Chemoresistance as a function of the pretherapy tumor burden and the chemotherapy regimen administered: differences observed with 2 current chemotherapy regimens for advanced Hodgkin lymphoma.

BACKGROUND: The mature results from trials comparing ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine) and BEACOPP (bleomycin, etoposide, Adriamycin [doxorubicin], cyclophosphamide, Oncovin [vincristine], procarbazine, prednisone) chemotherapies in advanced Hodgkin lymphoma will be available in some years. An early comparison of their curative potential can however be obtained from an assessment of initial tumor burden and chemoresistance. PATIENTS AND METHODS: Less than a complete remission after treatment and relapse occurring within 12 months thereafter were assumed to be clinical expressions of chemoresistance. The tumor burden was calculated from the measurements of all the lesions documented by staging computed tomography (CT) and was normalized to body surface area to give the relative tumor burden (rTB). Using logistic regression analysis, the relationship between initial rTB, chemoresistance, and chemotherapy regimen administered was retrospectively studied in 222 patients selected from those enrolled in 2 similar randomized trials. RESULTS: The median rTB volumes were 157.9 cm(3)/m(2) in the 115 patients treated with ABVD vs. 154.6 cm(3)/m(2) in the 107 patients treated with BEACOPP, and the distribution of the volumes was identical in the 2 groups. The rTB was confirmed as the best predictor of early treatment failures (22 less than complete responses plus 21 early relapses). For the same rTB, the risk of chemoresistance to BEACOPP was about half that of the chemoresistance to ABVD or, for a given risk of chemoresistance, BEACOPP cured patients with an rTB 89.1 cm(3)/m(2) greater than that cured by ABVD (ie, more than 50% of the median tumor load of patients with advanced-stage disease). CONCLUSION: This account of rTB allows an early comparative evaluation of the curative ability of different chemotherapy regimens.

ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned.

BACKGROUND: BEACOPP, an intensified regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, has been advocated as the new standard of treatment for advanced Hodgkin's lymphoma, in place of the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). METHODS: We randomly assigned 331 patients with previously untreated and unfavorable Hodgkin's lymphoma (stage IIB, III, or IV, or an international prognostic score of ≥3 on a scale of 0 to 7, with higher scores indicating increased risk), to receive either BEACOPP or ABVD, each followed by local radiotherapy when indicated. Patients with residual or progressive disease after the initial therapy were to be treated according to a state-of-the-art high-dose salvage program. The median follow-up period was 61 months. RESULTS: The 7-year rate of freedom from first progression was 85% among patients who had received initial treatment with BEACOPP and 73% among those who had received initial treatment with ABVD (P=0.004), and the 7-year rate of event-free survival was 78% and 71%, respectively (P=0.15). A total of 65 patients (20 in the BEACOPP group, and 45 in the ABVD group) went on to receive the intended high-dose salvage regimen. As of the cutoff date, 3 of the 20 patients in the BEACOPP group and 15 of the 45 in the ABVD group who had had progressive disease or relapse after the initial therapy were alive and free of disease. After completion of the overall planned treatment, including salvage therapy, the 7-year rate of freedom from a second progression was 88% in the BEACOPP group and 82% in the ABVD group (P=0.12), and the 7-year rate of overall survival was 89% and 84%, respectively (P=0.39). Severe adverse events occurred more frequently in the BEACOPP group than in the ABVD group. CONCLUSIONS: Treatment with BEACOPP, as compared with ABVD, resulted in better initial tumor control, but the long-term clinical outcome did not differ significantly between the two regimens. (Funded by Fondazione Michelangelo; ClinicalTrials.gov number, NCT01251107.).

Cardiopulmonary toxicity of different chemoradiotherapy combined regimens for Hodgkin's disease.

UNLABELLED: The majority of patients with Hodgkin's disease can be cured by combination of polychemotherapy and radiotherapy (RT) that can produce late toxic pulmonary and cardiac effects which often remain at a subclinical level. The aim of the present investigation was to compare the late pulmonary and cardiac toxicity of three chemotherapeutic regimens combined with RT and particularly doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD), vincristine, epirubicin, cyclophosphamide, etoposide and prednisone (VEBEP) and ABVD with mechloretamine, vincristine, procarbazine and prednisone (MOPP). PATIENTS AND METHODS: We investigated 147 patients suffering from Hodgkin's disease after a follow-up of at least 5 years from the completion of CT-RT. Seventy-eight patients were submitted to ABVD-RT, 36 to VEBEP-RT and 33 to MOPP-ABVD-RT. Patients underwent spirometry, 2D-doppler echocardiography at rest, cardiopulmonary exercise test on cycloergometer and determination of cardiac output by a non invasive method. RESULTS: Patients of the three different treatment groups showed tolerance to exercise, and oxygen consumption significantly lower than the predicted values but there were no statistically significant difference between the three groups. Nevertheless, patients treated with VEBEP and with MOPP-ABVD showed an ejection fraction at rest lower than those observed in the ABVD group and patients treated with VEBEP showed a cardiac output for oxygen uptake lower than those observed in the ABVD and MOPP-ABVD treatment groups. CONCLUSION: These data confirm that the combination of mediastinal RT with the more commonly used polychemotherapy regimens produce late toxic effects. The lower exercise capacity seems to be due to a combination of decreased cardiac performance and impairment of ventilation. The VEBEP regimens could be potentially more toxic for the heart, probably because of the higher cumulative dose of anthracyclines.

Long-term results of high-dose chemotherapy with autologous bone marrow or peripheral stem cell transplant as first salvage treatment for relapsed or refractory Hodgkin lymphoma: a single institution experience.

The introduction of high-dose (HD) chemotherapy (CT) and autologous stem cell (ASCT) or bone marrow transplant (ABMT) in the last two decades has improved the prognosis of patients with refractory or relapsed Hodgkin lymphoma (HL) over conventional-dose salvage CT. To evaluate the outcome of adult patients with HL treated with HD CT and ASCT or ABMT after failure or relapse from first-line treatment with CT +/- radiotherapy, we report the results of a retrospective analysis in 82 consecutive patients given HD CT and autologous transplant as second-line therapy between October 1984 and December 2006. Thirty-two patients were given sequential high-dose cytoreductive therapy while 50 received other conventional induction regimens. Seventy-three patients with chemoresponsive disease underwent the myeloablative phase, while eight patients had progressive disease during cytoreductive CT. After a median follow-up of 73 months, the 10-year progression-free survival (PFS) and overall survival (OS) were 57% and 51%, respectively. According to response to first-line treatment, PFS and OS were, respectively, 54% and 82% for patients with complete remission (CR) lasting 12 months or more; 49% and 51% for patients with CR less than 12 months; and 47% and 50% for patients who never achieved CR or progressed during first-line CT (induction failure). Response to cytoreductive CT significantly influenced outcome, with PFS and OS being, respectively, 56% and 68% vs. 44% and 47% (p = 0.009) in patients in CR versus patients not in CR after induction therapy. Treatment was well tolerated, and therapy related mortality was only 3.7%. These long-term results confirm that HD CT and ASCT or ABMT was feasible, safe, and very effective. Therefore, this therapeutic strategy may represent an active salvage approach even in the unfavorable group of patients with induction failure.

Radioimmunotherapy and secondary leukemia: a case report.

This study describes a patient with a relapsed, diffuse, large B cell lymphoma (DLBCL) treated with radioimmunotherapy (RIT) with yttrium-90 ((90)Y)-ibritumomab tiuxetan (Zevalin) who 5 months later developed acute myeloid leukemia (AML) with inversion of chromosome 16. Our data indicate that molecular biological techniques should be used in selected cases to integrate data obtained with standard cytogenetics: using RT-PCR we showed that inversion of chromosome 16 was already present before RIT, in striking contrast to the normal karyotype found with conventional cytogenetics. This approach will allow investigators to avoid misleading data and provide support for conclusions regarding the side effects of treatment.

Serum cytokine in response to chemo-radiotherapy for Hodgkin's disease.

AIMS AND BACKGROUND: Mediastinal radiotherapy and multiple-drug chemotherapy, including bleomycin employed in the treatment of Hodgkin's disease, can produce lung toxicity leading to fibrosis. There is increasing evidence of the involvement in the fibrosing process of different cytokines and growth factors such as TNF-alfa, IL-1 beta, TGF-beta and PDGF. MATERIAL AND METHODS: In a pilot study, we evaluated lung function in 20 patients suffering from Hodgkin's disease, mainly in stage II A, submitted to multiple-drug chemotherapy including bleomycin (ABVD) and mediastinal radiotherapy and correlated its modifications with serum concentration of the cytokines determined by immunoenzymatic assay. Spirometry and transfer lung function for carbon monoxide (DLCO) were performed before, at the end of chemotherapy, at the end of radiotherapy and after a follow-up of 6 and 12 months. RESULTS: DLCO decreased at the end of the combined treatment and then remained constantly decreased. TNF-alfa, TGF-beta and PDGF-alfa concentrations did not change, whereas IL-1 beta significantly increased after the completion of the combined treatment and after a follow-up of 6-months and then declined to normal values after 12 months. The serum concentration of the cytokine was significantly higher in patients who had a DLCO < 75% of predicted after 1 year than in patients with a DLCO > 75%. CONCLUSIONS: The results indicate a potential role of IL-1 beta in the pathogenesis of chemoradiotherapy-induced lung toxicity, which needs to be confirmed in a larger patient population.

Very high levels of soluble CD30 recognize the patients with classical Hodgkin's lymphoma retaining a very poor prognosis.

OBJECTIVES: To evaluate the prognostic role of pretreatment serum levels of soluble CD30 (sCD30) in patients with advanced stage classical Hodgkin's lymphoma (cHL) treated with adriamycin, bleomycin, vinblastine, and dacarbazine or equivalent regimens. METHODS: We identified 321 previously untreated patients with cHL who presented to the participating centers between 1985 and 2002, and had serum samples available for the determination of sCD30 levels. RESULTS: With a median follow-up of 72 months, the actuarial 5-year overall survival was 82%, and failure-free survival (FFS) was 71%. The median serum level of sCD30 was 65 U/mL (range: 1-2230), and was significantly higher (P < 0.0001) when compared with a group of 113 healthy controls (4 U/mL, range: 0-20). Increasing level of sCD30 was associated with a continuous worsening of FFS and OS, and patients with sCD30 >or=200 U/mL had a 5-year FFS of 39%. With multivariate analysis, sCD30, Ann Arbor stage, and lactic acid dehydrogenase were significant independent factors in terms of FFS. The association of the above-mentioned three independent prognostic variables could discriminate 22% of patients with 5-year FFS of 40%. CONCLUSIONS: Our data confirm the independent prognostic role of sCD30 in identifying the patients with high risk of treatment failure, and show that its association with other variables can recognize patients with FFS considerably lower than 50%.

Survival in Hodgkin's disease patients--report of 25 years of experience at the Milan Cancer Institute.

The aim of this study was to assess the long-term therapeutic outcome and risk of treatment-related complications in Hodgkin's disease. From May 1973 to September 1990, four randomised studies have been activated at the Milan Cancer Institute using nitrogen mustard, vincristine, procarbazine and prednisone (MOPP) and doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) regimens, with or without irradiation, involving a total of 811 patients with intermediate and advanced Hodgkin's disease. Overall, ABVD contributed to significantly reduce the relative risk of lymphoma progression and death compared with the MOPP regimen. With a prolonged follow-up, a total of 106 patients (75 of whom were in continuous complete remission after first-line chemotherapy) developed a variety of cancers, resulting in a total risk of 22.2%. Our 25 years of experience re-emphasises that ABVD can cure a high fraction of patients with Hodgkin's disease. However, patients in continuous complete remission, are at a high risk of developing second cancers, especially when the treatment strategy includes extensive irradiation. The main focus of future trials should be on reducing treatment sequelae to improve the quality of life of long-term survivors.

Elevated serum levels of IL-10 are associated with inferior progression-free survival in patients with Hodgkin's disease treated with radiotherapy.

Elevated pretreatment serum interleukin-10 (IL-10) is associated with inferior progression-free survival (PFS) in patients with Hodgkin's disease (HD) treated with ABVD or equivalent regimens. Therefore, we explored the association of serum IL-10 with presenting features and PFS in HD patients treated only by radiotherapy (RT) with curative intent. Eligible patients were previously untreated, had biopsy-proven HD, were older than 16 years, HIV-negative, and had unthawed pretreatment serum. Serum IL-10 levels were measured with ELISA and were considered high if > or = 10 pg/ml. We identified 69 patients with median age of 34 years (range 16 - 74), of who 52% were males, and 3% had B-symptoms. Ann Arbor Stage was I in 35%, II in 58%, and III in 7% of the patients. Histology was lymphocyte predominance in 26%, and classical HD in 74% of the patients. Serum IL-10 was elevated in 35% of the patients. After a median follow-up of 67 months for survivors, the 5-year PFS of patients with high vs. normal serum IL-10 was 50% vs. 81% (all patients, P = 0.006), and 43% vs. 77% for the subset with classical HD (P = 0.008). Multivariate analysis revealed that high serum IL-10 and beta2-microglobulin were independently associated with inferior PFS. Patients with none, 1, or 2 adverse features comprised 57%, 36%, and 7% of the population, and their 5-year PFS was 80%, 63%, and 0%, respectively (P < 0.0001). In conclusion, high serum IL-10 is independently associated with inferior PFS in patients with HD treated with RT.

ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin's disease: long-term results.

PURPOSE: Radiation therapy (RT) alone can cure more than 80% of all patients with pathologic stage IA, IB, and IIA Hodgkin's disease, but some prognostic factors unfavorably affect treatment outcome. Combined-modality approaches improved results compared with RT, but the optimal extent of RT fields when combined with chemotherapy warranted additional evaluation. PATIENTS AND METHODS: In February 1990, we activated a prospective trial in patients with early, clinically staged Hodgkin's disease to assess efficacy and tolerability of four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by either subtotal nodal plus spleen irradiation (STNI) or involved-field radiotherapy (IFRT). RESULTS: Main patient characteristics were fairly well balanced between the two arms. Complete remission was achieved in 100% and in 97% of patients, respectively. The 12-year freedom from progression rates were 93% (95% CI, 83% to 100%) after ABVD and STNI, and 94% (95% CI, 88% to 100%) after ABVD and IFRT, whereas the figures for overall survival were 96% (95% CI, 91% to 100%) and 94% (95% CI, 89% to 100%), respectively. Apart from three patients who developed second malignancies in the STNI arm, treatment-related morbidities were mild. CONCLUSION: Present long-term findings suggest that, after four cycles of ABVD, IFRT can achieve a worthwhile outcome. The limited size of our patient sample, however, had no adequate statistical power to test for noninferiority of IFRT versus STNI. Despite this, ABVD followed by IFRT can be considered an effective and safe modality in early Hodgkin's disease with both favorable and unfavorable presentation.

Expression of Epstein-Barr virus latent membrane protein-1 in Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma: associations with presenting features, serum interleukin 10 levels, and clinical outcome.

PURPOSE: EBV-latent membrane protein-1 (LMP-1) is often expressed in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin's lymphoma (cHL), but its clinical significance is controversial. We correlated LMP-1 with presenting features, including serum interleukin 10 levels and clinical outcome. EXPERIMENTAL DESIGN: Patients were eligible if they had biopsy-proven cHL, were untreated, HIV-1 negative, and had available archival tissue. LMP-1 expression was determined by immunohistochemistry. RESULTS: We identified 577 patients with cHL with a median age of 30 years, 55% of whom were male. LMP-1 was expressed in HRS cells of 124 patients (21%) and was detected in 78 of 461 (17%) patients with nodular sclerosis compared with 44 of 112 (39%) with mixed cellularity (P < 0.001 by Fisher's exact test). Patients with tumors with LMP-1-positive HRS cells had higher serum interleukin 10 levels (P = 0.009 by Mann-Whitney test). For the 303 patients treated with doxorubicin, bleomycin, vinblastine, and dacarbazine or equivalent regimens, the 5-year failure-free survival (FFS) for those with LMP-1-positive tumors was 74% compared with 81% for those with LMP-1-negative tumors (P = 0.23, by log-rank test). Overall survival (OS) at 5 years for patients with LMP-1-positive tumors was 90 versus 91% for patients with LMP-1-negative tumors (P = 0.8 by log-rank test). Expression of LMP-1 was not associated with different FFS and OS in patients treated with other regimens or with radiotherapy alone. CONCLUSIONS: LMP-1 was expressed by HRS cells in 21% of cHL and correlated with mixed cellularity type and higher serum interleukin 10 levels. The presence of LMP-1 was not associated with FFS or OS in uniformly treated patients.

BCL-2 expression in Hodgkin and Reed-Sternberg cells of classical Hodgkin disease predicts a poorer prognosis in patients treated with ABVD or equivalent regimens.

To determine the clinical significance of BCL-2 expression in Hodgkin-Reed-Sternberg (HRS) cells of classical Hodgkin disease (cHD), we correlated its expression with presenting clinical and laboratory features and failure-free survival (FFS). Eligible patients were untreated and negative for HIV-1; they had biopsy-proven cHD. BCL-2 expression was determined immunohistochemically in available pretreatment tissue biopsy specimens without knowledge of clinical outcome. Tumors were considered positive if any HRS cells expressed BCL-2. We identified 707 patients with cHD, whose median age was 30 years; 54% were men. HRS cells expressed BCL-2 in 359 (65%) of 551 nodular sclerosis, 67 (47%) of 143 mixed cellularity, and all 5 lymphocyte depletion. For all patients, the 5-year FFS was 74% versus 84% for tumors with versus without BCL-2 expression (P =.0016, by log-rank test). For the 412 patients treated with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or equivalent regimens, the 5-year FFS for tumors with versus without BCL-2 expression was 74% versus 88% (P =.001, by log-rank test); for the 233 patients with Ann Arbor stage I or II, FFS was 84% versus 92% (P =.04, by log-rank test); and for the 179 patients with Ann Arbor stage III or IV, FFS was 62% versus 81% (P =.006, by log-rank test). Multivariate analysis confirmed that BCL-2 expression is independently associated with inferior FFS along with age 45 or older, Ann Arbor stage IV, low serum albumin and high serum lactate dehydrogenase levels. We conclude that BCL-2 is frequently expressed by HRS cells in cHD and is associated with inferior FFS in patients treated with ABVD or equivalent regimens.

Lung function and serum concentrations of different cytokines in patients submitted to radiotherapy and intermediate/high dose chemotherapy for Hodgkin's disease.

The aim of the present investigation was to evaluate lung function and the time course of serum concentration of selected cytokines known to be involved in pulmonary fibrosis, in 39 patients with stages IIB, III and IV Hodgkin's disease submitted to intermediate-high dose chemotherapy, (epirubicin, vincristine, cyclophosphamide, etoposide, prednisone) followed by radiotherapy. Lung function tests were performed before, at the end of treatment and after a follow-up of more than 12 months from the end of the combined therapy. Tumor necrosis factor alpha, fibronectin and Interleukins 4, 6 and 8 were determined on serum samples collected at the same time intervals. In the patients, spirometric parameters apparently improved whereas diffusing capacity for CO (DLCO) decreased, TNF-alpha concentrations constantly decreased, fibronectin and IL-8 showed a tendency to increase, but Interleukins 4 and 6 did not show significant modifications. No significant correlations were observed between the changes of lung function tests and serum cytokine concentrations, probably because cytokine serum levels were not able to reflect events occurring in the alveolar phase.

CD20 expression in Hodgkin and Reed-Sternberg cells of classical Hodgkin's disease: associations with presenting features and clinical outcome.

PURPOSE: CD20 can be expressed in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin's disease (HD), but its clinical significance remains controversial. Therefore, we correlated CD20 expression with presenting features and clinical outcome of untreated patients with classical HD. PATIENTS AND METHODS: Patients were eligible if they were previously untreated and human immunodeficiency virus-1 negative, had biopsy-proven classical HD, and if pretreatment paraffin-embedded tumor tissue was available. CD20 expression was determined by immunohistochemistry without knowledge of clinical outcome. A tumor was considered positive if any HRS cells expressed CD20, but other cutoffs for number of CD20-positive HRS were also investigated. RESULTS: We identified 598 patients whose median age was 30 years and of whom 55% were male. HRS cells expressed CD20 in 132 (22%) of 598 patients with classical HD. When any percentage of CD20 expression in HRS cells was used as a cutoff, the 5-year failure-free survival (FFS) for positive versus negative tumors was 86% versus 84%, respectively, for 302 patients treated with doxorubicin, bleomycin, vinblastine, and dacarbazine or equivalent regimens (P =.7 by log-rank test), 74% versus 77%, respectively, for 181 patients treated with mitoxantrone, vincristine, vinblastine, and prednisone and radiotherapy (P =.7 by log-rank test), 74% versus 84%, respectively, for 54 patients treated with MOPP (P =.4 by log-rank test), and 77% versus 88% for 53 patients treated only with radiotherapy (P =.5 by log-rank test). The 5-year FFS was not statistically different when cutoffs of 5% up to 50% for CD20-positive HRS cells were used. CONCLUSION: CD20 is expressed by HRS cells in 22% of patients with classical HD but is not associated with different FFS after treatment with equivalent regimens.

BAX expression in Hodgkin and Reed-Sternberg cells of Hodgkin's disease: correlation with clinical outcome.

PURPOSE: BAX, a proapoptotic member of the BCL-2 family of proteins, has been detected in Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin's disease (HD), but its clinical significance is unknown. Therefore, we correlated BAX expression with presenting features and clinical outcome in untreated patients with HD. DESIGN: Patients with biopsy-proven HD were eligible if they were untreated previously and if pretreatment paraffin-embedded tumor tissue was available. BAX was detected by immunohistochemistry without knowledge of clinical features or outcome. A tumor was considered as positive if any number of HRS cells expressed BAX, but other cutoffs of BAX expression were examined for analysis of clinical outcome. RESULTS: We identified 260 patients with HD. The median age was 31 years, and 55% were male. HRS cells expressed BAX in 181 of 195 (93%) nodular sclerosis, 47 of 48 (98%) mixed cellularity, 1 case of lymphocyte depletion, all 6 unclassified classical HD, and all 10 lymphocyte predominance tumors. Using a cutoff of 50% positive HRS cells for BAX expression, the 5-year failure-free survival (FFS) for patients with high versus low BAX expression was 83 versus 93%, respectively (P = 0.19 by Log-rank) for 116 patients treated with doxorubicin, bleomycin, vinblastine, and dacarbazine or equivalent regimens; it was 78 versus 79%, respectively, for 79 patients treated with mitoxantrone, vincristine, vinblastine, and prednisone and radiotherapy (P = 0.45 by Log-rank); it was 71 versus 81%, respectively, for 26 patients treated with nitrogen mustard, vincristine, prednisone, and procarbazine (P = 0.6 by Log-rank); and it was 72 versus 82% for 29 patients treated only with radiotherapy (P = 0.57 by Log-rank). The 5-year FFS was not statistically different when we used cutoffs of 20, 30, and 75% for BAX expression. CONCLUSION: BAX is often expressed by HRS cells in HD and does not correlate with FFS.