Insights in primary central nervous system lymphoma: a role for glymphatics?

Brain Tumor Pathology -     

Radiotherapy followed by adjuvant temozolomide with or without neoadjuvant ACNU-CDDP chemotherapy in newly diagnosed glioblastomas: a prospective randomized controlled multicenter phase?III trial

A prospective randomized controlled multicenter phase III trial was conducted to evaluate the effects of neoadjuvant chemotherapy with nimustine (ACNU)-cisplatin (CDDP) when used in conjunction with radiotherapy plus adjuvant temozolomide in patients with newly diagnosed glioblastoma. The study population was randomly assigned into one treatment and one control group. Both groups received radiotherapy followed by six cycles of adjuvant oral temozolomide (150-200 mg/m(2)) for 5 days every 28 days after surgery. Prior to radiotherapy, the treatment group also received two cycles, 6 weeks apart, of neoadjuvant chemotherapy with ACNU (40 mg/m(2)/day) and CDDP (40 mg/m(2)/day) infused continuously for 72 h. The primary end-point was median survival time. The study has closed after interim analysis with a total of 82 patients (48.8% of target number) due to unacceptable high frequency of toxicity profiles in spite of the promising actuarial survival outcome. Median survival time was 28.4 months [90% confidence interval (CI), 21.1 months to not available] in the treatment group and 18.9 months (90% CI, 17.1-27.4 months) in the control group (P = 0.2). The 2-year survival rate and progression-free survival time were 50.9% and 6.6 months (90% CI, 3.5-9.5 months) in the treatment group and 27.8% and 5.1 months (90% CI, 3.8-8.8 months) in the control group. Grade 3 or 4 toxicity was documented in 26 (68.4%) patients in the treatment group, including three neutropenic fever and one death from sepsis, while grade 3 or 4 toxicity occurred in 6 patients (15.8%) in the control group. The high frequency of serious hematological toxicity with ACNU-CDDP neoadjuvant chemotherapy followed by radiotherapy and adjuvant temozolomide limits its usage as primary treatment for glioblastoma. Future studies should aim to identify a subpopulation at reduced risk for ACNU-CDDP toxicity so that the potential of this protocol can be realized.     

Benefits of interferon-β and temozolomide combination therapy for newly diagnosed primary glioblastoma with the unmethylated MGMT promoter: A multicenter study

BACKGROUND:

The aim of the current study was to catalog genomic and epigenomic abnormalities in newly diagnosed glioblastoma patients and determine the correlation among clinical, genetic, and epigenetic profiles and clinical outcome.

METHODS:

This study retrospectively included 68 consecutive patients who underwent surgical treatment and received standard radiotherapy with temozolomide (TMZ)‐based chemotherapy. Of a total of 68 patients, 39 patients (57.4%) received interferon (IFN)‐β in combination of TMZ.

RESULTS:

The genetic and epigenetic alterations frequently observed were EGFR amplification (51.5%), TP53 mutation (33.8%), CDKN2A loss (32.4%), TP53 loss (16.2%), methylation of the MGMT promoter (33.8%) and IDH1 mutation (5.9%). Multivariate analysis revealed that methylated MGMT promoter and the combination of TMZ and IFN‐β were independent prognostic factors associated with survival. The median survival time (MST) of the patients who received the combination of IFN‐β and TMZ was significantly greater with 19.9 months as compared to the TMZ alone group (12.7 months). Notably, in even patients whose tumors had unmethylated MGMT promoter, the MST prolonged to 17.2 months when receiving TMZ with IFN‐β, compared to 12.5 months in those receiving TMZ without IFN‐β.

CONCLUSIONS:

Taken together, addition of IFN‐β for newly diagnosed primary GBM achieved a favorable outcome, particularly in patients with unmethylated MGMT promoter. Cancer 2011. © 2010 American Cancer Society.     

Phase Ⅱ study of induction chemotherapy followed by concurrent chemoradiotherapy with raltitrexed and cisplatin in locally advanced nasopharyngeal carcinoma

Objective: For locally advanced nasopharyngeal carcinoma(LA-NPC) patients, high incidences of distant metastases and severe treatment related toxicities are the main obstacles needed to be overcome. Raltitrexed, a specific thymidylate synthase inhibitor with a convenient administration schedule, has an acceptable and manageable toxicity, and possesses radio-sensitizing properties. To investigate the efficacy and safety of raltitrexed and cisplatin induction chemotherapy and concurrent chemoradio...     

Consolidation regimens in primary central nervous system lymphoma: a single-center retrospective cohort evaluating survival outcomes and cost–benefit analysis

Journal of Neuro-Oncology - Optimal treatment for primary central nervous system lymphoma (PCNSL) comprises polychemotherapy induction with high-dose methotrexate followed by consolidation therapy,...     

Phase II trial of sunitinib as adjuvant therapy after stereotactic radiosurgery in patients with 1–3 newly diagnosed brain metastases

Journal of Neuro-Oncology - Patients with 1–3 brain metastases (BM) often receive sterotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT). SRS without WBRT carries a high rate...     

JCOG0911 INTEGRA study: a randomized screening phase II trial of interferonβ plus temozolomide in comparison with temozolomide alone for newly diagnosed glioblastoma

Purpose

This study explored the superiority of temozolomide (TMZ)?+?interferonβ (IFNβ) to standard TMZ as treatment for newly diagnosed glioblastoma (GBM) via randomized phase II screening design.

Experimental design

Eligibility criteria included histologically proven GBM, with 50% of the tumor located in supratentorial areas, without involvement of the optic, olfactory nerves, and pituitary gland and without multiple lesions and dissemination. Patients in the TMZ?+?radiotherapy (RT) arm received RT (2.0 Gy/fr/day, 30 fr) with TMZ (75 mg/m², daily) followed by TMZ maintenance (100–200 mg/m²/day, days 1–5, every 4 weeks) for 2 years. Patients in the TMZ?+?IFNβ?+?RT arm intravenously received IFNβ (3 MU/body, alternative days during RT and day 1, every 4 weeks during maintenance period) and TMZ?+?RT. The primary endpoint was overall survival (OS). The planned sample size was 120 (one-sided alpha 0.2; power 0.8).

Results

Between Apr 2010 and Jan 2012, 122 patients were randomized. The median OS with TMZ?+?RT and TMZ?+?IFNβ?+?RT was 20.3 and 24.0 months (HR 1.00, 95% CI 0.65–1.55; one-sided log rank P?=?0.51). The median progression-free survival times were 10.1 and 8.5 months (HR 1.25, 95% CI 0.85–1.84). The incidence of neutropenia with the TMZ?+?RT and the TMZ?+?IFNβ?+?RT (grade 3–4, CTCAE version 3.0) was 12.7 versus 20.7% during concomitant period and was 3.6 versus 9.3% during maintenance period. The incidence of lymphopenia was 54.0 versus 63.8% and 34.5 versus 41.9%.

Conclusions

TMZ?+?IFNβ?+?RT is not considered as a candidate for the following phase III trial, and TMZ?+?RT remained to be a most promising treatment. This trial was registered with the UMIN Clinical Trials Registry: UMIN000003466.

     

Incidence of hand–foot syndrome with capecitabine in combination with chemotherapy as first-line treatment in patients with advanced and/or metastatic gastric cancer suitable for treatment with a fluoropyrimidine-based regimen

Introduction

Hand?Cfoot syndrome (HFS) is a limiting toxicity of capecitabine, which is not life-threatening but could compromise capecitabine efficacy.

Materials and methods

This phase II, multicenter, non-controlled study assessed the safety, particularly grade three HFS incidence, and efficacy of four capecitabine-based chemotherapy regimens [cisplatin/capecitabine (CX), epirubicin/cisplatin/capecitabine (ECX), epirubicin/oxaliplatin/capecitabine (EOX) and docetaxel/cisplatin/capecitabine (DCX)] as first-line treatment for advanced and/or metastatic gastric cancer.

Results

One hundred and eight patients were assigned to one of the four treatment groups, according to investigator??s criteria, and grouped together for both safety and efficacy primary analyses. HFS was reported in 31 patients (19.6?%) and its first presentation occurred at a median of 72?days (range 19?C209?days). Grade 3 HFS developed in 6.3, 5.2, 3.7 and 2.4?%, of patients receiving ECX, DCX, EOX or CX chemotherapy regimen, respectively. Capecitabine dose reduction/discontinuation due to HFS was required in 5.7?% of patients (9/158). The most common (>10?%) grade 3?C4 treatment-related AEs were neutropenia (15.2?%), asthenia (12.0?%) and diarrhoea (11.4?%).

Conclusions

A moderate incidence of HFS was reported in patients treated with capecitabine, which generally presented late and required dose reduction in <1/3 of patients. The results suggest that capecitabine may be useful in combination with standard fluorouracil-based regimens in patients with advanced and/or metastatic gastric cancer with favourable safety profile.     

R-FPD方案治疗初治原发中枢神经系统淋巴瘤的前瞻性研究

目的:评估利妥昔单抗联合福莫司汀、培美曲塞、地塞米松方案(R-FPD)治疗原发中枢神经系统淋巴瘤(primary central nervous system lymphoma,PCNSL)的安全性、有效性和可行性,初步探索生物标志物在PCNSL治疗中的意义。方法:本研究为前瞻性、单中心、单臂Ⅱ期临床试验。分析2018年7月至2019年7月郑州大学第一附属医院确诊的初治PCNSL患者。全组患者均接受R-FPD方案一线化疗。主要研究终点为客观缓解率(objective response rate,ORR),疾病控制率(disease control rate,DCR),无进展生存期(progression free survival,PFS),总生存期(overall survival,OS)。次要研究终点为不良反应(adverse reaction,ADR)。结果:共12例患者纳入此研究,4个周期治疗后疗效评估为完全缓解(complete response,CR)6例,部分缓解(partial response,PR)2例,疾病稳定(stable disease,SD)1例,疾病进展(...     

原发中枢神经系统淋巴瘤诊疗进展

原发中枢神经系统淋巴瘤是一种少见的中枢神经系统恶性肿瘤,以大剂量甲氨蝶呤为基础方案诱导化疗是目前一线治疗,随后全脑放疗作为巩固治疗.迟发神经认知功能障碍出现,尤其是老年人,使缓解患者是否需要全脑放疗或减量放疗需要进一步明确.利妥昔单抗治疗PCNSL,初步研究表明美罗华可能给患者带来获益,但研究证据水平较低.HDC/ASCT对于治疗复发性或难治性PCNSL虽有疗效但毒副作用较大,临床价值尚存争议.     

Prolonged remission of primary central nervous system lymphoma after discontinuation of steroid therapy

Summary The case of a 63-year old man is presented in whom remission of a primary central nervous system lymphoma was achieved by corticosteroids only. After discontinuation of steroid therapy the remission persisted for two and a half years. Recurrences appeared at other sites of the brain, and were steroid resistant.     

Combined modality therapy versus chemotherapy alone as an induction regimen for primary central nervous system lymphoma: a cost-effectiveness analysis

Background

In immunocompetent patients with primary central nervous system lymphoma (PCNSL), combined modality therapy (CMT) using high-dose methotrexate and radiotherapy (WBRT) has improved response rates compared with chemotherapy alone. The trade-off is delayed and potentially devastating treatment-related neurotoxicity (NT).

Methods

A cost-effectiveness analysis using a Markov model compared CMT with chemotherapy alone in age-stratified patients with PCNSL. Baseline probabilities were derived from a systematic literature review. Direct and lost productivity costs were collected from a Canadian perspective and presented in Can$ in 2011. Outcomes were life expectancy, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio.

Results

The quality-adjusted life expectancy was 1.55 QALYs for CMT and 1.53 QALYs for chemotherapy alone. In younger patients (aged <60 years), CMT yielded 2.44 QALYs, compared with 1.89 QALYs for chemotherapy alone, yielding an expected benefit with CMT of 0.55 QALYs or 6.6 quality-adjusted months. The CMT strategy dominated in younger patients, as it was Can$11 951 less expensive than chemotherapy alone. The chemotherapy-alone strategy dominated in older patients, as it was Can$11 244 less expensive than CMT, and there was no difference in QALYs between the strategies. The model was robust in sensitivity analyses of key variables tested through the plausible ranges obtained from costing sources and published literature.

Conclusion

The preferred induction strategy for younger patients with PCNSL appears to be CMT, which minimized cost while maximizing life expectancy and QALYs. This analysis confirms that the preferred strategy for older patients is chemotherapy alone.     

利妥昔单抗联合大剂量甲氨蝶呤在原发性中枢神经系统淋巴瘤患者中的应用效果

目的 探讨利妥昔单抗联合大剂量甲氨蝶呤在原发性中枢神经系统淋巴瘤患者中的应用效果.方法 按照入院顺序将84例原发性中枢神经系统淋巴瘤患者分为对照组和观察组,每组42例,对照组接受大量甲氨蝶呤治疗,观察组患者接受利妥昔单抗联合大剂量甲氨蝶呤治疗.比较两组患者的临床疗效、不良反应、生存期和生活质量.结果 观察组患者的治疗总...     

Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma

BACKGROUND:

Despite initial treatment with high‐dose methotrexate‐based regimens, many patients with primary central nervous system lymphoma (PCNSL) relapse and die from their disease. No standard of care exists at progression or relapse, but chemotherapy and in some cases radiation are usually used. Pemetrexed is a multitargeted antifolate, similar to methotrexate, but with a broader spectrum of activity. Because methotrexate is an integral part of PCSNL treatment, the authors assessed the antitumor activity and safety of pemetrexed in recurrent PCNSL.

METHODS:

Patients with relapsed/refractory PCNSL were enrolled in this trial. Treatment consisted of pemetrexed 900 mg/m² given every 3 weeks with low‐dose dexamethasone, folate, and B12 supplementation. Each cycle was 6 weeks, and follow‐up imaging was done before each new cycle. Treatment was continued until complete remission, progression, or toxicity.

RESULTS:

Eleven patients were treated, with a median age of 69.8 years and Karnofsky performance status of 70%; 10 of 11 patients had failed prior high‐dose methotrexate. The median number of pemetrexed cycles given was 5, with an associated overall response rate of 55% and disease control rate of 91%. The 6‐month progression‐free survival (PFS) was 45%, median PFS was 5.7 months, and median overall survival was 10.1 months. Toxicities were primarily hematologic and infectious.

CONCLUSIONS:

Pemetrexed has single‐agent activity in relapsed/refractory PCNSL. Toxicities were seen likely because of the higher than standard dose used. Further investigation of this agent or other multitargeted antifolates in PCNSL is warranted to determine optimal dose and efficacy in a more homogeneous population. Cancer 2012. © 2011 American Cancer Society.     

原发中枢神经系统恶性淋巴瘤的诊断及治疗

目的：探讨原发中枢神经系统恶性淋巴瘤（PCNSL）的临床、影像学表现,治疗方案选择和预后。方法：对24例PCNSL的诊断、治疗过程、预后进行回顾性分析。结果：PCNSL的临床表现以颅内压增高、局灶占位性病变损伤症状为主,肿瘤可单发或多发;肿瘤影像学缺乏特异性,确诊依靠病理学诊断。结论：PCNSL恶性度高,预后不良,手术全切率低;对确诊病例采用个体化的手术方案结合术后放、化疗是治疗本病的关键,可显著延长患者生存时间。     

Second malignancies in patients with primary central nervous system lymphoma

Background

Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphoma with distinctive biological behaviors. The evolving treatment of PCNSL has greatly improved the outcome for patients with this disease and has stimulated interest in second malignancies (SMs) in patients diagnosed with PCNSL.

Methods

The records of 129 cases of PCNSL at Mayo Clinic, diagnosed between January 1, 1988, and November 26, 2012, were reviewed. Data on clinical characteristics, laboratory parameters, treatments, outcomes, and SMs were collected. The mean follow-up time was 44.8 months (range, 0.5–240 months; median, 28.0 months).

Results

Altogether, 28 cases with 30 (23.26%) SMs were identified. Twenty (15.50%) patients had prior or synchronous SM. Ten (7.76%) patients developed a subsequent primary cancer after PCNSL. The most common sites of prior or synchronous SMs were prostate (4/20), skin (4/20), and gastrointestinal (3/20). The most common site of the subsequent SM was skin (4/10). Two cases were identified with both prior SM and subsequent SM.

Conclusions

Second malignancies in cases with PCNSL were not uncommon and occurred in nearly a quarter of our cohort. Nonmelanoma skin cancers were frequently seen. Therefore, screening for SMs should also be considered in long-term follow-up of patients with PCNSL. In addition, the high incidence of subsequent cancer, synchronous cancer, and frequently seen nonmelanoma skin cancers may all indicate an immunosuppressed state in patients with PCNSL.