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.     

Incidence of late-relapse germ cell tumor and outcome to salvage chemotherapy.

PURPOSE: To define the incidence, clinical features, and outcome to salvage chemotherapy in patients with late-relapse germ cell tumor (GCT) after a complete response to first-line chemotherapy. PATIENTS AND METHODS: Two patient populations were examined. First, retrospective analysis of 246 patients treated on a clinical trial with salvage chemotherapy was performed; 29 patients with late-relapse GCT were identified and evaluated for treatment outcome and survival. Salvage regimens included paclitaxel, ifosfamide, and cisplatin, single agents, or a high-dose chemotherapy program. Second, the incidence of late relapse was assessed by retrospective analysis of 551 patients after a complete response (CR) to first-line chemotherapy. RESULTS: Twenty-nine patients received salvage chemotherapy on a clinical trial for late relapse GCT. The median survival was 23.9 months. At a median follow-up of 50.6 months, there were nine survivors. The chemotherapy regimens varied, but the only CRs were observed in patients treated with paclitaxel, ifosfamide, and cisplatin. Seven (50%) of 14 patients treated with paclitaxel, ifosfamide, and cisplatin achieved a continuous CR. Among the second population of 551 patients who had previously achieved a CR to a first-line chemotherapy trial, 17 were identified as having a late relapse (3%). The median time to relapse for these 17 patients was 7.8 years. CONCLUSION: Late-relapse GCT is uncommon and is associated with a poor prognosis resulting from a high degree of resistance to chemotherapy. Chemotherapy with paclitaxel, ifosfamide, and cisplatin followed by surgery may be effective in patients with late-relapse GCT who are not considered candidates for primary surgery.     

Third-line chemotherapy and novel agents for metastatic germ cell tumors

Although germ cell tumors (GCT) are among the most curable solid tumors, a subset of patients with GCT experience relapse or progression despite appropriate cisplatin-based therapy or first-line salvage therapy. This article describes the molecular mechanisms of cisplatin resistance, outlines single-agent chemotherapy and combination chemotherapy regimens that are active against GCT in the third-line or later setting, discusses the use of drug therapy for treating growing teratoma syndrome and teratoma with malignant transformation, outlines novel agents used to treat GCT, and highlights ongoing clinical trials and future directions in the treatment of refractory GCT.     

The role of ifosfamide plus cisplatin-based chemotherapy as salvage therapy for patients with refractory germ cell tumors

A prospective study of four cycles of etoposide with ifosfamide and cisplatin (VIP) chemotherapy was conducted in 42 germ cell tumor (GCT) patients who were refractory to cisplatin with etoposide/vinblastine-based therapy. Forty patients were evaluable for response. Ten patients (25%) had a complete response: seven to chemotherapy alone and an additional three patients after surgical resection of viable GCT. With a median follow-up of 15 months, four complete responders relapsed, and six patients (15%) remain in remission. Hematologic and nephrotoxicity were moderately severe. Durable complete responses with VIP as second salvage were achieved and suggests that ifosfamide adds efficacy to standard first-salvage therapy. The observed nephrotoxicity and myelotoxicity are considerations in the design of ifosfamide-cisplatin-based regimens. Hematopoietic growth factors may be useful in ameliorating myelotoxicity. The early use of ifosfamide-based chemotherapy may reduce the nephrotoxicity exacerbated by prior cisplatin. A trial of VIP as first salvage after a relapse from a complete response to platinum-based induction therapy is warranted. The modest proportion of patients who achieve a durable remission to VIP as second salvage emphasizes the need for more efficacious salvage therapy for patients who do not achieve a durable complete response.     

High-dose chemotherapy and stem cell transplantation for advanced testicular cancer

High-dose chemotherapy (HDCT) with autologous stem cell support has been studied in both the salvage and first-line setting in advanced germ cell tumor (GCT) patients with poor-risk features. While early studies reported significant treatment-related mortality, introduction of peripheral blood stem cell transplantation, recombinant growth factors and better supportive care have decreased toxicity; and in more recent reports treatment-related deaths are observed in <3% of patients. Two to three cycles of high-dose carboplatin and etoposide is the standard backbone for HDCT, given with or without additional agents including ifosfamide, cyclophosphamide and paclitaxel. Three large randomized Phase III trials have failed to show a benefit of HDCT over conventional-dose chemotherapy (CDCT) in the first-line treatment of patients with intermediate- or poor-risk advanced GCT, and to date the routine use of HDCT has been reserved for the salvage setting. Several prognostic models have been developed to help predict outcome of salvage HDCT, the most recent of which applies to both CDCT and HDCT in the initial salvage setting. Patients that relapse after HDCT are usually considered incurable, and additional therapy is provided with palliative intent.     

High-dose chemotherapy and stem cell transplantation for advanced testicular cancer

High-dose chemotherapy (HDCT) with autologous stem cell support has been studied in both the salvage and first-line setting in advanced germ cell tumor (GCT) patients with poor-risk features. While early studies reported significant treatment-related mortality, introduction of peripheral blood stem cell transplantation, recombinant growth factors and better supportive care have decreased toxicity; and in more recent reports treatment-related deaths are observed in <3% of patients. Two to three cycles of high-dose carboplatin and etoposide is the standard backbone for HDCT, given with or without additional agents including ifosfamide, cyclophosphamide and paclitaxel. Three large randomized Phase III trials have failed to show a benefit of HDCT over conventional-dose chemotherapy (CDCT) in the first-line treatment of patients with intermediate- or poor-risk advanced GCT, and to date the routine use of HDCT has been reserved for the salvage setting. Several prognostic models have been developed to help predict outcome of salvage HDCT, the most recent of which applies to both CDCT and HDCT in the initial salvage setting. Patients that relapse after HDCT are usually considered incurable, and additional therapy is provided with palliative intent.     

Identification of Risk Factors in Patients Treated for First Relapse of Hodgkin's Disease

This review focuses on potential risk factors in patients relapsing with Hodgkin's disease after a first chemotherapy/radiation therapy induced complete remission. This patient group usually presents with highly treatment responsive disease and has become one of the target groups for consideration of salvage high dose chemotherapy with stem cell/autologous marrow support (HDC/ABMT). It is currently not clear to which patients in first relapse this treatment should be offered. The knowledge of certain risk factors could be of great help in assessing such patients. A first group of risk factors are those assessable at initial diagnosis: sex, age, histology, Ann Arbor stage, tumour bulk and some laboratory parameters. A second group of risk factors are those present at the time of relapse: time to relapse, extent of disease at relapse, B-symptoms and performance status, extra nodal lesions at relapse or a relapse within an irradiated field. Age below 50 years seems to exert a small influence on outcome but becomes a major problem above that. There is a small number of characteristics such as the time from the end of initial treatment to relapse or B-symptoms at relapse which seem to be the most prominent factors predicting for freedom from second failure (FF2F). Patients who relapse more than one year after finishing primary chemotherapy and who are free of B symptoms at relapse have a quite favourable outcome after salvage treatment. If their disease is not bulky and is confined entirely to a modest number of previously unirradiated lymph node sites, wide field irradiation offers a reasonable chance of disease control. If their recurrence is bulky, extra-nodal or in a previously irradiated site, the patient's prognosis after HDC/ABMT is excellent. Patients who relapse less than one year after primary chemotherapy or with B symptoms at the time of relapse have a less satisfactory outcome after any available salvage treatment. Trials comparing various HDC/ABMT regimens or novel approaches built on standard dose chemotherapy and irradiation are needed to find better treatments for such patients. Such patients with early or symptomatic relapses who cannot be enrolled in prospective comparative trials should be offered HDC/ABMT while we search for better treatments. Larger trials with a prospective analysis of the risk factors are needed for us to be able to decide which treatment will be the optimal choice for our patients.     

Treatment of recurrent malignant sacrococcygeal germ cell tumors: analysis of 22 patients registered in the German protocols MAKEI 83/86, 89, and 96.

PURPOSE: To evaluate therapeutic options for recurrent malignant sacrococcygeal germ cell tumors (GCT) following three-agent, cisplatinum-based, first-line chemotherapy and tumor resection. PATIENTS AND METHODS: Twenty-two patients were evaluated in 22 first-, 14 second-, five third-, and two fourth-relapse situations. One patient, who relapsed with pure teratoma, was excluded from the analysis of adjuvant treatment. RESULTS: Seventeen patients presented with an isolated local recurrence, two patients showed a distant relapse, and three patients suffered from a combined local and distant recurrence. Twelve patients achieved complete remission (CR) after surgery (n = 12) and adjuvant platinum chemotherapy (n = 10). Seven of these patients remain in continuous CR, and five patients relapsed. All patients who achieved only a partial remission developed a second relapse. Three of 14 patients could be cured after a second (or further) relapse. Altogether, 10 patients survived disease free, and 12 patients died as a result of tumor progression (n = 11) or therapy-related complications (n = 1). The completeness of salvage surgery and clinical remission status after first salvage treatment were the most important prognostic parameters. In addition, patients in first or second relapse with locally advanced or poorly responding tumors benefited from preoperative chemotherapy in combination with regional hyperthermia (RHT). In some patients after microscopically incomplete resection, irradiation at doses > 45 Gy contributed to a favorable outcome. CONCLUSION: The complete resection of the local recurrence represents the cornerstone of salvage treatment. Preoperative platinum-based chemotherapy, combined with RHT in some patients, facilitates complete tumor resection. Radiotherapy should be reserved for those patients with microscopically incomplete tumor resection. As the chance of cure decreases with further relapses, it is important to establish a stringent therapeutic strategy to avoid significant treatment delays and, most importantly, insufficient local therapy.     

Stellenwert der Hochdosischemotherapie (HDCT) beim männlichen Keimzelltumor

Context

As a consequence of the unsatisfactory results of conventional dose regimens (CDCT), particularly in patients with poor prognostic features at the time of first-line therapy or at relapse, high-dose chemotherapy (HDCT) was introduced into clinical practice in the late 1980s.

Material and methods

Research of literature and analysis of clinical trials.

Results

The combination of carboplatin and etoposide (CE) remains the backbone of most high-dose salvage regimens. With improved expertise in supportive care and the use of peripheral blood stem cells, hematopoietic recovery time was significantly shortened and the initially high treatment-related mortality was reduced from more than 10?% to about 3?%. Since the incorporation of HDCT even patients with unfavorable prognostic features or patients with a second or subsequent relapse can achieve long-term remission. However, the role of HDCT as first-line treatment in selected patients with “poor prognosis” metastatic disease as well as first salvage treatment in relapsed patients with favorable prognostic characteristics remains controversial. To avoid overtreatment HDCT should only be administered at a few experienced centers and only be recommended for patients with unfavorable prognostic factors or for patients with a second or subsequent relapse. However, current data now allow a better assessment and limitation of its role. In addition an international prospective randomized phase III study (TIGER) is planned which will compare a conventional salvage regimen with sequential HDCT for the first relapse.     

Phase II trial of pembrolizumab in patients with platinum refractory germ-cell tumors: a Hoosier Cancer Research Network Study GU14-206

BackgroundDespite remarkable results with salvage standard-dose or high-dose chemotherapy ~15% of patients with relapsed germ-cell tumors (GCT) are incurable. Immune checkpoint inhibitors have produced significant remission in multiple tumor types. We report the first study of immunotherapy in patients with GCT.Patients and methodsSingle arm phase II trial investigating pembrolizumab 200 mg i.v. Q3weeks until disease progression in patients with relapsed GCT and no curable options. Patients age ≥18 with GCT who progressed after first-line cisplatin-based chemotherapy and after at least one salvage regimen (high-dose or standard-dose chemotherapy) were eligible. Centrally assessed programmed death-ligand 1 (PD-L1) on tumor and infiltrating immune cells was scored. Primary end point was overall response rate using immune-related response criteria. Simon two-stage design with type I error 20% and power 80% was utilized.ResultsTwelve male patients were enrolled. Median age was 38 years. All patients had nonseminoma. Primary site was testis (11) or mediastinum (1). Median AFP 615 (range 1–32, 760) and hCG 4 (range 0.6–37, 096). Six patients had late relapse (>2 years). Median number of previous chemotherapy regimens was 3. Six patients received prior high-dose chemotherapy. Two patients had positive PD-L1 staining (H-score 90 and 170). Median number of pembrolizumab doses was 2 (range 1–8). There were six grade 3 adverse events. No immune-related adverse events were reported. No partial or complete responses were observed. Two patients achieved radiographic stable disease for 28 and 19 weeks, respectively; both had continued rising AFP level despite radiographic stability and had negative PD-L1 staining.ConclusionThis is the first reported trial evaluating immune checkpoint inhibitors in GCT. Pembrolizumab is well tolerated but does not appear to have clinically meaningful single-agent activity in refractory GCT.Clinical trial informationNCT02499952.     

Salvage high-dose chemotherapy in female patients with relapsed/refractory germ-cell tumors: a retrospective analysis of the European Group for Blood and Marrow Transplantation (EBMT)

BackgroundHigh-dose chemotherapy (HDC) with hematopoietic progenitor cell transplantation is a standard option for relapsed/refractory testicular germ-cell tumor (GCT), but only few data have been reported in female patients with GCT. We conducted a retrospective analysis of female patients with GCT treated with HDC and registered with the European Society for Blood and Marrow Transplantation.Patients and methodsBetween 1985 and 2013, 60 registered female patients with GCT, median age 27 years (range 15–48), were treated with salvage HDC. Forty patients (67%) had primary ovarian GCT, 8 (13%) mediastinal, 7 (12%) retroperitoneal and 5 (8%) other primary sites/unknown. Twenty-two patients (37%) received HDC as second-line therapy, 29 (48%) as third-line, and 9 (15%) as fourth- to sixth-line. Nine of 60 patients (15%) received HDC as late-intensification with no evidence of metastasis before HDC. The conditioning HDC regimens comprised carboplatin in 51 of 60 cases (85%), and consisted of a single HDC cycle in 31 cases (52%), a multi-cycle HDC regimen in 29 (48%).ResultsNine cases who underwent late intensification HDC were not evaluable for response. Of the other 51 assessable patients, 17 (33%) achieved a complete response (CR), 8 (16%) a marker-negative partial remission (PRm−), 5 (10%) a marker-positive partial remission, 5 (10%) stable disease, and 13 (25%) progressive disease. There were 3 toxic deaths (6%). With an overall median follow-up of 14 months (range 1–219), 7 of 9 (78%) patients with late intensification and 18 of the 25 patients (72%) achieving a CR/PRm− following HDC were free of relapse/progression. In total, 25 of 60 patients (42%) were progression-free following HDC at a median follow-up of 87 months (range 3–219 months).ConclusionsSalvage HDC based on carboplatin represents a therapeutic option for female patients with relapsed/refractory GCT.     

Transplantation for Refractory Germ Cell Tumors: Does it Really Make a Difference?

High-dose chemotherapy (HDC) has been used over the past 25 years for germ-cell tumors in a variety of clinical scenarios. There is consensus at this point that its use as part of first-line treatment does not benefit patients with high-risk tumors. Long-term results of prospective trials in patients with relapsed or with refractory disease indicate that a fraction of them achieve long-term remissions consistent with cures. While HDC constitutes for many oncologists in the US an accepted treatment modality for relapsed or refractory GCT, controversy surrounds its use in those settings. Prognostic models have been developed that allow to prospectively identify poor prognosis patients that might benefit from novel HDC-based approaches.     

Treatment and outcomes of UK and German patients with relapsed intracranial germ cell tumors following uniform first‐line therapy

We aimed to retrospectively assess treatments/outcomes, including the value of high‐dose‐chemotherapy and autologous‐stem‐cell‐rescue (HDC + AuSCR) and re‐irradiation, in a large, European patient‐cohort with relapsed intracranial germ‐cell‐tumors (GCTs) receiving uniform first‐line therapy, including radiotherapy as standard‐of‐care. Fifty‐eight UK/German patients (48 male/10 female) with relapsed intracranial‐GCTs [13 germinoma/45 non‐germinomatous GCT (NGGCT)] treated 1996–2010 as per the SIOP‐CNS‐GCT‐96 protocol were evaluated. For germinoma, six patients relapsed with germinoma and five with NGGCT (one palliative, one teratoma patient excluded). Five‐year overall‐survival (OS) for the whole‐group (n = 11) was 55%. Four of six germinoma relapses and two of five relapsing with NGGCT were salvaged; patients were salvaged with either standard‐dose‐chemotherapy (SDC) and re‐irradiation or HDC + AuSCR with/without re‐irradiation. Of 45 relapsed NGGCT patients, 13 were excluded (three non‐protocol adherence, five teratoma, five palliation). Five‐year OS for the remaining 32 relapsed malignant NGGCT patients treated with curative intent was 9% (95%CI: 2–26%). By treatment received, 5‐year OS for the 10 patients receiving SDC and 22 patients treated with intention for HDC + AuSCR was 0% (0–0%) and 14% (3–36%), respectively. The three relapsed NGGCT survivors had raised HCG markers alone; two received additional irradiation. Patients with relapsed germinoma had better 5‐year OS than those with relapsed NGGCT (55 vs. 9%; p = 0.007). Patients with relapsed germinoma were salvaged both with SDC and re‐irradiation or HDC + AuSCR with/without re‐irradiation; both represent valid treatment options. Outcomes for malignant relapse following initial diagnosis of NGGCT were exceptionally poor; the few survivors received thiotepa‐based HDC + AuSCR, which is a treatment option at first malignant relapse for such patients, with further surgery/irradiation where feasible.     

Autogreffe dans les cancers du testicule

The majority of patients with advanced germ cell tumours (GCT) achieve a continuous and complete response to first-line cisplatin combination chemotherapy. Nevertheless, patients with poor prognosis respond less well. Moreover, patients with progressive or recurrent GCT require effective salvage therapy. Using conventional-dose chemotherapies in salvage therapy, 20 to 30% of patients will become long-term survivors. Studies of high-dose chemotherapy have reported promising results on its effectiveness in treating recurrent GCT. However, randomized trials do not demonstrate an impact on the clinical benefit of high-dose chemotherapy as a first-line treatment for patients with poor prognosis or recurrent GCT. A better understanding of prognostic factors, the use of new drugs in high-dose protocols and the evaluation of targeted molecular therapies could increase the clinical benefit of high-dose strategies.     

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.     

Salvage high-dose chemotherapy for children with extragonadal germ-cell tumours

We reviewed the European Group for Blood and Marrow Transplantation (EBMT) experience with salvage high-dose chemotherapy (HDC) in paediatric patients with extragonadal germ-cell tumour (GCT). A total of 23 children with extragonadal GCT, median age 12 years (range 1-20), were treated with salvage HDC with haematopoietic progenitor cell support. The GCT primary location was intracranial site in nine cases, sacrococcyx in eight, retroperitoneum in four, and mediastinum in two. In all, 22 patients had a nongerminomatous GCT and one germinoma. Nine patients received HDC in first- and 14 in second- or third-relapse situation. No toxic deaths occurred. Overall, 16 of 23 patients (70%) achieved a complete remission. With a median follow-up of 66 months (range 31-173 months), 10 (43%) are continuously disease-free. Of six patients who had a disease recurrence after HDC, one achieved a disease-free status with surgical resection followed by chemotherapy and radiotherapy. In total, 11 patients (48%) are currently disease-free. Eight of 14 patients (57%) with extracranial primary and three of nine patients (33%) with intracranial primary GCT are currently disease-free. HDC induced impressive long-term remissions as salvage treatment in children with extragonadal extracranial GCTs. Salvage HDC should be investigated in prospective trials in these patients.     

Analysis of salvage treatments for germ cell cancer patients who have relapsed after primary high-dose chemotherapy plus autologous stem cell support

The aim of this study was to identify treatment strategies and therapeutic or clinical factors that predict for response to salvage therapy and survival in patients with metastatic 'Indiana advanced' or International Germ-Cell Cancer Collaborative Group (IGCCCG) poor prognosis' germ cell cancer (GCT) failing first-line sequential high-dose chemotherapy plus autologous stem cell support (HD-CT). A total of 58 'poor prognosis' patients who had relapsed after HD-CT were identified within two large prospective German first-line HD-CT trials (n=286) performed between March 1993 and March 2001. Salvage treatment consisted of the following: cisplatin-based conventional dose CTx+/-resection (19/58; 33%), non-cisplatin based CTx (16/58; 28%) or salvage HD-CT (14/58; 24%)+/-resection; resection (n=3) and/or radiation (n=5) only: 7 patients (12%); no specific therapy: 2 patients. 21 (38%) patients responded favourably (Complete Response (CR)/Partial Response (PR) marker-negative) to salvage therapy. The use of salvage HD-CT (2-year survival 48%; P=0.03, the complete resection of residual masses (2-year survival 42%; P=0.015) as well as a favourable response to salvage therapy (2-year survival: 31%, P=0.014) were the only variables on univariate analysis associated with an improved survival. The estimated 2-year overall survival rate is 32% (95% Confidence Interval CI: 29-45%). Approximately 30% of patients relapsing after first-line HD-CT will survive>2 years, particularly those patients who can be treated with a second HD-CT +and/or surgical resection. If feasible, complete surgical resection of residual tumours appears to be the most efficient treatment.     

Definition of refractoriness against conventional chemotherapy in acute myeloid leukemia: a proposal based on the results of retreatment by thioguanine, cytosine arabinoside, and daunorubicin (TAD 9) in 150 patients with relapse after standardized first line therapy

Response to salvage therapy at first and second relapse was analyzed in 150 patients with acute myeloid leukemia (AML) to improve the characterization of relapsed AML and to deduce from this analysis a proposal for the definition of refractoriness against conventional therapy. Salvage treatment consisted of a repetition of the TAD 9 regimen which was already applied as induction protocol at initial diagnosis. All patients were recruited from the multicenter 1982 trial of the German AML Cooperative Group and had thus received a standardized first line treatment. Response at first relapse was significantly related to the duration of the first remission. From 38 patients relapsing within 6 months after successful induction therapy, only 11 (28%) achieved a second complete remission as compared to 58 of 98 (59%) cases with later occurring relapses (p less than 0.01). This difference was due to a significantly higher incidence of persistent leukemia in the former group and not biased by differences in early death rates. No other variable was found predictive for the response to salvage treatment including age, WBC, serum LDH, morphologic subtype, presence or absence of DNA aneuploidy as detected by flow cytometry or maintenance chemotherapy. A low remission rate of 28% was also obtained in the 14 patients at second relapse. These data indicate that patients with a duration of their first remission of more than 6 months cannot be considered as being refractory against standard chemotherapy while patients with early relapses and second recurrences have a response rate of less than 30% due to refractory disease. Hence, the following criteria are proposed for the definition of refractoriness against standard chemotherapy in advanced AML: (a) nonresponse to first-line induction therapy, (b) early relapse within 6 to 12 months of first remission, (c) relapse after 6 to 12 months of first remission and failure on a reinduction attempt with established regimens, (d) second and subsequent relapses. These criteria may provide a useful rationale for the selection of the most appropriate treatment at relapse. They may also serve as eligibility criteria for clinical phase I/II studies and will facilitate interstudy comparisons.     

Use of rituximab in patients with follicular lymphoma

Advanced stage symptomatic follicular non-Hodgkin's lymphoma (NHL) is rarely, if ever, curable with conventional chemotherapy. Patients classically experience a pattern of remission and relapse, eventually dying of their disease. Data from a number of large-scale randomised phase III trials, both as first-line therapy and in relapsed/refractory patients, comparing rituximab plus chemotherapy with chemotherapy alone indicate that the addition of rituximab to a number of different chemotherapy regimens increases response rates and progression-free survival (PFS), without significantly increasing toxicity. Moreover, in four trials, three in first-line and one in relapsed disease, a significant overall survival benefit has been observed for rituximab combination therapy. These data indicate that patients with follicular NHL who require therapy should now receive rituximab plus chemotherapy as first-line treatment. Additionally, a strong case remains for offering rituximab-based therapy to patients with relapsed disease who have not previously received it, and in those who have previously responded well to this agent. Rituximab maintenance therapy has also been shown to significantly prolong PFS after rituximab in combination with chemotherapy in patients with relapsed disease and in newly diagnosed patients who have not received rituximab during induction, and the benefit of maintenance after immunochemotherapy in relapsed patients may yet be mirrored by ongoing studies in the first-line setting. This overview considers the most recently published clinical trials of rituximab and their potential effect on clinical practice in the treatment of follicular NHL.     

A phase II trial of high-dose chemotherapy (HDCT) supported by hematopoietic stem-cell transplantation (HSCT) in germ-cell tumors (GCTs) patients failing cisplatin-based chemotherapy: the Multicentric TAXIF II study

BackgroundHigh-dose chemotherapy (HDCT) is an effective salvage treatment of germ-cell tumors (GCTs) patients. In the first salvage setting, 30%–70% of patients may achieve durable remissions. Even when HDCT is administered as subsequent salvage treatment, up to 20% of patients may still be definitively cured. However, patients with refractory/relapsed disease still have a very poor long-term prognosis, requiring earlier intervention of HDCT.Patients and methodsThis phase II trial was addressed to nonrefractory patients failing Cisplatin-based chemotherapy. Inclusion criteria included seminomatous GCT in relapse after two lines of chemotherapy, nonseminomatous GCT in relapse after first or second lines, partial remission after first line, primary mediastinal GCT in first relapse. Patients received two cycles combining Epirubicin and Paclitaxel (Epi-Tax), followed by three consecutive HDCT, one using a Paclitaxel/Thiotepa (Thio-Tax) association and two using the 5-day Ifosfamide–Carboplatin–Etoposide regimen. The main objective was to determine the complete response rate.ResultsForty-five patients were included between September 2004 and December 2007: 44 received the first HDCT cycle, 39 two HDCT cycles, 29 could receive the whole protocol. Sixteen patients did not receive the entire protocol, including eight (17.7%) for toxic side-effects. Two patients (4.4%) died of toxicities, and 17 (37.7%) of disease progression. With a median follow-up time of 26 months (range, 4–51), the final overall response rate was 48.8% (including a complete response rate of 15.5% and a partial response/negative serum markers rate of 26.6%) in an intent-to-treat analysis. The median progression-free survival (PFS) and overall survival (OS) times were 22 months [95% confidence interval (CI) 2–not reached] and 32 months (95% CI 4–49), respectively. The 2-year PFS was a plateau setup at 50% (95% CI 32–67) and the 2-year OS was 66% (95% CI 44–81).ConclusionThe TAXIF II protocol was effective in nonrefractory GCT patients failing Cisplatin-based chemotherapy. The toxic death rate remained acceptable in the field of HDCT regimens.Trial registration numberNCT00231582.