83% (p=ns) for ABVD, MEC and SV respectively. In addition 5-yrs FFP was 86% for ABVD, 93% for MEC and 76% for SV (p<0.01). Hematological toxicity was higher for MEC than for the other two regimens; grade III-IV leukopenia: 13% vs. 51% vs. 30% (p<0.01). Grade III-IV infections: 1% vs. 14% vs. 0% (p<0.01). Other extra-hematological toxicities were comparable in the three arms. At the time of present analysis, 2 pts per each arm died due to second cancer. Conclusions: The results of the HD9601 trial show an advantage of ABVD and MEC over SV in terms of response, FFS and FFP. No significant financial relationships to disclose.