Valeria Bonfante

Gonadal toxicity after combination chemotherapy for Hodgkin's disease. Comparative results of MOPP vs ABVD

The comparative gonadal toxicity following two equally effective and non-cross-resistant regimens (MOPP and ABVD) was prospectively evaluated in 53 males with Hodgkins disease. The median age was 29 yr (range 16-45). MOPP produced azoospermia in 28/29 patients (97%) while ABVD induced oligoazoospermia in 13/24 patients (54%). Follicle-stimulating hormone levels were consistently and significantly increased after MOPP while their median value remained within normal range after ABVD. Sperm count was repeated in 34 patients. Recovery of spermatogenesis occurred in 3/21 cases treated with MOPP and in all 13 cases given ABVD. Present findings confirm that the two alkylating agents, mechlorethamine and procarbazine, included in the MOPP regimen cause sterility in most patients while the drugs included in ABVD are not associated with permanent gonadal dysfunction.

Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy.

In an attempt to reduce some of the delayed sequelae associated with combined modality therapy in Hodgkins disease, we randomly tested stages IIB, IIIA, and IIIB MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) v ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine). In 232 previously untreated patients, three cycles of either combination preceded and followed extensive irradiation. The complete remission rate was 80.7% following MOPP and 92.4% following ABVD (P less than .02). The 7-year results indicated that ABVD was superior to MOPP in terms of freedom from progression (80.8% v 62.8%; P less than .002), relapse-free survival (87.7% v 77.2%; P = .06), and overall survival (77.4% v 67.9%; P = .03). Moreover, the comparative iatrogenic morbidity showed that irreversible gonadal dysfunction as well as acute leukemia occurred only in patients subjected to MOPP, while cardiopulmonary studies failed to document significant laboratory differences between the two treatment groups. Present findings indicate that ABVD followed by extensive irradiation represents a valid therapeutic alternative to the widely used alkylating agent-containing regimens plus radiotherapy.

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 Hodgkins 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 Hodgkins 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 Hodgkins disease with both favorable and unfavorable presentation.

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 Hodgkins lymphoma, in place of the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). METHODS We randomly assigned 331 patients with previously untreated and unfavorable Hodgkins 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.).

Salvage Chemotherapy with ABVD in MOPP-Resistant Hodgkin's Disease

Fifty-five consecutive patients with advanced recurrent Hodgkins disease resistant to MOPP chemotherapy (mechlorethamine, vincristine, procarbazine, and prednisone) were given ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine). In 54 patients evaluable for response, complete remission after pathologic restaging was seen in 59% and partial remission in 13%. Fifteen of 29 patients (52%) showing disease progression during primary MOPP treatment achieved complete remission after ABVD. The median time to complete response was 3 months. The median duration for complete remission was 17 months, and 38% of patients who attained complete remission have remained alive and continuously disease free at 5 years from start of ABVD treatment. The median survival of complete responders was more than 60 months. Toxic manifestations were moderate, aside from pronounced vomiting in more than half of patients. These results indicate that ABVD is an effective salvage regimen for MOPP-resistant Hodgkins disease.

Alternating Drug Combinations in the Treatment of Advanced Hodgkin's Disease

Of 75 consecutive patients with Stage IV Hodgkins disease, we assigned 38 to receive MOPP alone (mechlorethamine, vincristine, procarbazine, and prednisone) and 37 to receive MOPP alternating monthly with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) - a combination of drugs not cross-resistant with MOPP. Complete remission was documented in 71 percent of the patients receiving MOPP alone and in 92 per cent of those receiving the alternating regimen (P = 0.02). At five years, there was no progression of disease in 37 per cent of the MOPP group and in 70 per cent of the MOPP-plus-ABVD group (P less than 0.0001). After chemotherapy, the median relapse-free survival period was 20 months in the MOPP group and over 31 months in the MOPP-plus-ABVD group (P less than 0.01). Five-year survival with no evidence of disease was 84 per cent in patients given MOPP and ABVD and 54 per cent in those given MOPP alone (P less than 0.005). We conclude than alternating non-cross-resistant combinations appear promising in the management of advanced Hodgkins disease and are worthy of trial in other malignant diseases.

Outcome of patients with Hodgkin's disease failing after primary MOPP-ABVD.

PURPOSE This study analyzed long-term results in patients with Hodgkins disease who were resistant to or relapsed after first-line treatment with MOPP and ABVD. Response to salvage treatments and prognostic factors were also evaluated. PATIENTS AND METHODS The study population included 115 refractory or relapsed patients among a total of 415 patients treated with alternating or hybrid MOPP-ABVD followed by radiotherapy (25 to 30 Gy) to initial bulky sites. The median follow-up duration of the present series was 91 months. Thirty-nine of 115 patients (34%) showed disease progression while on primary treatment (induction failures); 48 relapsed after complete remissions that lasted < or = 12 months and 28 after complete remission that lasted more than 12 months from the end of all treatments. RESULTS At 8 years, the overall survival rate was 27%, being 54% and 28% in patients whose initial complete remission was longer or shorter than 12 months, respectively, and 8% in induction failures (P < .001). Response to first-line chemotherapy and disease extent at first progression significantly influenced long-term results, as well as the incidence and duration of complete remission. CONCLUSION The present data confirm previous observations that showed the main prognostic factors to influence outcome after salvage treatment are response duration to first-line therapy and disease extent at relapse. The results indicate that patients who relapse after the alternating MOPP/ABVD regimen have a prognosis similar to that of patients who relapse after a four-drug regimen (MOPP or ABVD alone). Re-treatment with initial chemotherapy seems the treatment of choice for patients who relapse after an initial complete remission that lasts greater than 12 months, while the real impact of high-dose chemotherapy or new regimens should be assessed in resistant patients.

Alternating versus hybrid MOPP and ABVD combinations in advanced Hodgkin's disease: ten-year results.

PURPOSE To compare, in a prospective randomized trial, the efficacy of two different sequences of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy in untreated advanced Hodgkins disease. PATIENTS AND METHODS From June 1982 to September 1990, 427 consecutive previously untreated patients with pathologic stage IB, IIA bulky, IIB, III (A and B), and IV (A and B) disease were prospectively randomized to receive two different sequences of MOPP and ABVD for a minimum of six cycles followed by radiotherapy (median dose, 30 Gy) to the nodal site(s) of pretreatment bulky disease. Of 415 assessable patients, 211 received one cycle of MOPP monthly, alternated with one cycle of ABVD (alternating regimen), and 204 patients received one-half cycle of MOPP alternated with one-half cycle of ABVD within a 1-month period (hybrid regimen). RESULTS The complete remission (CR) rate was 91% with the alternating regimen and 89% with the hybrid regimen. At 10 years, the freedom-from-progression (FFP) rate was 67% versus 69% and the overall survival (OS) rate was 74% versus 72%, respectively. After attainment of CR, 85 patients relapsed in nodal (n = 60) versus extranodal with or without nodal (n = 25) sites. In patients given consolidative radiation because of bulky lymphoma, the true recurrence rate was 13%. A total of 23 second malignancies (6%) were documented, including 11 cases of acute nonlymphocytic leukemia. No cases of congestive heart failure attributable to doxorubicin or pulmonary toxicity related to bleomycin were documented. CONCLUSION By delivering MOPP and ABVD, it is possible to cure approximately 70% of patients with advanced Hodgkins disease. The two different drug sequences yielded superimposable results.

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 Hodgkins 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.

Elevated pretreatment serum levels of Il-10 are associated with a poor prognosis in hodgkin's disease, the Milan Cancer Institute Experience

Alterated cytokine secretion may play a role in determining Hodgkins disease-related immunosuppression. The aim of this study was to analyze the clinical significance of interleukin-10(IL-10) serum levels in 73 chemotherapy-naive patients with Hodgkins disease. We evaluated the relationship between pretreatment circulating values of IL-10 and both the clinical characteristics of the disease as well as the prognosis in terms ofreedom from progression and overall survival. Abnormally high pre-treatment serum levels (mean±standard error: 26.79±13.24 pg/ml) were detected in 33/73 (45%) patients. The percentage of patients with enhanced IL-10 secretion was significantly higher in the presence of advanced disease (56% vs 32%,P<0.03), systemic symptoms (57%vs 34%,P<0.04) and more than 3 involved sites (61%vs 36%,P<0.03).The high basal levels of IL-10 negatively influenced long-term results: at 8-years freedom from progression (FFP) and overall survival (OS) for patients with IL-10>6 pg/mlvs≤6 pg/ml were 69% and 76%vs 97.5% and 95%, respectively. The multivariate analysis confirmed the prognostic value of IL-10 basal serum levels (FFP,P=0.0001; OS,P=0.06). Our study suggests that high pre-treatment circulating levels of IL-10 are associated with a poor prognosis, irrespective of other common prognostic variables.