Intensive sequential chemotherapy (ISC 95) with growth factors and blood stem cell support in high–intermediate and high-risk (IPI 2 and IPI 3) aggressive non-Hodgkin’s lymphoma: an oligocentric report on 42 patients

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Summary:The aim of this study was to evaluate and to compare in terms of toxicity the modulations of dose intensity of cyclophosphamide and doxorubicin in adjuvant chemotherapy for high-risk breast cancer. Four cycles of sequential high-dose chemotherapy with doxorubicin and cyclophosphamide (AC), supported with G-CSF and peripheral blood stem cells (PBSC) were administered to 81 women. Three successive cohorts were studied: doxorubicin (75 mg/m 2 ) + cyclophosphamide (3000 mg/m 2 ) every 21 days (group 1), doxorubicin (75 mg/m 2 ) + cyclophosphamide (3000 mg/m 2 ) every 15 days (group 2), and doxorubicin (75 mg/m 2 ) + cyclophosphamide (6000 mg/m 2 ) every 21 days (group 3). Seventy-five patients received four cycles of treatment with a total of 310 cycles administered. The received dose intensity of doxorubicin was higher in group 2 and that of cyclophosphamide was lower in group 1 than in the other two groups. Hematological and extra-hematological toxicities, as well as the number and duration of hospitalizations for toxicity, were significantly higher in group 3. We conclude that the group 3 regimen is associated with toxicities comparable to autologous transplantation. Increasing dose intensity of doxorubicin and cyclophosphamide is feasible in an outpatient setting and safe in groups 1 and 2 with the support of hematopoietic factor and PBSC. The efficacy of adjuvant chemotherapy for patients with node positive breast cancer is now clearly demonstrated and widely used in standard clinical practice. In this situation, anthracyclines and cyclophosphamide are validated as effective and are part of the most active regimens without taxanes. Since the 1990s, following the work of the National Surgical Adjuvant Breast and Bowel Project (NSABBP), four cycles of doxorubicin (60 mg/m 2 ) and cyclophosphamide (600 mg/m 2 ), every 21 days, are considered as the minimum requirement for effective adjuvant chemotherapy in breast cancer (AC regimen). 1 With these two drugs, the importance of dose intensity has been clearly established in experimental models. 2 Furthermore, clinical data have suggested and frequently demonstrated the relevance of dose and dose intensity in the breast cancer setting. 3,4 Relatively modest dose variations of these drugs have been tested without the use of hematopoietic growth factors, resulting in benefits in dose escalation of anthracyclines but not clearly for cyclophosphamide.We and others 5-9 were able to develop much larger dose escalation of anthracyclines and cyclophosphamide in breast cancer when hematopoietic growth factors and/or peripheral blood stem cells (PBSC) were added to cycles of chemotherapy. In a previous report, 10 we demonstrated that, when compared to the standard dose intensity of the AC regimen of the NSABBP, we could safely increase the relative dose intensity (RDI) of doxorubicin (ϫ1.25) and cyclophosphamide (ϫ5) (group 1) in intensive outpatient chemotherapy designed for poor risk patients.We designed the present study to further increase relative dose intensity of...

Section: Discussionmentioning

confidence: 98%

Modulations of dose intensity of doxorubicin and cyclophosphamide in association with G-CSF and peripheral blood stem cells in adjuvant chemotherapy for breast cancer: comparative evaluation of completion and safety of three intensive regimens

Genre

Viens

Bertucci

et al. 2002

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“…18 The regimen for ISC 95 was COP and four cycles of high-dose CHOP, the last two cycles including etoposide 500 mg/m 2 and cisplatin 100 mg/m 2 and supported by PBPC. 19 Eighty-five percent of patients completed therapy, with a CR rate of 65% and OS and FFS of 73% and 56% at 2 years for ISC 92; and a CR rate of 69% and OS of 58% at 3 years for ISC 95. Of 33 age-adjusted-IPI 3 (AA-IPI) patients treated in these two pilot studies, there was one toxic death, 61% of patients achieved a CR, and the OS and EFS at 5 years was 51% and 42% respectively.…”

Section: Tandem Intensive Sequential Chemotherapy and Autologous Tranmentioning

confidence: 93%

“…This dose-intense strategy has been applied as both first-line and salvage therapy to poor risk patients Ͻ60 years (Table 1). [18][19][20][21][22] Two pilot studies of intensive sequential chemotherapy as first-line treatment in patients with aggressive NHL were conducted by Bouaddallah and colleagues. 23 For study ISC 92, patients received three cycles of high-dose CHOP (cyclophosphamide 3 g/m 2 , doxorubicin 75 mg/m 2 , vincristine 2 mg, and prednisone 60 mg/m 2 for 5 days) followed by three intensified stem cell supported cycles of high-dose CHOP with etoposide (300 mg/m 2 ) and cisplatin (100 mg/m 2 ).…”

Section: Tandem Intensive Sequential Chemotherapy and Autologous Tranmentioning

confidence: 99%

Tandem transplantation in lymphoma

Papadopoulos

Noguera-Irizarry

Hesdorffer

2001

Summary:The majority of poor-risk lymphoma patients are not cured with conventional chemotherapy. There is evidence for the superiority of single high-dose chemotherapy in such patients, but many still die from recurrent disease. Strategies to improve survival in these poor-risk patients include dose-intensification with high-dose chemotherapy and PBPC support, tandem autologous HDC with PBPC support, and autologous followed by non-myeloablative allogeneic transplantation. These more aggressive strategies are feasible and tolerable. Whether tandem transplantation will prove more effective than current single high-dose therapy in appropriately selected patients remains to be determined. Bone Marrow Transplantation (2001) 28, 529-535. Keywords: tandem transplantation; lymphoma; autologous; allogeneicThe majority of patients with lymphoma achieve remission with standard therapy. A small percentage of patients are refractory to initial therapy, and approximately one-third of patients with stage III-IV disease will relapse after achieving a complete response. Treatment of minimally responsive or refractory lymphoma patients remains a challenge. Single transplantation and the poor prognosis patientProspective randomized trials show single HDC with autologous transplantation to be superior to standard-dose chemotherapy for relapsed and resistant Hodgkin's disease, 1 for consolidative therapy of poor-risk B cell NHL in first remission 2 and for relapsed chemo-sensitive intermediate or high-grade NHL. 3 An update of the PARMA study reports an 8-year EFS of 36% and OS of 47% for these latter patients. 4 Fewer than 5% of patients with poor-risk NHL or HD who have induction failure and receive conventional salvage chemotherapy are alive at 5 years. NHL patients with induction failure who undergo HDC and autotransplantation have an overall survival at 5 years of 37%. 5 Data from the ABMTR show HD patients with induction Correspondence: DR CS Hesdorffer, Division of Medical Oncology, MHB 6N 435, 177 Ft. Washington Avenue, New York, NY 10032, USA failure who subsequently undergo HDC have progressionfree and overall survivals at 3 years of 38% and 50%, respectively. 6 Data by Sweetenham et al 7 from the EBMT are similar, reporting an actuarial 5-year OS rate of 36% and PFS rate of 32%.Allogeneic transplantation alone does not appear to offer a survival advantage over autologous transplant for lymphoma. 8,9 Studies suggest a graft-versus-lymphoma effect, but this has not translated into increased survival due to the high treatment-related mortality associated with allogeneic transplantation. Further prospective trials, randomized on the basis of HLA-identical donor availability, may provide more reliable data on this issue. 10 While salvage rates of 45-60% are achieved with HDC in patients with relapsed NHL and HD with good prognostic factors, adverse prognostic factors, such as relapse within 1 year of initial treatment, stage III/IV relapse or chemoresistance, portend a poorer outcome, with likely cure in less than 40%. The IP...

“…We concluded that multiple cycles of high-dose CHOP supported by both HGF and PBSC could cure half of poor-risk NHL patients who have nearly 70% risk of dying of their disease when treated with standard CHOP regimen. 10,11 However, such an issue remains confusing as recent meta-analysis data failed to show an improvement in EFS or OS for patients undergoing early autologous. 12 Whatever the chemotherapy schedule used, 30-40% of high-risk NHL patients still remain refractory to treatment or relapse from their disease.…”

Section: Introductionmentioning

confidence: 99%

A phase II trial of rituximab as adjuvant to intensive sequential chemotherapy in patients under 60 years with untreated poor-prognosis diffuse large B-cell lymphoma

Coso

Sebban

Boulat

et al. 2006

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The potential benefit of rituximab as adjuvant to highdose therapy (HDT) has been investigated in patients under 60 years with poor-risk (age-adjusted international prognostic index at 2-3) CD20 þ diffuse large B-cell lymphoma (DLBCL). The treatment consisted of four cycles of high-dose CEOP (cyclophosphamide, epirubicin, vincristine, prednisone), plus etoposide and cisplatin during the two last cycles. Peripheral blood stem cells were collected after cycle 1, and reinfused after cycles 3 and 4. Four weekly rituximab infusions were subsequently delivered. Among the 36 patients included, 30 could complete chemotherapy schedule, and 24/36 received rituximab. A complete response occured in 26/36 patients (72%). With a median follow-up of 30 months, the estimated 5-year overall survival (OS) and event-free survival (EFS) rates (mean7s.d.) were 65716 and 63715%, respectively. For the 24 patients who received both chemotherapy and rituximab, the estimated 5-year OS and EFS rates were 86714 and 82715%. These data suggest that rituximab after HDT is feasible. Both complete remission rate and survival curves compare favorably with the poor outcome usually observed in high-risk DLBCL patients managed with HDT without rituximab.