Aggressive surgical approach in patients with adrenal-only metastases from hepatocellular carcinoma enables higher survival rates than standard systemic therapy.

BACKGROUND: Although guidelines recommend systemic therapy even in patients with limited extrahepatic metastases from hepatocellular carcinoma (HCC), a few recent studies suggested a potential benefit for resection of extrahepatic metastases. However, the benefit of adrenal resection (AR) for adrenal-only metastases (AOM) from HCC was not proved yet. This is the first study to compare long-term outcomes of AR to those of sorafenib in patients with AOM from HCC. METHODS: The patients with adrenal metastases (AM) from HCC were identified from the electronic records of the institution between January 2002 and December 2018. Those who presented AM and other sites of extrahepatic disease were excluded. Furthermore, the patients with AOM who received other therapies than AR or sorafenib were excluded. RESULTS: A total of 34 patients with AM from HCC were treated. Out of these, 22 patients had AOM, 6 receiving other treatment than AR or sorafenib. Eventually, 8 patients with AOM underwent AR (AR group), while 8 patients were treated with sorafenib (SOR group). The baseline characteristics of the two groups were not significantly different in terms of age, sex, number and size of the primary tumor, timing of AM diagnosis, Child-Pugh and ECOG status. After a median follow-up of 15.5 months, in the AR group, the 1-, 3-, and 5-year overall survival rates (85.7%, 42.9%, and 0%, respectively) were significantly higher than those achieved in the SOR group (62.5%, 0% and 0% at 1-, 3- and 5-year, respectively) (P = 0.009). The median progression-free survival after AR (14 months) was significantly longer than that after sorafenib therapy (6 months, P = 0.002). CONCLUSIONS: In patients with AOM from HCC, AR was associated with significantly higher overall and progression-free survival rates than systemic therapy with sorafenib. These results could represent a starting-point for future phase II/III clinical trials.

Retinoic acid postconsolidation therapy for high-risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation.

BACKGROUND: Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumours mainly develop in the adrenal medullary tissue, with an abdominal mass as the most common presentation. About 50% of patients have metastatic disease at diagnosis. The high-risk group is characterised by metastasis and other features that increase the risk of an adverse outcome. High-risk patients have a five-year event-free survival of less than 50%. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome of patients with high-risk neuroblastoma. This review is an update of a previously published Cochrane Review. OBJECTIVES: To evaluate the efficacy and safety of additional retinoic acid as part of a postconsolidation therapy after high-dose chemotherapy (HDCT) followed by autologous haematopoietic stem cell transplantation (HSCT), compared to placebo retinoic acid or to no additional retinoic acid in people with high-risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2016, Issue 11), MEDLINE in PubMed (1946 to 24 November 2016), and Embase in Ovid (1947 to 24 November 2016). Further searches included trial registries (on 22 December 2016), conference proceedings (on 23 March 2017) and reference lists of recent reviews and relevant studies. We did not apply limits by publication year or languages. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating additional retinoic acid after HDCT followed by HSCT for people with high-risk neuroblastoma compared to placebo retinoic acid or to no additional retinoic acid. Primary outcomes were overall survival and treatment-related mortality. Secondary outcomes were progression-free survival, event-free survival, early toxicity, late toxicity, and health-related quality of life. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: The update search did not identify any additional studies. We identified one RCT that included people with high-risk neuroblastoma who received HDCT followed by autologous HSCT (N = 98) after a first random allocation and who received retinoic acid (13-cis-retinoic acid; N = 50) or no further therapy (N = 48) after a second random allocation. These 98 participants had no progressive disease after HDCT followed by autologous HSCT. There was no clear evidence of difference between the treatment groups either in overall survival (hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.46 to 1.63; one trial; P = 0.66) or in event-free survival (HR 0.86, 95% CI 0.50 to 1.49; one trial; P = 0.59). We calculated the HR values using the complete follow-up period of the trial. The study also reported overall survival estimates at a fixed point in time. At the time point of five years, the survival estimate was reported to be 59% for the retinoic acid group and 41% for the no-further-therapy group (P value not reported). We did not identify results for treatment-related mortality, progression-free survival, early or late toxicity, or health-related quality of life. We could not rule out the possible presence of selection bias, performance bias, attrition bias, and other bias. We judged the evidence to be of low quality for overall survival and event-free survival, downgraded because of study limitations and imprecision. AUTHORS' CONCLUSIONS: We identified one RCT that evaluated additional retinoic acid as part of a postconsolidation therapy after HDCT followed by autologous HSCT versus no further therapy in people with high-risk neuroblastoma. There was no clear evidence of a difference in overall survival and event-free survival between the treatment alternatives. This could be the result of low power. Information on other outcomes was not available. This trial was performed in the 1990s, since when many changes in treatment and risk classification have occurred. Based on the currently available evidence, we are therefore uncertain about the effects of retinoic acid in people with high-risk neuroblastoma. More research is needed for a definitive conclusion.

Refractory diarrhea: A paraneoplastic syndrome of neuroblastoma.

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Diarrheal NB is quite rare and is not easy to diagnose in the early stage. Six cases of diarrheal NB in our hospital treated from 1996 to 2006 were retrospectively analyzed, including characteristics such as electrolyte imbalance, pathologic features, vasoactive intestinal peptide (VIP) immunohistochemical staining results, treatment, and prognosis. All patients were boys with 3-8 loose or watery stools each day and routine fecal tests were normal. Abdominal tumors were identified by B-ultrasound. Drugs were ineffective. Three patients underwent surgery, and the remaining three patients received surgery and chemotherapy. Diarrhea stopped after treatment in five patients. Two patients died due to intractable hypokalemia. The tumor was located in the adrenal gland in four patients, in the upper retroperitoneum in one patient, and in the presacral area in one patient. Pathologic findings were NB and ganglioneuroblastoma. Five patients were at clinical stage I-II, and one was at stage III. Four patients survived (followed-up for 6 mo to 4 years). Immunohistochemical staining for VIP was positive. Refractory diarrhea is a paraneoplastic syndrome of NB and is rare. Patients aged 1-3 years who present with chronic intractable diarrhea should be followed closely. Intractable diarrhea, hypokalemia, and dysplasia are the initial clinical manifestations. Increased VIP is characteristic of this disease. Potassium supplementation plays a vital role in the treatment procedure, especially preoperatively. The prognosis of diarrheal NB is good following appropriate treatment.

Retinoic acid post consolidation therapy for high-risk neuroblastoma patients treated with autologous hematopoietic stem cell transplantation.

BACKGROUND: Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumors mainly develop in the adrenal medullary tissue and an abdominal mass is the most common presentation. About 50% of patients have metastatic disease at diagnosis. The high-risk group is characterized by metastasis and other characteristics that increase the risk for an adverse outcome. High-risk patients have a five-year event-free survival of less than 50%. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome of patients with high-risk neuroblastoma. OBJECTIVES: To evaluate efficacy and adverse events of retinoic acid after consolidation with high-dose chemotherapy followed by bone marrow transplantation as compared to placebo or no therapy in patients with high-risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system). Our outcomes of interest were overall survival and treatment-related mortality as primary outcomes; and progression- and event-free survival, early and late toxicity, and health-related quality of life as secondary outcomes. SEARCH METHODS: We searched the electronic databases CENTRAL (2014, Issue 8) on The Cochrane Library, MEDLINE (1946 to October 2014), and EMBASE (1947 to October 2014). Further searches included trial registries, conference proceedings, and reference lists of recent reviews and relevant articles. We did not apply limits on publication year or languages. SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating retinoic acid post consolidation therapy for high-risk neuroblastoma patients treated with autologous hematopoietic stem cell transplantation (HSCT) compared to placebo or no further treatment. DATA COLLECTION AND ANALYSIS: Two review authors performed the study selection, extracted the data on study and patient characteristics and assessed the risk of bias independently. We resolved differences by discussion or by appeal to a third review author. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. The authors of the included study did not report the results specifically for the treatment groups relevant to this Cochrane Review. Therefore, we deduced the appropriate survival data from the published survival curves and calculated a hazard ratio (HR) based on the deduced data. MAIN RESULTS: We identified one RCT (CCG-3891) that included patients with high-risk neuroblastoma who received high-dose chemotherapy followed by autologous HSCT (N = 98) after a first random allocation and who received retinoic acid (13-cis-retinoic acid; N = 50) or no further therapy (N = 48) after a subsequent second random allocation. These patients had no progressive disease after consolidation therapy. There was no clear evidence of difference between the treatment groups in both overall survival (HR 0.87, 95% CI 0.46 to 1.63; one trial; P = 0.66, low quality of evidence) and event-free survival (HR 0.86, 95% CI 0.50 to 1.49; one trial; P = 0.59, low quality of evidence). We calculated these HR values using the complete follow-up period of the trial. The study also reported five-year overall survival rates: 59% for the retinoic acid group and 41% for the no further therapy group (P value not reported). We did not identify results for treatment-related mortality, progression-free survival, early or late toxicity, or health-related quality of life. Also, we could not rule out the possible presence of selection bias, performance bias, attrition bias, and other bias. AUTHORS' CONCLUSIONS: We identified one RCT that evaluated retinoic acid as a consolidation therapy versus no further therapy after high-dose chemotherapy followed by bone-marrow transplantation in patients with high-risk neuroblastoma. The difference in overall survival and event-free survival between both treatment alternatives was not statistically significantly different. This could be the result of low power. Information on other outcomes was not available. This trial was performed in the 1990s, since then many changes in for example treatment and risk classification have occurred. Therefore, based on the currently available evidence, we are uncertain about the effects of retinoic acid in patients with high-risk neuroblastoma. More research is needed for a definitive conclusion.

Neuroblastoma: treatment outcome after incomplete resection of primary tumors.

PURPOSE: For International Neuroblastoma Staging System (INSS) stages III or IV neuroblastoma (intermediate or high risk), complete excision of the primary tumor is not always feasible. Most current studies on the treatment outcome of these patients have reported on the complete excision status. The aim of this study is to review the treatment outcome after the incomplete resection. METHODS: The medical records of 37 patients that underwent incomplete resection between January 1986 and December 2005 were reviewed retrospectively. Incomplete resection was assessed by review of the operative notes and postoperative computerized tomography. Age, gender, tumor location, INSS stage, N-myc gene copy number, pre- and postoperative therapy, and treatment outcome were reviewed. The treatment outcome was evaluated according to the postoperative treatment protocol in the high-risk group. RESULTS: Intermediate-risk patients were treated with conventional chemotherapy, isotretinoin (ITT) and interleukin-2 (IL-2). High-risk patients were treated with peripheral blood stem cell transplantation (PBSCT), ITT, and IL-2 (N = 11). Before the introduction of PBSCT, the high-risk patients were also treated with the conventional chemotherapy (N = 19). Intermediate-risk patients (N = 5) currently have no evidence of disease (NED). For the high-risk patients (N = 32), 19 patients were treated with chemotherapy alone; 15 patients died of their disease while four patients currently have an NED status. Eight of 11 patients that underwent PBSCT are currently alive. CONCLUSIONS: For intermediate risk, conventional chemotherapy appears to be acceptable treatment. However, for high-risk patients, every effort should be made to control residual disease including the use of myeloablative chemotherapy, differentiating agents and immune-modulating agents.

Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma.

PURPOSE: To evaluate the safety and efficacy of high-dose [(131)I]metaiodobenzylguanidine ([(131)I]MIBG) in the treatment of malignant pheochromocytoma (PHEO) and paraganglioma (PGL). METHODS: Fifty patients with metastatic PHEO or PGL, age 10 to 64 years, were treated with [(131)I]MIBG doses ranging from 492 to 1,160 mCi (median, 12 mCi/kg). Cumulative [(131)I]MIBG administered ranged from 492 to 3,191 mCi. Autologous hematopoietic stem cells were collected and cryopreserved before treatment with [(131)I]MIBG greater than 12 mCi/kg or with a total dose greater than 500 mCi. Sixty-nine [(131)I]MIBG infusions were given, which included infusions to 35 patients treated once and infusions to 15 patients who received two or three treatments. Response was evaluated by [(123)I]MIBG scans, computed tomography/magnetic resonance imaging, urinary catecholamines/metanephrines, and chromogranin A. RESULTS: The overall complete response (CR) plus partial response (PR) rate in 49 evaluable patients was 22%. Additionally, 35% of patients achieved a CR or PR in at least one measure of response without progressive disease, and 8% of patients maintained stable disease for greater than 12 months. Thirty-five percent of patients experienced progressive disease within 1 year after therapy. The estimated 5-year overall survival rate was 64%. Toxicities included grades 3 to 4 neutropenia (87%) and thrombocytopenia (83%). Grades 3 to 4 nonhematologic toxicity included acute respiratory distress syndrome (n = 2), bronchiolitis obliterans organizing pneumonia (n = 2), pulmonary embolism (n = 1), fever with neutropenia (n = 7), acute hypertension (n = 10), infection (n = 2), myelodysplastic syndrome (n = 2), and hypogonadism (n = 4). CONCLUSION: Although serious toxicity may occur, the survival and response rates achieved with high-dose [(131)I]MIBG suggest its utility in the management of selected patients with metastatic PHEO and PGL.

The impact of gross total resection on local control and survival in high-risk neuroblastoma.

BACKGROUND/PURPOSE: Gross total resection of the primary tumor in treatment of high-risk neuroblastoma remains controversial. Furthermore, there are few reports of the effect of primary tumor resection on local control as opposed to overall survival. The authors reviewed their institutional experience to assess the effect of primary tumor resection on local control and overall survival. METHODS: A total of 141 patients were treated on protocol between November 1, 1979 and June 25, 2002 and are the subject of this report. Gross total resection was assessed by review of operative notes, postoperative computerized axial tomograms, and postoperative meta-iodobenzyl guanidine (MIBG)1 scans when available. RESULTS: The median age was 3.3 years, and all patients were International Neuroblastoma Staging System (INSS) stage 4 with 79% having metastases to cortical bone. The primary site was the adrenal gland in 74%, the central abdominal compartment in 13%, the posterior mediastinum in 7%, and other sites in 6%. Gross total resection was accomplished in 103 (73%) but was more than 90% for the last 3 protocols. Five kidneys were lost overall. The probability of local progression was 50% in unresected patients compared with 10% in patients undergoing gross total resection (P <.01). Overall survival rate in resected patients was 50% compared with 11% in unresected patients (P <.01). CONCLUSIONS: Our data indicate that local control and overall survival rate are correlated with gross total resection of the primary tumor in high-risk neuroblastoma. Gross total resection should be part of the management of stage 4 neuroblastoma in patients greater than 1 year of age.

[(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas.

Selecting the appropriate approach for resection and follow-up of pheochromocytomas (PCCs) is highly dependent upon reliable localization and exclusion of multifocal, bilateral, or metastatic disease. Metaiodobenzylguanidine (MIBG) scintigraphy was developed for functional localization of catecholamine-secreting tissues. Somatostatin receptor imaging (SRI) has a high sensitivity for localizing head and neck paragangliomas, but studies of intraabdominal PCCs are rare. In this study we review our experience of [(123)I]MIBG and SRI, performed since 1983 and 1989, respectively, in the work-up of primary and recurrent PCCs. Scintigraphic results were correlated with catecholamine secretion, size and site, malignancy, associated tumor syndromes, and morphological features. [(123)I]MIBG scans were performed in a total of 75 patients, in 70 cases before resection of primary PCCs and in 5 cases because of recurrent disease. Ninety-one PCCs were resected. The overall detection rates were 83.3% and 89.8% for PCCs larger than 1.0 cm. Multifocal disease was detected in 4 patients with [(123)I]MIBG. [(123)I]MIBG uptake correlated with greater size of PCC (r = 0.33; P = 0.008) and greater concentration of plasma epinephrine (r = 0.32; P = 0.006). [(123)I]MIBG-negative PCCs (n = 14) had significantly (P = 0.01) smaller diameters than [(123I)]MIBG-positive tumors. Furthermore, [(123)I]MIBG uptake was significantly higher in unilateral (P = 0.02), benign (P = 0.02), sporadic (P = 0.02), intraadrenal (P = 0.02), and capsular invasive (P = 0.03) PCCs than in bilateral, malignant, MEN2A/2B-related, extraadrenal, and noninvasive PCCs, respectively. The detection rate of SRI was only 25% (8 of 32) for primary benign PCCs. In 14 patients metastases occurred, which were effectively visualized with [(123)I]MIBG in 8 of 14 cases. SRI was able to detect metastases in 7 of 8 cases, including 3 [(123)I]MIBG-negative metastatic cases. In addition, [(123)I]MIBG and SRI detected 2 recurrences. In conclusion, [(123)I]MIBG uptake is correlated with the size, epinephrine production, and site of PCCs. Its role in bilateral and MEN2A/2B-related PCCs seems limited. In cases of recurrent elevation of catecholamines, localization of metastases and/or recurrence should be attempted with [(123)I]MIBG scintigraphy. In suspicious metastatic PCCs, SRI might be considered to supplement [(123)I]MIBG scintigraphy.

[Therapeutic possibilities in metastatic pheochromocytoma]. / Die therapeutischen Möglichkeiten bei metastasiertem Phäochromozytom.

Malignant pheochromocytomas are rare. Although 5-year survival is less than 50%, the prognosis varies. Some patients, even those with extensive metastases, have been followed up for many years. If the tumor tissue's uptake is adequate (> 5 Gy/100 mCi) the therapeutic use of 131I-meta-iodobenzylguanidin (131I-MIBG) is at present the therapy of first choice. The use of cytostatic chemotherapy should be limited to patients with rapidly progressive disease.

Pretreatment with [131I] metaiodobenzylguanidine and surgical resection of advanced neuroblastoma.

Pretreatment with [131I] metaiodobenzylguanidine (MIBG) followed by surgical resection in advanced neuroblastoma (stage 3 and 4) has been studied in relation to resectability, morbidity and mortality, survival rate after two years, control of distant metastasis and serum levels of LDH as prognostic factors. Twenty-one patients with advanced neuroblastoma were primarily treated with MIBG radiotherapy, followed by surgical resection. Sixteen patients had stage 4 disease. Between 2 and 6 courses of MIBG treatment were given per patient. In 17 patients gross complete resection was achieved. Two patients developed complications directly related to the operation, one died as a result of this. The overall mortality was 38%. MIBG therapy resulted in partial response in 13 patients and in stable disease in 8 patients. Two years survival in the group with partial response was 86% and in the group with stable disease 28%. Because of the resulting excellent general condition of the patients the interval between pretreatment with MIBG and surgery could be very short. Follow-up till December 1994 showed that 13 children were alive for 3 to 47 months. Seven had no evidence of disease. Preoperative MIBG de novo treatment in advanced neuroblastoma is equal to induction chemotherapy, but less toxic.