Chemo-radiation association in head and neck squamous cell carcinoma: Evidences and criticisms

Recently new strategies such as the association of chemotherapy with radiotherapy have emerged for the improvement of therapeutic outcome in the curative treatment of HNSCC: for patients with locally advanced HN-SCC, where outcome with radiotherapy alone is poor. More than one-hundred Phase III trials collected in large meta-analyses have showed that loco regional control and overall survival may be improved at high level of evidence by chemoradiotherapy especially if delivered with synchronous approach. Sequential or synchronous chemo-radiotherapy regimens can also play a crucial role in larynx-function preservation programs without the risk of overall survival reduction for patients with larynx or hypo pharynx tumors who are candidates to radical surgery. Recently, strong evidence for an improved outcome for high-risk resected patients has been shown by the use of adjuvant concomitant chemoradiotherapy. Despite hundreds of clinical trials in patients with advanced disease, there is no absolute consensus about patient selection for type of chemo-radiotherapy association, radiation or chemotherapy dose schedule. Nevertheless, awaiting for the results from ongoing trials where chemo-radiotherapy is explored in conjunction with new targeted therapies, many well-conducted clinical studies have expanded therapy options besides standard radiotherapy and have contributed to defining the evolving standard of care for patients with HNSC

Cyclosporin A and short-term methotrexate versus cyclosporine A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from HLA-identical sibling: results of a GITMO/EBMT randomized trial

A randomized trial was carried out comparing cyclosporin A (CsA) and short-term methotrexate (MTX) versus CsA alone for graft versus host disease (GVHD) prophylaxis in patients with severe aplastic anemia (SAA) undergoing allogeneic bone marrow transplantation (BMT) from a compatible sibling. Seventy-one patients (median age, 19 years; range, 4-46 years) were randomized to receive either CsA and MTX or CsA alone for the first 3 weeks after BMT. Subsequently, both groups received CsA orally, with gradual drug reduction until discontinuation 8 to 12 months after BMT. Patients randomized in both arms had comparable characteristics and received the same preparative regimen (ie, cyclophosphamide 200 mg/kg over 4 days). The median time for neutrophil engraftment was 17 days (range, 11-31 days) and 12 days (range, 4-45 days) for patients in the CsA/MTX group and the CsA alone group, respectively (P =.01). No significant difference was observed in the probability of either grade 2, grade 3, or grade 4 acute GVHD or chronic GVHD developing in the 2 groups. The Kaplan-Meier estimates of 1-year transplantation-related mortality rates for patients given either CsA/MTX or CsA alone were 3% and 15%, respectively (P =.07). With a median follow-up of 48 months from BMT, the 5-year survival probability is 94% for patients in the CsA/MTX group and 78% for those in the CsA alone group (P =. 05). These data indicate that the use of CsA with MTX is associated with improved survival in patients with SAA who receive transplants from compatible siblings

Severe thrombotic microangiopathy: an infrequent complication of bone marrow transplantation. Gruppo Italiano Trapianto Midollo Osseo (GITMO).

Thrombotic microangiopathy (TMA) usually occurs during the first weeks following transplantation in the setting of systemic infections or graft-versus-host reaction. However, some cases without any evidence of other complications or after autologous transplantation have been reported. Transplant-associated TMA (BMT-TMA) incidence ranges from 0% to 74%, possibly due to different diagnostic criteria. The GITMO Group provided the opportunity to retrospectively study 4334 consecutive Italian patients who received bone marrow transplants (1759 allogeneic and 2575 autologous BMT), during the 1985-1995 period. The present report focuses on patients with severe TMA requiring specific treatment. We identified nine cases of TMA as a complication of allogeneic BMT (0.51%), whereas three patients developed the syndrome after ABMT (0.13%); four of the 12 patients were not receiving CsA at the time of TMA onset. Finally, it is noteworthy that TMA occurred in seven patients as a late complication (up to 90 days after BMT). Despite intensive treatment, five of the seven patients with thrombotic thrombocytopenic purpura died. One death was observed among the five cases with hemolytic uremic syndrome

Early Treatment of Acute Graft versus Host disease With High or Low-dose 6 Methylprednisolone: A multicenter Randomized Trial From the Italian Group for Bone Marrow Transplantation (GITMO)

Ninety-five patients undergoing an allogeneic bone marrow transplant (BMT) and developing acute graft-versus-host disease (aGvHD) were randomized to receive low-dose intravenous 6-methylprednisolone (6MPred; 2 mg/kg /d; n = 47) or high-dose 6MPred (10 mg/kg/d; n = 48) for 5 days, with subsequent tapering doses. On day 5 patients not responding or progressing on low-dose 6MPred could be switched to high-dose 6MPred. All patients, aged 1 to 55 years, were recipients of unmanipulated BMT from HLA identical sibling donors. Patients were stratified at randomization for age (/= 20 years), disease (acute leukemia, chronic myeloid leukemia [CML], nonneoplastic disease), disease status (early/advanced), and GvHD prophylaxis (cyclosporin/cyclosporin + methotrexate). Primary endpoints were response to treatment and evolution of aGvHD to grade III-IV. Secondary endpoints were cytomegalovirus (CMV) infections, transplant-related mortality (TRM), and relapse. The median interval between BMT and treatment was 12 days (6 to 43). Results in the two groups (2 v 10 mg/kg) were as follows: response of aGvHD 68% versus 71% (P = .9), evolution to aGvHD grade III-IV 17% versus 20% (P = . 6), CMV infections 55% versus 60% (P = .7), 3-year actuarial TRM 28% versus 32% (P = .7), relapse 17% versus 7% (P = .1). The actuarial survival at 3 years was 63% versus 62% (P = .9) with a median follow up of 580 and 778 days. On day 5 of therapy, 26 patients assigned to low-dose (2 mg/kg) 6MPred were switched to a higher dose of 6MPred because of no response or progression. Their actuarial TRM was 46%, which is significantly higher than TRM of patients who responded on 2 mg/kg and continued with tapering doses (TRM = 16%, P = .007). In conclusion, early treatment of acute GvHD with 6MPred 10 mg/kg/d does not improve the response rate as compared with 2 mg/kg/d, nor does it prevent evolution to aGvHD grade III-IV. CMV infections, TRM, and survival were also comparable. A group of patients at high risk of TRM can be identified after 5 days of treatment with 6MPred 2 mg/kg and could be eligible for alternative forms of therapy

Treatment of childhood acute lymphoblastic leukemia in second remission with allogeneic bone marrow transplantation and chemotherapy: 10-year GITMO/AIEOP experience

To compare the results of allogeneic bone marrow transplantation (AlloBMT) with those obtained with chemotherapy (CHEMO) in children with acute lymphoblastic leukemia (ALL) in second complete remission (CR) after a marrow relapse. The experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association is summarized. All children who had a relapse in the period 1980 to 1989 in 27 centers in Italy were eligible for the study. Of 287 eligible patients, 230 were treated with CHEMO, most of them (93%) according to a standard multiple-drug relapse protocol. The remaining 57 children underwent AlloBMT. Preparative regimens included total-body irradiation and chemotherapy (n = 51) or chemotherapy alone (n = 6). Statistical analysis was performed with a Cox regression model adjusting for waiting time to transplant and prognostic factors. In the whole series, minimum and median follow-up after second CR were 3 and 6.2 years, respectively; at 8 years from second CR, disease-free survival (DFS) was 20.0% (SE 2.5) and survival was 26.4% (SE 2.9). In the group of patients with an early first relapse, DFS was significantly longer after AlloBMT than after CHEMO (relative risk [RR] = 0.45, P = .002). No significant advantage of AlloBMT over CHEMO was found for patients with a late relapse (> 30 months since diagnosis). Duration of first CR significantly influenced prognosis in the CHEMO group (RR = 0.32, P = .0001 for patients with late first relapse versus patients with early first relapse). Results suggest an advantage in DFS of AlloBMT over CHEMO in ALL patients who experienced an early first medullary relapse. Prospective trials are needed to address efficacy of AlloBMT versus CHEMO in patients with late bone marrow relapse

Allogeneic bone marrow transplantation versus chemotherapy in high-risk childhood acute lymphoblastic leukaemia in first remission

We compared the outcome of children with high-risk acute lymphoblastic leukaemia (HR-ALL) in first complete remission (first CR) treated with chemotherapy (CHEMO) or with allogeneic bone marrow transplantation (BMT) in a multicentre study. All children treated by the Italian Paediatric Haematology Oncology Association for HR-ALL in first CR between 1986 and 1994 were eligible for the study. 30 children were given BMT at a median of 4 months from first CR, with preparative regimens including total-body irradiation (n = 25/30). 130 matched controls for BMT patients were identified among 397 HR-ALL CHEMO patients. Matching on main prognostic factors and duration of first CR was adopted to control the selection and time-to-transplant biases. The comparative analysis was based on the results of a stratified Cox model. The estimated hazard ratios of BMT versus CHEMO at 6 months, 1 year and 2 years after CR were 1.38 (CI 0.59-3.24), 0.69 (CI 0.27-1.77) and 0.35 (CI 0.06-1.91), with an overall non-significant difference between the two groups (P = 0.34). With a median follow-up of 4 years, the disease-free survival was 58.5% (SE 9.3) in the BMT group and 47.7% (SE 4.8) in the CHEMO group, at 4 years from CR. Non-leukaemic death occurred in 4% of CHEMO and 10% of BMT patients. In the BMT group the estimated cumulative incidence of relapse at 1.5 years from CR was 31.5% (SE 8.8) and did not change thereafter, whereas in the CHEMO group the corresponding figure was 29.2% (SE 4.1) and the incidence continued to increase thereafter (48.2% (SE 4.8) at 4 years from CR). The results of this study suggest that, with respect to the CHEMO group, the higher risk of early failure in the BMT group is outweighed by the lower risk of relapse after 1 year. Results prompt the need for a prospective study, in order to demonstrate the likely advantage of BMT in HR childhood ALL in first CR