In transit metastases in children, adolescents and young adults with localized rhabdomyosarcoma of the distal extremities: Analysis of the EpSSG RMS 2005 study.

In-transit metastases (ITM) are defined as metastatic lymph nodes or deposits occurring between the primary tumor and proximal draining lymph node basin. In extremity rhabdomyosarcoma (RMS), they have rarely been reported. This study evaluates the frequency, staging and survival of patients with ITM in distal extremity RMS. METHODS: Patients with extremity RMS distal to the elbow or knee, enrolled in the EpSSG RMS 2005 trial between 2005 and 2016 were eligible for this study. RESULTS: One hundred and nine distal extremity RMS patients, with a median age of 6.2 years (range 0-21 years) were included. Thirty seven of 109 (34%) had lymph node metastases at diagnosis, 19 of them (51%) had ITM, especially in lower extremity RMS. 18F-FDG-PET/CT detected involved lymph nodes in 47% of patients. In patients not undergoing 18F-FDG-PET/CT lymph node involvement was detected in 22%. The 5-yr EFS of patients with ITM vs proximal lymph nodes vs combined proximal and ITM was 88.9% vs 21.4% vs 20%, respectively (p = 0.01) and 5-yr OS was 100% vs 25.2% vs 15%, respectively (p = 0.003). CONCLUSION: Our study showed that in-transit metastases constituted more than 50% of all lymph node metastases in distal extremity RMS. 18F-FDG-PET/CT improved nodal staging by detecting more regional and in-transit metastases. Popliteal and epitrochlear nodes should be considered as true (distal) regional nodes, instead of in-transit metastases. Biopsy of these nodes is recommended especially in distal extremity RMS of the lower limb. Patients with proximal (axillary or inguinal) lymph node involvement have a worse prognosis.

CyberKnife robotic image-guided stereotactic radiotherapy for oligometastic cancer : A prospective evaluation of 95 patients/118 lesions.

PURPOSE: To evaluate the outcome of robotic CyberKnife (Accuray Inc. Sunnyvale, USA)-based stereotactic radiotherapy (CBK-SRT) for oligometastic cancer patients. PATIENTS AND METHODS: Between May 2007 and December 2009, 95 patients with a total of 118 lesions underwent CBK-SRT (median dose 24 Gy in 3 fractions). INCLUSION CRITERIA: adult patients with limited volume cancer; suitability for SRT but not for other local therapies. Primary diagnoses included breast, lung, head and neck, gastrointestinal and other malignancies. Prostate cancer patients were excluded. Concomitant systemic therapy was given in 40 % of cases and median follow-up was 12 months. Toxicity and tumor response were evaluated using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) Scale and Response Evaluation Criteria in Solid Tumors RECIST. RESULTS: Toxicity was rare and observed mainly in patients with comorbidities or uncontrolled cancer. Out of 87 evaluable lesions, complete radiological response, partial response, stabilization and progressive disease were observed in 15 (17 %), 25 (29 %), 34 (39 %) and 13 (15 %) lesions, respectively. Upon restricting the analysis to lesions treated with CBK-SRT alone (no concomitant therapy), response- and local control (LC) rates remained similar. Actuarial 3-year in-field progression-free survival- (i.e. LC), progression-free survival- (PFS) and overall-survival (OS) rates were 67.6, 18.4, and 31.2 %, respectively. LC was reduced in cases of early recurrence. OS- and cause-specific survival (CSS) rates were significantly lower in patients treated for visceral lesions. Failures were predominantly out-field. CONCLUSION: CBK-SRT is a feasible therapeutic approach for oligometastastic cancer patients that provides long-term in-field tumor control with a low toxicity profile. Further investigations should focus on dose escalation and optimization of the combination with systemic therapies.

[Role of mutilating surgery in the treatment of non-chemosensitive pediatric soft tissue sarcomas. Experience of the Italian Cooperative Group Studies RMS-79 and RMS-88]. / Ruolo della chirurgia mutilante nel trattamento dei sarcomi delle parti molli non chemiosensibili in età pediatrica. Esperienza degli studi Cooperativi Italiani RMS-79 ed RMS-88.

UNLABELLED: Aim of the study was to evaluate the role of mutilating surgery in the patients with non chemosensitive soft tissue sarcomas (STS) registered in the Italian Studies. Between 1979 and 1995, 114 patients (pts) with "non chemosensitive" localized STS were enrolled in the cooperative studies RMS-79 (33) and RMS-88 (81). Median age: 89 months (range 1-194). HISTOLOGY: fibrosarcoma 29, Malignant Perpheral Nerve Sheath Tumors (MPNST) 40, malignant fibrous histiocytoma 5, hemangiopericytoma 6, leiomyosarcoma 4, others 20, STS nos 10. The cases were classified according to the IRS staging system as Gr. I 46, Gr. II 24, Gr. III 44. Twelve out of 114 pts (7%), 5/33 (14%) in the first study and 7/81 (8%) in the second, underwent mutilating surgery: 8 pts (of whom 3 were < 2 y of age) had a fibrosarcoma and 4 a MPNST. The mutilating procedure was carried out at diagnosis in 6 cases (4 in RMS-79 and 2 in RMS-and 88) and achieved radicality in 5/6 cases. It was performed after ineffective chemotherapy (CT) in 5 pts (1 in RMS-79 and 4 in RMS-88). One pt (RMS-88) underwent mutilation after multiple local recurrences treated with CT, radiotherapy and conservative excisions (RMS-88) and died. The procedures consisted of 5 amputations, 4 demolitive excisions of extremities with functional impairment, 1 nephrectomy, 1 excision of deferents with spermatic vesicae and 1 mastectomy. OUTCOME: At present 6/12 pts, 5 with fibrosarcoma and 1 with MPNST, are alive with no evidence of disease (NED), 4 of the first and 2 of the second study. Of the 5 Gr. I patients, 4 are alive (NED) and 1 died of 2nd tumor; 1 Gr. II pt is alive NED; of the 5 Gr. III pts 1 is alive NED and 4 died (3 of metastatic spread and 1 of 2nd tumor); the pt amputated after repeated local relapses (Gr. II) is dead of pulmonary metastases. CONCLUSIONS: In the RMS-79 study the mutilations were frequent and were performed at diagnosis in several cases; this trend decreased in the 2nd study in which chemotherapy was attempted in most of the patients. Probably the timing of mutilating procedures was not always adequate (too early or too late). The outcome of pts undergone mutilations is similar to that of the whole group of 114 pts, whose overall survival at 10 years is 64% (C.I. 60-77). Only fibrosarcomas and MPNST probably requires a more aggressive surgical behaviour. At present we avoid initial demolitive surgery; it should be planned without delay after the first local relapse or after initial ineffective CT and RT.

Paratesticular rhabdomyosarcoma: report from the Italian and German Cooperative Group.

PURPOSE: We report the experience of the German-Italian Cooperative Group with 216 pediatric patients with paratesticular rhabdomyosarcoma treated over 20 years. PATIENTS AND METHODS: At diagnosis, 198 patients had localized disease and 18 had distant metastases. Among the nonmetastatic patients, complete tumor resection was performed in 83% of cases. Evaluation of the retroperitoneal lymph nodes changed over the years from routine surgical staging to radiologic assessment. All patients received chemotherapy, which was reduced in intensity and duration for patients with low-risk features in subsequent protocols. Radiotherapy was administered to 10% of patients. RESULTS: Among 72 patients with a negative retroperitoneal computed tomography (CT) scan, surgical assessment detected nodal involvement in only one case. Among 23 patients with enlarged nodes on CT scans, surgery confirmed nodal spread in 65% of patients. No differences in the rate of nodal involvement were observed over the years. With a median follow-up of 110 months, 5-year survival was 85.5% for the series as a whole, 94.6% for patients with localized disease, and 22.2% for metastatic cases. Retroperitoneal nodal recurrence was the major cause of treatment failure. Univariate analysis revealed the prognostic value of tumor invasiveness, size, and resectability, as well as of nodal involvement and age, in patients with localized tumor. CONCLUSION: The outcome for patients with localized paratesticular rhabdomyosarcoma is excellent, despite the reduction in chemotherapy over the years: an alkylating agent-free and anthracycline-free regimen is adequate treatment for low-risk patients. Surgical assessment of the retroperitoneum must be reserved for patients with enlarged nodes on CT scans. Children over 10 years old carry a higher risk of nodal involvement and relapse.

Fibrosarcoma in pediatric patients: results of the Italian Cooperative Group studies (1979-1995).

BACKGROUND AND OBJECTIVES: Fibrosarcoma is a rare soft tissue sarcoma (STS) that has two peaks of incidence in pediatric patients: one in infants and young children (infantile fibrosarcoma), another in older children ("adult type" fibrosarcoma). The purpose of this study was to describe the clinical features and the treatment results in patients affected by fibrosarcoma enrolled in two consecutive studies run by the STS-Italian Cooperative Group (ICG) between 1979 and 1995. PATIENTS AND METHODS: Twenty-five evaluable patients were grouped according the intergroup rhabdomyosarcoma staging (IRS) system: 12 Gr I, 5 Gr II, 8 Gr III. The cut-off point between the two forms was considered the age of 2 years: 14 patients were affected by infantile and 11 by adult type of fibrosarcoma. The therapeutic guidelines were not strict and not different for the two forms: patients with initial macroscopic excision (Gr I-II) were given IVA or VAC; Gr III had VAC or VAIA and subsequent excision, if feasible. Radiation therapy (RT) was delivered in patients > 3 years with microscopic (42 Gy) and macroscopic (54 Gy) residuals. RESULTS: Thirteen patients are alive without evidence of disease: 10 in first complete remission (CR), 7 Gr I, 1 Gr II, 2 Gr III, 3 in second CR after local relapse (LR) (2 Gr I, 1 Gr II). Two Gr I patients are alive with metastatic relapse. Nine patients died: six of progressive disease (PD) (three Gr II, three Gr III), two because of a second tumor (one Gr I, one Gr III) and one because of other causes (Gr III). One Gr III patient was lost at follow up, 2 years from diagnosis. The 10 years overall survival (OS) is 67.4% and the progression-free survival (PFS) is 52.2%. The OS for patients < 2 years is 78.6% (11 of 14), versus 51% for patients > 2 years (5 of 11). CONCLUSIONS: The complete excision at diagnosis was the treatment of choice and was related to the best outcome. Microscopical residuals were difficult to treat with chemo-radiotherapy in both forms of fibrosarcoma. Neoadjuvant chemotherapy (CT) obtained a partial remission (PR) only in three of eight cases, while no conclusions concerning the efficacy of CT for infantile forms are possible. Patients < 2 years had a better outcome than the older ones: most of them had a tumor on extremities which was excised at diagnosis.

Primary re-excision: the Italian experience in patients with localized soft-tissue sarcomas.

Primary re-excision (PRE) is a wide, non-mutilating procedure carried out in patients with soft-tissue sarcomas (STS) when microscopic residuals are left after initial excision or when there are insufficient data on its completeness. The aim of this study was to evaluate the role of PRE in patients enrolled in two consecutive Italian studies between January 1988 and September 1999. Of 126 patients with grade IIa tumors. 53 underwent PRE (23 rhabdomyosarcomas [RMS] and 30 non-RMS STS [NRSTS]). The primary sites were the extremities in 20, paratesticular 15, trunk 9, head-neck-non-parameningeal (HNnPM) 6, bladder 1, other sites in 2; the tumor (T) status was T1a in 30, T1b in 10, T2a in 9, and T2b in 4; the median interval between primary surgery and PRE was 36 days. Of the 53 patients, 45 had complete histologic excision of the tumor (residuals were found in 21/45 specimens) and subsequently received chemotherapy (CT) alone: 39/45 are in their first complete remission (CR) with a median follow-up of 53 months; 6/45 (3 RMS, 3 NRSTS) relapsed, 4 locally (2 extremities, 2 trunk), and 1 of these died of progressive disease, and 2 with metastatic spread died of their disease. In 8/53 cases (HNnPM 4. extremities 2, bladder 1, trunk 1) PRE did not achieve complete removal of the residuals (3 T1a, 2 Tlb, 2 T2a, 1 T2b); these patients were treated with CT and/or radiotherapy (RT); 1 also underwent further surgery. PRE was able to achieve or confirm complete excision in 45/53 patients, and 39 maintained the first CR without RT. The histologic types and the presence of residuals at PRE did not predict the failures; PRE was effective especially in extremity, trunk, and paratesticular sites, whereas its role was uncertain in large sarcomas over 5 cm in size.

Childhood leiomyosarcoma: a report from the soft tissue sarcoma Italian Cooperative Group.

BACKGROUND: Only a few reports on the clinical features and management of childhood leiomyosarcoma are available. To contribute additional information on the management of this rare tumor, we report on a series of 16 pediatric patients treated from 1982 to 1998 by the Soft Tissue Sarcoma Italian Cooperative Group. PATIENTS AND METHODS: Primary surgery was conservative in all but two patients, and consisted of biopsy--three cases, non-radical excision--four, and radical resection--nine (involving a primary re-excision in 4 of 9). In two cases secondary radical surgery was performed after primary chemotherapy. Chemotherapy was administered to 9 of 16 patients, radiotherapy to three. RESULTS: After a median follow-up of seven years (range 3-18), the five-year event-free survival (EFS) and overall survival were 56.3% and 72.9%, respectively; 12 of 16 patients were alive (nine of them in continuos complete remission). Univariate analysis was performed to compare EFS according to different subgroups: size represented the most significant prognostic factor. CONCLUSIONS: Complete surgical resection is the mainstay of treatment for leiomyosarcoma. The role of both adjuvant chemotherapy and radiotherapy has yet to be established, and awaits cooperative multicentric studies.