Massimo Provenzi

Disseminated Neuroblastoma in Children Older Than One Year at Diagnosis: Comparable Results With Three Consecutive High-Dose Protocols Adopted by the Italian Co-Operative Group for Neuroblastoma

PURPOSE To compare the outcomes associated with modifications in three consecutive protocols employed by the Italian Co-Operative Group for Neuroblastoma (ICGNB) in disseminated neuroblastoma. PATIENTS AND METHODS Between January 1985 and November 1997, a total of 359 children aged 1 to 15 years with newly diagnosed stage 4 neuroblastoma were enrolled in three consecutive protocols. Compared with ICGNB-85, the ICGNB-89 protocol contained two more chemotherapy cycles, and some drugs were given at greater doses, whereas in the ICGNB-92 protocol, the induction phase included a chelating agent, and individual cycles contained four drugs instead of two. RESULTS A total of 330 of 359 evaluable children were included in this analysis; 106 children were treated with ICGNB-85, 65 children were treated with ICGNB-89, and 159 children were treated with ICGNB-92 protocols. Radical resection of primary tumor was carried out in 59.4%, 50.8%, and 57.9% of the patients, respectively. Major tumor response after induction therapy was achieved in 66.7%, 69.2%, and 68.6% of the patients, respectively. A total of 218 of 232 patients received consolidation therapy consisting of conventional chemotherapy in 65 patients and of high-dose chemotherapy in 153 patients. Disease recurrence or progression occurred in 82.1%, 69.2%, and 74.8% of the patients, respectively. Therapy-related deaths occurred in 1.9%, 12.3%, and 6.9% of the patients, respectively. Five-year overall survival (OS) for the three studies was 26%, 23%, and 28%, and event-free survival (EFS) was 19%, 17%, and 17%, respectively. CONCLUSION The therapeutic modifications adopted in the ICGNB-89 and ICGNB-92 protocols were not associated with a significant improvement in response rate or in the 5-year OS and EFS as compared with the ICGNB-85 protocol. Attempts at intensifying chemotherapy were associated with greater toxicity.

Vinorelbine and low-dose cyclophosphamide in the treatment of pediatric sarcomas: Pilot study for the upcoming European rhabdomyosarcoma protocol

Following their previous report on the activity of vinorelbine in the treatment of rhabdomyosarcoma, the authors report the results of a pilot study aimed at defining the optimal dose of vinorelbine when this agent is used in conjunction with continuous, orally administered low‐dose cyclophosphamide to treat patients with refractory or recurrent sarcoma. It is hoped that the combination of vinorelbine and low‐dose cyclophosphamide can be used as a maintenance regimen in an upcoming European trial involving high‐risk patients with rhabdomyosarcoma.

Phase II study of a protracted irinotecan schedule in children with refractory or recurrent soft tissue sarcoma

Irinotecan (CPT‐11) is a novel antineoplastic agent that takes effect by inhibiting topoisomerase I. The Italian Soft Tissue Sarcoma (STS) Committee performed a multiinstitutional Phase II study to evaluate its effect on STS.

Neuroblastoma in the newborn. A study of the Italian Neuroblastoma Registry

AIM Presenting features, treatment and outcome of 134 newborns with neuroblastoma diagnosed over a 27-year period are described. METHODS Analyses were performed on the entire cohort and on patients distributed over three periods of diagnosis. RESULTS Twenty-seven tumours (20.1%) were detected prenatally. Localised disease prevailed (65.7%) with an increase of stage 1 patients over time from 18.8% to 46.5%. Disseminated disease accounted for 34.3% of tumours with only one stage 4 and 45 stage 4S. Five-year overall survival (OS) of the entire cohort was 88.3%. Five/88 patients with localised disease died, including three who died of complications (OS, 95.3%). The only stage 4 patient survived. Eleven/45 stage 4S patients died, including 7/18 symptomatic and 4/27 asymptomatic (OS, 74.1%). CONCLUSION The outcome of neuroblastoma in newborns is excellent. In localised tumours, surgery-related deaths outnumbered deaths due to disease. Symptomatic stage 4S patients were at greater risk of dying.

Heterogeneity of Disease Classified as Stage III in Wilms Tumor: A Report From the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP)

PURPOSE We analyzed whether the prognosis can differ among Wilms tumors (WT) labeled as Stage III according to currently adopted classification systems. METHODS AND MATERIALS Patients with nonanaplastic Stage III WT consecutively registered in two Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) trials (CNR-92, TW-2003) were the subjects in the present analysis. The steady mainstay of therapy was primary nephrectomy, followed by three-drug chemotherapy with vincristine, dactinomycin, doxorubicin, and abdominal radiotherapy (RT). RESULTS Ninety-nine WT patients met the criteria for classification as Stage III according to a revised version of the National Wilms Tumor Study-3 staging system (51 patients in CNR-92, 48 patients in TW-2003). Regional lymph nodes (LN) were not biopsied in 16 patients. After a median follow-up of 66 months, the 4-year disease-free survival (DFS) and overall survival (OS) rates were 85% ± 4% and 92% ± 3%, respectively, for the whole group. For 38 children with positive LN, the 4-year DFS rate was 73% ± 7%, as opposed to 98% ± 2% for the 45 children with Stage III WT according to the other criteria but with negative biopsied LN (p = 0.001). The subgroup with the worst prognosis consisted of children more than 2 years old with positive LN (DFS 67% ± 8%). A delay between surgery and RT > 30 days had an adverse impact on the abdominal tumor relapse rate. CONCLUSIONS This study provides further evidence that Stage III tumors with LN metastases might be distinguished from WTs meeting the other criteria for classification as Stage III. The worse outcome of the former may warrant a prospective study on the effects of intensified therapy. A subclassification of Stage III tumors is discussed.

The prognostic value of biological markers in paediatric Hodgkin lymphoma

BACKGROUND Many biological and inflammatory markers have been proposed as having a prognostic value at diagnosis of Hodgkin lymphoma (HL), but very few have been validated in paediatric patients. We explored the significance of these markers in a large population of 769 affected children. PATIENTS AND METHODS By using the database of patients enrolled in A.I.E.O.P. (Associazione Italiana di Emato-Oncologia Pediatrica) trial LH2004 for paediatric HL, we identified 769 consecutive patients treated with curative intent from 1st June 2004 to 1st April 2014 with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), or hybrid COPP/ABV (cyclophosphamide, vincristine, prednisone, procarbazine, doxorubicin, bleomycin and vinblastine) regimens. RESULTS On multivariate analysis with categorical forms, the 5-year freedom from progression survival was significantly lower in patients with stage IV or elevated value of platelets, eosinophils and ferritin at diagnosis. Furthermore, stage IV and eosinophils seem to maintain their predictive value independently of interim (after IV cycles of chemotherapy) positron emission tomography. CONCLUSION Using the combination of four simple markers such as stage IV and elevated levels of platelets, ferritin and eosinophils, it is possible to classify the patients into subgroups with very different outcomes.

Results of the Third AIEOP Cooperative Protocol on Wilms Tumor (TW2003) and Related Considerations

Purpose: TW2003, the third Italian prospective study on Wilms tumor, aimed to improve survival in patients with stage III‐IV tumors, de‐escalate therapy for stage I‐II nonanaplastic tumors, refine the risk stratification of therapy, and develop a national infrastructure for biobanking and central pathology review. Materials and Methods: TW2003 recruited children 18 years old or younger with primary intrarenal tumors. Local physicians chose nephrectomy with or without preoperative chemotherapy as the initial treatment based on the risk of unsafe and/or incomplete immediate surgery. The main drivers for adjuvant therapy were tumor stage and diffuse anaplasia. A new risk stratification schema was investigated, incorporating patient age, reason for stage III designation and completeness of lung nodule response in stage IV disease. Results: We report on 453 patients with unilateral Wilms tumor. Preoperative chemotherapy was administered to 42% of patients. The 5‐year event‐free survival and overall survival rates were 89.1% (95% CI 83.6–94.9) and 97.0% (93.7–100) for stage I; 85.1% (79.6–91.1) and 94.0% (90.1–98.1) for stage II (160); 82.7% (75.3–90.8) and 90.9% (85.0–97.1) for stage III (101); and 72.1% (61.9–84.0) and 82.5% (73.1–93.1) for stage IV (69), respectively. On multivariable analysis only anaplasia was significant for event‐free survival (HR 2.68, 95% CI 1.48–4.86, p=0.001; bias corrected c‐index 0.580) and overall survival (HR 5.29, 95% CI 2.52–11.12, p <0.001; bias corrected c‐index 0.697). Conclusions: The survival rates achieved and the proposed risk stratification schema provide a basis for future comparisons of Wilms tumor treatment burden and patient outcome.

Biliary tract rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Associazione Italiana Ematologia Oncologia Pediatrica

Introduction: Rhabdomyosarcoma is a soft tissue malignant musculoskeletal tumor frequent in children. Biliary duct localization is extremely rare, but it is the most common cause of malignant obstructive jaundice in pediatric patients. Methods: This report describes a series of 10 patients under 18 years of age with biliary tract rhabdomyosarcoma who were enrolled, from 1979 to 2004, in 3 consecutive Italian pediatric cooperative protocols that had been drawn up by the Soft Tissue Sarcoma Committee of the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP). Results: Considering initial and delayed surgery, tumor resection was achieved in 7 cases, 3 complete with free margins (2 liver transplants) and 4 with microscopic residual disease. Chemotherapy was given to all patients and radiotherapy to 3. At present, 5 patients survive in complete remission 90-200 months after diagnosis while 4 died of disease progression or relapse and 1 of liver transplant-related complications. Conclusions: Better outcomes in this series were associated with the feasibility of conservative surgery due to the favorable location of the tumor, in particular in the common bile duct. Chemotherapy and radiotherapy might obviate the need for demolitive surgery or liver transplant, which were linked to worse outcomes in our series.

Classical pediatric Hodgkin lymphoma in very young patients: the Italian experience

Abstract Many studies have reported a more favorable outcome in younger patients with Hodgkin lymphoma (HL). The aims of this study were to find an appropriate age cutoff able to identify low-risk children and to describe the natural history of 135 very young patients affected by classic HL (cHL). The best age cutoff was identified at 7 years of age. EFS (p = .0451) and PFS (p = .00921) were significantly better in the group of younger patients. The OS rate at 10 years was 97.0% in the younger group and 92.5% in the older one (p = .0448). However, age was not found to be an independent prognostic factor in multivariate analysis and the better prognosis in younger patients seems to be related to more favorable disease characteristics at presentation.

Vinorelbine and low dose cyclophosphamide in pediatric sarcoma. A pilot study for the future European rhabdomyosarcoma protocol

8540 Background: Following our previous report (Casanova et al. Cancer 2002; 94: 3263) on the activity of vinorelbine (VNB) in rhabdomyosarcoma (RMS), we report the results of a pilot study aimed to define the dose of VNB in combination with low dose continuous oral cyclophosphamide (CTX) in patients with refractory or recurrent sarcomas. The study was performed in the view of utilizing this treatment as maintenance therapy in the future European protocol for high risk RMS patients. METHODS The dose of CTX was fixed at 25 mg/m2/day for 28 days. VNB given i.v. on days 1, 8, and 15 was escalated from a starting dose of 15 mg/m2 by 5-mg/m2 increments in subsequent cohorts of at least 3 patients until the maximum tolerated dose was reached. RESULTS Between April 2003 and November 2003, 18 patients (10 M, 8 F) aged 2-23 years (median 12) received 88 cycles (9 had RMS). There was a median of 2 prior regimens (range 1-4); 5 patients previously received high dose chemotherapy with PBSC rescue and 12 prior radiotherapy. Three patients were treated at dose level 1, 4 at dose level 2, and 3 at dose level 3. Among 5 patients treated at dose level 4 (VNB 30 mg/m2) 2 dose limiting toxicities (grade 4 neutropenia) were observed in the first 2 cycles therefore a decision was made to enter 3 more patients at dose level 3. In the 39 cycles administered at dose level 3, neutropenia grade ≥ 3 was observed in 14 (36%) with no other major toxicity. The interval between courses 1 and 2 was as scheduled (28 days) in 12 patients, 5 had a delay ≤ 3 days. One patient, with parameningeal RMS who underwent RT a few weeks before study entry, had a delay of 2 weeks due to prolonged grade 2 mucositis. A median of 5 cycles (range 1-10) were administered per patient. Four patients were still on treatment after 5-10 cycles. Partial responses were observed in 7/17 assessable patients: 3/8 RMS (2 embryonal, 1 alveolar), 1/1 clear cell sarcoma, 1/2 synovial sarcoma, 1/2 desmoplastic small round cell tumor, 1/1 osteosarcoma. CONCLUSIONS This combination appears to be feasible and active in relapsed sarcoma. Recommended doses for the new study will be CTX 25 mg/m2/day for 28 days and VNB 25 mg/m2 on days 1,8, and 15. No significant financial relationships to disclose.