Integrating irinotecan in standard chemotherapy: A novel dose-density combination for high-risk pediatric sarcomas.

BACKGROUND: Irinotecan is a drug active against pediatric sarcomas with a toxicity profile that theoretically allows for its association with more myelotoxic drugs. We examined the feasibility of a dose-density strategy integrating irinotecan in standard chemotherapy regimens for patients with high-risk sarcomas. METHODS: Between November 2013 and January 2020, 23 patients ≤25 years old were included in the study. Eleven patients newly diagnosed with metastatic disease received nine cycles of IrIVA (irinotecan-ifosfamide-vincristine-actinomycin D; ifosfamide 3 g/m2 on days 1 and 2, vincristine 1.5 mg/m2 on day 1, actinomycin D 1.5 mg/m2 on day 1, irinotecan 20 mg/m2 for 5 consecutive days starting on day 8) as first-line therapy. Two relapsed patients received IrIVA and 10 IrVAC (irinotecan-vincristine-actinomycin D-cyclophosphamide; cyclophosphamide 1.5 g/m2 on day 1 instead of ifosfamide). Feasibility was assessed in terms of toxicity and time to complete the treatment. RESULTS: Seventeen rhabdomyosarcomas, four Ewing sarcomas, two desmoplastic small round cell tumors received a total of 181 cycles (range 2-10). Grade 4 neutropenia occurred in 62.4% of the cycles. Thirteen patients had febrile neutropenia. Diarrhea occurred in 14 cycles. The median time to complete the treatment was 195 days (range 170-231), 83.4% of cycles were administered on time or with a delay <1 week. With a median follow-up of 2.6 years (range 0.2-5.0), 12 patients are alive, nine complete remissions, three with the disease. CONCLUSIONS: A dose-density strategy combining irinotecan with standard chemotherapy is feasible. This approach will be investigated in the next trial coordinated by the European pediatric Soft tissue sarcoma Study Group.

Treatment Strategies for Children With Relapsed Pancreatoblastoma: A Literature Review.

Pancreatoblastoma (PB) is a tumor typically seen in childhood. Despite its rarity, there are some internationally agreed recommendations for its first-line treatment, but very little is known about the management of relapse. We reviewed the literature on the treatment and outcome of children with progressing/recurrent PB, and the role of high-dose chemotherapy (HD-CT) or liver transplantation in difficult cases. A first analysis concerned 15 patients: liver metastases were the most frequent cause of first-line treatment failure. Eight patients underwent surgery, only 3 were irradiated. Various second-line chemotherapy regimens were adopted, with evidence of response in 8 children. The most often-used combinations included etoposide, cyclophosphamide/ifosfamide, and cisplatin/carboplatin. Overall, 7 patients are alive with a median follow-up of 24 months (range, 3 to 88 mo). In a separate analysis, considering patients in first-line or second-line treatment, we found 5 of 6 patients alive after HD-CT and 3 of 3 after liver transplantation. Our review shows that the outcome for patients with recurrent PB is not always dismal, especially when surgery is possible. Different chemotherapy combinations can be used, and HD-CT or liver transplantation may be considered in selected cases.

Pleuropulmonary blastoma: a report from the TREP (Tumori Rari in Età Pediatrica) Project.

INTRODUCTION: Pleuropulmonary blastoma (PPB) is a rare, aggressive mesenchymal tumor of childhood. The Italian Tumori Rari in Età Pediatrica (TREP) Registry was the first in Europe dedicated to prospective data collection on rare pediatric tumors. We analyzed data from an Italian series of patients with PPB, focusing on the role of the TREP Project. METHODS: We considered patients aged 0-14 with histologically confirmed diagnosis, registered in population-based cancer registries (before 2000) or the TREP Registry (2000 to 2014), and analyzed data on clinical characteristics, treatment, and outcome. Event-free survival (EFS) and overall survival (OS) were estimated. Relevant prognostic factors were identified performing a univariate analysis. RESULTS: Thirty-seven cases were included (7 type I, 13 type II, 17 type III). The average diagnosis rate rose from 1.10 to 1.73 cases/year after the TREP Project started. All patients underwent surgery, 33 received chemotherapy, and 9 had radiotherapy. The median follow-up was 8.7 years. For type I, II, and III, respectively, the 5-year OS was 85.7% (33.4-97.9), 52.7% (23.4-75.5), and 57.8% (31.1-77.3); the 5-year EFS was 85.7% (33.4-97.9), 52.7% (23.4-75.5), and 52.9% (27.6-73.0). Favorable prognostic factors for EFS were Intergroup Rhabdomyosarcoma Study (IRS) stage I (p = 0.03) and T1 tumor (p = 0.05). A total of 78.3% of patients who had chemotherapy after 2000 received a standardized treatment. CONCLUSIONS: The TREP Registry showed an excellent capacity for registering cases of PPB. Patients received homogeneous treatment after the TREP Project started. Long-term outcomes were excellent for type I and unsatisfactory for type II and III. Tumor invasiveness and IRS stage were of prognostic value.

Topotecan/carboplatin regimen for refractory/recurrent rhabdomyosarcoma in children: Report from the AIEOP Soft Tissue Sarcoma Committee.

INTRODUCTION: From 2002 to 2011, the Italian Soft Tissue Sarcoma Committee explored a combination of topotecan and carboplatin as a second-line strategy for children with resistant or relapsing rhabdomyosarcoma. METHODS: Patients received two blocks of topotecan 2 mg/m2 on days 1, 2, and 3, and carboplatin 250 mg/m2 on days 4 and 5, followed by alternating blocks of topotecan-cyclophosphamide and carboplatin-etoposide for a total of six courses with 3-week intervals. Tumor response was assessed after two cycles, and local control was implemented when feasible. RESULTS: A total of 38 patients were included in this study: 18/38 had alveolar rhabdomyosarcoma (RMS), 10/38 had metastatic disease at diagnosis, 8/38 had tumor progression during first-line chemotherapy, 21/38 had locoregional relapses, and 9/38 had distant relapses. Thirty-two patients could be assessed for tumor response to topotecan-carboplatin, and 9 (28%) showed a complete or partial response. Twenty-four patients experienced grade IV hematologic toxicity, while transient grade 1 tubulopathy, grade 3 mucositis, transient grade 2 nephrotoxicity, and a grade 2 decline in cardiac function occurred in one patient each. The 5-year overall and progression-free survival rates were 17% and 14%, respectively. CONCLUSION: the prognosis for children with resistant or relapsing RMS remains unsatisfactory. The topotecan-carboplatin regimen was well-tolerated. Though in case of late relapse the response rate was similar to those reported for other regimes, the result achieved remains unsatisfactory. New approaches, possibly including target agents, seem more attractive for future studies.

Pediatric patients with cutaneous melanoma: A European study.

INTRODUCTION: Cutaneous melanoma is rare in childhood and published studies have mainly been retrospective single-institution series or small case series. Given the absence of clinical protocols dedicated to pediatric melanoma, the treatment approach is generally extrapolated from the ones applied to adults. METHODS: Coordinated by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT), this study collected patients prospectively registered between 2002 and 2012 under national cooperative projects dedicated to rare pediatric tumors in Italy, Poland, Germany, and France. Additional cases were collected from dermatology registries in Germany and Israel. RESULTS: A total of 219 patients aged 0-18 years (median 14.4) were included in the analysis. Sentinel lymph node biopsy was performed in 112 patients (76% of those with Breslow thickness > 0.75 mm) and was positive in 37.5%. Systemic therapy was used in 33 cases. In stage III cases, survival rates were similar for patients who received (23 cases) or not (21 cases) adjuvant therapy. For the whole series, 3-year overall and disease-free survival rates were 91.4% and 84.0%, respectively (median follow-up 41.8 months). Tumor site, tumor stage, and ulceration influenced survival rates. Patients treated by pediatric oncologists (n = 140) were more likely to have advanced disease than those treated by dermatologists (n = 79). DISCUSSION: This study would suggest that the clinical history of melanoma in children and adolescents might resemble that of adult counterpart. Cooperative efforts are needed to make new drugs more readily available to pediatric patients to increase the outcome of patient with advanced disease.

Gastrointestinal tract carcinoma in pediatric and adolescent age: The Italian TREP project experience.

BACKGROUND: Gastrointestinal (GI) carcinomas are very rare in the pediatric and adolescent age range. We report the clinical features, treatment, and outcome of a series of children and adolescents with GI carcinoma prospectively registered in the Italian Tumori Rari in Età Pediatrica (TREP) project. METHODS: The TREP project developed diagnostic and therapeutic guidelines based on recommendations currently in use for adults. Clinical data were centrally registered and reviewed. RESULTS: Fifteen patients were registered over the years 2000-2016. Most of the tumors were colorectal carcinomas (12 cases). All but one patient had advanced-stage disease (American Joint Committee on Cancer stages III-IV), and the majority of patients had aggressive histological subtypes, i.e. poorly differentiated (G3) (five patients), mucinous (four patients), and signet ring (two patients) adenocarcinomas. Surgery was performed in 13 of 15 patients, and was radical in nine of 13 patients. Only one patient received postoperative radiotherapy. All patients received chemotherapy, with the addition of bevacizumab in two cases. Nine patients were still alive at the time of the present report, but two of them had only just completed their treatment program and one patient is still on treatment. Six patients died due to disease progression. CONCLUSIONS: This prospective report on pediatric GI tract carcinomas confirms the rarity and biological aggressiveness of these diseases in pediatric and adolescent age. Further prospective studies are needed to explore the distinct biology of tumor in this age group in order to find new therapeutic targeted agents.

Pressure ulcers in ICU patients: Incidence and clinical and epidemiological features: A multicenter study in southern Brazil.

OBJECTIVES: To evaluate the incidence and risk factors of pressure ulcers (PU) in adult patients admitted to intensive care units (ICUs), as well as the outcome (including ICU and hospital mortality) of these patients. METHODS: Epidemiological cohort multicenter prospective study, evaluating patients admitted for a period of 31days (June 01 to July 01, 2015) until hospital discharge. Epidemiological and clinical data were collected daily until ICU discharge, as was the incidence of PU, either new or present on admission. SETTING: 10 general adult ICUs. RESULTS: We evaluated 332 patients, 52.1% male, mean age 63.1 years. The most common cause of admission was medical diseases (50.3%), and the mean APACHE II score was 14.9. A total of 45 patients (13.6%) had PU; the most common sites were sacral, calcaneal, ears, and trochanter. The incidence of PU was related to predictive factors, such as the Braden Scale and length of lack of nutrition. The presence of PU was strongly related to unfavorable outcomes, such as Mechanical Ventilation (MV) duration and ICU and hospital mortality. CONCLUSIONS: PU incidence is related to severity of the patient's condition and predicted by Braden Scale score. The presence of PU is also related to adverse outcomes, such as MV duration and ICU and hospital mortality. It was also shown that patients with PU have a higher incidence of medical complications, such as acute renal failure, pneumonia, and the need for vasoactive drugs.