Effects Of High-dose Chemotherapy Research Articles

Effect of high-dose chemotherapy with upfront autologous hematopoietic stem cell transplantation on the prognosis of patients with stage IV diffuse large B-cell lymphoma.

Актуальность: Повышение эффективности первой линии терапии диффузной В-крупноклеточной лимфомы (ДВКЛ), особенно высокого риска, остается сложной и актуальной клинической задачей онкогематологии. Преимущество применения высокодозной химиотерапии с трансплантацией аутологичных гемопоэтических стволовых клеток (ВДХТ с ауто-ТГСК) в первой линии ДВКЛ с целью снижения риска развития рецидива и улучшения прогноза не определено и актуально для клинических исследований. Цель: изучение влияния ВДХТ с ауто-ТГСК в первой линии на прогноз у пациентов с IV стадией ДВКЛ. Материалы и методы: Ретроспективно проанализировано 105 пациентов, в возрасте 18-65 лет, с IV стадией ДВКЛ NOS, IPI ≥ 2, достигших ПО/ЧО (полного ответа/частичного ответа) после 6 курсов R-CHOP/R-DA-EPOCH. Пациенты получали лечение в ФГБУ «НМИЦ онкологии им. Н.Н. Петрова» Минздрава России с 2010 по 2019 годы. В группе ТГСК (n=35) проводилась ВДХТ с ауто-ТГСК в первой ремиссии. Группа контроля (n=70) находилась под наблюдением после 6 курсов иммунохимиотерапии (ИХТ) при достижении ПО. Первичные конечные точки – 1-годичная, 3-летняя безрецидивная выживаемость (БРВ), вторичная конечная точка – 3-летняя общая выживаемость (ОВ). Результаты: ВДХТ с ауто-ТГСК в первой линии продемонстрировала преимущество в показателях 1-годичной (р = 0,01) и 3-летней БРВ (р = 0,029), ОВ (р = 0,047). У пациентов с лимфомой с коэкспрессией myc, bcl-2 (double-expressor lymphoma, DEL) отмечено более значимое улучшение 1-годичной (р <0,001) и 3-летней БРВ (р <0,001), ОВ (р <0,001) при проведении ВДХТ с ауто-ТГСК в первой линии. В группе ТГСК наличие DEL не влияло на 1-годичную (р = 0,44), 3-летнюю БРВ (р = 0,17) и ОВ (р = 0,34). Заключение: ВДХТ с ауто-ТГСК в первой линии улучшает прогноз у пациентов с IV стадией ДВКЛ, IPI ≥ 2. У пациентов с DEL позитивное влияние ВДХТ с ауто-ТГСК в первой линии на БРВ, ОВ выше. Неблагоприятное влияние DEL на прогноз нивелируется проведением ВДХТ с ауто-ТГСК в первой линии.

Effect of high-dose chemotherapy plus stem cell rescue on the survival of patients with neuroblastoma modified by MYCN gene gain/amplification and remission status: a nationwide registration study in Japan.

In high-risk neuroblastoma, the presence of an MYCN gain/amplification (MYCN-GA) is not always a risk factor of cancer-specific death. We herein examined the effect modification of high-dose chemotherapy with autologous hematopoietic stem cell rescue (HDC-autoSCR) in terms of the interaction between MYCN status and remission status (complete remission or very good partial remission [CR/VGPR] vs. partial remission or less [≤PR]). The present study recruited patient data from 1992 to 2017 in the Japan Society of Hematopoietic Cell Transplantation's national registry. The MYCN status was known in 586 of 950 patients with a single course of HDC-autoSCR. Cumulative hazard curves for neuroblastoma-specific death showed that a subgroup with MYCN-GA and ≤PR had a significantly poorer prognosis than three other subgroups, namely, the MYCN-NGA/ ≤ PR, MYCN-NGA/CR/VGPR, and MYCN-GA/CR/VGPR subgroups even after adjusting for non-infants and stage IV disease (hazard ratio: 2.79; 95% confidence interval: 1.91-4.09; P < 0.001). The interaction between MYCN-GA and ≤PR was significant (pinteraction = 0.006). Hence, the patients with MYCN-GA with non-remission status at HDC-autoSCR had a significantly poorer prognosis than the other subgroups, suggesting that HDC-autoSCR may be effective in patients with CR/VGPR regardless of MYCN gene status and in patients with MYCN-NGA regardless of remission status.

Effect of high-dose chemotherapy with autologous stem cell rescue (HDC-aSCR) on outcome in ovarian small-cell carcinoma, hypercalcemic type (SCCOHT): Prospective series from the French Rare Gynecologic Malignant Tumors Network (TMRG).

6023 Background: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and rapidly lethal disease affecting young women with over half dying within 2 years of diagnosis. We previously reported improved outcomes with cytoreductive surgery followed by HDC-aSCR in a prospective study, but these encouraging results needed to be confirmed in an independent and larger cohort. Methods: Between 2008 and 2019, out of 44 patients (pts) diagnosed with centrally confirmed SCCOHT in 16 referent centers of the TMRG network, 38 were treated prospectively according to the French recommendations of the network with complete surgery (primary or after neoadjuvant chemotherapy), 4 to 6 cycles of PAVEP chemotherapy (cisplatin, doxorubicin, vepeside, and cyclophosphamide), and for pts with complete response (CR), HDC-aSCR, followed by pelvic radiotherapy. The 6 patients who could not receive PAVEP (unfit or diagnostic delay) relapsed and died rapidly. The primary endpoint was the event-free survival (EFS) in the intention-to-treat cohort. Results: Median age at diagnosis was 33 years (14-76). 13 pts presented with FIGO stage I, 17 stage III and 6 stage IV, 2 unknown. Median follow-up was 55.5 months. 34 patients achieved CR with CT + surgery and 30 received HDC-aSCR (40%, 47% and 10% with stages I, III and IV diseases respectively) and 21 received also pelvic radiotherapy. Median overall and event-free survival was 36.4 and 15.9 months respectively, and 2-years event-free survival rate was 40% (CI95% 25-56). Median OS was respectively not reached, 18 and 9.6 months for FIGO I, III and IV patients. Among the pts (N = 14) who did not receive HDC-aSCR (rapid progression during or after PAVEP), the 2-yr EFS was 0% compared to 50.5% for the 30 patients receiving HDC. In multivariate analysis, HDC was significantly correlated with better outcomes (p &lt; 0.001). For the 21 patients receiving also pelvic radiotherapy, 57% (12/21) are free of recurrence at 4 years. Grades 3/4 adverse events were frequent (78%) but, in most cases, manageable, although one toxic death (3%) occurred during HDC (fungal septic shock). Conclusions: Treatment of SCCOHT, with intensive multimodal therapy, is associated with a 40% 2-yr event-free survival. However, this protocol is associated with significant toxicity and should be restricted to good performance status patient and expert centers.

The effectiveness of high-dose chemotherapy with autologous hematopoietic stem cell transplantation in the treatment

Background. Ewing sarcoma (EWS) is a second most common pediatric bone tumor. About one quarter of all patients belong to a high-risk group characterized by a poor prognosis. In spite of high-dose chemotherapy (HDCT) with autologous hemopoietic stem cell transplantation (auto-HSCT) being traditionally viewed as a possible option for high-risk patients, there is stills no consensus on indications for this method in EWS patients. Study objective: to evaluate the HDCT effectiveness and most important prognostic factors in a prospective cohort of high-risk EWS patients. Materials and methods. A total of 73 EWS patients receiving treatment in R.M. Gorbacheva Memorial Institute were included in the study. All patients were characterized by one or several high-risk features: local (primary tumor volume &gt;200 ml, axial localization, poor response to chemotherapy; n = 55; 76 %), primary disseminated disease (n = 58; 80 %), first chemoresponsive relapse (n = 7; 9 %). All patients received a myeloablative consolidation regimen consisting of busulfan 16mg/kg and melphalan 140mg/m 2 . In patients with primary disseminated disease an additional evaluation according to risk scale by R. Ladenstein et al. was performed. Based on risk points all patients were stratified as standard (n = 20), high (n = 26), and ultrahigh risk (n = 12). Results. The 5-year overall and event-free survivalfor a whole studied cohort were 40 and 37 %, accordingly. In patients with high-risk localized disease the 5-year overall and event-free survival were 48 and 45 %, accordingly. The HDCT regimen was characterized by acceptable toxicity. The main non-hematologic toxicities were infectious complications (n = 61) and gastrointestinal tract mucositis (n = 31). One patient of 76 died due to treatment-related complications. The multivariate analysis revealed the following risk factors: therapy response (hazard ratio (HR) 2.2; p &lt;0.01), bone marrow involvement (HR 5.0; p = 0.01), primary tumor volume (HR 1.9; p = 0.01), and number of bone metastases (HR 2.2; p = 0.05). The risk group determined by R. Ladenstein score was also a good predictor for outcome with only 8 % of ultrahigh risk patients surviving 5 years past auto-HSCT. Conclusion. HDCT with auto-HSCT may potentially improve treatment results in some high-risk patient subgroups. While risk scale may help to determine patients most likely to benefit from this approach, the outcome in ultrahigh risk patients are still dismal.

What are the effects of high-dose chemotherapy with autologous stem cell transplantation for the treatment of aggressive non-Hodgkin lymphoma?

What are the effects of high-dose chemotherapy with autologous stem cell transplantation for the treatment of aggressive non-Hodgkin lymphoma?

Tandem high‐dose chemotherapy and autologous stem cell rescue in children with newly diagnosed high‐risk medulloblastoma or supratentorial primitive neuro‐ectodermic tumors

To assess the feasibility and effectiveness of high-dose chemotherapy (HDC) with stem cell support followed by conventional craniospinal radiotherapy (RT) as treatment for children older than 5 years of age with newly diagnosed high-risk medulloblastoma (MB) or supratentorial PNET (sPNET). Between May 2001 and April 2010, 24 children older than 5 years of age (MB = 21; sPNET = 3), fulfilling inclusion criteria at diagnosis, were treated at Gustave Roussy. After conventional chemotherapy, they received two courses of high-dose thiotepa (600 mg/m(2)) followed by craniospinal RT. The median follow-up was 4.4 years (range, 0.8-11.3 years). For children with metastatic MB, the 5-year event-free survival (EFS) and overall survival (OS) were 72% and 83%, respectively. The toxicity was manageable. No toxic death occurred. At the most recent evaluation, among the 24 children who had at least one Full Scale Intellectual Quotient (FSIQ) examination at a median follow-up of 3.79 years after diagnosis, the mean estimated FSIQ was 82 (range, 56-114). In children with metastatic MB, tandem HDCT with ASCT followed by conventional craniospinal RT proved its feasibility without jeopardizing survival.

Autologous stem cell transplantation with busulfan, cyclophosphamide, and etoposide as an intensifying frontline treatment in patients with peripheral T cell lymphomas: a multicenter retrospective trial

The effectiveness of high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) as a frontline treatment in peripheral T cell lymphomas (PTCLs) is still unclear. We retrospectively investigated the clinical outcomes of HDT/ASCT as an intensifying frontline treatment in 31 patients with newly diagnosed PTCLs. The conditioning regimen of HDT/ASCT consisted of busulfan, cyclophosphamide, and etoposide (BuCyE). At diagnosis, five (16.1 %) patients were classified as high risk according to the prognostic index for PTCL (PIT). The disease status of the patients before HDT/ASCT consisted of 23 patients (74.2 %) with complete response (CR) and eight patients (25.8 %) with partial response (PR). Six (75 %) out of eight patients with PR at pretransplantation were improved in terms of the response to CR after HDT/ASCT. At a median follow-up of 32.4 months, the 3-year probability of overall survival (OS) and progression-free survival (PFS) was 64.5 ± 8.6 %. Transplant-related mortality occurred in three patients (9.7 %), due to septic shock, hemorrhage, and delayed pneumonia, respectively. Bone marrow involvement of PTCL at diagnosis was a poor prognostic factor for OS. In conclusion, frontline HDT/ASCT with a conditioning regimen of BuCyE may be an effective and tolerable intensifying therapeutic option to improve outcomes in patients with PTCLs.

Evaluating the Effect of High Dose Chemotherapy and Autologous Bone Marrow Transplantation (ASCT) on Hypertension (HTN) in Multiple Myeloma (MM) Patients

Evaluating the Effect of High Dose Chemotherapy and Autologous Bone Marrow Transplantation (ASCT) on Hypertension (HTN) in Multiple Myeloma (MM) Patients

Effects of high-dose chemotherapy on bone marrow multipotent mesenchymal stromal cells isolated from lymphoma patients

High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation is a widely applied treatment for hematological and autoimmune diseases. Little is known about the effects of this therapy on multipotent mesenchymal stromal cells (MSCs). We aimed to characterize, morphologically and functionally, MSCs isolated from bone marrow aspirates of patients after HDCT. We studied 12 consecutive lymphoma patients submitted to BEAM conditioning regimen followed by autologous stem cell transplantation 28 to 1836 days before the sample collection. Thirteen normal donors were used as control. MSCs were isolated by adherence to plastic and expanded ex vivo by culture in flasks containing alpha-minimum essential medium plus 15% fetal bovine serum. The cell population isolated showed a typical MSC morphology, immunophenotype, and differentiation capacity into adipogenic, osteogenic, and chondrogenic lineages. The MSCs obtained from patients with Hodgkin's disease and non-Hodgkin's lymphoma showed decreased fibroblastoid colony-forming unit count (p = 0.023) and increased doubling time (p = 0.031) related to the control group. The total cell expansion of MSCs from normal subjects was marginally superior to the patient group (p = 0.064). There were no differences in gene expression profile, MSCs plasticity, or hematopoiesis support capability between control and patient group. Results suggest that HDCT applied to lymphoma patients damaged MSCs, which was demonstrated by their reduced clonogenic potential, doubling time, and cell expansion rates when compared to controls.

Prophylactic ciprofloxacin treatment prevented high mortality, and modified systemic and intestinal immune function in tumour-bearing rats receiving dose-intensive CPT-11 chemotherapy

Infectious complications are a major cause of morbidity and mortality from dose-intensive cancer chemotherapy. In spite of the importance of intestinal bacteria translocation in these infections, information about the effect of high-dose chemotherapy on gut mucosal immunity is minimal. We studied prophylactic ciprofloxacin (Cipro) treatment on irinotecan (CPT-11) toxicity and host immunity in rats bearing Ward colon tumour. Cipro abolished chemotherapy-related mortality, which was 45% in animals that were not treated with Cipro. Although Cipro reduced body weight loss and muscle wasting, it was unable to prevent severe late-onset diarrhoea. Seven days after CPT-11, splenocytes were unable to proliferate (stimulation index=0.10±0.02) and produce proliferative and inflammatory cytokines (i.e., Interleukin (IL)-2, interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α) IL-1β, IL-6) on mitogen stimulation in vitro (P<0.05 vs controls), whereas mesenteric lymph node (MLN) cells showed a hyper-proliferative response and a hyper-production of pro-inflammatory cytokines on mitogen stimulation. This suggests compartmentalised effects by CPT-11 chemotherapy on systemic and intestinal immunity. Cipro normalised the hyper-responsiveness of MLN cells, and in the spleen, it partially restored the proliferative response and normalised depressed production of IL-1β and IL-6. Taken together, Cipro prevented infectious challenges associated with immune hypo-responsiveness in systemic immune compartments, and it may also alleviate excessive pro-inflammatory responses mediating local gut injury.

High-dose chemotherapy with autologous stem-cell support versus standard-dose chemotherapy: meta-analysis of individual patient data from 6 randomized metastatic breast cancer trials.

Abstract Abstract #6113 Background: The role of high-dose chemotherapy (HDC) with autologous hematopoietic stem-cell transplantation for metastatic breast cancer has not been well defined. The statistical power of the available trials has limited precision for determining whether HDC has any benefit for this indication, or for any subset of patients.&amp;#x2028; Methods: Individual patient data from the 6 known randomized trials were merged into a single database. The primary endpoint was overall survival (OS): time from randomization to death. The secondary endpoint was progression-free survival (PFS). Cox proportional hazards regression compared the effect of HDC vs standard-dose chemotherapy (SDC) on PFS and OS adjusted for age, trial and hormone receptor (HmR) status (positive if either estrogen (ER) or progesterone (PgR) receptor positive), and other variables. Among the subset analyses considered were by age, HmR status, number metastatic sites, and soft tissue metastases.&amp;#x2028; Results: A total of 846 patients (433 HDC, 413 SDC) had median follow-up of 1.9 years. Median age was 47 years (range 23 to 65). Preliminary analyses show that after adjusting for age and trial, HDC significantly prolonged OS (hazard ratio (HR) 0.86; 95%CI 0.73-1.00; p=0.05) and PFS (HR 0.73; 95%CI 0.63-0.84; p&amp;lt;0.0001). Mean improvement (out to 8 yrs) was 4 months for both OS and PFS. Both age (p=0.023) and soft tissue disease (p=0.0025) had statistically significant interactions with treatment for OS, but neither remain significant after adjusting for multiple comparisons.&amp;#x2028; Conclusions: HDC may have a modest benefit on OS that may be greater in patients younger than 50 years. However, we were not able to draw firm conclusions about age or other subset analyses.&amp;#x2028; &amp;#x2028; Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6113.

Stem cell transplantation in rheumatoid arthritis

The therapeutic potential of high dose cytotoxic therapy and stem cell transplantation (SCT) in severe rheumatoid arthritis (RA) was originally supported by animal studies and serendipitous clinical cases where allogeneic and autologous procedures were shown to ameliorate and potentially cure the disease. Phase I and Phase II clinical studies established the feasibility, safety and efficacy of autologous stem cell mobilisation and transplantation. Although it was clear that the effects of high dose chemotherapy and autologous SCT could safely achieve profound responses, sustained control of disease usually required the reintroduction of disease modifying agents. Responses were improved with dose escalation of the conditioning regimen, and also with post-SCT therapy, such as rituximab, but were not observed with graft manipulation. Phase III studies were attempted, but recruitment was compromised by the increasingly widespread use of biological anti-rheumatic agents. Autologous SCT is now only reasonably considered in relatively rare patients whose disease has resisted conventional and biological treatments, and small numbers of cases continue to be registered with the EBMT. Occasional patients treated with allogeneic and syngeneic SCT continue to stimulate academic interest, particularly as some appear to be cured, but significant logistical and toxicity issues mean that routine and widespread application is unrealistic. In summary, SCT continues to have a limited therapeutic potential in rare patients with RA refractory to modern therapy and sufficient fitness for the procedure. From a scientific perspective, ablation of the dysfunctional rheumatoid immune system and its reconstruction with SCT has provided useful insights into the pathophysiology of RA.

Effects of high-dose chemotherapy (HDCT) and stem cell transplant (SCT) on cardiac function: A prospective study

7106 Background: The effects of HDCT on Cardiac function have not been well defined. In our experience the deleterious effect of HDCT on cardiac function has been overestimated. There is recent evidence that infused peripheral blood progenitor cells have a reparative effect on the myocardium. We prospectively analyzed cardiac function in adult recipients of HDCT and stem cell transplantation before and 100 days after they received HDCT and SCT. Methods: From 1997 to 2004, 109 adult patients received HDCT and SCT. Of these, 34 were male and 51 were female. 55 patients received autologous SCT and 30 patients received allogeneic SCT from HLA matched siblings. Cardiac function was measured by 2D-ECHO two weeks prior to and 100 days post-HDCT and SCT. HDCT was administered according to standard protocols. An ejection fraction [E.F] of greater than 45% was defined as normal. Post-HDCT E.F decrease was defined as reduction of &gt; 10% from baseline. An increase in the EF of greater than 10% from baseline was considered an improvement in cardiac function. Results: 85 patients were evaluable. Median age was 56 years. Auto SCT: Pre-HDCT E.F was normal in 53 auto- SCT and was &lt; 45% in 2 patients. EF declined by 15 and 20% in 2/53 patients (3.7%) who had a normal E.F at baseline. Neither were symptomatic. There was no change in E.F, in patients who had a decreased E.F at baseline. Allogeneic SCT: Pre-HDCT was normal in 29 patients and was &lt; 45% in 1 patient. Post-HDCT E.F remained unchanged in all 29 patients, who had a normal E.F at baseline. The EF improved to normal in the recipient who had a low EF prior to transplant. Conclusions: There was no significant change in cardiac function after HDCT and SCT by 2D-ECHO. The improvement in cardiac function in one of our allogeneic recipients was quite impressive and long lasting and seemed to coincide with engraftment of healthy donor stem cells suggesting that there may be a role for healthy stem cells in improving myocardial dysfunction. No significant financial relationships to disclose.

Pre-Transplant 5-Azacitidine (Vidaza®) May Improve Outcome of Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients with Myelodysplastic Syndrome (MDS).

Most patients with MDS are older than 60 yrs and, because of age, many have previously been excluded from HCT due to the high risk of transplant related mortality. Reduced intensity conditioning has decreased regimen related mortality in HCT and has increased the age of patients for whom this treatment is offered. There remains substantial risk of relapse after HCT especially in patients with > Int-1 MDS who benefit the most from immediate HCT. One strategy to suppress leukemia burden and potentially decrease the risk of relapse is pre-transplant treatment with 5-azacitidine (Vidaza®). This DNA hypomethylating drug is FDA approved for the treatment of MDS. We analyzed the outcome for 34 MDS patients who received a myeloablative HCT from an HLA compatible sibling or unrelated donor from July 2004 through June of 2006, to investigate the potential impact of pre-transplant 5-azacitidine on response and post-transplant relapse. Fourteen of thirty-four patients received a median of 2 (1–7) cycles of 5-azacitidine prior to HCT. Median age was 59 (49 – 69) yrs. Diagnosis and IPSS category included MDS (8) [Int-1 (1) and Int-2 (7)], MDS-AML (5) and CMML (1). Two patients had induction chemotherapy with residual MDS prior to 5-azacitidine. Subsequent to 5-azacitidine: ten responded [CR (2), PR (1) improvement (7)] three progressed and one was not evaluable. The IPSS category after 5-azacitidine treatment and prior to HCT was Int-2(1), Int-1 (4), and Low (5; 3 in CR) in addition to AML (2) and CMML (1). One was unable to assess. The median follow-up in the survivors is 191 (47 – 524) days. Of the fourteen 5-azacitidine treated patients, none have relapsed post-HCT including patients who progressed on 5-azacitidine. Four have died from non-Hodgkins lymphoma (1), DAH (1), adenovirus pneumonia (1) and chronic GVHD (1). Ten are alive in remission, two for greater than one year. Twenty patients did not receive 5-azacitidine. Diagnosis and IPSS category included MDS (9) [Int-1 (3) and Int-2 (6)], MDS-AML (9) and CMML (1) and one not determined due to lack of cytogenetics. Their median age was 53 (33 – 68) yrs. Treatment included supportive care, induction chemotherapy (9) and SCIO-469 (1). IPSS distribution prior to HCT was Int-2 (7), Int-1 (5) Low (5; 4 in CR); in addition to AML (1) and CMML (1). One was unable to assess. The median follow-up in the survivors is 420 (21 – 742) days. Ten of twenty are alive without relapse and eight have relapsed. Five have died, with relapse (3), fungal pneumonia (1) or multi-organ failure (1). The 1 year K-M estimates of overall and progression free survivals are 64% (SEM 15%) and 64% (SEM 15%), respectively for 5-azacitidine group and 70% (SEM 11%) and 51% (SEM 13%) for non-5-azacytidine group. We conclude from this preliminary analysis that pre-HCT conditioning treatment with 5-azacitidine may reduce the risk for MDS relapse after allogeneic transplant in higher risk patients. In addition to its direct anti-tumor effect, 5-azacitidine may sensitize neoplastic cells to the effects of high dose chemotherapy or promote the expression of antigens critical to effective graft-vs-tumor response. This treatment strategy will be evaluated in a prospective trial to investigate the role of pre-transplant 5-azacitidine on transplant outcomes in patients with higher risk MDS.

Final analysis of the phase II, randomized, double-blind, placebo-controlled trial of single dose velafermin (CG53135–05) for the prevention of oral mucositis

6537 Background: Oral mucositis (OM) is a commonly occurring side effect of high-dose chemotherapy (HDCT) in patients (pts) undergoing autologous hematopoietic stem cell transplant (AHSCT). Velafermin, recombinant human fibroblast growth factor 20, is being investigated for prevention of OM. Velafermin promotes epithelial and mesenchymal cell proliferation in vitro and in vivo. Methods: A phase II trial was conducted to evaluate safety, efficacy, and pharmacokinetics (PK) of velafermin. Inclusion criteria: pts undergoing HDCT and AHSCT with or without total body irradiation (TBI) were enrolled. Velafermin at 0.03, 0.1, or 0.2 mg/kg or placebo was administered as single dose IV at 24h after stem cell infusion. Safety and PK were assessed. Pts were scored daily for presence of OM using the WHO grading scale. The primary endpoint was the incidence of Grade 3/4 OM. Results: A total of 212 pts were randomized to either placebo (n=51) or velafermin at 0.03 (n=50), 0.1 (n=56), or 0.2 (n=55) mg/kg (intent-to-treat or ITT sample). 206 pts (97%) received study drug or placebo. Pt diagnoses included multiple myeloma (57%), non-Hodgkin’s (25%), or Hodgkin’s (11%) lymphoma and 13 pts (6%) received TBI as part of the conditioning regimen. The Grade 3/4 OM incidence rates (%) in the placebo or velafermin arms (0.03, 0.1, and 0.2 mg/kg) were 37, 18, 38, and 36, respectively. The primary analysis of dose dependent reduction of severe OM was not statistically significant (p = 0.549). However, velafermin at 0.03 mg/kg did reduce the incidence of Grade 3/4 OM when compared to placebo alone (p = 0.031). Duration of Grade 3/4 OM was reduced significantly in the 0.03 mg/kg when every pt was evaluated or in the 0.1 mg/kg dose when only pts with Grade 3/4 OM were included in the analysis (p = 0.037 and 0.014, respectively). A total of 5 related SAEs (3 in 0.1 mg/kg, 1 in 0.03 mg/kg, and 1 in placebo cohort) occurred within 4hr of study drug infusion. All symptoms were transient. Conclusion: Single dose velafermin at 0.03mg/kg is may be active in reducing CT induced severe OM in AHSCT pts. Safety profile supports continuing study to define the optimal dose for prevention of severe OM. A new Phase II study will be conducted to confirm velafermin activity at 0.03mg/kg dose. [Table: see text]

Vaccinating transplant recipients

Immunity is partly destroyed by the effects of high-dose chemotherapy associated with hematopoietic stem cell transplantation. A new strategy restores impaired immunity in people and offers clues to improving vaccination against pathogens and tumors ( pages 1230–1237 ).

High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer

There is a hypothesis that high dose chemotherapy with autologous bone marrow or peripheral stem cell transplantation (autograft) may improve survival for women with metastatic breast cancer. To compare the effectiveness of high dose chemotherapy and autologous bone marrow or stem cell transplantation with conventional chemotherapy for women with metastatic breast cancer. We used the Cochrane Breast Cancer Group search strategy, adding these terms: bone marrow transplantation, stem cell transplantation, autologous stem cell support. The following databases were searched: MEDLINE (until November 2004), EMBASE (until November 2004), ASCO (American Society of Clinical Oncology) (1995-2004) and the COCHRANE LIBRARY (Issue 4 2004). We searched the Cochrane Breast Cancer Group database and cooperative research groups' websites for unpublished trials. Randomised controlled trials comparing the effectiveness of high dose chemotherapy and autograft with conventional chemotherapy for women with metastatic breast cancer. Studies included one or more of the following outcomes: treatment related mortality, overall or progression-free survival at 1, 2, 3, 5 or 7 years, morbidity, quality of life measures, time to tumour progression, overall survival time. Six randomised controlled trials met the inclusion criteria. Two independent reviewers extracted data. In total 438 eligible women were randomised to receive high dose chemotherapy with autograft and 412 were randomised to receive conventional treatment. There were fifteen treatment-related deaths among the high dose group and two in the control (conventional dose) group (RR 4.07 (95% CI 1.39, 11.88)). There was no statistically significant difference in overall survival between the high dose and control groups at one year, three years or five years. At one and five years of follow up, there was a statistically significant difference in event-free survival, favouring the high dose group (one year: RR 1.76 (95% CI 1.40, 2.21); five years: RR 2.84 (95% CI 1.07, 7.50). Toxicity was more severe in the high dose group. Only one of the trials has followed up all women for five years and further data are awaited. Although there is statistically significant evidence that high dose chemotherapy and autograft improves event free survival compared to conventional chemotherapy, there is no statistically significant evidence of benefit in overall survival for women with metastatic breast cancer. High dose chemotherapy with bone marrow or stem cell transplantation should not be given to women with metastatic breast cancer outside of clinical trials.

High dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer.

There is a hypothesis that high dose chemotherapy with autologous bone marrow or stem cell transplantation (autograft) may improve survival for women with metastatic breast cancer. To compare the effectiveness of high dose chemotherapy and autologous bone marrow or stem cell transplantation with conventional chemotherapy for women with metastatic breast cancer. We used the Cochrane Breast Cancer Group search strategy, adding these terms: bone marrow transplantation, stem cell transplantation, autologous stem cell support. The following databases were searched: MEDLINE (until August 2002), EMBASE (until July 2002), ASCO (American Society of Clinical Oncology) (1995-2002) and the COCHRANE LIBRARY (Issue 3 2002). We searched the Cochrane Breast Cancer Group database and cooperative research groups' websites for unpublished trials. Randomised controlled trials comparing the effectiveness of high dose chemotherapy and autograft with conventional chemotherapy for women with metastatic breast cancer. Studies included one or more of the following outcomes: treatment related mortality, overall or progression-free survival at 1, 2, 3, 5 or 7 years, morbidity, quality of life measures, time to tumour progression, overall survival time. Five randomised controlled trials met the inclusion criteria. Two independent reviewers extracted data. In total 382 women were randomised to receive high dose chemotherapy with autograft and 358 were randomised to receive conventional treatment. There were ten treatment related deaths among the high dose group and none reported in the control (conventional dose) group (RR 5.70, 95%CI (1.30, 25)). There was no statistically significant difference in overall survival between the high dose and control groups (at one year: RR 0.99, 95% CI (0.91, 1.08); three years: RR 1.16 95% CI (0.90, 1.51); five years: RR 1.28, 95% CI (0.72, 2.27)). At one and two years of follow up, a statistically significant difference in progression free survival was reported, favouring the high dose group (one year: RR 1.81, 95% CI (1.39,2.34); two years: RR 1.96, 95% CI (1.32, 2.90 ). However this difference was not evident at three or five years (three years: RR 1.44, 95% CI (0.85, 2.44); five years: RR 1.21, 95% CI (0.40, 3.69). Toxicity was more severe in the high dose group. None of the trials has completed follow up and further data are awaited. Although there is evidence that high dose chemotherapy and autograft improves progression free survival at one and two years' follow up compared to conventional chemotherapy, there is no evidence of benefit in overall survival.

Chemotherapy-induced immunosuppression and reconstitution of immune function

In the cancer patient, there are a variety of factors that favor the suppression of the immune system, including the cancer itself (especially, malignancies of B and T lymphocytes), high dose chemotherapeutic agents, and corticosteroids. In addition, by its very nature, the myeloablative conditioning regimen used for stem-cell transplantation is immunosuppressive. It is important that immune function is restored so that the patient can resist infection, but it may be equally important to reconstitute immunity due to the potential added benefit of an anti-leukemic response. It is the intent of this commentary/review to discuss the effects of chemotherapy on selected immune cell populations and approaches to reconstitute immune function following chemotherapy. In this issue, Slater et al. [1] illustrate the double-edged sword of high dose chemotherapy. Their laboratory investigations demonstrate the cytotoxic efficacy, yet immunosuppressive effects, of high dose topoisomerase II inhibitor VP-16. As a result, treating L1210 tumor-bearing mice with 20 mg/kg VP-16 resulted in a relatively high 60 days survival rate, however, cured mice could not resist a L1210 tumor challenge. In contrast, when tumor-bearing mice were treated with 3 or 5 mg/kg VP-16, correspondingly fewer mice survived, but most survivors were able to reject a tumor challenge. Mitogenic assays revealed a suppressed proliferation potential of splenic lymphocytes treated with the higher dose of VP-16. These investigations exemplify the opposing effects of high dose chemotherapy, i.e. tumor cytotoxic efficacy coupled with immunosuppression. In discussing the effects of chemotherapy on immune function, it is important to differentiate between the terms immunosuppression and myelosuppression [2]. Many chemotherapeutic agents are myelosuppressive in that they inhibit bone marrow production of blood cells and platelets

悪性骨軟部腫よう初診時Ｍ１症例の治療成績 末梢血幹細胞移植による予後改善の可能性

Although the overall treatment of osteosarcoma, Ewing’s sarcoma and rhabdomyosarcoma has improved, patients with metastases (M1) at diagnosis continue to have poor prognoses. The effects of high-dose chemotherapy and autologous peripheral blood stem cell transplantation (PBSCT) on sarcoma patients at M1 have been reported. Here we assess the results of treatment for 22 M1 patients including osteosarcoma (7), Ewing’s sarcoma (10) and rhabdomyosarcoma (5). Original locations were 12 bony lesions and 10 soft tissues. All patients were treated with systemic chemotherapy; five patients (Ewing’s sarcoma, 3; rhabdomyosarcoma, 2) were treated using high-dose chemotherapy with PBSCT. Most patients were also treated with radiation and/or surgery. The results were DOD 18, CDF 3 and AWD 1. The mean survival time for DOD patients was 14.8 months. All surviving patients were treated using high-dose chemotherapy with PBSCT. None of the patients who received conventional chemotherapy survived. The poor prognoses of M1 sarcoma patients might be improved by high-dose chemotherapy with PBSCT, however, true prognostic value of the treatment should be evaluated by prospective randomized studies.