Combination chemotherapy of solid tumors: an American-Italian collaboration: a celebration of the work of Gianni Bonadonna.

This article highlights the important collaboration between the U.S. NCI in Bethesda, Maryland and the Istituto Tumori in Milan, Italy that had a major impact on the development of curative regimens for breast cancer, Hodgkin's disease and diffuse large B cell lymphoma.In addition to his contribution to developing new therapies, Gianni Bonadonna played an important role in bringing highly focused, disciplined, ethical clinical trials to the European continent.

Interim [(18)F]fluorodeoxyglucose positron emission tomography imaging in stage I-II non-bulky Hodgkin lymphoma: would using combined positron emission tomography and computed tomography criteria better predict response than each test alone?

Our objective was to validate the International Harmonization Project (IHP) positron emission tomography (PET) response criteria and correlate with the Deauville criteria and diagnostic computed tomography-based (dCT) lesion size changes. All patients were recruited prospectively to the Cancer and Leukemia Group B (CALGB) 50203 trial for the treatment of stage I-II, non-bulky Hodgkin lymphoma (HL). [(18)F]Fluorodeoxyglucose (FDG) PET and dCT were performed at baseline and after two doxorubicin, vinblastine and gemcitabine (AVG) cycles (PET-2, dCT-2) in 88 patients. IHP and Deauville criteria and percent decrease in the sum of the products of the perpendicular diameters (%SPPD) after two cycles were correlated with progression-free survival (PFS). After a median follow-up of 3.3 years, 23.9% of patients relapsed/progressed (3-year PFS 77%). By IHP, the 2-year PFS was 88% and 54% for PET-2 negative and positive groups, respectively (p = 0.0009). Similar results were obtained for Deauville criteria. In a univariate analysis, PET-2 predicted PFS better than %SPPD, and in a combinatorial analysis, in the PET-2 positive group, a negative dCT-2 increased PFS by 27-35%. However, some confidence intervals were large due to small sample sizes. In conclusion, IHP and Deauville criteria-based interpretation of PET-2 was strongly associated with 2-year PFS. The combined analysis of PET-2 with dCT-2 suggested a better predictive value for PFS compared to either test alone. Further studies are under way to confirm these findings.

A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype.

BACKGROUND: A phase II trial of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) from the National Cancer Institute showed promising activity in untreated diffuse large B-cell lymphoma. The Cancer and Leukemia Group B conducted a study to determine if these results could be reproduced in a multi-institutional setting. DESIGN AND METHODS: The study included 69 patients with untreated diffuse large B-cell lymphoma at least 18 years of age and at least stage II. Radiaton therapy was not permitted on study. Median age was 58 years (range 23-83) and 40% had high-intermediate or high International Prognostic Index risk. Immunohistochemical biomarkers for cell of origin and proliferation were performed. RESULTS: With a median follow up of 62 months, time to progression and overall survival were 81% and 84%, respectively, and time to progression was 87%, 92% and 54% for low/low-intermediate, high-intermediate and high International Prognostic Index risk groups, respectively, at 5-years and beyond. The time to progression and event-free survival of germinal center B-cell lymphoma were 100% and 94%, respectively, and non-germinal center B-cell GCB diffuse large B-cell lymphoma were 67% and 58%, respectively, at 62 months (germinal center vs. non-germinal center B cell P=0.008). DA-EPOCH-R was tolerated without significant grade 4 non-hematologic toxicities. CONCLUSIONS: These results provide the first confirmation by a multi-institutional group that DA-EPOCH-R provides high durable remissions in diffuse large B-cell lymphoma and is effective in both germinal center and non-germinal center B-cell subtypes. The trial was registered at ClinicalTrials.Gov (NCT00032019).

Can low-risk, early-stage patients with Hodgkin lymphoma be spared radiotherapy?

Advances in the treatment of Hodgkin lymphoma since about 1970 have led to a remarkable improvement in the long-term outcomes of what was once considered an incurable disease. The prolonged survival of cured patients has revealed new issues concerning the toxicity of successful therapy, however, including an increased risk of secondary malignancies and end-organ damage such as heart disease. This concern has led to the clinical research question of whether the de-escalation of treatment intensity could allow high cure rates to continue with less long-term toxicity. In young patients with favorable early-stage disease, the challenge has been to use systemic therapy while omitting radiation therapy as part of the initial treatment. This review briefly summarizes past data and updates readers regarding recent publications on this topic.

Doxorubicin, vinblastine, and gemcitabine (CALGB 50203) for stage I/II nonbulky Hodgkin lymphoma: pretreatment prognostic factors and interim PET.

To reduce doxorubicin, bleomycin, vinblastine and dacarbazine toxicity, the Cancer and Leukemia Group B conducted a phase 2 trial of doxorubicin, vinblastine, and gemcitabine for newly diagnosed, nonbulky stages I and II Hodgkin lymphoma. Ninety-nine assessable patients received 6 cycles of doxorubicin 25 mg/m(2), vinblastine 6 mg/m(2), and gemcitabine 800 mg/m(2) (1000 mg/m(2) in first 6) on days 1 and 15 every 28 days. Computed tomography (CT) and positron emission tomography (PET) were performed before and after 2 and 6 cycles. Complete remission (CR)/CR unconfirmed was achieved in 72 of 99 patients (72.7%) and partial remission in 24 of 99 patients (24.2%). The CR rate was 81% when using PET criteria. Two patients have died of Hodgkin lymphoma progression. Median follow-up for nonprogressing patients is 3.3 years. The progression-free survival (PFS) at 3 years was 77% (95% confidence interval, 68%-84%). The relapse rate was less than 10% for patients with favorable prognostic factors. The 2-year PFS for cycle 2 PET-negative and -positive patients was 88% and 54%, respectively (P = .0009), compared with 89% and 27% for cycle 6 PET-negative and -positive patients (P = .0001). Although the CR rate and PFS were lower than anticipated, patients with favorable prognostic features had a low rate of relapse. Cycle 2 PET and cycle 6 PET were predictive of PFS.

Hematology in 2010: New therapies and standard of care in oncology.

2010 was not a year of survival breakthroughs in hematologic malignancies. However, in Hodgkin's disease and multiple myeloma new therapies emerged as the standard of care and nilotinib may be considered the treatment choice for newly diagnosed chronic myeloid leukemia.

Treatment of favorable, limited-stage Hodgkin's lymphoma with chemotherapy without consolidation by radiation therapy.

PURPOSE: Limited-stage Hodgkin's lymphoma (HL) has been treated with radiation alone or radiation combined with chemotherapy. Although results in progression-free survival and overall survival have been excellent, the long-term, radiation-induced, toxic cardiac and secondary oncologic complications occurring in succeeding decades have compromised survival of young patients. This study examines the impact of chemotherapy alone in treatment of limited-stage, nonbulky HL, radiation therapy eliminated from primary treatment. PATIENTS AND METHODS: From 1992 to May 2008, 71 patients with a median age of 29 years (range, 17-44 years) with stages I and II HL without bulky nodes were treated with six cycles of classic combination doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Two patients received six cycles of ABVD-like modification. Two patients received four cycles of ABVD. The ABVD regimen was known to be curative in more advanced disease without radiation therapy. RESULTS: All patients achieved a clinical complete response (CR) or CR unconfirmed. After a median follow-up of at least 60 months (range, at least 12 to at least 204 months), six patients experienced relapse at 6, 10, 11, 16, 20, and 58 months. All relapses occurred at site of presenting disease. No patients have died. Salvage therapy was successful with second-line chemotherapy/radiation and autologous stem-cell transplantation. CONCLUSION: Six cycles of ABVD is an effective and safe treatment for limited-stage, nonbulky HL and would spare young patients radiation toxicity. Interim positron emission tomography/computed tomography scans in current and future trials may identify those patients who require less than six cycles of chemotherapy.

Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909.

PURPOSE Mantle-cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with a poor prognosis. We explored the feasibility, safety, and effectiveness of an aggressive immunochemotherapy treatment program that included autologous stem-cell transplantation (ASCT) for patients up to age 69 years with newly diagnosed MCL. PATIENTS AND METHODS The primary end point was 2-year progression-free survival (PFS). A successful trial would yield a 2-year PFS of at least 50% and an event rate (early progression plus nonrelapse mortality) less than 20% at day +100 following ASCT. Seventy-eight patients were treated with two or three cycles of rituximab combined with methotrexate and augmented CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). This treatment was followed by intensification with high doses of cytarabine and etoposide combined with rituximab and filgrastim to mobilize autologous peripheral-blood stem cells. Patients then received high doses of carmustine, etoposide, and cyclophosphamide followed by ASCT and two doses of rituximab. Results There were two nonrelapse mortalities, neither during ASCT. With a median follow-up of 4.7 years, the 2-year PFS was 76% (95% CI, 64% to 85%), and the 5-year PFS was 56% (95% CI, 43% to 68%). The 5-year overall survival was 64% (95% CI, 50% to 75%). The event rate by day +100 of ASCT was 5.1%. CONCLUSION The Cancer and Leukemia Group B 59909 regimen is feasible, safe, and effective in patients with newly diagnosed MCL. The incorporation of rituximab with aggressive chemotherapy and ASCT may be responsible for the encouraging outcomes demonstrated in this study, which produced results comparable to similar treatment regimens.