Thiotepa-based high-dose chemotherapy with autologous stem-cell rescue in patients with recurrent or progressive CNS germ cell tumors.

PURPOSE: To evaluate the efficacy and toxicity of high-dose chemotherapy (HDC) followed by autologous stem-cell rescue (ASCR) in patients with relapsed or progressive CNS germ cell tumors (GCTs). PATIENTS AND METHODS: Twenty-one patients with CNS GCTs who experienced relapse or progression despite having received initial chemotherapy and/or radiotherapy were treated with thiotepa-based HDC regimens followed by ASCR. RESULTS: Estimated overall survival (OS) and event-free survival (EFS) rates for the entire group 4 years after HDC were 57% +/- 12% and 52% +/- 14%, respectively. Seven of nine (78%) patients with germinoma survived disease-free after HDC with a median survival of 48 months. One patient died as a result of progressive disease (PD) 39 months after HDC, and another died as a result of pulmonary fibrosis unrelated to HDC 78 months after ASCR without assessable disease. However, only four of 12 patients (33%) with nongerminomatous germ cell tumors (NGGCTs) survived without evidence of disease, with a median survival of 35 months. Eight patients with NGGCTs died as a result of PD, with a median survival of 4 months after HDC (range, 2 to 17 months). Patients with germinoma fared better than those with NGGCTs (P =.016 and.014 for OS and EFS, respectively). Patients with complete response to HDC also had significantly better outcome (P <.001 for OS and EFS) compared with patients with only a partial response or stable disease. There were no toxic deaths because of HDC. CONCLUSION: Dose escalation of chemotherapy followed by ASCR is effective therapy for patients with recurrent CNS germinomas and might be effective in patients with recurrent NGGCTs with a low tumor burden.     

Concurrent cyclophosphamide and craniospinal radiotherapy for pediatric high-risk embryonal brain tumors

Embryonal tumors are an aggressive subtype of high-grade, pediatric central nervous system (CNS) tumors often with dismal survival rates. The 5-year survival for highest-risk embryonal tumors may be as low as 10?%. We report feasibility and efficacy from our experience using intravenous (IV) cyclophosphamide concurrently with craniospinal radiation (CSI) in high-risk embryonal CNS tumors of childhood. Ten consecutive children (aged: 3.5?C15.5?years, median: 10.2?years, six male) with high-risk embryonal tumors, including: large cell/anaplastic medulloblastoma (6), atypical teratoid rhabdoid tumor (1), and leptomeningeal primitive neuroectodermal tumor (3), were treated with IV cyclophosphamide 1?g/M² on days 1 and 2 of CSI. Following a median of 36?Gy CSI plus tumor boosts, adjuvant treatment consisted of 21 doses of oral etoposide (7) and alkylator based chemotherapy from five to eight cycles in all. Of the ten patients thus treated, six remain alive with no evidence of disease and four are deceased. Median survival was 3.3?years, with a 3-year progression-free survival of 50?% (5/10). Median follow-up was: 3.3?years (range: 5?months??12.9?years) in the five patients with progression, median time-to-progression was: 1.3?years (range: 1?month??3?years). Median follow-up in the patients without progression is 8.8?years (range: 3?C12.9?years). Complications due to adjuvant chemotherapy were typical and included myelosupression (10), necessitating shortened duration of chemotherapy in three, and hemorrhagic cystitis (1). In high-risk embryonal CNS tumors, cyclophosphamide given concurrently with CSI is well tolerated. Early results suggest that a phase II trial is warranted.     

Intraarterial chemotherapy and osmotic blood-brain barrier disruption for patients with embryonal and germ cell tumors of the central nervous system

BACKGROUND: The rate of durable responses in embryonal and certain germ cell tumors of the central nervous system (CNS) is unsatisfactory. Intraarterial chemotherapy and osmotic blood-brain barrier disruption (IA/BBBD) increases drug delivery to the CNS. METHODS: Data of patients treated with carboplatin or methotrexate-based IA/BBBD on prospective phase 2 trials conducted at 3 centers were collected. Study outcomes included overall survival (OS), time to progression (TTP), and toxicity. RESULTS: Fifty-four patients were treated. Twenty-seven patients received IA/BBBD as salvage treatment. The median OS was 2.8 years for all patients, 2.5 years for supratentorial and disseminated primitive neuroectodermal tumors (PNETs, n = 29), 1.7 years for medulloblastomas (n = 12), and 5.4 years for germ cell tumors (n = 13). OS and TTP for all patients were better with a Karnofsky Performance Status > or =70% (P = .0013 and .0070) and IA/BBBD as first-line treatment (P = .0059 and .029). In PNETs, OS was higher with pineal location (P = .045) and IA/BBBD as first-line treatment (P = .0036), and TTP was improved with radiotherapy before IA/BBBD (P = .036) and IA/BBBD as first-line treatment (P = .0079). Seventeen of 54 patients (31%) are alive, and 16 are alive at 4+ to 18+ years. Three survivors were not treated with radiotherapy and 4 were treated with focal radiotherapy only. The patients who were not irradiated did not develop dementia. CONCLUSIONS: Survival and toxicity data appear promising, considering the cohort's adverse prognostic profile. A plateau in survival curves suggests a cure for some patients. Long-term survival may be achieved with focal or reduced-dose radiotherapy in some IA/BBBD patients.     

Autologous stem-cell transplantation in diffuse large B-cell non-Hodgkin's lymphoma not achieving complete response after induction chemotherapy: the GEL/TAMO experience.

BACKGROUND: Here we evaluate the results of high-dose chemotherapy and autologous stem-cell transplantation (HDC/ASCT) in 114 patients included in the GEL/TAMO registry between January 1990 and December 1999 with diffuse large B-cell lymphoma who failed to achieve complete remission (CR) with front-line conventional chemotherapy. PATIENTS AND METHODS: Sixty-eight per cent had a partial response (PR) and 32% failed to respond to front-line therapy. At transplant, 35% were chemoresistant and 29% had two to three adjusted International Prognostic Index (a-IPI) risk factors. RESULTS: After HDC/ASCT, 57 (54%) of 105 patients evaluable for response achieved a CR, 16 (15%) a PR and 32 (30%) failed. Nine patients were not assessed for response because of early death due to toxicity. With a median follow-up of 29 months for alive patients, the survival at 5 years is 43%, with a disease-free survival for complete responders of 63%. The lethal toxicity was 8%. Multivariate analysis revealed a-IPI and chemoresistance to be predicting factors. CONCLUSIONS: Our results show that one-third of patients who do not obtain a CR to front-line chemotherapy may be cured of their disease with HDC/ASCT. However, most chemoresistant patients pretransplant failed this therapy. For this population, as well as for those who presented with adverse factors of the a-IPI, pretransplant novel therapeutic modalities need to be tested.     

Outcome and prognostic factors in advanced Hodgkin's disease treated with high-dose chemotherapy and autologous stem cell transplantation: a study of 341 patients.

BACKGROUND: The reported probability of survival of patients with Hodgkin's disease (HD) following high-dose chemotherapy with autologous stem cell transplantation (HDC/ASCT) is 35-65% at 5 years. The Polish Lymphoma Research Group investigated retrospectively prognostic factors for overall survival (OS) and event-free survival (EFS), and the risk of secondary malignancies in a large series of patients who underwent HDC/ASCT. PATIENTS AND METHODS: The data of 341 consecutive patients treated in 10 centers from 1990 to 2002 were collected and analyzed. RESULTS: The actuarial 5-year OS and EFS were 64% [95% confidence interval (CI) 57% to 71%] and 45% (95% CI 39% to 51%), respectively. In the multivariate model, unfavorable prognostic factors for EFS were less than partial response at the time of ASCT [relative risk (RR), 2.92 (95% CI 1.68-5.08); P<0.001] and three or more previous chemotherapy lines (RR, 2.16; 95% CI 1.42-3.30; P<0.001). These two factors were also associated with unfavorable OS (RR, 3.32; 95% CI 1.90-5.79; P<0.001 and RR, 2.34, 95% CI 1.51-3.64; P<0.001). Five-year cumulative risk of secondary malignancy was 8.4% (95% CI 2% to 13%) and the only identified risk factor was splenectomy (P=0.02). CONCLUSIONS: HDC/ASCT should be considered early in the course of disease for patients with a response after standard therapy.     

High-dose thiotepa and etoposide in children with poor-prognosis brain tumors

BACKGROUND: Outcome data were analyzed for 27 patients who were affected with recurrent or newly diagnosed high-risk brain tumors and who underwent high-dose chemotherapy with triethylenethiophosphoramide (thiotepa) and etoposide in addition to autologous stem cell transplantation between May 1992 and September 2002. METHODS: Fifteen males and 12 females (median age, 11 years) were included in the study. Twelve patients had newly diagnosed high-risk brain tumors, and 15 patients had recurrent brain tumors. The conditioning regimen consisted of thiotepa 900 mg/m2 and etoposide 1500 mg/m2 over 3 days starting on Day -5. Stem cell rescue was performed using bone marrow (BM) in 8 patients, peripheral blood stem cells (PBSCs) in 18 patients, and BM and PBSCs in 1 patient. RESULTS: For the BM group, neutrophil (PMN) engraftment was achieved on Day +14 (median value), whereas platelet (PLT) engraftment was achieved on Day +68 (median value). One patient did not achieve PLT engraftment. For the PBSC group, the PMN engraftment was achieved on Day +10.0 (median value), and the PLT engraftment was achieved on Day +15.5 (median value). Transplantation-related toxicity (evaluated using the Bearman score) included Grade 2-3 mucositis in 16 patients, Grade 1 kidney toxicity in 6 patients, Grade 1 liver toxicity in 6 patients, and Grade 2 liver toxicity in 1 patient. Transplantation-related mortality was observed in 1 patient (3.6%), who died of Candida pneumonia. The 3-year overall survival (OS) rate was 44.6%, and the 3-year event-free survival (EFS) rate was 31%. There was a statistically significant difference in OS and EFS rates for patients who underwent ASCT and achieved complete remission compared with patients who had measurable disease. CONCLUSIONS: The results of the current study suggest that high-dose chemotherapy followed by ASCT may be beneficial for patients who achieve complete remission before ASCT, whereas for other patients, new strategies are required.     

Radiotherapy followed by high dose busulfan and thiotepa: a prospective assessment of high dose chemotherapy in children with diffuse pontine gliomas

BACKGROUND: The role of high dose chemotherapy (HDC) in patients with pediatric brain tumors currently is ill-defined. The purpose of this pilot study was to assess the feasibility and the benefit of HDC after radiotherapy in a group of children with newly diagnosed diffuse pontine gliomas. METHODS: Patients eligible for study were ages 3-18 years with diffuse intrinsic tumors arising in the pons, who were not treated previously with radiotherapy or chemotherapy. Histologic confirmation was not mandatory, provided clinical findings and magnetic resonance imaging were typical. Patients were given focal radiotherapy followed 2-3 months later by HDC. Busulfan (150 mg/m(2) on Days 8, 7, 6, and 5) and thiotepa (300 mg/m(2) on Days 4, 3, and 2) were administered prior to autologous bone marrow transplantation. Survival was the endpoint, and the statistical procedure was based on sequential subgroup analysis. RESULTS: Thirty-six patients were entered on to the study, 12 of whom underwent stereotactic biopsy or open surgery at the time of diagnosis. One patient eventually was excluded due to inappropriate eligibility criteria. All 35 eligible patients received irradiation. Early progression (9 patients) and parental refusal (2 patients) precluded the use of HDC in 11 patients. Three patients died of HDC-related complications. All 21 patients who survived HDC eventually died of disease progression. The median survival time was 10 months for the study group. The median survival time in the subgroup of patients who received HDC was 10 months (range, 3-26 months). Statistical analysis did not suggest any evidence of survival benefit. CONCLUSIONS: For patients with diffuse pontine gliomas, survival using this aggressive treatment modality does not appear to be any better than that reported for conventional radiotherapy.     

High-dose chemotherapy and autologous stem cell transplantation in peripheral T-cell lymphoma: the GEL-TAMO experience.

BACKGROUND: T-cell immunophenotype constitutes an unfavorable prognostic factor in aggressive non-Hodgkin's lymphomas. High-dose chemotherapy with autologous stem-cell rescue (HDC/ASCT) is the best salvage therapy for patients with aggressive B-cell lymphomas. However, results with this therapy in peripheral T-cell lymphoma (PTCL) are not well defined. PATIENTS AND METHODS: From January 1990 to December 1999, 115 patients with PTCL underwent HDC/ASCT inside the Grupo Espa?ol de Linfomas/Trasplante Autólogo de Médula Osea (GEL-TAMO) registry. At diagnosis the median age was 41 years and 60% of patients presented with two or three risk factors from the adjusted International Prognostic Index (a-IPI). Thirty-two per cent of patients were transplanted in first complete response (CR), 62% in chemosensitive disease and 5% in refractory disease. RESULTS: Eighty-six per cent of the patients attained a CR and 5% a partial response (PR). With a median follow-up of 37 months (range 1-133), overall survival (OS), time-to-treatment failure (TTF) and disease-free survival (DFS) at 5 years was 56%, 51% and 60%, respectively; for the 37 patients transplanted in first CR, OS and DFS at 5 years were 80% and 79%, respectively. Lactase dehydrogenase (LDH), a-IPI and disease status pre-transplant were associated with outcome. CONCLUSIONS: More than half of patients with chemosensitive disease who were transplanted are expected to be alive at 5 years. We confirm the utility of the pre-transplant IPI system in predicting outcome. Salvage treatment results with HDC/ASCT in PTCL are similar to those found in corresponding aggressive B-cell lymphomas.     

Salvage chemotherapy for patients with advanced pure seminoma.

PURPOSE: We describe the response to conventional or high-dose salvage chemotherapy in patients with advanced seminoma who experience disease progression after receiving first-line platinum-based treatment. PATIENTS AND METHODS: Twenty-seven patients with progressive, advanced, pure seminoma were treated with salvage chemotherapy. Fifteen patients were treated with conventional-dose cisplatin-and-ifosfamide combination chemotherapy. Twelve patients were treated with high-dose chemotherapy followed by autologous stem-cell rescue. RESULTS: Fifteen patients (56%) achieved a complete response (CR), nine achieved CR with a conventional-dose cisplatin and ifosfamide program, and six experienced CR after high-dose chemotherapy. Fourteen patients (52%) are alive and disease-free, with 13 (48%) continuously disease-free at a median follow-up of 72 months. Twelve (57%) of 21 patients whose pretreatment tumors were studied morphologically were found to have seminoma with atypia. Eight patients underwent resection after salvage chemotherapy; six with histologic findings of necrotic debris/fibrosis alone are alive and disease-free at last follow-up. Both patients with viable seminoma found at surgery died of disease. CONCLUSION: Most patients with advanced seminoma are cured with standard first-line programs of cisplatin and etoposide with or without bleomycin. A small minority of patients with pure seminoma have resistant tumors and require salvage chemotherapy. In this setting, approximately 50% of patients with recurrent pure seminoma achieve durable CR with conventional or high-dose salvage chemotherapy. Identification of biologic markers to predict clinical outcome and an enhanced understanding of the basic biologic features of seminoma may lead to improvements in the management of this disease.     

Biochemotherapy for metastatic melanoma with limited central nervous system involvement

OBJECTIVES: Biochemotherapy outcomes were examined in stage IV melanoma patients with previously treated or active central nervous system (CNS) metastases prior to systemic therapy. PATIENTS AND METHODS: Patients who received biochemotherapy for metastatic melanoma with active or pretreated CNS metastases were compared to patients without evidence of CNS metastases in terms of response, time to progression (TTP), overall survival (OS), and treatment toxicity. RESULTS: Twenty-six (16%) of 159 total patients began biochemotherapy with previously treated or active CNS metastases (group I), compared to 133 (84%) who were radiographically free of CNS involvement (group II). A partial or complete response to biochemotherapy was seen in 13 (50%) group I patients, compared to 56 (42%) group II patients (p = 0.243). The median TTP and median survival were 5.5 and 7.0 months, respectively, for group I patients and 6.0 and 9.9 months, respectively, for group II patients (p = 0.222 and 0.434 for TTP and OS, respectively). Five (19%) group I patients survived longer than 24 months. Gamma Knife radiosurgery or surgical resection of CNS disease prior to biochemotherapy improved survival versus delayed treatment (p = 0.017 and 0.005, respectively). CONCLUSION: Patients with limited CNS metastases and widespread systemic disease can achieve prolonged survival with targeted treatment of CNS lesions and aggressive systemic therapy.     

Outcomes of Autologous Stem Cell Transplantation as a Consolidative Strategy for the Treatment of Primary and Isolated Secondary Central Nervous System Diffuse Large B Cell Lymphomas

IntroductionStandard consolidation for primary diffuse large B cell lymphoma (DLBCL) of the central nervous system (CNS) (PCNSL) is not established. This single center, retrospective observational study aims to define the outcomes of consolidative high dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) in patients with PCNSL and isolated secondary CNS DLBCL (SCNSL) and evaluate the prognostic factors.Patients and MethodsAll consecutive patients performed an HDC/ASCT for PCNSL or isolated SCNSLs between October 2012 and February 2022 were identified. Primary endpoints were progression-free survival (PFS) and overall survival (OS).ResultsAmong 35 patients included, 28 had PCNSL and 7 had isolated SCNSL. Median age was 51 (16-78). Males constituted 48.6%. Median follow-up after HDC/ASCT was 42.0 months. MATRIX (51.4%) and TEAM (80.0%) were the most frequent regimens of induction and conditioning, respectively. OS and PFS 1- and 2-year after HDC/ASCT were 68.0%, 57.0%, 58.0%, 48.0%, respectively. Increasing age, poor performance and comorbidities were associated with lower OS and PFS and higher non-relapse mortality (NRM). Complete response (CR) 1 at HDC/ACST was independently associated with higher OS and PFS [hazard ratio (HR): 4.67 and 6.99, respectively].ConclusionIn patients < 60 years consolidative HDC/ASCT yields promising OS and PFS. Patients ≥ 60 years may less likely benefit from consolidative HDC/ASCT and should be studied further in trials of novel agents, lower doses of consolidative radiotherapy and dose-adjusted conditioning regimens. Not only age, but also comorbidities, clinical performance and response to induction correlate with outcomes. Patients with isolated SCNSL may achieve similar outcomes.     

Phase II study of PEND chemotherapy in patients with refractory/relapsed Hodgkin lymphoma

High-dose chemotherapy with autologous marrow or stem cell rescue (HDC/ASCT) is an effective strategy in patients with relapsed Hodgkin lymphoma. Various chemotherapy regimens have been used for cytoreduction prior to HDC/ASCT. In this study, our objective was to determine the response rate to PEND in a group of patients with relapsed Hodgkin lymphoma. Nineteen patients with relapsed or primary refractory Hodgkin lymphoma underwent treatment with the PEND regimen and received a median of 2 cycles (1 - 6 cycles). The PEND regimen builds on our prior results with ABDIC and consists of prednisone 40 mg/m² orally (PO) daily × 5 days; etoposide 50 mg/m² PO daily × 14 days; mitoxantrone 5 mg/m²/d IV, days 1 and 3; and DTIC 200 mg/m²/d intravenous continuous infusion (CIV) over 24 h, days 1 to 5, via central venous catheter. The treatment was given every 28 days. There were 3 complete responses (16%) and 10 partial responses (53%) yielding a total response rate of 69% (95% C.I. 43%, 87%). Myelosuppression was the predominant toxicity; no deaths were due to toxicity. After achieving maximum response to PEND, 10 eligible patients received a consolidative treatment with HDC/ASCT. All 6 patients who did not respond to PEND died from disease progression whereas 5 of 13 responders were alive after 10 years of follow-up (3 without disease). There were 11 deaths due to disease progression; three from other causes. The initial response to PEND before subsequent ASCT consolidation treatment appears to be associated with survival. All patients who failed to achieve a response have died. We conclude that PEND is an effective treatment strategy in Hodgkin lymphoma patients previously treated with both ABVD and MOPP.     

High-dose chemotherapy with autologous stem cell rescue followed by posterior fossa irradiation for local medulloblastoma recurrence or progression after conventional chemotherapy

BACKGROUND: The objective of the current study was to determine the outcome of children with local recurrence or progression of medulloblastoma in patients who received high-dose chemotherapy (HDC) and posterior fossa (PF) irradiation. METHODS: HDC consisted in busulfan at a dose of 600 mg/m(2) and thiotepa at a dose of 900 mg/m(2) followed by autologous stem cells transplantation (ASCT). PF radiotherapy was delivered at doses from 50 grays (Gy) to 55 Gy on Day +70 after ASCT. Twenty-seven patients developed local recurrence of an initially completely resected medulloblastoma. Twelve patients had local residual disease after surgery and were enrolled into the salvage protocol at the time of local disease progression under conventional chemotherapy. RESULTS: Acute toxicity consisted mainly in hepatic veno-occlusive disease (33% of patients) and bone marrow aplasia. Two toxic deaths (5%) from infections were reported. The 5-year overall survival rate after this salvage treatment (OS(5y)) for the 39 children who were treated was 68.8% (95% confidence interval [95% CI], 53-81.2%). In the group of patients who were treated for local recurrence, the OS(5y) was 77.2% (95% CI, 58.3-89.1%). Patients with local residual disease who were treated at the time of disease progression had an OS(5y) after salvage treatment of only 50% (95% CI, 25.4-74.6%; P = .09). CONCLUSIONS: The treatment strategy that was used in this study had manageable immediate toxicity and resulted in a high overall survival rate in the setting of young children with medulloblastoma who developed local recurrence or disease progression.     

High-dose therapy and autologous stem-cell transplantation for adult patients with Hodgkin's disease who do not enter remission after induction chemotherapy: results in 175 patients reported to the European Group for Blood and Marrow Transplantation. Lymphoma Working Party.

PURPOSE: To investigate the results of high-dose therapy and autologous stem-cell transplantation (ASCT) in adults with Hodgkin's disease who do not enter remission after induction therapy, to determine overall survival (OS) and progression free survival (PFS), and to identify prognostic factors. PATIENTS AND METHODS: A retrospective analysis of 175 patients reported to the European Group for Blood and Marrow Transplantation between November 1979 and October 1995. One hundred were male and 75 were female, with a median age of 26.5 years. Responses to first-line therapy were defined as progressive disease (PD) in 88 and stable/minimally responsive disease (SD/MR) in 87. Seventy-five patients received ASCT after failure of one induction regimen. Second-line therapy was given to the remaining 100 patients. Response to second-line therapy was PD in 34 and SD/MR in 66. OS and PFS rates were determined, and prognostic factors were investigated using univariate and multivariate analyses. RESULTS: Responses to high-dose therapy and ASCT were complete response (30%), partial response (28%), no response (14%), PD (14%), and toxic death (14%). Actuarial 5-year OS and PFS rates were 36% and 32%, respectively. In univariate analysis for PFS and OS, adverse factors were use of a second-line chemotherapy regimen and interval of more than 18 months between diagnosis and ASCT. In multivariate analysis, the interval between diagnosis and ASCT maintained prognostic significance for OS. Response to the chemotherapy regimen given immediately before ASCT had no predictive value. CONCLUSION: High-dose therapy and ASCT is an effective treatment strategy for patients with Hodgkin's disease for whom induction chemotherapy fails. Outcome was equivalent for those with obvious PD or SD/MR in response to the regimen given immediately before high-dose therapy. Prospective randomized studies are required to compare this approach with conventional-dose salvage therapy.     

Vinorelbine in combination with interleukin-2 as second-line treatment in patients with metastatic melanoma. A phase II study of the Hellenic Cooperative Oncology Group

OBJECTIVES: To evaluate the efficacy and toxicity of the combination of vinorelbine and interleukin (IL)-2 in patients with metastatic melanoma as second-line chemotherapy. PATIENTS AND METHODS: Twenty-two patients with histologically confirmed stage IV melanoma previously treated with temozolomide-based chemotherapy--only one regimen of chemotherapy for disseminated disease was allowed--were treated with vinorelbine 30 mg/m2 on days 1 and 15 and IL-2 subcutaneous 9 x 10(6) once daily on days 2-6 and 16-19 every 4 weeks for maximum of six cycles. RESULTS: From January 2000 to July 2001, 22 patients entered the study; the median age was 56 years. Among 20 evaluable patients there were 2 (9.1%) objective responses including 1 complete response and 1 partial response. Five (22.7%) had stabilization of their disease, and 13 (59.1%) progressed. The median time to progression (TTP) was 2.9 months and the median overall survival was 9.1 months. There was a significant difference in TTP in patients who responded or remained stable (median TTP 10.75 months) and those who progressed (median TTP 2.1 months) (p<0.05). There was also a difference in survival in the two groups (p<0.05 (28 vs. 8 months). The most common side effects were flulike symptoms, such as fever, chills, fatigue, and injection site reaction. Grade 3 hematological toxicity rarely occurred. One patient discontinued therapy because of fatigue and anorexia. There were no treatment-related deaths. CONCLUSIONS: The combination of vinorelbine and IL-2 provides clinical benefit in patients recurring or progressing on first-line chemotherapy for metastatic melanoma, with manageable toxicity.     

Diffuse large-cell lymphoma of the testis.

PURPOSE: To evaluate clinical outcome of patients with testicular diffuse large-cell lymphoma treated with conventional-dose systemic chemotherapy. PATIENTS AND METHODS: This study is a retrospective analysis of adult patients with testicular diffuse large-cell lymphoma who were treated with a doxorubicin-based chemotherapy regimen at our institution, the Istituto Nazionale Tumori of Milan. Twenty-nine assessable patients, with a median age of 61 years, were identified. Sixteen patients had limited stage (Ann Arbor stage I/II) disease, whereas 13 patients had a testicular mass and distant organ involvement (Ann Arbor stage IV). Patients were retrospectively classified according to the International Prognostic Index. RESULTS: After a median follow-up of 82 months, 22 patients presented disease progression and 22 patients had died. Actuarial median time to treatment failure and overall survival were 44 and 41 months for patients with limited stage and 9 and 16 months for patients with advanced stage, respectively. Eight patients failed initial treatment, and 14 patients relapsed from clinical remission after a median disease-free time of 17 months (range, 6 to 98 months). Median survival time after progression of lymphoma was 5 months (range, 0 to 22 months). In nine (41%) of the 22 failing patients, the initial site of relapse was either the CNS or the contralateral testis; the remaining patients experienced relapse in multiple extranodal sites. CONCLUSION: Poor prognosis of patients with diffuse large-cell lymphoma calls for more effective treatment strategies, such as high-dose chemotherapy programs for younger patients or specifically designed chemotherapy regimens for patients not suitable for high-dose treatment, with the purpose to provide control of both systemic disease and disease of the CNS and contralateral testis. The potential benefit of contralateral testicular irradiation has to be taken into account in the treatment planning.     

Consolidative involved field radiotherapy after high dose chemotherapy and autologous stem cell transplantation for non-Hodgkin's lymphoma: a case-control study

The role of involved field radiation therapy (IF-RT) after high dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) for non-Hodgkin's lymphoma (NHL) has not been conclusively defined. It has been hypothesized that HDC might obviate the need of consolidative IF-RT. A retrospective matched-pair analysis of patients undergoing HDC and ASCT with or without consolidative IF-RT has been performed. Fifteen patients treated with IF-RT after ASCT were compared with 15 patients without IF-RT, identical for histology, stage and treatment response to HDC/ASCT as well as comparable for international prognostic index (IPI) score, age and gender. After a mean follow-up time of 65 +/- 45 months, none of the patients with consolidative IF-RT following HDC and ASCT relapsed within the involved field compared to six patients without consolidative IF-RT (IF-failure risk at 5 years: 0% vs. 40%; p < 0.005). In most of the cases, local relapse was seen in patients with bulky disease. The 5-year risk for loco-regional failure was 7% after consolidative IF-RT and 38% in patients without IF-RT (p = 0.02) while the 5-year risk for developing distant recurrences was similar in both groups (30% with IF-RT vs. 35% non-IF-RT; p = 0.7). Overall survival at 5 years was similar with 79% (IF-RT) and 65% (non-IF-RT), respectively (p = 0.2). Acute toxicity due to consolidative IF-RT was mild in most cases and severe acute toxicity was noticed in only one patient (7%). Long-term toxicities observed after IF-RT were coronary artery disease, secondary malignancy unrelated to the RT-field, angina abdominalis, hypothyroidism and teeth decay. Recurrence of NHL at sites of macroscopic disease remains common despite HDC. IF-RT achieves excellent local regional control and consolidative IF-RT after ASCT seems indicated, particularly in patients with bulky disease. In the absence of a prospective randomized trial and proven impact on survival rates, IF-RT can be recommended as an option post-ASCT to enhance local disease control.     

Anthracycline-based chemotherapy as primary treatment for intravascular lymphoma.

BACKGROUND: Optimal therapeutic management of intravascular lymphoma (IVL) lacks precise guidelines. PATIENTS AND METHODS: The clinico-pathological features of 38 HIV-negative patients with IVL were reviewed to define efficacy of chemotherapy in these malignancies. Clinical characteristics of 22 patients treated with chemotherapy and of 16 untreated patients were compared in order to understand better the impact and causes of potential patient selection. RESULTS: Median age was 70 years (range 34-90), with a male/female ratio of 0.9; 23 (61%) patients had Eastern Cooperative Oncology Group performance status (ECOG-PS) > 1; 21 (55%) had systemic symptoms. Cutaneous lesions and anemia were significantly more common among patients treated with chemotherapy; central nervous system (CNS) and renal involvement were significantly more common among untreated patients. Chemotherapy was associated with a response rate of 59% and a 3-year overall survival of 33 +/- 11%. Five of six patients with CNS involvement received chemotherapy: four of them died early; only one patient, treated with adriamycin, cyclophosphamide, vincristine, methotrexate, bleomycin and prednisolone (MACOP-B) followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT), was alive at 19 months. High-dose chemotherapy supported by ASCT was indicated at diagnosis in another patient (43 years of age, stage I), who was alive at 71 months, and at relapse after cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) in two patients who died early after transplantation. PS < or = 1, disease limited to the skin, stage I, and use of chemotherapy were independently associated with better outcome. CONCLUSIONS: Anthracycline-based chemotherapy is the standard treatment for IVL. However, survival is disappointing, with a relevant impact of diagnostic delay and lethal complications. More intensive combinations, containing drugs with higher CNS bioavailability, are needed in cases with brain involvement, and the role of high-dose chemotherapy supported by ASCT should be further investigated in younger patients with unfavorable features.     

Efficacy of high-dose chemotherapy or standard salvage therapy in patients with recurrent medulloblastoma

The efficacy of high-dose chemotherapy (HDC) or standard salvage therapy was evaluated in patients with recurrent medulloblastoma (MBL) using retrospective chart review of all patients with recurrent MBL treated at Duke University Medical Center between 1995 and 2005 and who had undergone HDC with or without radiotherapy (RT) or standard salvage therapy after relapse. A total of 30 patients were diagnosed with recurrent MBL after standard RT alone or chemotherapy with RT. Nineteen patients (7 who received no RT before recurrence [group A] and 12 who received definitive RT before recurrence [group B]) underwent surgery and/or induction chemotherapy followed by HDC plus autologous stem-cell rescue. Eleven patients (group C) underwent standard salvage therapy. Six of seven group A patients also received standard RT just before or after recovery from HDC, and 5 of 12 group B patients received adjuvant palliative focal RT post-HDC. At a median follow-up of 28 months, three of seven patients in group A are alive and disease-free at >or=34, >or=110, and >or=116 months, respectively, post-HDC. All patients in groups B and C have died of tumor, at a median of 35 months and 26 months from HDC and standard salvage therapy, respectively. HDC or standard salvage therapy was ineffective in our patients with recurrent MBL who had received standard RT before recurrence. The favorable impact of HDC on disease control in the two long-term survivors cannot be clearly established due to the cofounding effect of definitive RT postrecurrence.     

Carboplatin‐based primary chemotherapy for infants and young children with CNS tumors

BACKGROUND:

A carboplatin‐based chemotherapy regimen was used as primary postoperative therapy in infants with central nervous system (CNS) tumors to limit renal and ototoxicity and to target systemic exposure.

METHODS:

Fifty‐three patients aged <age 3 years with embryonal CNS tumor medulloblastoma (n = 20), ependymoma (EP, n = 21), choroid plexus carcinoma (CPCA, n = 5), and primitive embryonal neoplasms including atypical teratoid rhabdoid tumors (n = 7) were treated with cyclophosphamide, etoposide, and carboplatin. Radiation therapy was used only for residual disease at the end of chemotherapy or disease progression.

RESULTS:

The response rate after 2 cycles of chemotherapy was 34% (complete response, 13.8%; partial response, 20.7%). Myelosuppression was the dominant toxicity; 2 patients had toxic deaths related to thrombocytopenia with trauma. The 5‐year overall survival (OS) was 49% ± 7%, and the progression‐free survival (PFS) was 31% ± 7%, with a median follow‐up of 11.4 years (range, 5.2‐15.0 years). For medulloblastoma, the 5‐year PFS was 26% ± 9%; for EP it was 33% ± 10%; for CPCA it was 80% ± 18%; and for primitive neuroectodermal and atypical teratoid rhabdoid tumors it was 0%. Localized EP patients with gross total resection who did not undergo radiotherapy had a 5‐year PFS of 57% ± 17% and OS of 71% ± 16%. Two patients developed late second malignancies; 1 was associated with germline p53 mutation.

CONCLUSIONS:

The results confirm that carboplatin has similar activity to cisplatin in otherwise similar regimens. Five‐year survival data are comparable to those reported in other recent studies, including high‐dose chemotherapy studies. Of note is the marked activity in CPCA and gross totally resected EP. Cancer 2009. © 2009 American Cancer Society.