Clinical impact of primary tumour 123ImIBG response to induction chemotherapy in children with high-risk neuroblastoma

International Journal of Clinical Oncology - More than 50% children with high-risk neuroblastoma (HR-NBL) experience disease progression, which we hypothesise is due to non-response of primary...     

Hyperfractionated low-dose radiotherapy for high-risk neuroblastoma after intensive chemotherapy and surgery.

PURPOSE: To assess prognostic factors for local control in high-risk neuroblastoma patients treated with hyperfractionated 21-Gy total dose to consolidate remission achieved by dose-intensive chemotherapy and surgery. PATIENTS AND METHODS: Patients with high-risk neuroblastoma in first remission received local radiotherapy (RT) totaling 21 Gy in twice-daily 1.5-Gy fractions. RT to the primary site followed dose-intensive chemotherapy and tumor resection; the target field encompassed the extent of tumor at diagnosis, plus 3-cm margins and regional lymph nodes. RT to distant sites followed radiologic evidence of response. Local failure was correlated with clinical factors (including other consolidative treatments) and biologic findings. RESULTS: Of 99 consecutively irradiated patients followed for a median of 21.1 months from RT, 10 relapsed in or at margins of RT fields at 1 to 27 months (median, 14 months). At 36 months after RT, the probability of primary-site failure was 10.1% +/- 5.3%. No primary-site relapses occurred among the 23 patients whose tumors were excised at diagnosis, but there were three such relapses among the seven patients who were irradiated with evidence of residual disease in the primary site. Four of 18 patients with MYCN-amplified disease and serum lactate dehydrogenase greater than 1,500 U/L had local failures (23.4% +/- 10.7% risk at 18 months). Acute radiotoxicities were insignificant, but three of 35 patients followed for > or = 36 months had short stature from decreased growth of irradiated vertebra. CONCLUSION: Hyperfractionated 21-Gy RT is well tolerated and, together with dose-intensive chemotherapy and surgery, may help in local control of high-risk neuroblastoma. Extending the RT field to definitively encompass regional nodal groups may improve results. Visible residual disease may warrant higher RT dosing. Patients with biologically unfavorable disease may be at increased risk for local failure. RT to the primary site may not be necessary when tumors are excised at diagnosis.     

Impact of metaiodobenzylguanidine scintigraphy on assessing response of high-risk neuroblastoma to dose-intensive induction chemotherapy.

PURPOSE: The International Neuroblastoma Response Criteria (INRC) recommend, but do not make mandatory, metaiodobenzylguanidine (MIBG) scans. We present the first report on the effect of MIBG scans on the classification of response to dose-intensive induction therapy. PATIENTS AND METHODS: After dose-intensive induction and before consolidative therapy, 162 Memorial Sloan-Kettering Cancer Center (MSKCC) patients with high-risk neuroblastoma (NB) had MIBG scans (99 with (131)I, 63 with (123)I), computed tomography, (99m)Tc-bone scan, bone marrow (BM) tests, and urine catecholamine measurements. Induction included high-dose cyclophosphamide (140 mg/kg) plus other agents and high-dose cisplatin (200 mg/m(2))/etoposide (600 mg/m(2)). RESULTS: In 90 patients treated with dose-intensive therapy from diagnosis at MSKCC, the use of MIBG scintigraphy increased the incomplete response numbers from 14 (15.5%) to 20 (22%), giving a complete remission/very good partial remission (CR/VGPR) rate of 78%. In 72 patients treated before referral to MSKCC for intensified therapy, MIBG findings changed the response classification of one patient; the CR/VGPR rate was 43%. MIBG scans showed no BM disease in 15 of 38 patients with histologically evident NB in BM but did show uptake consistent with BM involvement in five patients who had no NB observed in BM tests. CONCLUSION: With the less effective therapy consequent to the intensification of induction only after initial exposure to standard-dose chemotherapy, MIBG scintigraphy merely confirms the findings of other staging modalities for detection of relatively widespread residual NB. However, when dose-intensive therapy is initiated at diagnosis, the reliable achievement of major disease responses makes extensive BM testing and MIBG scintigraphy prerequisites for accurate determination of disease status.     

Treatment of advanced neuroblastoma with emphasis on intensive induction chemotherapy. A report from the Study Group of Japan

One hundred nine newly treated patients with advanced neuroblastoma were entered in this study between January 1985 and May 1989. The eligible patients included infants younger than 12 months of age with Stage IVA disease (bone cortex, distant lymph node, and/or remote organ metastases) and patients aged 12 months or older with Stage III or IV disease (IVA plus IVB with tumor crossing the mid-line and with metastases confined to bone marrow, liver, and skin). The patients first received six cyclic course of intensive chemotherapy (regimen A1), consisting of cyclophosphamide (1200 mg/m2), vincristine (1.5 mg/m2), tetrahydropyranyl adriamycin (pyrarubicin; 40 mg/m2), and cisplatin (90 mg/m2). Original tumors and the regional lymph node metastases were removed some time during these first six cycles of chemotherapy. The patients were further divided into three groups. Patients in course 1 received alternating treatment by regimen B (cyclophosphamide and ACNU) and intensified regimen A1, and those in course 2 were treated with alternating administration of regimen C (cyclophosphamide and DTIC) and intensified A1. Patients in course 3 were treated with bone marrow transplantation (BMT) preceded by high-dose preconditioning chemotherapy. Survival rates were 77% in Stage III and 54% in Stage IV at 2 years, and 70% in Stage III and 45% in Stage IV at 3 years. The major toxicities encountered were bone marrow suppression with leukocyte counts down to 100/mm3, mild cystitis, and hearing impairment. The 2-year survival rate was 78% in 21 patients who underwent BMT when complete remission was achieved. We concluded that our intensive induction chemotherapy is of significant value in increasing the rate of complete response, and in widening the indications for and achieving improved results of treatment with BMT.     

Granulocyte-colony stimulating factor and multiple cycles of strongly myelosuppressive alkylator-based combination chemotherapy in children with neuroblastoma

BACKGROUND: The authors assessed key effects of granulocyte-colony stimulating factor (G-CSF) used prophylactically with multiple cycles of strongly myelosuppressive alkylator-based combination chemotherapy. To the authors' knowledge, no large study has focused on G-CSF in this setting, yet this kind of treatment has recently become standard for poor risk pediatric solid tumors such as neuroblastoma. PATIENTS AND METHODS. Children with neuroblastoma received cyclophosphamide 140 mg/kg (i.e., 4200 mg/m(2)), doxorubicin 75 mg/m(2), and vincristine (CAV) in cycles 1, 2, 4, and 6 and cisplatin 200 mg/m(2) and etoposide 600 mg/m(2) (P/VP) in cycles 3, 5, and 7. To maximize dose intensity, chemotherapy was begun as soon as the absolute neutrophil count (ANC) was > or = 500/microL and platelet count was > or = 100,000/microL. No cytokines were used during 1990-1994 (control group; n = 28), but G-CSF was used from 1995 to 1998 (G-CSF group; n = 30) at 5 microg/kg/day subcutaneously from 1 day after chemotherapy until the ANC was > or = 500/microL on 2 successive days or was > or = 1000/microL. RESULTS: Each cycle of CAV decreased ANCs to < 200/microL in all 58 patients; recovery to 200/microL and to 500/microL was significantly sooner with G-CSF. In contrast, P/VP did not invariably cause severe neutropenia: similar numbers of patients in each group maintained ANCs > or = 200/microL and > or = 500/microL; recovery to 500/microL (but not to 200/microL) was significantly faster in the G-CSF group. G-CSF had no impact on rates of febrile episodes. Bacterial/fungal infections were slightly less frequent in the G-CSF group with CAV (P = 0.11) but not with P/VP. Dose intensity through cycle 4 was the same in both groups. Beginning with cycle 3, G-CSF patients had slower recovery to platelet counts > or = 100,000/microL. Response rates were similar in the two groups. CONCLUSIONS: With multiple cycles of strongly myelosuppressive alkylator-based combination chemotherapy, prophylactic use of G-CSF hastened ANC recovery but did not reduce the incidence of febrile episodes, had little impact on infection rates, did not yield augmented dose intensity, was associated with prolonged thrombocytopenia, and had no effect on response rates of neuroblastoma. The data support more limited use of G-CSF.     

Tandem high-dose therapy in rapid sequence for children with high-risk neuroblastoma.

PURPOSE: Advances in chemotherapy and supportive care have slowly improved survival rates for patients with high-risk neuroblastoma. The focus of many of these chemotherapeutic advances has been dose intensification. In this phase II trial involving children with advanced neuroblastoma, we used a program of induction chemotherapy followed by tandem high-dose, myeloablative treatments (high-dose therapy) with stem-cell rescue (HDT/SCR) in rapid sequence. PATIENTS AND METHODS: Patients underwent induction chemotherapy during which peripheral-blood stem and progenitor cells were collected and local control measures undertaken. Patients then received tandem courses of HDT/SCR, 4 to 6 weeks apart. Thirty-nine patients (age 1 to 12 years) were assessable, and 70 cycles of HDT/SCR were completed. RESULTS: Pheresis was possible in the case of all patients, despite their young ages, with an average of 7.2 x 10(6) CD34(+) cells/kg available to support each cycle. Engraftment was rapid; median time to neutrophil engraftment was 11 days. Four patients who completed the first HDT course did not complete the second, and there were three deaths due to toxicity. With a median follow-up of 22 months (from diagnosis), 26 of 39 patients remained event-free. The 3-year event-free survival rate for these patients was 58%. CONCLUSION: A tandem HDT/SCR regimen for high-risk neuroblastoma is a feasible treatment strategy for children and may improve disease-free survival.     

Short topotecan-based induction regimen in newly diagnosed high-risk neuroblastoma

Purpose

Topotecan is an active drug in relapsed neuroblastoma. We investigated the efficacy and toxicity of a topotecan-based induction regimen in newly diagnosed neuroblastoma.

Methods

Patients older than 1 year with either metastatic or localised stage 2-3 MYCN-amplified neuroblastoma received 2 courses of high-dose topotecan (HD-TPT) 6 mg/m² and high-dose cyclophosphamide (HD-CPM) 140 mg/kg, followed by 2 courses of ifosfamide, carboplatin and etoposide (ICE) every 28 days. After surgery on primary tumour, a fifth course with vincristine, doxorubicin and CPM was given, followed by high-dose chemotherapy with stem cell support. Response was assessed in accordance with the International Neuroblastoma Response Criteria.

Results

Of 35 consecutive patients, 33 had metastatic disease. The median length of induction phase was 133 days (range 91-207) and time to high-dose chemotherapy was 208 days (range 156-285). The median tumour volume reduction was 55% after two HD-TPT/HD-CPM courses and 80% after four courses. Radical surgery was performed in 16/27 patients after chemotherapy. After the fifth course, 29/34 patients (85%) had achieved a partial remission (12) or a CR/very good partial remission (17). CR of metastases was achieved in 13/32 (41%) and bone marrow was in complete remission in 16/24 patients (67%). Grade 4 neutropenia and/or thrombocytopenia occurred in 100% of HD-TPT/HD-CPM and in 95% of ICE courses, while non-haematological toxicities were manageable.

Conclusions

These data indicate that our induction regimen is feasible and well tolerated. A major response rate of 85% with 41% complete metastatic response confirms this regimen as effective induction in high-risk neuroblastoma.     

儿童多发性神经母细胞瘤7 例临床分析*

目的：总结儿童多发性神经母细胞瘤（neurobl astoma ,NB）的临床特征及生物学行为,以期对这类肿瘤的治疗及预后判断提供依据。方法：回顾性分析天津医科大学肿瘤医院儿童肿瘤科1995年1 月至2015年12月收治的7 例多发性NB患儿的临床资料并对其随访。结果：共收治360 例NB患儿,其中多发NB仅7 例（1.9%）。 患儿平均年龄（19.4 ± 11.9）个月;原发部位胸腹多发3 例,双肾上腺多发4 例;临床分期4S 期4 例（57.1%）,3 期2 例（28.6%）,4 期1 例（14.3%）。 7 例共15个原发灶：14个手术完整切除;组织学预后良好型（favorable histology ,FH）12个（85.7%）,组织学预后不良型（unfavorable histology,UH）2 个（14.3%）;13个（92.9%）MYCN 基因无扩增。随访满3 年的5 例患儿,3 年总生存率（overall survivalrate ,OS）为100% 。结论：多发性NB极其罕见,具有初次诊断年龄较低、以4S 期为主、手术易完整切除的临床特征,肿瘤细胞分化较成熟、FH居多、少见MYCN 基因扩增等生物学行为。该病多数预后较好,应避免过度治疗。     

儿童高危神经母细胞瘤免疫治疗进展

神经母细胞瘤（neuroblastoma,NB）是儿童最常见的颅外实体瘤,具有明显的异质性及独特而多变的生物学和临床特征。高危NB属于免疫学“冷肿瘤”,具有多方位的免疫逃避策略,众多研究者针对这些免疫逃避策略开展了一系列免疫治疗相关探索。目前双唾液酸神经节苷脂（GD2）单抗治疗已被纳入国内外NB多模式治疗共识。尽管如此,高危NB患儿5年生存率仍然低于50%。针对高危NB细胞及其免疫微环境中各种效应分子的免疫治疗研究正在持续进行中,有望为此类患儿带来新希望。本文对目前高危NB患儿采用的免疫治疗方法和研究中的免疫治疗策略进行综述。     

Prognostic factors including neoadjuvant chemotherapy in Mexican children with neuroblastoma

INTRODUCTION: There are several prognostic factors in children with neuroblastoma that have been outlined in the international literature. MATERIAL AND METHODS: A retrospective study was carried out analysing the medical records of patients with the pathological diagnosis of neuroblastoma seen at the Department of Oncology from the Instituto Nacional de Pediatriá (Mexico) between January 1984 to January 1997. A total of 32 clinical prognostic factors were assess in our population. RESULTS: Fifty five patients whose age ranged from 1 to 168 months old, mean of 35 months were included. Out of 32 prognostic factors only 6 including sex (p= 0.0039), metastatic disease to bone (p= 0.003), bone marrow involvement (p= 0.0027), staging system (p= 0.000015), surgical treatment (p 0,0022) and neoadjuvant chemotherapy (p.005) were the most significant. CONCLUSIONS: It was concluded that besides the prognostic factors outlined, neoadjuvant chemotherapy is of utmost importance. It decreases tumor volume and allows surgery to be more successful, therefore believing that this variable represents a specific prognostic factor in cases of advanced neuroblastoma.     

Total-body sequential segmental irradiation and combination chemotherapy for children with disseminated neuroblastoma.

Fourteen children with disseminated neuroblastoma were treated with segmental total-body irradiation and a combination of cyclophosphamide, vincristine and Adriamycin. Six others had localized tumors and were treated with either surgery alone or limited irradiation and chemotherapy. The main objective of the study was to find out if this aggressive therapy for disseminated neuroblastoma would be tolerated and would promote longer disease-free remissions and possibly, cures. Complete responses were obtained in all patients with localized tumors. Of the 14 patients with disseminated disease, three had complete responses, five had partial responses, two had objective responses, and four were classified as nonresponders. Survival rates for this group are poor. Only two patients are still alive, and the single patient who survives free of disease has had a complex clinical course that is only indirectly a result of treatment. The median survival for patients with disseminated tumor was 9 months, not appreciably different from earlier result. Although toxicity was clinically manageable, it interfered with the planned schedule of therapy. Continuous weight loss combined with severe bone marrow suppression due to irradiation prevented about 50% of the scheduled drug dose from being administered. This resulted in poor control of tumor outside of radiation ports and eventually led to progressive disease within previously irradiated sites. We conclude that irradiation used in this manner will not improve disease-free survival of children with disseminated neuroblastoma. It is essential that disseminated disease be controlled before extensive irradiation is attempted.     

Cardiotoxicity from intensive chemotherapy combined with radiotherapy in breast cancer.

Cardiac function was evaluated in 86 breast cancer patients after standard chemotherapy, followed by ablative chemotherapy and chest irradiation. One patient died of subacute heart failure 3 months after ablative chemotherapy. At a minimum of 1 year''s follow-up (range 1-11 years) left vertricular ejection fraction (LVEF) was marginally abnormal in 4 of 27 disease-free survivors. One exceptional patient who received two transplantations is alive, with serious heart failure occurring after the second ablative chemotherapy. Including this patient, the percentage of patients free of clinical and subclinical cardiac dysfunction at 7 years is 78% (95% CI 61-95%). After ablative chemotherapy, cardiotoxicity was rarely life-threatening. The impact of subclinical cardiotoxicity in the long term is not clear and needs continued evaluation.     

High-dose chemotherapy in high-risk myelodysplastic syndrome: covariate-adjusted comparison of five regimens

BACKGROUND: Antileukemic chemotherapy has been used for two decades to treat high-risk myelodysplastic syndrome (refractory anemia with excess of blasts [RAEB] and RAEB in transformation into acute leukemia [RAEB-t]) patients. Because the results of standard regimens have been disappointing, high-dose chemotherapeutic regimens were investigated recently. In the absence of randomized trials, the relative merits of various treatment regimens are unknown. METHODS: The authors analyzed the outcome for 394 newly diagnosed patients treated between 1991 and 1999 with five regimens consisting of intermediate- or high-dose cytosine arabinoside (A) in combination with idarubicin (I), and introduced cyclophosphamide (C) and the new agents fludarabine (F) and topotecan (T) into new combinations with A. In addition to defining the role of high-intensity chemotherapy in the overall outcome for patients with RAEB-t and RAEB, the authors determined the relative merits of the five regimens (IA, FA, FAI, TA, and CAT), accounting for the nonrandom distribution of the prognostic covariates. RESULTS: The overall complete response (CR) rate of 58% was significantly associated with karyotype, performance status (PS), treatment in the laminar air flow room, duration of antecedent hematologic disorder and age, but not French-American-British or International Prognostic Scoring System risk categories. Multivariate analysis did not identify statistically significant differences in CR rates obtained with each regimen. Induction death rates increased with age with all but the TA regimen; they were lowest with TA (5.4%) and highest with FAI (20.7%), and these differences were significant in patients older than 65 years. The trend for time to death was the same as for time to recurrence in all groups. Multivariate analysis of time to death identified treatment regimen (FA, FAI, and CAT), cytogenetic status (-5/-7), increasing age, and PS greater than 2 as significant independent unfavorable prognostic factors. After prognostic variables were accounted for, survival with IA treatment remained superior to that of FA and FAI but comparable to TA, and CR duration was only marginally shorter with FA. Landmark analysis showed the overall survival of responders to be superior to that of nonresponders, the difference remaining significant after adjustment for prognostic covariates. CONCLUSIONS: Although the newer regimens did not improve outcome, TA and CAT produced results comparable to those of IA and may be considered treatment alternatives. The TA regimen was particularly effective in RAEB patients and could be delivered safely, with low induction mortality. Our results indicated that although CR seemed associated with survival advantage, innovative post-remission managements represent a challenge because improvement in outcome is not likely to come from intensified therapy.     

An intensive, five course, alternating combination chemotherapy induction regimen used in patients with advanced, unresectable head and neck cancer

Progress in the treatment of advanced squamous cell cancer (SCC) of the head and neck (H & N) has included the development of combination chemotherapeutic regimens that achieve impressive complete response (CR) rates using two to three courses therapy with minimal toxicity and good patient tolerance. Further improvements in these results will require intensification of induction regimens. Therefore, a five course, alternating combination chemotherapy induction trial was initiated in an attempt to test the feasibility and toxicity of a prolonged, intensive induction regimen in patients with advanced SCC of H & N. Courses 1, 3, and 5 consisted of fluorouracil as a 120-hour infusion (5FU-I) with cisplatin (CACP) as an intravenous (IV) bolus. Courses 2 and 4 consisted of 3 weekly doses of high-dose methotrexate (HDMTX) followed by 5FU (5FU-b) and leucovorin rescue (LR). Forty-six stage IV patients with SCC of H & N (85% T4 and 58% N3) were entered. Thirty-one patients completed the study and 15 did not. Twenty-one of the 46 patients (46%) achieved a CR. Twenty-five of the 46 patients had N3 neck disease, ten of these 25 achieved a CR (40%), and eight did not complete therapy. Of the 15 patients not completing this study, one patient achieved a CR and eight achieved a partial response (PR). Eight of 46 (17%) were removed from study for reasons of toxicity (6% to 13%) or tumor progression (2% to 4%). The remaining seven were removed due to intercurrent medical conditions (four uncomplicated pneumonias and one gun shot wound) or lost to follow-up (2). Myelosuppression, mucositis, and skin toxicity increased in frequency by the end of the trial but were acceptable and reversible. The activity of this five-course regimen is promising given the advanced disease status of patients treated. Consideration of concurrent medical conditions, patient compliance, intensity of medical, nutritional and social support, and levels of acceptable toxicity will be necessary in the design of future, intensive induction trials.     

Prognosis in Black children with neuroblastoma.

Thirty white and 15 black children with neuroblastoma were compared with respect to survival. Patient age and tumor stage at diagnosis were similar in the two groups, as was duration of symptoms prior to diagnosis. There was no significant difference between the white and black children in regard to median duration of survival or percentage of long-term survivors. The results of this study indicate that race is not a factor in the prognosis of this tumor.     

High-dose chemotherapy with autologous bone marrow transplantation in children with high-risk malignant neoformations

The role of high-dose chemotherapy; with subsequent autologous bone marrow rescue (AutoBMR) for high risk or recurrence of advanced solid tumor was evaluated in 16 children (August 1998-March 2001). At present, 11 (69%) patients are still alive, showing no evidence of the disease, 11-31 mo after therapy (median follow-up of 17 mo). Tumor progression was reported in 5 (31%) at months 5, 6, 8, 9 and 11 (after AutoBMR rhabdosarcoma--3; Ewing's sarcoma--2). Overall and recurrence-free survival among all patients was 74 and 66%, respectively.     

Ascending myelitis after intensive chemotherapy and radiation therapy in children with cranial parameningeal sarcoma.

In 1977, a program of early, wide-field radiation therapy (RT) to the central nervous system and repeated lumbar intrathecal (IT) medications along with systemic chemotherapy was begun by the Intergroup Rhabdomyosarcoma Study (IRS) for patients younger than 21 years of age with cranial parameningeal sarcoma and a high risk of meningeal extension. From 1977 until 1987, 149 eligible patients with high-risk cranial parameningeal sarcoma were enrolled in IRS trials. None had evidence of lower extremity or sphincter impairment at diagnosis. Five of the 149 (3.4%) had ascending myelitis at 5.5 to 9 months after the initiation of therapy, with loss of sphincter control and inability to walk; this progressed to severe flaccid quadriparesis and necessitated long-term ventilatory support in 4. All five had received vincristine, dactinomycin, cyclophosphamide, and doxorubicin; four also had received cisplatin and three also had received etoposide. All patients received 4770 to 5500 cGy to the primary tumor, and four patients received 3000 cGy of cranial RT. Three patients received cervical RT and two received spinal RT. The patients also received four to seven courses of IT methotrexate, hydrocortisone, and cytosine arabinoside. Three patients died: one after local tumor recurrence with central nervous system extension and two without known recurrence. In one of the latter patients, the results of an autopsy showed necrosis of the cervical spinal cord and caudal medulla. Although the exact cause of this complication is unclear, no additional cases have been reported to the IRS since the protocol was revised in 1987 to reduce the doses of the IT drugs and to limit them to four courses each.