Investigation of the Role of Dinutuximab Beta-Based Immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1).

To explore the effects of immunotherapy in the International Society of Paediatric Oncology Europe Neuroblastoma Group SIOPEN high-risk neuroblastoma 1 trial (HR-NBL1 trial), two cohorts were studied: one prior to and one after the introduction of dinutuximab beta. All patients received standard induction and high-dose therapy (HDT) with autologous stem cell rescue (ASCR); the local control comprised surgery and radiotherapy to the primary tumour site, followed by isotretinoin. A landmark timepoint of 109 days, resulting from the median time between ASCR and initiation of immunotherapy, was used to define patients' eligibility in the pre-immunotherapy analysis cohort. Median follow-up was 5.8 years (inter-quartile range (IQR): 4.2-8.2 years) for 844 eligible patients balanced for risk factors, such as age, sex, stage 4, MYCN amplification and response prior to HDT. The five-year event-free and overall survival (95% confidence interval (CI) of 466 patients not receiving immunotherapy was 42% (38-47%) and 50% (46-55%) but was 57% (51-62%) and 64% (59-69%) for 378 patients receiving immunotherapy (p < 0.001). A multivariate analysis identified absence of immunotherapy (p = 0.0002, hazard ratio (HR) 1.573); type of HDT (p = 0.0029, HR 1.431); less than complete response prior to maintenance therapy (p = 0.0043, HR 1.494) and >1 metastatic compartment at diagnosis (p < 0.001, HR 2.665) as risk factors for relapse or progression. Results suggest an important role for dinutuximab beta-based immunotherapy within the treatment concepts applied in HR-NBL1/SIOPEN.

Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial.

BACKGROUND: Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma. METHODS: We did an international, open-label, phase 3, randomised, controlled trial in patients with high-risk neuroblastoma at 104 institutions in 12 countries. Eligible patients were aged 1-20 years and had MYCN-amplified neuroblastoma with stages 2, 3, or 4S, or stage 4 neuroblastoma of any MYCN status, according to the International Neuroblastoma Staging System. Patients were eligible if they had been enrolled at diagnosis in the HR-NBL1/SIOPEN trial, had completed the multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, with or without topotecan, vincristine, and doxorubicin), had achieved a disease response that fulfilled prespecified criteria, had received high-dose therapy (busulfan and melphalan or carboplatin, etoposide, and melphalan) and had received radiotherapy to the primary tumour site. In this component of the trial, patients were randomly assigned (1:1) to receive dinutuximab beta (20 mg/m2 per day as an 8 h infusion for 5 consecutive days) or dinutuximab beta plus subcutaneous IL-2 (6 × 106 IU/m2 per day on days 1-5 and days 8-12 of each cycle) with the minimisation method to balance randomisation for national groups and type of high-dose therapy. All participants received oral isotretinoin (160 mg/m2 per day for 2 weeks) before the first immunotherapy cycle and after each immunotherapy cycle, for six cycles. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17, and recruitment to this randomisation is closed. FINDINGS: Between Oct 22, 2009, and Aug 12, 2013, 422 patients were eligible to participate in the immunotherapy randomisation, of whom 406 (96%) were randomly assigned to a treatment group (n=200 to dinutuximab beta and n=206 to dinutuximab beta with subcutaneous IL-2). Median follow-up was 4·7 years (IQR 3·9-5·3). Because of toxicity, 117 (62%) of 188 patients assigned to dinutuximab beta and subcutaneous IL-2 received their allocated treatment, by contrast with 160 (87%) of 183 patients who received dinutuximab beta alone (p<0·0001). 3-year event-free survival was 56% (95% CI 49-63) with dinutuximab beta (83 patients had an event) and 60% (53-66) with dinutuximab beta and subcutaneous IL-2 (80 patients had an event; p=0·76). Four patients died of toxicity (n=2 in each group); one patient in each group while receiving immunotherapy (n=1 congestive heart failure and pulmonary hypertension due to capillary leak syndrome; n=1 infection-related acute respiratory distress syndrome), and one patient in each group after five cycles of immunotherapy (n=1 fungal infection and multi-organ failure; n=1 pulmonary fibrosis). The most common grade 3-4 adverse events were hypersensitivity reactions (19 [10%] of 185 patients in the dinutuximab beta group vs 39 [20%] of 191 patients in the dinutuximab plus subcutaneous IL-2 group), capillary leak (five [4%] of 119 vs 19 [15%] of 125), fever (25 [14%] of 185 vs 76 [40%] of 190), infection (47 [25%] of 185 vs 64 [33%] of 191), immunotherapy-related pain (19 [16%] of 122 vs 32 [26%] of 124), and impaired general condition (30 [16%] of 185 vs 78 [41%] of 192). INTERPRETATION: There is no evidence that addition of subcutaneous IL-2 to immunotherapy with dinutuximab beta, given as an 8 h infusion, improved outcomes in patients with high-risk neuroblastoma who had responded to standard induction and consolidation treatment. Subcutaneous IL-2 with dinutuximab beta was associated with greater toxicity than dinutuximab beta alone. Dinutuximab beta and isotretinoin without subcutaneous IL-2 should thus be considered the standard of care until results of ongoing randomised trials using a modified schedule of dinutuximab beta and subcutaneous IL-2 are available. FUNDING: European Commission 5th Frame Work Grant, St. Anna Kinderkrebsforschung, Fondation ARC pour la recherche sur le Cancer.

Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials.

BACKGROUND: Validation of the prognostic value of the SIOPEN mIBG skeletal scoring system in two independent stage 4, mIBG avid, high-risk neuroblastoma populations. RESULTS: The semi-quantitative SIOPEN score evaluates skeletal meta-iodobenzylguanidine (mIBG) uptake on a 0-6 scale in 12 anatomical regions. Evaluable mIBG scans from 216 COG-A3973 and 341 SIOPEN/HR-NBL1 trial patients were reviewed pre- and post-induction chemotherapy. The prognostic value of skeletal scores for 5-year event free survival (5 yr.-EFS) was tested in the source and validation cohorts. At diagnosis, both cohorts showed a gradual non-linear increase in risk with cumulative scores. Several approaches were explored to test the relationship between score and EFS. Ultimately, a cutoff score of ≤3 was the most useful predictor across trials. A SIOPEN score ≤ 3 pre-induction was found in 15% SIOPEN patients and in 22% of COG patients and increased post-induction to 60% in SIOPEN patients and to 73% in COG patients. Baseline 5 yr.-EFS rates in the SIOPEN/HR-NBL1 cohort for scores ≤3 were 47% ± 7% versus 26% ± 3% for higher scores at diagnosis (p < 0.007) and 36% ± 4% versus 14% ± 4% (p < 0.001) for scores obtained post-induction. The COG-A3973 showed 5 yr.-EFS rates for scores ≤3 of 51% ± 7% versus 34% ± 4% for higher scores (p < 0.001) at diagnosis and 43% ± 5% versus 16% ± 6% (p = 0.004) for post-induction scores. Hazard ratios (HR) significantly favoured patients with scores ≤3 after adjustment for age and MYCN-amplification. Optimal outcomes were recorded in patients who achieved complete skeletal response. CONCLUSIONS: Validation in two independent cohorts confirms the prognostic value of the SIOPEN skeletal score. In particular, patients with an absolute SIOPEN score > 3 after induction have very poor outcomes and should be considered for alternative therapeutic strategies.

Validation of Postinduction Curie Scores in High-Risk Neuroblastoma: A Children's Oncology Group and SIOPEN Group Report on SIOPEN/HR-NBL1.

A semiquantitative 123I-metaiodobenzylguanidine (123I-MIBG) scoring method (the Curie score, or CS) was previously examined in the Children's Oncology Group (COG) high-risk neuroblastoma trial, COG A3973, with a postinduction CS of more than 2 being associated with poor event-free survival (EFS). The validation of the CS in an independent dataset, International Society of Paediatric Oncology European Neuroblastoma/High-Risk Neuroblastoma 1 (SIOPEN/HR-NBL1), is now reported. Methods: A retrospective analysis of 123I-MIBG scans obtained from patients who had been prospectively enrolled in SIOPEN/HR-NBL1 was performed. All patients exhibited 123I-MIBG-avid, International Neuroblastoma Staging System stage 4 neuroblastoma. 123I-MIBG scans were evaluated at 2 time points, diagnosis (n = 345) and postinduction (n = 330), before consolidation myeloablative therapy. Scans of 10 anatomic regions were evaluated, with each region being scored 0-3 on the basis of disease extent and a cumulative CS generated. Cut points for outcome analysis were identified by Youden methodology. CSs from patients enrolled in COG A3973 were used for comparison. Results: The optimal cut point for CS at diagnosis was 12 in SIOPEN/HR-NBL1, with a significant outcome difference by CS noted (5-y EFS, 43.0% ± 5.7% [CS ≤ 12] vs. 21.4% ± 3.6% [CS > 12], P < 0.0001). The optimal CS cut point after induction was 2 in SIOPEN/HR-NBL1, with a postinduction CS of more than 2 being associated with an inferior outcome (5-y EFS, 39.2% ± 4.7% [CS ≤ 2] vs. 16.4% ± 4.2% [CS > 2], P < 0.0001). The postinduction CS maintained independent statistical significance in Cox models when adjusted for the covariates of age and MYCN gene copy number. Conclusion: The prognostic significance of postinduction CSs has now been validated in an independent cohort of patients (SIOPEN/HR-NBL1), with a postinduction CS of more than 2 being associated with an inferior outcome in 2 independent large, cooperative group trials.

Neuroblastoma (Peripheral neuroblastic tumours).

Peripheral neuroblastic tumours (PNTs), a family of tumours arising in the embryonal remnants of the sympathetic nervous system, account for 7-10% of all tumours in children. In two-thirds of cases, PNTs originate in the adrenal glands or the retroperitoneal ganglia. At least one third present metastases at onset, with bone and bone marrow being the most frequent metastatic sites. Disease extension, MYCN oncogene status and age are the most relevant prognostic factors, and their influence on outcome have been considered in the design of the recent treatment protocols. Consequently, the probability of cure has increased significantly in the last two decades. In children with localised operable disease, surgical resection alone is usually a sufficient treatment, with 3-year event-free survival (EFS) being greater than 85%. For locally advanced disease, primary chemotherapy followed by surgery and/or radiotherapy yields an EFS of around 75%. The greatest problem is posed by children with metastatic disease or amplified MYCN gene, who continue to do badly despite intensive treatments. Ongoing trials are exploring the efficacy of new drugs and novel immunological approaches in order to save a greater number of these patients.

Pitfalls in oncology: a unique case of thoracic splenosis mimicking malignancy in a patient with resected breast cancer.

Thoracic splenosis (TS) is a condition of autotransplantation of splenic tissue into the pleural cavity after thoraco-abdominal trauma, with diaphragmatic and spleen injury. It is usually asymptomatic and discovered as an incidental finding at imaging performed for other reasons. Its differential diagnosis regards different benign and malignant conditions and should be discerned avoiding invasive procedures. We report a case of thoracic mass associated with pleural nodules mimicking malignancy in a patient with resected breast cancer for whom a diagnosis of TS was made early by using non-invasive methods. Briefly, we review the literature data on TS, comment concisely the possible implications of using invasive procedures and describe the current non-invasive techniques available. Furthermore, we highlight the importance of an accurate medical history collection, the role of the multidisciplinary board and their impact on treatment decision making. Finally, we conclude that clinical information and imaging would be the discriminating factors to avoid unnecessary invasive procedures.

Matched pairs dosimetry: 124I/131I metaiodobenzylguanidine and 124I/131I and 86Y/90Y antibodies.

The technological advances in imaging and production of radiopharmaceuticals are driving an innovative way of evaluating the targets for antineoplastic therapies. Besides the use of imaging to better delineate the volume of external beam radiation therapy in oncology, modern imaging techniques are able to identify targets for highly specific medical therapies, using chemotherapeutic drugs and antiangiogenesis molecules. Moreover, radionuclide imaging is able to select targets for radionuclide therapy and to give the way to in vivo dose calculation to target tissues and to critical organs. This contribution reports the main studies published on matched pairs dosimetry with (124)I/(131)I- and (86)Y/(90)Y-labelled radiopharmaceuticals, with an emphasis on metaiodobenzylguanidine (MIBG) and monoclonal antibodies.

Neuroblastoma in patients over 12 years old: a 20-year experience at the Istituto Nazionale Tumori of Milan.

AIMS AND BACKGROUND: Neuroblastoma is the most common solid extracranial tumor in children. The median age of onset is 2 years, with more than 95% of patients younger than 10 years at diagnosis. As neuroblastoma is rare in adolescents and exceedingly rare in adults, few series are reported in the literature. In the present study, we analyzed the outcomes and clinical characteristics of a mono-institutional series. METHODS: We describe 27 consecutive patients over 12 years of age (range, 12-69) with previously untreated neuroblastoma treated at our Institution between 1982 and 2001. RESULTS: Overall survival at 5 and 10 years was 40% and 20%, respectively, and progression-free survival at 5 and 10 years was 18%. In the present series, there was a long interval between the onset of signs/symptoms and diagnosis, and between recurrence/progression and death. None had MYCN amplification. CONCLUSIONS: The passive course of the disease in most of our patients did not reflect a more favorable outcome compared with younger patients, thus suggesting a possible genetically different subset of neuroblastoma in older patients.

Conservative surgical approach for thyroid and lymph-node involvement in papillary thyroid carcinoma of childhood and adolescence.

BACKGROUND: Prior to 1990s, papillary thyroid carcinomas (PTCs) in childhood/adolescence underwent a standard therapeutic approach (total thyroidectomy plus elective neck dissection, followed by radioactive iodine (RAI) ablation), with an overall survival of about 100%. The aim of this study is to outline the possibility of a conservative approach (hemithyroidectomy plus selective neck dissection of clinically involved nodes, followed by TSH-suppressive therapy) in a selected group of patients. PROCEDURE: From 1968 to 2001, 42 pediatric PTC patients were treated at our institution. Absence of distant metastases and a tumor clinically limited to one lobe were both present in 28 cases that underwent a radical (20 cases) or a conservative (8 cases) surgical approach at the thyroid level. At cervical node level, 10 patients underwent a radical and 32 a conservative surgical approach. Clinicopathologic features at onset, type of therapy (radical vs. conservative), post-operative complications, and outcome till May 31, 2004 were recorded. The impact of the type of surgery on outcome was evaluated. RESULTS: Overall and progression-free survival (PFS) curves were found to be independent of the type of therapy (radical vs. conservative) in subgroups of patients matched for extent of disease at onset. Post-operative complications occurred only with radical surgical approaches. CONCLUSIONS: Childhood and adolescence PTCs show a high rate of spread but an excellent outcome independent of the type of therapy (radical vs. conservative). Taking into account the marked responsiveness to TSH-suppression and the complications after radical therapy, in selected cases, a conservative approach should be considered, reserving more aggressive therapies in case of metastases or relapse.

Papillary thyroid carcinoma of childhood and adolescence: a 30-year experience at the Istituto Nazionale Tumori in Milan.

BACKGROUND: Survival rates are reportedly excellent for papillary thyroid carcinomas (PTCs) in childhood/adolescence, despite their strong tendency to spread. The aim of this study was to verify this assumption in a single-institution series spanning a 30-year period with a very long follow-up. PROCEDURE: From 1968 to 2001, 74 cases of thyroid carcinoma were collected. The papillary histological type was confirmed in 42 cases with available slides; we recorded the sex, age at diagnosis, age of menarche, tumor side and size, TNM/pTNM classification, multicentricity, vascular invasion, type of surgery, post-operative complications, post-surgical therapies and outcome up to May 31, 2004. RESULTS: The female/male ratio was 2.2; pT4, pN1 and M1 cases were 52%, 95%, and 12% (four in lungs and one in bone), respectively. Total thyroidectomy was performed in 33 patients, hemithyroidectomy in 8, and a biopsy in 1 inoperable case. Nine patients (21%) relapsed, six in the cervical lymph nodes and three in the lungs. After a median follow-up of 189 months, all patients were alive, two of them with evidence of disease. Overall and progression-free survival curves were independent of sex, age, TNM/pTNM classification, or type of surgery. Overall survival was also independent of recurrence. CONCLUSIONS: Unlike its adult counterpart, PTC of childhood and adolescence is a cancer with a high frequency of spread, but an excellent outcome irrespective of sex, age at diagnosis, TNM/pTNM classification, type of surgery, recurrence. Since pediatric PTCs proved highly responsive to hormone manipulation, it is worth considering a different therapeutic approach from adult cases.

Sentinel lymph node detection following the hysteroscopic peritumoural injection of 99mTc-labelled albumin nanocolloid in endometrial cancer.

PURPOSE: The purpose of this study was to assess the feasibility of sentinel lymph node (SLN) detection in endometrial cancer patients with a dual-tracer procedure after hysteroscopic peritumoural injection. METHODS: Twenty-six women with previously untreated endometrial adenocarcinoma underwent the hysteroscopic injection of 111 MBq 99mTc-Nanocoll and blue dye administered subendometrially around the lesion. On the same day, all 26 patients underwent lymphoscintigraphy, followed 3-4 h later by hysterotomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy. Para-aortic lymphadenectomy was also performed in cases of either serous or papillary carcinoma (n=7/26). All SLNs were removed and examined with haematoxylin and eosin staining and immunohistochemical techniques. RESULTS: The procedure was well tolerated by patients, only two experiencing transient vagal symptoms. The sensitivity of this technique for correct identification of SLNs was 100%. Lymph node metastases were found in 4 out of the 26 patients (15%), bilaterally in the external iliac region (n=1), unilaterally in the external iliac region (n=1), unilaterally in the common iliac region (n=1) and unilaterally in the para-aortic region (n=1). In all four cases, nodal metastases were located within SLNs detected by lymphoscintigraphy. Only 10 of the 26 patients (38%) had significant blue dye staining. All blue-stained SLNs were radioactive. CONCLUSION: In patients with endometrial cancer, it is feasible to use lymphatic mapping and SLN biopsy to define the topographic distribution of the lymphatic network and also to accurately detect lumbo-aortic and pelvic metastases within SLNs. In the majority of patients with early stage endometrial cancer, this procedure may avoid unnecessary radical pelvic lymphadenectomy. It may also guide para-aortic lymph node dissection on the basis of the SLN status.

The role of radionuclide therapy in medullary thyroid cancer.

In medullary thyroid carcinoma (MTC) the detection of occult metastases is difficult and the prognosis of widespread disease is poor. In recent years several radiopharmaceuticals have become available for the diagnosis of this tumor. None of these tracers, however, has satisfactory diagnostic sensitivity and specificity. Furthermore, only few radiopharmaceutical compounds proved to have clinical value in therapeutic applications. Radionuclide therapy utilizes unsealed radioactive sources in order to deliver selective irradiation to the target organs or cancer lesions. This approach is only clinically indicated when there is a scintigraphic evidence of sufficient tumor uptake and a favorable biodistribution. When these conditions are present, radionuclide therapy can be adopted in MTC patients. Due to the low incidence of this tumor, the poor sensitivity of the available radiopharmaceuticals and their limited indications, the clinical experience in radionuclide therapy of MTC is still limited and there is general agreement among experts that it has only a palliative role. Here we briefly report the main experiences in radionuclide therapy in the past and in recent years. In addition, we summarize the results obtained with 131I-MIBG therapy at the Istituto Nazionale Tumori of Milan, as well as the most important ongoing preclinical and phase I/II trials.

Diagnostic procedures in the follow-up of patients affected by MEN type 2.

Multiple endocrine neoplasia type 2 (MEN 2) is an inherited disease caused by germline mutations in the RET proto-oncogene. The most distinctive MEN 2 variants are MEN 2A, MEN 2B and familial medullary thyroid cancer (FMTC). The hallmark of these syndromes is the development of medullary thyroid carcinoma (MTC), which occurs in almost all patients with MEN 2 syndromes. Other endocrinopathies are variably expressed. Pheochromocytoma and hyperparathyroidism occur in patients with MEN 2A with a frequency of about 50% and 30%, respectively. In this paper we summarize the most relevant diagnostic methods to detect and monitor MTC, pheochromocytoma and hyperparathyroidism.