Prognosis of High Dose Chemotherapy/Autologous Bone Marrow Transplantation Candidates not Receiving This Treatment after Failure of Primary Therapy of Hodgkin's Disease

In a multicenter study on the therapy of Hodgkin's disease, in 88 out of 297 patients with primary advanced stages IIIB/IV, a failure to the treatment with the alternating chemotherapy COPP/ABVD ± radiation was recorded. The cause of failure was as follows: tumor progression under current therapy (PD) 23/88, partial response at the end of therapy (PR) 28/ 88, early nodal relapses 13/88, late nodal relapses 16/88, extranodal relapses 7/88, undetermined localization 1/88.36 months after manifestation of the failure to treatment, 45% of all patients were still alive. In cases of primary PD the prognosis was the worst of all. Only 1/23 of these patients received a long-term continuous complete remission (cCR) with the salvage therapy. 11 patients with only a nodal relapse received a cCR with irradiation alone. These cases could be regarded as low risk relapses. For the high risk relapse group (n = 57) an indication for high dose chemotherapy with subsequent autologous bone marrow transplantation (HDC/ABMT) would have been imperative, following the present-day definition. The probability of survival of these patients who, however, only received a conventional salvage therapy was up to 38% (95% confidence interval 22-54%). Comparing these data with the literature our results seem not to be substantially worse than those for patients who underwent HDC/ABMT. Only in a randomized comparison can the decision be made on whether HDC/ABMT would be superior to high dose conventional chemotherapy supported by hematopoietic growth factors. It is suggested that such a therapy study be performed as soon as possible.     

Salvage Therapy in Hodgkin's Lymphoma

Hodgkin's lymphoma (HL) is a commonly cured malignancy. Unfortunately, patients who are refractory to or relapse after first‐line treatment pose a significant therapeutic challenge. There is evidence that these patients are best treated with an approach involving salvage chemotherapy followed by high‐dose chemotherapy and autologous stem cell transplant (HDCT/ASCT). This approach may result in cure, with better results in patients with low‐risk relapse. In patients with high‐risk relapse and refractory disease, HDCT/ASCT is rarely curative. More aggressive transplant approaches have shown promising results in this group and are currently under active investigation. For those relapsing after HDCT/ASCT, there exists a range of therapeutic options, including further salvage chemotherapy, reduced‐intensity allogeneic transplantation, monoclonal antibody therapy, and novel agents. All patients in this category should be considered for enrollment in clinical trials. This review discusses the evidence behind the current practice in patients with relapsed or refractory HL. Specifically, the efficacy of various salvage chemotherapy regimens, the risk factors influencing outcome with HDCT/ASCT, and the results with alternative transplant approaches, monoclonal antibody therapies, and novel agents are addressed. We conclude by providing our approach to these patients, with the hope that this will serve as a framework for the practicing oncologist.     

Does bulky disease at diagnosis influence outcome in childhood Hodgkin's disease and require higher radiation doses? Results from the German-Austrian Pediatric Multicenter Trial DAL-HD-90

PURPOSE: The identification of risk factors is required for risk-adapted treatment strategies in the treatment of Hodgkin's disease. To assess the influence of bulky disease at diagnosis as compared with other risk factors on event-free survival (EFS) in pediatric Hodgkin's disease such as stage, B-symptoms, number of involved lymph node regions, histology, and remission status after chemotherapy, we analyzed the outcome of 552 patients treated with a risk-adapted treatment strategy consisting of OPPA(OEPA)/COPP (vincristine, procarbazine, etoposide, prednisone, adriamycin, cyclophosphamide) and involved-field radiotherapy. METHODS AND MATERIALS: Between 1990 and 1995, 578 patients with primary Hodgkin's disease (HD) were enrolled in the German/Austrian Pediatric Hodgkin's Disease Study Group (DAL) Multicenter Study (HD-90). Patients were stratified into three treatment groups (TGs) for early, intermediate, and advanced stage. All patients received induction chemotherapy (CT) with two cycles of OEPA for boys and two cycles of OPPA for girls. Patients in TG2 and TG3 received another two or four cycles, respectively, of COPP. Chemotherapy was followed by involved-field radiotherapy. The radiation field, which was prescribed by the study center, was treated with a dose of 25 Gy/25 Gy/20 Gy (TG1/TG2/TG3), and in case of insufficient remission with a local boost of 5 Gy to 10 Gy. The following prognostic factors were analyzed with regard to their impact on EFS: bulky disease, mediastinal tumor, number of involved lymph node regions, histology, treatment group, B-symptoms, sex, age, and remission status after chemotherapy. RESULTS: Significant univariate predictive factors for the EES were: nodular sclerosis type 2 (NS2) histology (relative risk [RR] 3.43; p = 0.0002), presence of B-symptoms (RR 2.70; p = 0.0014), number of involved regions (1.55; p = 0.019), and treatment groups (RR 1.33; p = 0.017). There was a higher risk (RR 1.92; p = 0.040) for patients with bulky compared with nonbulky disease (5-year EFS 89.6%/94.6%). In the multiple regression model, only NS2 and B-symptoms remained strong predictive factors. The remission status after chemotherapy did not correlate with EFS (p = 0.66). CONCLUSION: Treatment strategies in Hodgkin's disease have an impact on different risk factors. In the risk-adapted treatment strategy of the HD-90 study, tumor burden indicated as bulky disease or as number of involved lymph nodes loses its importance, whereas NS2 histology and B-symptoms have a major impact on treatment outcome. Bulky disease at diagnosis might require higher radiation doses only in case of insufficient remission.     

Autologous bone marrow transplantation for patients with poor-prognosis lymphoma

Review of prognostic factors at Memorial Hospital in New York City has shown that adult patients with large-cell lymphoma (diffuse histiocytic lymphoma by Rappaport classification) who have high lactic dehydrogenase (LDH) and/or bulky mediastinal or abdominal disease are destined to do poorly with conventional combination chemotherapy, with a 2-year disease-free survival of about 20%. Patients who relapse after conventional combination chemotherapy have a similar poor prognosis. Thirty-one such patients with lymphoma were studied to evaluate the efficacy of intensive radiotherapy (hyperfractionated total body irradiation [TBI] [1,320 rad]), and cyclophosphamide (60 mg/kg/d for two days) followed by autologous bone marrow transplantation (ABMT). Our results show a disease-free survival advantage (P = .002) for 14 patients who underwent ABMT immediately after induction of remission with 79% surviving at a median follow-up 49.2+ months, compared with a median survival of 5.2 months for 17 patients administered ABMT while in relapse and/or after failing conventional treatment. Our results support the use of aggressive therapy as early treatment for patients with poor prognostic features.     

Improved survival of poor prognosis diffuse histiocytic (large cell) lymphoma managed with sequential induction chemotherapy, "boost" radiation therapy, and autologous bone marrow transplantation

From 1981 to 1985, 33 patients with the diagnosis of diffuse histiocytic (large cell) lymphoma (DHL) with a poor prognosis received induction multi-drug chemotherapy followed by autologous marrow cryopreservation. Thirty patients who had residual disease after chemotherapy were given "boost" irradiation to these sites, followed immediately by hyperfractionated total body irradiation, 1320 to 1375 cGy in 11 fractions over 4 days, then cyclophosphamide (60 mg/kg/d) for 2 days. All patients received an autologous bone marrow transplant (ABMT), with 15 patients receiving marrow purged with 4-hydroperoxycyclophosphamide. Patients were transplanted either as part of a planned induction-transplant approach (Group I), or as salvage after relapse on the same induction regimen (Group II), or other conventional chemotherapy regimens (Group III). In the entire group, 16 of 33 patients (48%) are alive free of lymphoma with a median follow-up of 32 months (11 to 53 mo). Actuarial (Kaplan-Meier) survival is 51% at 2 years and 46% at 3 years, with only 1 patient dying after 2 years out of 11 at risk. Eight patients (24%) succumbed to early treatment related complications. Nine patients (27%) died from relapse. Patients receiving ABMT as planned sequential therapy post-induction (Group I) did significantly better than patients given ABMT as salvage therapy after relapse on prior chemotherapy (Groups II and III) and better than the historical group of patients treated with chemotherapy alone. At 2 years, the survival in Group I is 79% versus 0% for Group II versus 48% for Group III. Historically, this group of high risk patients had a 2-year disease-free survival of 20% or less with chemotherapy alone.     

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.     

The optimal timing of autologous bone marrow transplantation in Hodgkin's disease patients after a chemotherapy relapse.

PURPOSE: The optimal sequence of salvage chemotherapy (SC) and autologous bone marrow transplantation (ABMT) for Hodgkin's disease (HD) patients who relapse after primary chemotherapy is unknown. We created a decision analysis model to determine the optimal treatment strategy and the most cost-effective approach. METHODS: The decision tree simulated a 25-year-old HD patient who relapsed less than 12 months after mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy. Four strategies used ABMT in some sequence with SC; the final strategy considered SC alone. Clinical data were derived from 17 published reports chosen by explicit criteria. Costs of care were estimated from the published literature and institutional experience. RESULTS: The optimal strategy was ABMT in second relapse, which was superior to the SC-only option by 1.9 years at an incremental cost of $26,200 per each year of life saved. When the probabilities of complete remission and disease-free survival were reduced for SC, similar to the clinical expectation of SC after a seven- or eight-drug regimen like MOPP/doxorubicin, bleomycin, and vinblastine with or without dacarbazine (MOPP/ABV[D]), ABMT in first relapse was the preferred strategy and provided 6 additional months. However, when the data from favorable (or unfavorable) SC and ABMT reports were compared head-to-head in this model, SC followed by ABMT in second relapse was always optimal. CONCLUSIONS: All relapsed HD patients should plan to use ABMT in some sequence with SC, if necessary. In most situations the optimal strategy is ABMT in second relapse. This analysis will assist clinicians in planning treatment for relapsed HD patients. It could be refined if historical series were updated to report the incidence and outcomes of SC relapse from seven- or eight-drug regimens.     

New prognostic score based on treatment outcome of patients with relapsed Hodgkin's lymphoma registered in the database of the German Hodgkin's lymphoma study group.

PURPOSE: To evaluate salvage treatment outcome of patients with relapsed Hodgkin's disease (HD) and to distinguish different risk groups using identified prognostic factors. PATIENTS AND METHODS: From 4,754 patients registered in the German Hodgkin's Lymphoma Study Group (GHSG) database between 1988 and 1999, 422 patients with early (n = 170) or late (n = 252) relapsed HD were identified. One hundred seven patients (25%) relapsed after radiotherapy (RT) for early stages, 133 patients (32%) after combined-modality therapy for intermediate stages, and 182 patients (43%) after chemotherapy (CT) and RT to initial bulky disease or residual lymphoma for advanced stages. At relapse, characteristics of these 422 patients (median age, 38 years; range, 17 to 77) were stage III/IV, 45%; B symptoms, 24%; elevated erythrocyte sedimentation rate, 29%; anemia, 13%; and Karnofsky performance score, less than 90 in 13%. At first relapse, salvage treatment was RT in 13%, CT in 54%, and high-dose chemotherapy (HDCT) with autologous stem-cell transplantation (ASCT) in 33%. RESULTS: Median follow-up time after relapse was 45 months. Freedom from second failure (FF2F) and overall survival (OS) were 81% and 89% for relapse after RT, 33% and 46% for early relapse after CT, and 43% and 71% for late relapse after CT, respectively. In multivariate analysis, independent risk factors were time to relapse, clinical stage at relapse, and anemia at relapse. Four subgroups with significantly different FF2F and OS were identified. The prognostic score was predictive for patients who relapsed after RT, CT with conventional CT salvage, and CT with HDCT/ASCT. CONCLUSION: In the GHSG database, time to relapse and clinical stage and anemia at relapse are relevant factors and can be used to form a prognostic score for HD patients at relapse.     

High dose cyclophosphamide, fractionated total body irradiation with involved field irradiation and autologous bone marrow transplantation in malignant lymphoma

The objective of this clinical trial was to determine if radiation to areas of recurrence or bulky disease prior to total body irradiation (TBI) and chemotherapy followed by autologous bone marrow transplantation (ABMT) altered the site of relapse andlor prolonged survival. Forty-eight patients with recurrent or refractory malignant lymphoma were treated with high-dose cyclophosphamide and fractionated TBI followed by ABMT. Thirty-four patients were eligible to receive involved field radiation therapy (IF-RT) to sites of recurrence or bulky disease. The overall response rate in 46 evaluable patients was 89% with 33 complete remissions (CR) and 8 partial remissions (PR). In a multivariant analysis increasing LDH, decreased serum albumin, older age, and lack of sensitivity to prior chemotherapy were associated with poorer survival. There were 10 deaths due to treatment related complications, 8 died of pulmonary complications of whom 6 were in CR. Of 11 who had received IF-RT and subsequently relapsed, 4 recurred in or adjacent to the involved field. We conclude that intensive chemo-radiotherapy proved to be an effective salvage therapy for patients with recurrent malignant lymphoma, resulting in a projected actuarial 33% DFS at 5 years, but was associated with a high transplant-related mortality.     

High-dose chemotherapy with autologous stem-cell support for germ cell tumors: a critical review

High-dose chemotherapy (HDC) with autologous stem-cell support (ASCS) has been investigated in patients with cisplatin-resistant, relapsed, or poor-prognosis germ cell tumor (GCT). Although some of these patients have benefited from this approach, it is unknown when best to administer such therapy. This review categorizes the HDC/ASCS trials into those performed as (1) salvage therapy for second or greater relapse, (2) salvage therapy for first relapse, and (3) first-line therapy. From the trials performed to date, earlier use of HDC/ASCS (first-line or salvage therapy in first relapse) achieved a higher durable remission rate than when used later as salvage therapy in second or greater relapse (approximately 50% v 15%, respectively). HDC/ASCS is not beneficial for relapsed or cisplatin-resistant primary extragonadal GCT patients, but may have a role in testicular GCT who are not "absolutely" cisplatin-resistant. Trial differences regarding the patients selected and the high-dose transplant preparative regimen used have made precise comparative analyses difficult. There has been only one phase III trial and it did not show a survival advantage to the HDC/ASCS arm, although this trial had significant methodological difficulties. In the future, more definitive treatment recommendations may be made upon completion of two ongoing phase III trials comparing HDC/ASCS with standard chemotherapy in the first salvage and front-line settings.     

Favorable Outcome After Adjuvant Involved-Field Radiotherapy After Autologous Hematopoietic Stem-Cell Transplantation in Patients With High-Risk Relapsed/Refractory Lymphoma: A Single-Center Experience

BackgroundPatients with refractory or relapsed lymphoma diagnosed with bulky disease at relapse or with residual disease after salvage treatment are considered to have a dismal outcome, even after autologous hematopoietic stem-cell transplantation, as a result of disease recurrence. To minimize the risk of relapse after receipt of a transplant, involved-field radiotherapy (IFRT) to sites of either bulky or localized residual disease has been utilized; however, the ideal timing for irradiation remains controversial. The aim of this study was to assess the safety and efficacy of IFRT in the early period after transplantation.Patients and MethodsWe retrospectively evaluated the outcome of 24 autografted patients with relapsed/refractory lymphoma who presented with bulky disease at relapse or who had a persistent localized residual mass after salvage treatment and consolidated with IFRT within 4 months after autografting.ResultsNo significant toxicity was noticed during the early postradiotherapy period, while graft function was not impaired. After a median follow-up of 3 years for survivors, 21 patients were alive, 19 of whom were event free, while 2 patients died of disease recurrence and 1 died of treatment-related myelodysplastic syndrome. The 3-year overall, lymphoma relapse-free, and event-free survival rates were 86%, 86%, and 82%, respectively.ConclusionTaking into consideration the poor-risk features of the study cohort, IFRT provided early after autologous hematopoietic stem-cell transplantation showed a safe and well-tolerated toxicity profile and demonstrated long-term effective tumor control, as reflected in the promising survival rates.     

Salvage therapy with ProMACE-MOPP followed by intensive chemoradiotherapy and autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma who failed to respond to first-line CHOP.

PURPOSE: We used alternative chemotherapy immediately followed in early-response patients by high-dose chemoradiotherapy and autologous bone marrow transplantation (ABMT) to treat patients with non-Hodgkin's lymphoma (NHL) who had failed to respond to first-line chemotherapy. PATIENTS AND METHODS: Thirty-one patients with NHL of intermediate- or high-grade malignancy who had failed to respond to first-line cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy were treated. Seventeen patients had primary refractory disease and 14 had relapsed from first complete response (CR). The treatment consisted of prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, and procarbazine (ProMACE-MOPP) salvage chemotherapy, followed, in case of responsive disease (at least partial response [PR]), by high-dose cyclophosphamide and total-body irradiation (TBI) with ABMT. RESULTS: Twenty-eight of 31 (90%) patients achieved PR (23 patients) or CR (five patients) with ProMACE-MOPP, and three failed to respond. Seventeen of 28 (61%) patients who responded underwent the ABMT procedure, which resulted in CR in 14 patients (82%); three failed to respond. Eleven responsive patients were not transplanted because of residual bone marrow infiltration (five patients), patient refusal (four patients), and ProMACE-MOPP-related mortality (two patients). To date, nine patients are alive and in CR, seven with a median follow-up of 41 months (range, 17 to 84 months). Referring to the original CHOP treatment, five of 17 (29%) patients with primary refractory disease remain free of disease at a median of 36 months after ABMT, and four of 14 (29%) patients in first relapse remain free of disease at a median of 33 months after ABMT. One patient died of AMBT-related toxicity. CONCLUSION: ProMACE-MOPP salvage chemotherapy produces a high early-response rate in patients who fail to respond to first-line CHOP, and more than half of the responding patients can be scheduled to receive ABMT, resulting in disease-free survival (DFS) at 3 years in 50% of the transplanted patients and in 25% of the original number of patients intended to receive this treatment.     

Relapse after high-dose therapy in relapsed Ewing's tumor patients: effects of maintenance chemotherapy in two selected patients?

BACKGROUND: The prognosis for patients with high-risk Ewing's tumor, i.e. primarily multifocal or early relapsed disease, is extremely poor with conventional relapse therapy. High-dose radio/chemotherapy (HDC) with subsequent stem cell transplantation seems to improve outcome in this patient cohort. In spite of this intensified therapy however, relapse remains the most frequent cause of death. In the majority of patients the time to second relapse after HDC is shorter than the time to first relapse after conventional therapy (3.4 vs. 18 months). Event-free survival in Ewing's tumor patients who suffer a second relapse after first-line therapy (EICESS 92) is 2% after 18 months. CASE REPORT: The present report describes the clinical course of two girls who relapsed after HDC and subsequently received low-dose oral trofosfamide and etoposide. The patient with very late multifocal relapse after first-line treatment and a second localized relapse 30 months after HDC remains disease-free for 5 years after the last relapse. However, the other patient with 2 early relapses after first-line treatment and HDC, respectively, did not benefit from this regime. CONCLUSION: We propose that low-dose maintenance therapy may be beneficial in the subgroup of Ewing's tumor patients with late relapse after HDC.     

Salvage chemotherapy with mini-BEAM for relapsed or refractory non-Hodgkin's lymphoma prior to autologous bone marrow transplantation

Background: The role of intensive chemotherapy with autologous blood andmarrow transplantation (ABMT) for patients with relapsed or refractoryintermediate grade non-Hodgkins lymphoma has recently been established.However, conventional dose salvage chemotherapy is frequently used todetermine chemotherapy sensitivity and reduce tumor bulk prior to intensivetherapy. Different salvage regimens have been proposed but none appearssignificantly superior. The purpose of this study was to determine theefficacy of mini-BEAM salvage chemotherapy in patients referred for ABMT andto define prognostic factors of response.Patients and methods: One hundred four patients referred forconsideration of ABMT after failure of primary anthracycline-basedchemotherapy received BCNU 60 mg/m² day 1, etoposide 75mg/m² day 2–5, ara-C 100 mg/m² q12h day2–5, melphalan 30 mg/m² day 6 (mini-BEAM) until maximumtumor reduction. Median age was 52 (range 18–65); 57% had failedto achieve a complete response (CR) to doxorubicin-based chemotherapy atdiagnosis and only 13% had a previous CR lasting > 12 months.Seventy-six received mini-BEAM as first salvage chemotherapy.Results: The overall response rate (RR) was 37% (95%confidence interval (CI) 28–46%) with 12 patients achieving CRand 25 achieving PR. Theresponse rate among patients treated as first salvage was 43% comparedto 20% for patients who had failed to respond to a previous salvageregimen. Only 15% of patients who failed to respond to mini-BEAMresponded to another conventional dose salvage regimen. Thirty-eight of 104patients ultimately demonstrated sufficient response to proceed to ABMT.Actuarial survival at four years is 22% for all 104 patients, and36% for those who went on to ABMT. For those who were not transplanted,four-year survival was 18%. B symptoms and tumor burden at relapse weresignificant predictors of response to mini-BEAM in multivariate analysis, andidentified a poor prognosis group of patients unlikely to be cured by thisapproach.Conclusions: Mini-BEAM does not appear to be a superior salvage regimen inthis high-risk group of relapsed or refractory NHL patients for whom ABMT wasthe ultimate treatment intention. Only one-third of patients referred for ABMTultimately proceed to transplant; alternative treatment strategies should bedeveloped for those with a low likelihood of cure by this approach.     

Outcome of Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma Referred for Autologous Bone Marrow Transplantation

Fifty-one patients with relapsed or refractory intermediate- or high-grade non-Hodgkin's lymphoma were referred for autologous bone marrow transplantation (ABMT). The primary criterion for eligibility was sensitivity to conventional-dose salvage chemotherapy. Of 47 patients who received salvage chemotherapy, 30 demonstrated chemotherapy-sensitive disease. Six eligible patients did not undergo ABMT for various reasons. A total of 24 patients underwent ABMT, with etoposide, melphalan ± total body irradiation as the intensive therapy regimen. There was one early treatment-related death and three non-responders. Of the remaining patients, 9 relapsed, while 11 remain in continuous complete remission (CR) at a median follow-up of 21 months after transplant (range 5-37 months). Two patients with chemosensitive disease and bone marrow involvement underwent allogeneic BMT with marrow from HLA-identical siblings. Both are in continuous CR at 6 and 12 months follow-up. Of the 25 patients who did not undergo ABMT, all have died (median survival 5 months).

The results indicate that approximately one-half of relapsed or refractory aggressive histology lymphoma patients referred for ABMT eventually undergo transplantation, if chemotherapy-sensitive relapse is the major criterion for eligibility. Approximately 25% of the referred patients may become long-term disease-free survivors with this approach. Reports of marrow transplant series should include all patients referred for ABMT as the denominator for calculating disease-free survival in order to reduce the bias of patient selection.     

Intensive therapy and autotransplant for patients with an incomplete response to front-line therapy for lymphoma

BACKGROUND:: Patients with Hodgkin's disease (HD) and intermediate or high-gradenon-Hodgkin's lymphoma (NHL) who fail to achieve a completeremission (CR) with standard induction therapy have a poor prognosiswith conventional-dose salvage therapy alone. We examined therole of subsequent intensive therapy and autologous bone marrowtransplantation (ABMT) in patients who demonstrated a responseto conventional-dose salvage therapy. PATIENTS AND METHODS:: Sixty-six patients with either HD (n = 30) or NHL (n = 36) underwentintensive therapy with etoposide (60 mg/kg), intravenous melphalan(160–180 mg/m²) followed by infusion of unpurged autologousbone marrow and/or blood cells. All patients had advanced stageor bulky disease at diagnosis and failed to achieve a CR afteran anthracycline-containing front-line chemotherapy regimen(NHL) or ABVD or equivalent regimen (HD). Patients who achieveda CR after involved-field radiotherapy were excluded. All patientsdemonstrated sensitivity to conventionaldose salvage treatmentbefore advancing to intensive therapy and ABMT. RESULTS:: The CR, partial response (PR) and overall response rate (RR)following ABMT for HD patients was 48%, 17% and 65%, respectively.At a median follow-up of 35 months, the predicted three-yearoverall survival (OS) is 51% (95% CI: 44%–60%) and event-freesurvival (EFS) is 34% (95% CI: 26%–54%). For patientswith NHL, the CR, PR and RR were 68%, 9% and 77%, respectively.At a median follow-up of 28 months, the predicted three-yearOS is 51% (95% CI: 35%–66%) and EFS is 39%(95% CI: 21%–57%). CONCLUSIONS:: Intensive therapy with etoposide and melphalan followed by ABMTresults in prolonged survival in selected patients with lymphomawho fail to achieve a complete remission to front-line chemotherapy.Based on our previous studies of outcome to conventionaldosesalvage chemotherapy, we estimate that of all patients failinginduction therapy, 28% with HD and 15% with NHL will be eventfreeat three years after ABMT. induction failure, Hodglun's disease, non-Hodgkin's lymphoma, refractory lymphoma     

High-dose chemotherapy supported with autologous bone marrow transplantation (ABMT) in germ cell tumors: a phase two study.

In this paper, the first Italian multicentre experience with high-dose chemotherapy and ABMT in germ cell cancer is presented. Twenty-eight patients underwent treatment with a carboplatin-etoposide w/o ifosfamide high-dose combination. Seventeen patients were in progression of disease, 9 were responsive to salvage treatments or failed to achieve CR to front line, and 2 had stable disease (both with an elevated marker level) at the time of transplantation. Five patients, all of whom were in sensitive relapse at transplantation, are alive and disease-free at > 17 months' follow-up. Two patients died 15 days after ABMT, one of veno-occlusive disease and one of rapid uncontrolled tumor progression. In highly pretreated patients this schedule seems to provide an option of cure for a cohort of patients failing to achieve CR to standard salvage regimens for germ cell cancer. Definitive conclusions may eventually be drawn with a more homogeneous group of patients. This type of approach should continue to be taken in sensitive relapse patients only, as responses in progressive cases are very transient, with virtually no cures. The question of whether high-dose programs are better than standard chemotherapy will in any case be answered only in a randomized prospective trial.     

Will high dose chemotherapy followed by autologous bone marrow transplantation supplant cranio-spinal irradiation in young children treated for medulloblastoma?

Cranio-spinal irradiation is the gold standard treatment used in non metastatic medulloblastoma as prophylaxis against central nervous system (CNS) metastases. However, given the severe late effects caused by this procedure in children under 3 years of age, most pediatric oncologists are currently treating these patients with conventional chemotherapy in order to postpone or even avoid irradiation. In the French Society of Pediatric Oncology ('FOP) this attitude has been adopted since 1987.Among the patients treated without radiotherapy, 20 relapsed while on conventional chemotherapy and were entered in a study of high-dose chemotherapy (HDC) followed by ABMT. Their median age at diagnosis was 23 months (R5-71) and the relapse occurred at a median time of 6.3 months after the initiation of chemotherapy. Complete surgical removal of the local relapse was the first treatment in 4/20 patients who were not evaluable for response. Sixteen of the twenty patients had measurable disease at the primary site (9 patients), or at metastatic sites (3 patients) or both (4 patients). The conditioning regimen consisted of combination Busulfan 600 mg/m² over 4 days and Thiotepa 900 mg/m² over three days. After recovery from aplasia, patients with a local relapse received local radiotherapy limited to posterior fossa. Results. Among the 16 patients with measurable disease, 6 CR, 6 PR, 3 NR, were observed following HDC (response rate 75 %). One patient was not evaluable. For the 20 patients, the EFS is 50%. Among the surviving patients, the median follow up is 31 months post BMT (R12-82). Ten patients who developped a local relapse or local progression are alive with NED without craniospinal irradiation. Among the 7 patients who developped metastases or progression of metastases, only one is alive. Toxicity was high but manageable: the median duration of granulocytopenia < 0.5 × 109/1 and thrombocytopenia < 50 × 10⁹/1 was 13 and 41 days respectively. Bacteremia was documented in 4 cases. Grade > 2 mucositis and diarrhea were observed in 60% of patients. One complication-related death occurred 1 month post BMT. Conclusion. With a 75 % response rate, this HDC proved to be very efficient in relapsed medulloblastoma. A longer follow up is necessary to demonstrate whether, after a local relapse, HDC could replace craniospinal irradiation as prophylaxis against CNS metastases.     

Autologous Bone Marrow Transplantation for Hodgkin's Disease-A Five-Year Single Centre Experience

The results from 40 patients who have undergone autologous bone marrow transplantation (ABMT) for relapsed or refractory Hodgkin's disease between March 1988 and September 1992 have been analysed. In contrast to our results in patients with relapsed HD, our results in patients with refractory HD are comparatively poor. Conventional salvage chemotherapy also seems inappropriate in these patients and we therefore believe they should be offered high-dose chemotherapy before their disease becomes refractory to conventionally scheduled regimens. Peripheral blood stem cell (PBSC) transplant now offers an attractive alternative to ABMT and may replace both intensive salvage chemotherapy and ABMT as the optimum treatment for patients who fail to respond to conventional chemotherapy regimens.     

Rezidivtherapie und Prognosefaktoren im Rezidiv bei Hodentumoren

The majority of patients with germ cell tumors who fail first-line treatment will still be cured. Patients without first-line chemotherapy who fail surveillance, radiotherapy, or surgery are managed according to the treatment algorithms for primary metastatic disease. These patients will usually be rendered disease-free with three to four cycles of cisplatin, etoposide, and bleomycin. Salvage treatment of patients who relapse after first-line chemotherapy is complex and requires an experienced and highly specialized team. For patients with early relapse less than 2 years after first-line treatment, two strategies may be pursued: first, four cycles of conventional-dose chemotherapy with cisplatin, ifosfamide and either etoposide, paclitaxel, or vinblastine; second, early intensification of first-salvage treatment using sequential high-dose chemotherapy. Prognostic factors help in selecting the optimal salvage strategy. Additional salvage surgery is frequently required after completion of salvage chemotherapy to completely resect all radiologic residual manifestations. Patients with brain metastases should receive whole-brain radiation upfront, concurrent with salvage chemotherapy. Patients with late relapse more than 2 years after first-line treatment should receive immediate salvage surgery whenever this is technically feasible.