Benefit Of High-dose Chemotherapy Research Articles

Stem-Cell Therapy Following High-Dose Chemotherapy in Advanced Retinoblastoma: A Systematic Review.

To analyze the risk and benefit of high-dose chemotherapy followed by stem cell transplantation (HDCT-SCT) treatment in patients with advanced retinoblastoma. Systematic review. A comprehensive literature search from 4 online databases, including PubMed, Scopus, EBSCO, and Cochrane was done for original studies evaluating the use of HDCT followed by SCT in the treatment of patients with advanced retinoblastoma. The last search was performed on April 15, 2020. A total of 35 studies consisting of 160 patients were considered suitable for inclusion. After HDCT-SCT treatment, 108/160 (67.5%) patients were alive with no evidence of disease at the last follow-up. The incidence of secondary malignancy in our data was also relatively low, which was 16/160 (10%) patients. The side effects were mainly hematological and gastrointestinal toxicities. The prognosis for metastatic cases especially the one to the central nervous system (CNS) remains poor, as shown in our data that 22 of 44 (50%) patients died due to the evidence of disease, and 12 of 44 (27%) patients acquired CNS relapse and died. HDCT-SCT is a promising treatment option in patients with advanced retinoblastoma. The use of HDCT-SCT in CNS metastases needs to be carefully considered, possibly by adding thiotepa or topotecan to improve tumor control. Further randomized clinical trials are needed to draw firm conclusion regarding its safety and efficacy.

BRCAness digitalMLPA profiling predicts benefit of intensified platinum-based chemotherapy in triple-negative and luminal-type breast cancer

BackgroundWe previously showed that BRCA-like profiles can be used to preselect individuals with the highest risk of carrying BRCA mutations but could also indicate which patients would benefit from double-strand break inducing chemotherapy. A simple, robust, and reliable assay for clinical use that utilizes limited amounts of formalin-fixed, paraffin-embedded tumor tissue to assess BRCAness status in both ER-positive and ER-negative breast cancer (BC) is currently lacking.MethodsA digital multiplex ligation-dependent probe amplification (digitalMLPA) assay was designed to detect copy number alterations required for the classification of BRCA1-like and BRCA2-like BC. The BRCA1-like classifier was trained on 71 tumors, enriched for triple-negative BC; the BRCA2-like classifier was trained on 55 tumors, enriched for luminal-type BC. A shrunken centroid-based classifier was developed and applied on an independent validation cohort. A total of 114 cases of a randomized controlled trial were analyzed, and the association of the classifier result with intensified platinum-based chemotherapy response was assessed.ResultsThe digitalMLPA BRCA1-like classifier correctly classified 91% of the BRCA1-like samples and 82% of the BRCA2-like samples. Patients with a BRCA-like tumor derived significant benefit of high-dose chemotherapy (adjusted hazard ratio (HR) 0.12, 95% CI 0.04–0.44) which was not observed in non-BRCA-like patients (HR 0.9, 95% CI 0.37–2.18) (p = 0.01). Analysis stratified for ER status showed borderline significance.ConclusionsThe digitalMLPA is a reliable method to detect a BRCA1- and BRCA2-like pattern on clinical samples and predicts platinum-based chemotherapy benefit in both triple-negative and luminal-type BC.

Dose Adjusted R-EPOCH Does Not Improve Outcomes in High Grade B Cell Lymphoma with Double Expressor Status or Gain of MYC/BCL2

Introduction: Diffuse large B cell lymphoma is a heterogenous disease with prognosis known to vary based on histological changes including immunohistochemistry and gene rearrangements by florescence in situ hybridisation (FISH). Both immunohistochemical overexpression as well as gene rearrangements in MYC, BCL2 and BCL6 are thought to contribute to poor prognosis. The benefit of high dose chemotherapy is unclear for those with high grade B cell lymphoma with double hit status (DHL) by FISH , double expressor status (DEL) or gain of MYC/BCL2. The purpose of this study was to retrospectively analyse the effect of escalated chemotherapy in this population over a 5 year period. Methods: All patients with DLBCL treated between 2012-2017 were screened retrospectively for inclusion in the study based on immunohistochemistry and FISH at time of initial diagnosis. Immunohistochemistry was assessed on formalin fixed, paraffin embedded specimens with BCL2 and MYC considered positive at over 40% and 50% respectively. FISH was assessed using dual colour break apart probe. Results: 135 patients were diagnosed with DLBCL of which 53 patients had immunohistochemistry and FISH at diagnosis confirming either, DEL or gain of MYC/BCL2 status. The mean age was 65 years and median follow up 21 months. The overall response rate in DH treated with DA-R-EPOCH was 57%. There were insufficient cases treated with R-CHOP for comparison. Overall response rates in DEL were 94% for DA-R-EPOCH and 93% for R-CHOP. Overall survival (OS) and disease free survival (DFS) in DHL was 6 months and 2 months respectively when treated with DA-R-EPOCH. There was no significant difference in OS or DFS in DEL treated with DA-R-EPOCH compared with R-CHOP (OS: 42 months vs 38 months respectively (p=0.962), DFS 36 months vs 30 months (p=0.931)). Gain of MYC/BCL2 did not affect OS (p= 0.539) or DFS (p=0.439) when comparing treatment regimen. Conclusion: DA-R-EPOCH did not improve treatment response rates OS or DFS in patients with double expresser lymphoma or gain of MYC/BCL2. This study also confirms the previously reported poor outcomes associated with DHL Disclosures No relevant conflicts of interest to declare.

Autologous stem cell transplantation: is it still relevant in breast cancer?

447 ISSN 1758-1923 10.2217/BMT.13.56 © 2013 Future Medicine Ltd Breast Cancer Manage. (2013) 2(6), 447–450 The journey to personalized breast cancer (BC) care, based on molecular tumor characteristics, is still long in the majority of patients as cytotoxic chemotherapy (CT) remains a pivotal therapeutic approach in operable and advanced disease. The clinical correlation between dose-intensity of CT, that can be achieved by either increasing the single dose per cycle (i.e., higher dose) or by reducing the intervals between cycles (i.e., dose density), and outcome in BC has been described since the eighties [1], leading to the premature acceptance of high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) as a treatment option both in the adjuvant setting and for metastatic disease, with thousands of patients per year undergoing this procedure in the mid-1990s in Europe and North America [2]. Unfortunately, the vast majority of patients were treated outside prospective randomized studies. At the turn of the century, in view of early reports of randomized trials not showing a significant overall survival (OS) benefit of HDC in the adjuvant and metastatic settings [3], this procedure was no longer considered an option for the vast majority of medical oncologists. In the era of great expectations for targeted drugs, data from randomized studies demonstrating an OS benefit by HDC for high-risk breast cancer (HRBC) [4,5], along with additional evidence of the benefit of intensified CT [6], did not change this attitude. This article is aimed to clarify what happened over the years in this controversial field and whether today HDC with ASCT can be proposed in patients with BC.

Primary systemic chemotherapy for inflammatory breast cancer

The advent of multimodality therapy for patients with inflammatory breast cancer (IBC), consisting of neoadjuvant chemotherapy, particularly taxanes, surgery, radiotherapy, and hormonal therapy, has improved survival. A pathologic complete response to neoadjuvant chemotherapy in locally advanced breast cancer and IBC improves outcomes, which suggests that obtaining a pathologic complete response to neoadjuvant chemotherapy has prognostic significance. The benefit of high-dose chemotherapy has shown encouraging results; however, this approach needs to be prospectively evaluated and to date remains experimental. Vascular endothelial growth factor, a promoter of angiogenesis, is highly expressed in IBC, making the angiogenesis pathway an attractive therapeutic target. A better understanding of the complex biology of IBC is needed for the development of additional targeted agents to further improve outcomes for patients with this aggressive form of breast cancer.

High-Dose Chemotherapy for Patients With High-Risk Breast Cancer

The benefit of high-dose chemotherapy (HDC) has not been clearly demonstrated. It may offer disease-free survival improvement at the expense of major toxicity and increasing cost. We evaluated the trade-offs between toxicity, relapse, and costs using a quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis. The analysis was conducted in the context of a randomized trial (PEGASE 01) evaluating the benefit of HDC for 314 patients with high-risk breast cancer. A Q-TWiST analysis was first performed to compare HDC with standard chemotherapy. We then used the results of this Q-TWiST analysis to inform a cost per quality-adjusted life-year (QALY) comparison between treatments. Q-TWiST durations were in favor of HDC, whatever the weighting coefficients used for the analysis. This benefit was significant when the weighting coefficient related to the time spent after relapse was low (<0.38). For quite high values of this coefficient (>0.78), HDC offered no benefit. For intermediate values, the results depended on the weighting coefficient attributed to the toxicity period. The incremental cost per QALY ranged from 12,691euro/QALY to 26,439euro/QALY, according to the coefficients used to weight toxicity and relapse. The benefits of HDC outweigh the burdens of treatment for a wide range of utility coefficients. Economic impact is not a barrier to HDC diffusion in this situation. Nevertheless, no significant benefit was demonstrated for a certain range of utility values.

High-dose chemotherapy with autologous stem cell transplantation in the first line treatment of aggressive Non-Hodgkin Lymphoma (NHL) in adults

High-dose chemotherapy with autologous stem cell support (HDT) has been proven effective in relapsed aggressive non-Hodgkin lymphoma (NHL). However, conflicting results of HDT as part of first-line treatment have been reported in randomised controlled trials (RCTs). We undertook a systematic review and meta-analysis to assess the effects of such treatment. To determine whether high-dose chemotherapy with autologous stem cell transplantation as part of first-line treatment improves survival in patients with aggressive non-Hodgkin lymphoma. MEDLINE, EMBASE, Cancer Lit, the Cochrane Library and smaller databases, Internet-databases of ongoing trials, conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology were searched. We included full-text, abstract publications and unpublished data. Randomised controlled trials comparing conventional chemotherapy versus high-dose chemotherapy in the first-line treatment of adults with aggressive non-Hodgkin lymphoma were included in this review. Eligibility and quality assessment, data extraction and analysis were done in duplicate. All authors were contacted to obtain missing data and asked to provide individual patient data. Fifteen RCTs including 3079 patients were eligible for this meta-analysis. Overall treatment-related mortality was 6.0% in the HDT group and not significantly different compared to conventional chemotherapy (OR 1.33 [95% CI 0.91 to 1.93], P=0.14). 13 studies including 2018 patients showed significantly higher CR rates in the group receiving HDT (OR 1.32, [95% CI 1.09 to 1.59], P=0.004). However, HDT did not have an effect on OS, when compared to conventional chemotherapy. The pooled HR was 1.04 ([95% CI 0.91 to 1.18], P=0.58). There was no statistical heterogeneity among the trials. Sensitivity analyses underlined the robustness of these results. Subgroup analysis of prognostic groups according to IPI did not show any survival difference between HDT and controls in 12 trials (low and low-intermediate risk IPI: HR 1.41[95% CI 0.95 to 2.10], P=0.09; high-intermediate and high risk IPI: HR 0.97 [95% CI 0.83 to 1.13], P=0.71. Event-free survival (EFS) also showed no significant difference between HDT and CT (HR 0.93, [95% CI 0.81 to 1.07], P=0.31). Other possible risk factors such as the proportion of patient with diffuse large cell lymphoma, protocol adherence, HDT strategy, response status before HDT, conditioning regimens and methodological issues were analysed in sensitivity analyses. However, there was no evidence for an association between these factors and the results of our analyses. . Despite higher CR rates, there is no benefit for high-dose chemotherapy with stem cell transplantation as a first line treatment in patients with aggressive NHL.

Are metastatic testicular tumors curable with high-dose chemotherapy and stem-cell rescue?

Although cisplatin-based chemotherapy cures approximately 80% of patientswith newly diagnosed metastatic germ-cell tumours, the outcome in those failing initial chemotherapy is much less favourable and dependent on certainwell-defined clinical factors. Primary salvage options in patients who do not respond to firstline chemotherapy include conventionaldose cisplatin-based regimens, while high-dose chemotherapy (HDCT)with haematopoietic stem cell rescue has been actively investigated in the last two decades, with controversial results. Einhorn and colleagues have retrospectively analysed their experience of tandem HDCT with carboplatin and etoposide in a large series of consecutive men with metastatic testicular cancer that had progressed after receiving cisplatin-containing combination chemotherapy. This study shows 70%and 50% four-year disease-free survival in patients who received HDCT as second-line or third-line or later therapy, respectively.As it is a retrospective review, one may argue that the results are biased by patient selection. This does not seem to be the case, however, as even patients with very poor prognosis achieved longterm disease-free survival – 50% of survivors were classified high-risk by the International Germ Cell Cancer CollaborativeGroup classification and45% had platinum-refractory disease. It is important to note that all patients in this series receivedperipheral-bloodprogenitors as sources of haematopoietic stem cells. This strategy allowed a rapid engraftment, thereby permitting the administration of two courses of highdose carboplatin plus etoposide with planned delays at three-week intervals and acceptable toxicity. In addition, peripheral-blood progenitors were enriched for CD34+ haematopoietic cells, a procedure which may have a role in eliminating possible cancer cells from the graft. The source of stem cells and their ex vivomanipulationmaywell have contributed to the positive results of the study, although there are no evidence-based data to support this hypothesis at present. Results provided by Einhorn et al. are apparently in contradiction with data from two recently published randomised trials that fail to demonstrate a benefit of HDCT over conventional chemotherapy in patients with a poor prognosis, albeit in earlier phases of the disease. Both studies, designed in the early 1990s during an era of great expectations for HDCT, were planned to detect an overoptimistic improvement of event-free survival. The use of bonemarrow stem cells in some patients has resulted in high transplant-relatedmor-

High-dose chemotherapy and autologous peripheral blood stem cell transplantation in adult patients with high-risk or advanced Ewing and soft tissue sarcoma

Despite the availability of combined-modality treatment for Ewing sarcoma (ES) and soft tissue sarcomas (STS), results from independent groups still indicate a poor prognosis for high-risk and metastasized patients. The benefit of high-dose chemotherapy (HDCT) with autologous peripheral blood stem cell transplantation (ASCT) as compared to standard treatment is not defined. Here, we report of HDCT in 35 consecutive adult patients with poor-risk ES or rhabdomyosarcoma (n = 11) and STS (n = 24) undergoing ASCT between July 1992 and March 2003. At a median follow-up of 100.6 months after ASCT, 11 patients are alive, with nine in sustained complete remission (CR) and each one in partial remission (PR) and stable disease. Median overall survival (OS) from ASCT was 17.1 months. Response to pretreatment, Karnofsky index > 80%, R (0) resection and first-line ASCT were associated with long-term OS (p < 0.05). These data indicate that (1) patients achieving a CR or PR following induction, with preserved performance status and R (0) resection may benefit from ASCT and (2) that this can be an useful therapeutic modality in a subset of patients, in some achieving remarkable responses.

High-dose chemotherapy of cyclophosphamide, thiotepa, and carboplatin (CTCb) followed by autologous stem-cell transplantation for metastatic breast cancer patients: a 6-year follow-up result.

The benefit of high-dose chemotherapy (HDC) for metastatic breast cancer (MBC) is controversial. We evaluated the efficacy and safety of HDC with cyclophosphamide, thiotepa, and carboplatin (CTCb) followed by autologous stem-cell transplantation (ASCT) for MBC patients. From September 1994 to December 1999, 23 MBC patients were enrolled. All the patients received 2 to 10 cycles of induction chemotherapy. Before transplantation, 12 patients were in complete response (CR), nine were in partial response (PR), and two had progressive disease (PD). The HDC regimen consisted of cyclophosphamide 1,500 mg/m(2)/day, thiotepa 125 mg/m(2)/day and carboplatin 200 mg/m(2)/day intravenously for 4 consecutive days. After ASCT, 13 patients (56%) had a CR, five (22%) had a PR, three (13%) had no change, while two (9%) showed a PD. Seventeen patients relapsed or progressed during the median follow-up of 78 months. The median progression-free survival (PFS) time was 11 months and the median overall survival (OS) time was 23 months. The 5-year PFS and OS rates were 22% and 25%, respectively. On the multivariate analyses, less than 4 involved lymph nodes was predictive of a better PFS and OS. HDC with CTCb for MBC has acceptable toxicity; however, this treatment does not show a survival benefit.

Benefit of high-dose chemotherapy for small cell lung cancer (SCLC): An unsettled issue

Benefit of high-dose chemotherapy for small cell lung cancer (SCLC): An unsettled issue

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

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

Do we need a new strategy to treat metastatic breast cancer?

Four large randomized studies reported at the recent American Society for Clinical Oncology (ASCO) meeting have raised questions concerning the benefit of high-dose chemotherapy with hematopoietic progenitor cell support for the treatment of patients with high-risk primary breast cancer or metastatic disease. The preliminary nature of these findings was stressed by several investigators, who noted that long-term follow-up would be required to determine whether any survival benefit exists for patients in the highdose group. These results illustrate the need for additional well-controlled clinical trials before such strategies could become standard practice. Furthermore, it appears that even if any advantage is observed for high-dose treatment with stem cell support, this treatment is unlikely to result in a major survival benefit.

Studies suggest high-dose therapy for breast cancer has no advantage

The eagerly awaited results of 4 large-scale trials of high-dose chemotherapy in the treatment of breast cancer were discussed at a plenary session at the 35th Annual Meeting of the American Society of Clinical Oncology [Atlanta, US; May 1999]. The results had been released, somewhat controversially, one month prior to the conference to curb circulation of inaccurate information.*Results from 3 of the 4 trials do not support a benefit of high-dose chemotherapy, while the remaining trial noted significant benefits. All 4 trials were designed and analysed differently, making any comparisons or a meta-analysis difficult.