Real-world practice of acute leukemia intrathecal chemotherapy administration: A Mexican nationwide survey

ABSTRACT Introduction: Intrathecal chemotherapy is a mainstay component of acute lymphoblastic leukemia treatment. In Mexico, there is a considerable practice variability in aspects, such as the manner of preparation and the administration technique. Objective: Our objective was to describe the different techniques used for the application of ITC and review the existing recommendations in the literature. Method: A cross-sectional, nationwide survey study was conducted by an electronic questionnaire sent to hematologists and oncologists in Mexico. We collected demographic data, personal experience, intrathecal chemotherapy techniques, drug preparation and postprocedural conduct. Results: We received 173 responses. Twenty percent had an anesthesiologist administering sedation and pain management. The platelet count considered safe was 50 × 109/L in 48% of the participants. In 77% (n = 133) of the cases, the conventional needle with stylet used was, 49% did not receive any added diluent in the intrathecal chemotherapy and only 42% were recommended to rest in a horizontal position for more than 30 min. Conclusion: We identified a considerable variation in the administration of intrathecal chemotherapy across the hematologists in Mexico. We discuss the implications and opportunities in reducing the variation in our setting, highlighting the unmet need to establish guidelines that should be evaluated by the Mexican professional society to produce a position paper regarding practice standardization.

Clinical trials on intrathecal pemetrexed treated leptomeningeal metastases from solid tumors / 中华肿瘤杂志

Objective: To investigate the feasibility, safety and efficacy of intrathecal pemetrexed (IP) treated for patients with leptomeningeal metastases (LM) from solid tumors. Methods: Forty-seven patients receiving pemetrexed intrathecal chemotherapy in the First Hospital of Jilin University from 2017 to 2018 were selected. The study of pemetrexed intrathecal chemotherapy adopted the classical dose-climbing model and included 13 patients with meningeal metastasis of non-small cell lung cancer who had relapsed and refractory after multiple previous treatments including intrathecal chemotherapy. Based on the dose climbing study, 34 patients with meningeal metastasis of solid tumor who did not receive intrathecal chemotherapy were enrolled in a clinical study using pemetrexed as the first-line intrathecal chemotherapy combined with radiotherapy. Kaplan-Meier method and Log rank test were used for survival analysis, and Cox regression model was used for influencing factor analysis. Results: The dose climbing study showed that the maximum tolerated dose of pemetrexed intrathecal chemotherapy was 10 mg per single dose, and the recommended dosing regimen was 10 mg once or twice a week. The incidence of adverse reactions was 10 cases, including hematological adverse reactions (7 cases), transaminase elevation (2 cases), nerve root reactions (5 cases), fatigue and weight loss (1 case). The incidence of serious adverse reactions was 4, including grade 4-5 poor hematology (2 cases), grade 4 nerve root irritation (2 cases), and grade 4 elevated aminotransferase (1 case). In the dose climbing study, 4 patients were effectively treated and 7 were disease controlled. The survival time was ranged from 0.3 to 14.0 months and a median survival time was 3.8 months. The clinical study of pemetrexed intrathecal chemotherapy combined with radiotherapy showed that the treatment mode of 10 mg pemetrexed intrathecal chemotherapy once a week combined with synchronous involved area radiotherapy 40 Gy/4 weeks had a high safety and reactivity. The incidence of major adverse reactions was 52.9% (18/34), including hematologic adverse reactions (13 cases), transaminase elevation (10 cases), and nerve root reactions (4 cases). In study 2, the response rate was 67.6% (23/34), the disease control rate was 73.5% (25/34), the overall survival time was ranged from 0.3 to 16.6 months, the median survival time was 5.5 months, and the 1-year survival rate was 21.6%. Clinical response, improvement of neurological dysfunction, completion of concurrent therapy and subsequent systemic therapy were associated with the overall survival (all P<0.05). Conclusions: Pemetrexed is suitable for the intrathecal chemotherapy with a high safety and efficacy. The recommended administration regimen was IP at 10 mg on the schedule of once or twice per week. Hematological toxicity is the main factor affecting the implementation of IP. Vitamin supplement can effectively control the occurrence of hematological toxicity.

A case study of primary testicular lymphoma：diagnosis and treatment strategies / 中国肿瘤临床

Primary testicular lymphoma comprises 1% to 9% of testicular neoplasms and represents 1% to 2% of all non-Hodg-kin lymphomas. Histologically, the majority of the tumor consists of diffuse large B-cell non-Hodgkin lymphomas that are of intermedi-ate- or high-grade neoplasm. Clinically, the disease typically presents as a painless testicular swelling that develops over a span of weeks to months. B symptoms such as fever, weight loss, and anorexia are present in 25% to 41% of the patients. This tumor is an ag-gressive type, with frequent invasion of the epididymis, spermatic cord, and scrotum, as well as a marked tendency to relapse, especial-ly in the CNS. The treatment is mainly based on orchiectomy (mostly in stages ⅠE and ⅡE) regardless of its association with prophy-lactic irradiation of the scrotum and administration of intrathecal chemotherapy, cyclophosphamide, doxorubicin, vincristine, and pred-nisone regimen chemotherapy plus rituximab (R-CHOP) (stages ⅢE and ⅣE) and radiotherapy. The multi-modality treatment marked-ly improved progression-free and overall survival. We introduce as reference one case that received a multidisciplinary comprehensive discussion in the Department Lymphoma, Tianjin Medical University Cancer Hospital.

Neuropsychological profile of patients with acute lymphoblastic leukemia

The present study investigated cognitive function in children diagnosed with acute lymphoblastic leukemia (ALL). The subjects were 20 children between the ages of 6 and 12 years of both genders who were diagnosed with ALL and underwent exclusively triple intrathecal prophylactic chemotherapy of the central nervous system. The protocol used for the neuropsychological assessment included the following cognitive aspects: intellectual performance, attention, memory and executive function. Data were analyzed by descriptive and inferential statistics using the Mann-Whitney U test and Student t-test. The effects of gender, age at diagnosis, and time since the initiation of treatment on the children's performance were determined. The evaluation of intellectual performance revealed reduced scores in the group of children who were female and younger than 5 years of age at diagnosis, especially difficulty with verbal skills and working memory. With regard to attention systems, the different groups presented expected performance for their age. We observed lower scores in the different groups in executive function, aspects of the development of problem-solving strategies, self-regulation, cognitive flexibility and inhibitory control. Better performance was observed for episodic memory and semantic memory (immediate and recognition), but lower scores were found for learning and recall after interference. In conclusion, the present findings are both consistent and discordant with the literature in the field that alludes to the impact of chemotherapy on the maturation of the central nervous system.

Efficacy of intravenous dexamethasone for the prevention of vomiting associated with intrathecal chemotherapy and ketamine sedation in children: a randomized, double-blinded, crossover, placebocontrolled trial.

Background: Chemotherapy-induced nausea and vomiting remains a significant problem for children with leukemia. There is limited evidence to support using prophylactic antiemetic prior to the administration of intrathecal chemotherapy. Objective: Determine whether vomiting and nausea associated with intravenous ketamine and intrathecal chemotherapy may be reduced by the addition of prophylactic dexamethasone in children. Method: A randomized, double-blinded, crossover, placebo-controlled trial was completed in 33 children receiving intrathecal chemotherapy with methotrexate and ketamine sedation at Pharmongkutklao Hospital. Patients were randomly assigned in a double-blinded fashion to receive one of two interventions during the first period, either an infusion of normal saline or intravenous dexamethasone at 0.25 mg/kg/dose. Each patient acted as his or her own control, and each patient was studied at two time-points. Results: Period effect, sequence effect, and carry over effect were not demonstrated. The absolute risk reduction of vomiting was significantly greater after infusion of dexamethasone than after placebo at 33.3 % (p=0.02). The number needed to treat was three to prevent one episode of vomiting. Fifteen patients in the treatment group reported nausea versus 26 patients in the placebo group (p= 0.007). In the group of patients treated with dexamethasone, five required antiemetic vs. 16 of those receiving placebo (p=0.02). There was no complication from dexamethasone. Conclusion: Intravenous dexamethasone reduced vomiting associated with intrathecal chemotherapy and ketamine sedation, without significant side-effects. It may be recommended a reasonable option before intrathecal chemotherapy.

Intrathecal Chemotherapy Related Myelopathy Improved With Folate and Cyanocobalamin

Intrathecal chemotherapy with methotrexate and cytarabine arabinoside is used for the treatment and prophylaxis of malignancies, but can induce myelopathy. We report the case of a 50-year-old woman with stomach cancer who developed myelopathy after administration of intrathecal cytarabine arabinoside and methotrexate. The patient's neurologic status improved rapidly after the administration of folinate (15 mg) four times daily and cyanocobalamin (100 mug) once daily. The folate metabolites may be effective in the management of intrathecal-chemotherapy-induced myelopathy.

Irreversible Paraplegia Following One Time Prophylactic Intrathecal Chemotherapy in an Adult Patient with Acute Lymphoblastic Leukemia

We present an adult female patient who developed irreversible paraplegia and areflexia four days post intrathecal chemotherapy with methotrexate, cytosine arabinoside and hydrocortisone. On magnetic resonance imaging (MRI) of the lumbar spine, diffuse gadolinium enhancement of the anterior spinal nerve roots (ventral roots) was detected. Methylprednisolone was intravenously administered at a daily dose of 30mg/kg for three days. Despite this treatment, flaccid weakness in the lower extremities and urinary retention persisted. Following consolidation chemotherapy, no improvement in neurologic status was noted. Six months later, a follow-up MRI revealed severe atrophy of the thoracic spinal cord.

Leptomeningeal Carcinomatosis in Solid Tumors; Clinical Manifestation and Treatment / 대한암학회지

PURPOSE: Leptomeningeal carcinomatosis occurs in about 5% of patients with solid tumor and is being diagnosed with increasing frequency as patients live longer and as neuro-imaging studies improve. In general, the most commom cancers that involved the leptomeninges are breast cancer, lung cancer, and malignant melanoma. MATERIALS AND METHODS: We investigated 25 patients presented with multiple neurologic symptoms and signs who were diagnosed with leptomeningeal carcinomatosis at the Yonsei Cancer Center from January 1990 to December 1999. RESULTS: The primary disease of leptomeningeal carcinomatosis were stomach cancer (10 cases), breast cancer (7 cases), lung cancer (5 cases), unknown primary cancer (2 cases) and common bile duct cancer (1 case). All patients were presented with multiple neurologic symptoms and signs involving the central nervous system (CNS), cranial nerve or spinal nerves. Twenty-one of twenty- five patients were treated with intrathecal chemotherapy, radiotherapy, or combination therapy. Fourteen of them (66.7%) experienced improvement or stabilization of neurologic symptom and sign. The median survival was 122 days (10-2190). CONCLUSION: In conclusion, although early diagnosis and active treatment of leptomeningeal carcinomatosis may improve the quality of life in selected patients, the median survival was relatively short. Therefore, new diagnostic and therapeutic strategy for leptomeningeal carcinomatosis were needed.

Primary Central Nervous System Lymphoma: A Report of 33 Cases

The authors report 33 patients with primary central nervous system lymphoma (PCNSL) treated from 1989 to 1995. There were 19 males and 14 females. Median age was 46 years(range: 4-74). Patients were symptomatic for a median of 3.5 weeks. Headache was the most common complaint. Median Karnofsky performance score(KPS) at admission was 70. Twenty-eight of 33 patients had solitary PCNSL and 5 had multiple deposits. Lesion was confined to the supratentorium in 26 patients, 4 in cerebellum, 3 in intra- and extradural spinal cord and 1 in orbit. All patients except two who refused further treatments received whole brain and/or spinal irradiation with or without supplemental tumor boost. Radiation therapy(RT) without systemic chemotherapy was introduced in 17 patients. Systemic chemotherapy was introduced to 13 patients and additional intrathecal chemotherapy in 10 among 13 patients. After follow-up periods ranging from 2 to 70 months, median overall survival period was 56 months in patients treated with RT only and 43 months in those with RT plus systemic chemotherapy(p=0.37). Median progression-free survival period was 48 months in RT group and 21 months in RT plus Chemo group(p=0.05). All 4 patients with intermediate grade PCNSL are still alive: One patient with diffuse small cleaved subtype survived complete response at 41 months and 3 patients with diffuse mixed subtype also survived without recurrence at 25, 51 and 62 months. Median progression-free and overall survival for diffuse large cell subtype(high grade) was 36 and 51 months, respectively. This study proved that it was the histopathologic grade that has exerted a considerable influence on survival period and other variables were not significant factors to overall survival period.

Prophylactic Cranial Irradiation for Acute Lymphoblastic Leukemia in Childhood / 대한치료방사선과학회지

PURPOSE: This report is the result of retrospective analysis for children who received prophyactic cranial irradiation combined with intrathecal chemotherapy. METHODS AND MATERIALS: Ninety children with ALL who had got bone marrow remission after induction chemotherapy received PCI. All but 3 children were treated with a dose of 1800 cGy as a standard regimen. While the PCI was given, all patients received intrathecal chemotherapy. RESULTS: Nine of 90 patients experienced CNS relapse during the duration of follow-up ranged from 36 to 96 months (median 60 months). Three children experienced BM relapse prior to CNS relapse. Therefore, CNS relapse rate as the first adverse event was 6.7%. Median time interval of CNS relapse was 16 months from the first day of hematologic complete remission. Eighty-nine percent of patients who had CNS relapse occurred during maintenance chemotherapy (on-therapy relapse). The CNS RFS at 2 and 5 years are 68 % and 42 %, respectively with median of 43 months. The prognostic factors affecting CNS RFS are initial WBC count (cut-off point of 50,000/mul), FAB subtype and CALGB risk WBC count (cut-off point of 50,000/mul), FAB subtype, POG and CALGB risk criteria. CONCLUSION: In our study, 6.7% of CNS relapse rate as a first adverse event was comparable with other studies. Various risk criteria was based on age at diagnosis and initial WBC count such as POG and CALGB criteria, had prognostic significance for CNS RFS and DFS. Prospective randomized trial according to prognostic subgroup based on risk criteria and systematic study about neuropsychologic function for long term survivors, are essential to determine the most effective and least toxic form of CNS prophylaxis.

Intermittent central nervous system irradiation and intrathecal chemotherapy for recurrent central nervous system leukemia in children

Between 1986 and 1990, four children with recurrent CNS leukemia who had previous CNS prophylaxis therapy were treated with intermittent central nervous system irradiation and intrathecal chemotherapy (IIIC). There was no isolated CNS recurrence. One patient died form bone marrow relapse. Three patients are alive without evidence of disease for 3E3/12 year to 3E6/12 year after the diagnosis of recurrence of CNS leukemia. This experience suggests that IIIC may be an effective treatment for preventing the recurrence of CNS leukemia without any serious side effects.