Impact of young age on platinum response in women with epithelial ovarian cancer: Results of a large single-institution registry.

OBJECTIVE: In young women, EOC is a rare disease with an uncertain genetic and biological substrate. METHODS: We report a long follow-up of EOC patients treated at Gustave Roussy between 1990 and 2009. We matched young patients aged ≤30 years to randomly selected older patients aged ≥40 years according to known prognostic factors (i.e. FIGO stage, histology and surgical residual disease) and the date of diagnosis with a threshold at the year 2000 to balance the treatment procedures. RESULTS: EOC was diagnosed in 68 patients aged ≤30 years matched with 111 patients aged ≥40 years. Low-grade (LG) (i.e. serous and endometrioid) (52%, n = 35) and mucinous (i.e. 23%, n = 16 infiltrative and 12% n = 8 expansile) tumors are prevalent. High-grade (HG) tumors are rare (7%, n = 5). Early stage diseases (53%, n = 36 FIGO I/II) are predominant. Response to platinum based chemotherapy is observed to be inferior in young patients as compared to matched older patients (ORR, 29 vs 84% p = 0.0002). For HG tumors the PFS is of 0% at 5 and 10 years in younger as compared to 30% in older patients. No difference in PFS (median 4.9 vs 9.8 ms, p = 0.58) and OS (not reached vs 15.3 ms, p = 0.47) is found overall among younger and older patients respectively. The median follow-up was 72 months (range, 11-288 months). No genetic abnormalities were found. CONCLUSIONS: Young EOC patients are most often diagnosed at an early FIGO stage with LG serous or mucinous histology. Tumors are significantly more resistant to platinum-based chemotherapy in younger patients.

Prognostic significance of an early decline in serum alpha-fetoprotein during chemotherapy for ovarian yolk sac tumors.

BACKGROUND: The ovarian yolk sac tumor (OYST) is a very rare malignancy arising in young women. Our objective was to determine whether an early decline in serum alpha-fetoprotein (AFP) during chemotherapy has a prognostic impact. METHODS: This retrospective study is based on prospectively recorded OYST cases at Gustave Roussy (Cancer Treatment Center). Survival curves were estimated using the Kaplan-Meier method. The serum AFP decline was calculated with the formula previously developed and validated in male patients with poor prognosis non-seminomatous germ cell tumors. Univariate and multivariate analyses were performed using the log-rank test and logistic regression, respectively. RESULTS: Data on AFP were available to calculate an early AFP decline in 57 patients. All patients had undergone surgery followed by chemotherapy. The 5-year overall survival (OS) and event-free survival (EFS) rates were 86% (95% CI: 74%-93%) and 84% (95% CI: 73%-91%), respectively. The disease stage, presence of ascites at presentation, use of the BEP regimen, serum AFP half-life and an early AFP decline were significantly predictive factors for OS and EFS in the univariate analysis. The OS rate was 100% and 49% (95% CI: 26%-72%) in patients with a favorable AFP decline and in those with an unfavorable decline, respectively (p<0.001). In the multivariate analysis, only the presence of ascites at diagnosis (RR=7.3, p=0.03) and an unfavorable early AFP decline (RR=16.9, p<0.01) were significant negative predictive factors for OS. CONCLUSIONS: An early AFP decline during chemotherapy is an independent prognostic factor in patients with OYSTs. CONFLICT OF INTEREST STATEMENT: No conflict of interest.

Prognostic Factors for Outcome in Localized Extremity Rhabdomyosarcoma. Pooled Analysis from Four International Cooperative Groups.

BACKGROUND: Extremity rhabdomyosarcomas do not always show satisfactory outcomes. We analyzed data from 643 patients treated in 14 studies conducted by European and North American groups between 1983 and 2004 to identify factors predictive of outcome. PROCEDURE: Clinical factors, including age; histology; site of primary (hand and foot vs. other); size; invasiveness (T stage); nodal involvement (N stage); and treatment factors, including post-surgical group; chemotherapy type and duration; radiotherapy; and treatment (before or after 1995); were evaluated for impact on overall survival (OS). RESULTS: 5-year OS were 67% (se 1.8). Multivariate analysis showed that lower OS correlated with age >3 years, T2 and N1 stage, incomplete initial surgery, treatment before 1995, and European cooperative group treatment. Patients with gross residual disease after initial incomplete resection/biopsy had similar outcomes in both continental groups. The better global survival of patients treated in American studies was accounted for by differences in outcome in the subset of those with grossly resected tumors (OS 86% [se 3] for COG patients vs. 68% [se 4] for European patients (P = 0.004)). When excluding chemotherapy duration from the model, analysis in this subset of patients showed that cooperative group (P = 0.001), site (P = 0.001), and T stage (P = 0.05) were all significant. However, after adding duration of chemotherapy (≥27 weeks) to the model, only primary site remained significant (P = 0.006). CONCLUSION: This meta-analysis confirms the role of many established prognostic factors but identifies for the first time that chemotherapy duration may have an impact on outcome in patients with grossly resected tumors.

Relations between arthralgia and fear of recurrence: results of a cross-sectional study of breast cancer patients treated with adjuvant aromatase inhibitors therapy.

PURPOSE: The aim of this study was to explore associations between arthralgia and fear of recurrence in breast cancer patients treated by aromatase inhibitors (AI). METHOD: We sent a set of questionnaires to 100 patients examining their pain characteristics, anxiety (STAI), depression (BDI-SF), quality of life (SF-36), fear of recurrence (FCRI), and representations of AI treatment (ad hoc questionnaire). Nonparametric tests were used to investigate between-group comparisons (arthralgia vs. nonarthralgia) in these domains as well as the associations between arthralgia and fear of recurrence. RESULTS: Of the 77 patients who returned the questionnaires (response rate = 77%), 60 (78%) reported arthralgia. The mean score of fear of recurrence exceeded the pathological threshold in the arthralgia group and was significantly higher than that in the nonarthralgia group (14.8 vs. 10.7, p < 0.01). Significant associations were observed between fear of recurrence and pain intensity (r = 0.274, p < 0.05) and pain relief (r = -0.409, p < 0.05). More than 80% of the total sample declared that they were well informed about the aim of AI, their side effects, and the risk of developing arthralgia. Fear of recurrence did not appear to be associated with representations of AI. CONCLUSION: The study revealed a close relationship between pain intensity and fear of recurrence. In particular, it showed that effective pain management was accompanied by a reduced fear of recurrence. Information, although essential, appeared insufficient to overcome patients' concerns about pain. Therefore, the implement of a systematic screening for arthralgia and the improvement of analgesic treatment are essential issues. New strategies for pharmacological and nonpharmacological treatment must be developed.

Multimodal treatment with doxorubicin, cisplatin, and ifosfamide for the treatment of advanced or metastatic uterine leiomyosarcoma: a unicentric experience.

OBJECTIVE: Uterine leiomyosarcoma (ULMS) is a rare gynecologic malignancy characterized by a poor prognosis due to a high rate of local and metastatic recurrences. Chemotherapy with doxorubicin or ifosfamide or both is associated with a 10% to 30% objective response rate. We report a monocentric experience with doxorubicin, cisplatin, and ifosfamide (API) combination in the setting of multimodal treatment of advanced or metastatic ULMS. PATIENTS AND METHODS: This monocentric retrospective study included patients with metastatic or locally advanced ULMS with a physiological age younger than 65 years treated in first line with a multimodal aggressive approach with API chemotherapy. Treatment consisted of doxorubicin 50 mg/m2 d1, ifosfamide 3 g/m2 per day d1d2 plus mesna, cisplatin 75 mg/m2 d3, plus G-CSF; every 3 weeks up to 6 cycles. Surgery, radiation therapy, or radiofrequency ablation therapy of metastatic sites was associated whenever possible. RESULTS: Thirty-eight patients received API for metastatic or locally advanced ULMS. Median age was 51 years (40-64 years); 4 (11%) patients were treated for a locally advanced disease and 34 (89%) for metastatic disease. Sixteen patients responded (4 complete responses+12 partial responses) among 33 evaluable patients (objective response rate, 48%); 8 and 9 patients had, respectively, stable and progressive disease. Twelve patients had surgeries with 9 surgical complete responses and 3 surgical partial responses. Median progression-free and overall survival in the whole population were 9.8 and 27 months, respectively. Main grade 3-4 toxicities in 38 patients were neutropenia (74%), thrombocytopenia (60%), anemia (55%), fatigue (18%), and vomiting (13%). Febrile neutropenia was observed in 37% of patients. CONCLUSIONS: Despite the toxicity observed, API is an effective treatment which compares favorably with other first-line therapies for patients with metastatic or advanced ULMS.

Conservative approach in localised rhabdomyosarcoma of the bladder and prostate: results from International Society of Paediatric Oncology (SIOP) studies: malignant mesenchymal tumour (MMT) 84, 89 and 95.

BACKGROUND: The three sequential SIOP MMT studies provide the largest dataset available to date, to define the patient and tumour characteristics, treatment modalities and event-free and overall survival for children with non metastatic rhabdomyosarcoma (RMS) of the bladder and/or prostate (BP). PROCEDURE: The combined dataset of 172 patients with BP RMS treated on the SIOP MMT 84, 89 and 95 studies was reviewed to determine tumour characteristics, details of treatment and outcome. RESULTS: Median age at diagnosis was 2.5 years (range 2 months-17.8 years) and 138 (79%) were males. Median follow-up was 11.4 years (range 3 months-22 years). The 5-year overall survival of the combined cohort was 77% (CI 70-83%). The 5-year event-free survival was 63% and included 7 patients (4%) who did not achieve complete remission (CR), and 57 (33%) who relapsed. Age ≥ 10 years (RR 3.7) and alveolar pathology (RR 3.3) were identified as independent prognostic factors on multivariate analysis. Fifty-nine (50%) of the 119 survivors were cured without significant local therapy, improving from 31% in MMT84 study to 61% in MMT95 study. CONCLUSION: The clinical strategy of the MMT studies aims to minimise the burden of therapy whilst maintaining survival rates. Overall survival is comparable to that of other international groups, despite the lower use of radiotherapy and or radical surgery, although number of events experienced is higher. Further assessment of the late effects of therapy is required to confirm whether this approach results in lower morbidity in the long-term.

Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography imaging.

PURPOSE: The aim of this prospective study conducted in three French comprehensive cancer centers was to evaluate the therapeutic impact on survival of laparoscopic para-aortic (PA) staging surgery in locally advanced cervical cancer (LACC) before chemoradiotherapy. PATIENTS AND METHODS: We conducted a prospective multicenter study of 237 patients treated from 2004 to 2011 for LACC with negative positron emission tomography (PET) imaging of the PA area and undergoing laparoscopic PA lymphadenectomy. Radiation fields were extended to the PA area when PA nodes were involved. Chemoradiotherapy modalities were homogeneous across institutions. Patients with a poor prognosis histologic subtype or peritoneal carcinosis were excluded. RESULTS: Patients had clinical International Federation of Gynecology and Obstetrics stages IB2 (n = 79), IIA (n = 10), IIB (n = 121), III (n = 22), or IVA (n = 5). One hundred ninety-nine patients had squamous carcinoma, and 38 had adenocarcinoma/adenosquamous lesions. Twenty-nine patients (12%) had nodal involvement (false-negative PET-computed tomography [CT] results)-16 with a PA nodal metastasis measuring more than 5 mm and 13 with a nodal metastasis measuring ≤ 5 mm. Event-free survival rates at 3 years in patients without PA involvement or with PA metastasis measuring ≤ or more than 5 mm were 74% (SE, 4%), 69% (SE, 21%), and 17% (SE, 14%; P < .001). CONCLUSION: To our knowledge, this is the largest series of patients reported undergoing such a strategy. We obtained the same survival rate for patients with PA nodal metastasis ≤ 5 mm and patients without PA lymph node involvement, suggesting that this strategy is highly efficient in such patients. Conversely, the survival of patients with PA nodal involvement greater than 5 mm remained poor, despite the absence of extrapelvic disease on PET-CT imaging in this subgroup.

Phase I clinical trial combining imatinib mesylate and IL-2 in refractory cancer patients: IL-2 interferes with the pharmacokinetics of imatinib mesylate.

Imatinib mesylate (IM) is a small molecule inhibitor of protein tyrosine kinases. In addition to its direct effect on malignant cells, it has been suggested IM may activate of natural killer (NK) cells, hence exerting immunomodulatory functions. In preclinical settings, improved antitumor responses have been observed when IM and interleukin-2 (IL-2), a cytokine that enhances NK cells functions, were combined. The goals of this study were to determine the maximum tolerated dose (MTD) of IL-2 combined with IM at a constant dose of 400 mg, the pharmacokinetics of IM and IL-2, as well as toxicity and clinical efficacy of this immunotherapeutic regimen in patients affected by advanced tumors. The treatment consisted in 50 mg/day cyclophosphamide from 21 d before the initiation of IM throughout the first IM cycle (from D-21 to D14), 400 mg/day IM for 14 d (D1 to D14) combined with escalating doses of IL-2 (3, 6, 9 and 12 MIU/day) from days 10 to 14. This treatment was administered at three week intervals to 17 patients. Common side effects of the combination were mild to moderate, including fever, chills, fatigue, nausea and hepatic enzyme elevation. IL-2 dose level II, 6 MIU/day, was determined as the MTD with the following dose-limiting toxicities: systemic capillary leak syndrome, fatigue and anorexia. Pharmacokinetic studies revealed that the area under the curve and the maximum concentration of IM and its main metabolite CGP74588 increased significantly when IM was concomitantly administered with IL-2. In contrast, IM did not modulate IL-2 pharmacokinetics. No objective responses were observed. The best response obtained was stable disease in 8/17 (median duration: 12 weeks). Finally, IL-2 augmented the impregnation of IM and its metabolite. The combination of IM (400 mg/day) and IL-2 (6 MIU/day) in tumors that express IM targets warrants further investigation.

Phase I clinical trial combining imatinib mesylate and IL-2: HLA-DR+ NK cell levels correlate with disease outcome.

We performed a Phase I clinical trial from October 2007 to October 2009, enrolling patients affected by refractory solid tumors, to determine the maximum tolerated dose (MTD) of interleukin (IL)-2 combined with low dose cyclophosphamide (CTX) and imatinib mesylate (IM). In a companion paper published in this issue of OncoImmunology, we show that the MTD of IL-2 is 6 MIU/day for 5 consecutive days, and that IL-2 increases the impregnation of both IM and of its main metabolite, CGP74588. Among the secondary objectives, we wanted to determine immunological markers that might be associated with progression-free survival (PFS) and/or overall survival (OS). The combination therapy markedly reduced the absolute counts of B, CD4+ T and CD8+ T cells in a manner that was proportional to IL-2 dose. There was a slight (less than 2-fold) increase in the proportion of regulatory T cells (Tregs) among CD4+ T cells in response to IM plus IL-2. The natural killer (NK)-cell compartment was activated, exhibiting a significant upregulation of HLA-DR, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD56. The abundance of HLA-DR+ NK cells after one course of combination therapy positively correlated with both PFS and OS. The IL-2-induced rise of the CD4+:CD8+ T-cell ratio calculated after the first cycle of treatment was also positively associated with OS. Overall, the combination of IM and IL-2 promoted the rapid expansion of HLA-DR+ NK cells and increased the CD4+:CD8+ T-cell ratio, both being associated with clinical benefits. This combinatorial regimen warrants further investigation in Phase II clinical trials, possibly in patients affected by gastrointestinal stromal tumors, a setting in which T and NK cells may play an important therapeutic role.

Impact of extensive surgery in multidisciplinary approach of pterygopalatine/infratemporal fossa soft tissue sarcoma.

BACKGROUND: To evaluate a strategy whereby extensive surgery ± external radiotherapy (RT) could improve local control in pterygopalatine/infratemporal fossa (PIF) sarcoma. PROCEDURE: Forty-one patients with a diagnosis of sarcoma involving the PIF and referred to our Institute from 1984 to 2009 were included in the analysis. Patients received multidrug chemotherapy and radiotherapy ± surgery, depending on the period of treatment. RESULTS: The median age at diagnosis was 7.6 years (range: 0.1-22 years). There were 36 RMS, 3 undifferentiated sarcoma and 2 other soft-tissue sarcomas. Sixty-eight percent of patients had meningeal risk factors at diagnosis. Local treatment consisted of RT alone in 19 patients, surgery in combination to RT in 19 patients and surgery alone in 3 patients. The local progression rate (LPR) at 5 years was 45% for the entire population, 59% for the 19 patients treated with RT alone and 34% for the 22 patients who had surgery as part of their treatment. All locoregional failures after extensive surgery occurred at the skull base and/or in leptomeningeal spaces. CONCLUSIONS: Multidisciplinary approach including extensive surgery for PIF sarcoma is feasible and yields good local control with 15/22 patients in local complete remission. Future studies are warranted to confirm these promising results, to evaluate the possibility of avoiding RT or limiting the RT field, and to extend the indication for extensive surgery to other "worse" sites of PM sarcoma such as the paranasal sinuses.

Phase II study of cisplatin and oral VP16 in patients with refractory or relapsed Ewing sarcoma.

BACKGROUND: Phase II trials demonstrate the activity of cisplatin in patients with refractory Ewing sarcoma family tumours (ESFT) and also the feasibility of giving cisplatin with oral VP16 in a variety of different cancers. This trial was conducted to evaluate the activity and toxicity profile of this combination delivered as outpatient therapy in patients with refractory/relapsed ESFT. METHODS: Cisplatin was administered on days 1, 8 and 15 and days 29, 36 and 43 (70 mg/m(2)/dose for patients <21 years of age and 50 mg/m(2)/dose ≥21 years). VP16 was administered at a dose of 50 mg/m(2) on days 1-15 and days 29-43 inclusive. A three-stage Fleming statistical design was used for analysis. RESULTS: Between January 2003 and October 2006, 45 patients aged between 5 and 46 years (median 19) were enrolled. Thirty-eight were evaluable for response. Patients had previously received one to three lines of chemotherapy (median = one). Seventy-three per cent of the patients had grade 3/4 neutropenia, 20 % developed fever, 40 % had grade 3/4 anaemia, 68 % grade 3/4 thrombocytopenia and 16 % grade 2/3 ototoxicity. Measured response after 2 cycles: 0 CR, 7 PR (18 %), 13 SD (34 %), 18 PD (48 %). There was excellent concordance between unidimensional and bidimensional criteria in 31 of 33 responses (94 %). PFS at 1 year was 39 %, with a median PFS of 6 months. Overall survival at 1 year was 44 %; median survival was 11 months. CONCLUSIONS: Cisplatin combined with oral VP16 is well tolerated and has acceptable side effects, but limited clinical activity in refractory/relapsed ESFT.

Randomized multicenter and stratified phase II study of gemcitabine alone versus gemcitabine and docetaxel in patients with metastatic or relapsed leiomyosarcomas: a Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) French Sarcoma Group Study (TAXOGEM study).

BACKGROUND: This study aimed to evaluate the efficacy and toxicity of single-agent gemcitabine versus gemcitabine plus docetaxel as second-line therapy in patients with uterine and nonuterine leiomyosarcoma (LMS). PATIENTS AND METHODS: Patients had metastatic or unresectable LMS and had received one prior anthracycline-based regimen. A total of 90 patients received either single-agent gemcitabine (arm A; gemcitabine, 1,000 mg/m(2) i.v. for 100 minutes on days 1, 8, and 15 of a 28-day cycle) or a combination of gemcitabine and docetaxel (arm B; gemcitabine, 900 mg/m(2) i.v. for 90 minutes on days 1 and 8, plus docetaxel, 100 mg/m(2) i.v. for 1 hour on day 8 of a 21-day cycle with lenograstim). The primary endpoint was the objective response rate. RESULTS: The objective response rates were 19% and 24% in arm A (gemcitabine) and arm B (gemcitabine plus docetaxel), respectively, for patients with uterine LMS. For patients with nonuterine LMS, the objective response rates were 14% and 5% for arms A and B, respectively. The median progression-free survival times for arms A and B were 5.5 months and 4.7 months, respectively, for patients with uterine LMS. For patients with nonuterine LMS, the median progression-free survival times were 6.3 months and 3.8 months for arms A and B, respectively. One toxic death occurred in arm B. CONCLUSIONS: Both single-agent gemcitabine and gemcitabine plus docetaxel were found to be effective second-line therapies for leiomyosarcomas, with a 3-month progression-free survival rate of 40% for LMS with both uterine and nonuterine sites of origin. Single-agent gemcitabine yielded results similar to those of gemcitabine plus docetaxel in this trial, but patients using single-agent gemcitabine experienced less toxicity.

Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 study.

PURPOSE: MMT95 was the fourth of a series of International Society of Pediatric Oncology (SIOP) collaborations for children with high-risk nonmetastatic soft tissue sarcoma (STS). The principal objective was to explore survival advantage for an intensified chemotherapy strategy in a randomized trial. PATIENTS AND METHODS: From July 1995 to June 2003, 457 previously untreated patients with incompletely resected embryonal rhabdomyosarcoma (RMS), undifferentiated sarcoma, and soft tissue primitive neuroectodermal tumor at all sites except paratesticular, vagina, and uterus, or with alveolar RMS were randomly assigned to receive either ifosfamide, vincristine, and dactinomycin (IVA) or a six-drug combination (IVA plus carboplatin, epirubicin, and etoposide) both delivered over 27 weeks. Cumulative doses were as follows: ifosfamide 54 g/m(2) (both arms), epirubicin 450 mg/m(2), etoposide 1,350 mg/m(2) (six-drug regimen). Poor responders after three courses of IVA were to be switched to the other arm. Delivery of radiotherapy was determined according to site and/or response to chemotherapy with or without surgery. RESULTS: Overall survival (OS) for all patients was 81% (95% CI, 77% to 84%) at 3 years. No significant difference in outcome in either OS or event-free survival was noted between the two arms (3-year OS: 82% [95% CI, 76% to 86%] for IVA and 80% [95% CI, 74% to 85%] for the six-drug arm). Toxicity was significantly greater (infection, myelosuppression, and mucositis) in the six-drug arm. Overall burden of local therapy was consistent with data from previous SIOP studies and showed no difference between the two chemotherapy regimens. CONCLUSION: Intensification of chemotherapy for nonmetastatic RMS and other chemotherapy-sensitive STS provides no survival advantage or reduction in the intensity of local therapy and adds toxicity.

Risk adapted chemotherapy for localised Ewing's sarcoma of bone: the French EW93 study.

AIM OF THE STUDY: To determine whether a risk factor adapted chemotherapy would improve the outcome of non-metastatic bone Ewing's sarcoma. METHODS: Standard risk tumours (SR, good histological response to chemotherapy or small unresected tumours) received the previous EW88 chemotherapy. Ifosfamide/etoposide (IE) were introduced after 3 courses of cyclophosphamide/doxorubicine when tumour regression was <50% or during consolidation therapy for the intermediate risk tumours (IR, intermediate histological response 5-30% residual cells or large unresected tumours >100ml). High risk tumours (HR, histological poor response >30% residual cells or clinical poor response <50% for unresectable tumours), received IE prior high dose busulfan/melphalan with stem cell rescue. RESULTS: From 1993 to 1999, 214 patients were enrolled. 5 y-EFS and OS were 60% (95% confidence interval (CI), 53-66) and 69% (95% CI, 63-75), respectively. 116 (54%), 46 (21%), 48 (22%) patients were considered as SR, IR and HR of relapse, respectively. No advantage to IE was observed in the IR group. As compared to previous study, tumour with poor histological response to induction chemotherapy seemed to benefit from the consolidation strategy including busulfan/melphalan: EFS were 45% (95% CI, 30-60) and 20% (95% CI, 7-43) for EW93 and EW88, respectively. Despite a risk-adapted strategy, histological response to chemotherapy remains the main prognostic factor in resected tumours, while initial tumour volume is the main prognostic factor for unresected tumours. CONCLUSION: These results showing a potential benefit of a consolidation strategy including busulfan/melphalan as compared to conventional chemotherapy needed confirmation by a randomised trial and were one of the bases of the ongoing EuroEwing99.

Synovial sarcoma in children and adolescents: a critical reappraisal of staging investigations in relation to the rate of metastatic involvement at diagnosis.

BACKGROUND: European protocols for paediatric synovial sarcoma (SS) require that all children routinely undergo chest computed tomography (CT) scanning and bone scanning as initial staging procedures. This study aims to determine the rate of initial metastases in paediatric SS based on specific clinical characteristics, thereby investigating whether these diagnostic procedures are really necessary in all patients. METHODS: Data on 258 previously-untreated SS patients <21 years old were pooled from the databases of different European paediatric groups (study period 1988-2005) for this analysis, and the associations between patients' characteristics and any presence of metastasis were estimated. RESULTS: Fifteen cases (5.8%) had distant metastases at diagnosis (86% pulmonary). The presence of metastases was unassociated with patients' gender or age, tumour grade or site, but it was influenced by T-status, and especially primary tumour size: the risk of metastases was 32 times higher in cases of tumour >5 cm than for tumours ≤ 5 cm. CONCLUSIONS: Our findings suggest that tumour diameter can be used as a variable for identifying patients at greater risk of metastases and warranting more accurate radiological investigations. Chest CT scanning may improve the accuracy of pulmonary staging over X-ray, but requires different ionising radiation exposures that might have carcinogenic potential: it can be omitted for patients with tumours ≤ 5 cm. Given the very low risk of bone metastases, bone scans may be recommended only in cases with evidence of lung metastases.

Results of the GYNECO 02 study, an FNCLCC phase III trial comparing hysterectomy with no hysterectomy in patients with a (clinical and radiological) complete response after chemoradiation therapy for stage IB2 or II cervical cancer.

BACKGROUND: Concomitant chemoradiation (CRT) (including brachytherapy) is considered the standard management for stage IB2 or II cervical cancer in many countries. Nevertheless, some of them discuss completion surgery (hysterectomy [HT]) after CRT. The aim of this study was to investigate the therapeutic impact of such surgery. METHODS: A randomized trial was opened in France in 2003 to evaluate the interest in HT after CRT. Inclusion criteria were: (a) stage IB2 or II cervical cancer without extrapelvic disease on conventional imaging; (b) pelvic external radiation therapy (45 Gy with or without parametrial or nodal boost) with concomitant cisplatin chemotherapy (40 mg/m2 per week) followed by uterovaginal brachytherapy (15 Gy to the intermediate risk clinical target volume); and (c) complete clinical and radiological response 6-8 weeks after brachytherapy. Patients were randomized between HT (arm A) and no HT (arm B). Unfortunately this trial was closed because of poor accrual: 61 patients were enrolled (in 2003-2006) and are reported on here. RESULTS: Thirty one and 30 patients were enrolled, respectively, in arm A and arm B. Twelve patients recurred (five of them died): respectively, eight and four in arm A and arm B. The 3-year event-free survival rates were 72% (standard error [SE], 9%) and 89% (SE, 6%) (not significant [NS]) in arm A and arm B, respectively. The 3-year overall survival rates were 86% (SE, 6%) and 97% (SE, 3%) (NS) in arm A and arm B, respectively. CONCLUSIONS: Results of the current trial seem to suggest that completion HT had no therapeutic impact in patients with clinical and radiological complete response after CRT (but this conclusion is limited by the lack of power).

Local therapy is critical in localised pelvic rhabdomyosarcoma: experience of the International Society of Pediatric Oncology Malignant Mesenchymal Tumor (SIOP-MMT) committee.

BACKGROUND: Localised pelvic rhabdomyosarcomas (pRMS) are rare tumours with a poorer prognosis than the majority of RMS. This study analysed patient outcome according to the type of local therapy delivered and the effect of disease-related factors on prognosis. PATIENTS AND METHODS: 97 children with localised pRMS were enrolled in the SIOP-MMT84, 89 and 95 studies. After primary surgery or biopsy, all children received ifosfamide/actinomycin/vincristine-based chemotherapy. Radiotherapy and surgery were planned in patients failing to achieve complete remission. RESULTS: Median age at diagnosis was 52 months [5 months-18 years]. IRS staging was I for five patients, II for 15 and III for 77. Patients had embryonal RMS (N = 41), alveolar RMS (N = 29), botryoid RMS (N = 3), or not otherwise specified RMS (N = 24). OUTCOME: 87 patients achieved local control (90%), 37 relapsed (43%), mainly locally (84%). With a median follow-up of more than 10 years [4-22 years], 5-year OS was 66% (95% CI: 56-75%) and EFS was 52% (95% CI: 42-61%). Among the 18 IRS-I/II patients treated without radiotherapy, 15 survived. Seven out of the 20 IRS-III patients treated without local therapy died. In multivariate analysis, IRS staging, age greater than 10 years and lymph node involvement had a negative impact on OS. Perineal/perianal locations had a trend towards a worse prognosis. CONCLUSION: pRMS still have a relatively poor prognosis. Radiotherapy or brachytherapy is necessary for all IRS-III patients including those with radiological complete remission after neoadjuvant chemotherapy with or without surgery. Radiotherapy may be withheld in IRS-I patients and children under 3 years with IRS-II pRMS.

Accuracy of diffusion-weighted echo-planar MR imaging and ADC mapping in the evaluation of residual cervical carcinoma after radiation therapy.

OBJECTIVES: The impact of diffusion-weighted imaging (DWI) and apparent diffusion coefficients (ADCs) of MR imaging on the evaluation of residual Uterine Cervical Carcinoma after Radiation Therapy, in addition to conventional MR images. METHODS: Fourty-nine women presenting with a uterine cervical cancer were examined with 1.5 T MRI and DWI, 8 (4-20) weeks after treatment. Treatment response was determined based on the histopathological results after therapy and was classified as a complete response (CR) or residual disease (RD). Post-treatment DWI and ADC results were compared. RESULTS: Five (11%) and 44 (89%) patients were considered as having histologically-proven RD or a CR respectively. The mean ADC of cervical tissue for all patients was 1.74±0.324×10(-3) mm(2)/s and the SD was 1.94±1.11×10(-4). The mean ADC was 1.62±0.21×10(-3) mm(2)/s (SD=1.45×10(-4)) for the 5 patients with RD versus 1.76±0.33×10(-3) mm(2)/s (SD=1.99×10(-4)) for the 44 patients with a CR (p=0.09). Using 1.7×10(-3) mm(2)/s as a radiological cut-off value for the ADC, all patients classified as having histologically-proven RD had a mean ADC of ≤1.7×10(-3). In 12 (25%) cases, RD was suspected on T2-weighted MRI images alone. Eight of these cases were considered as false positives compared to the histological results. Their mean ADC was 1.98×10(-3) mm(2)/s and none of them had an ADC of <1.7×10(-3) mm(2)/s. CONCLUSION: Although our results were not statistically significant, ADC values could potentially be used to predict and monitor the response of uterine cervical cancer.

Sparing strategy does not compromise prognosis in pediatric localized synovial sarcoma: experience of the International Society of Pediatric Oncology, Malignant Mesenchymal Tumors (SIOP-MMT) Working Group.

BACKGROUND: The aim of this analysis was to identify if the modified indications of radiotherapy (RT) or radical surgery compromised survival in pediatric synovial sarcoma (SS). PROCEDURE: Children with non-metastatic SS, prospectively enrolled in three trials, were analyzed. After primary surgery or biopsy, they received chemotherapy. RT was planned after chemotherapy in patients who had not achieved a complete response (CR). The considered outcome was 5-year overall survival (OS) and event-free survival (EFS). RESULTS: Eighty-eight patients were identified. Primary tumors were mainly located in limbs (66%). The first-line therapy for 65 patients was primary resection. Of the 49 patients who had gross tumor resection, 43 received adjuvant chemotherapy, and 8 had RT. All of the 39 patients with macroscopic residual disease received chemotherapy, then only surgery (n = 12) ± RT (n = 22). The 5-year EFS and OS rates were 68% and 85%, respectively. The TNM stage was a prognostic factor for relapse, whereas primary site of the tumor and TNM stage were prognostic factors for death. CONCLUSIONS: Only 32% of survivors received RT. OS was similar to published data. Omission of RT may be considered in younger children, to limit the potential sequelae in patients with tumors less than 5 cm in size initially submitted to marginal resection. This strategy may also be considered in initially unresected cases, when the tumor is resected at delayed surgery with microscopically free margins, and in patients in complete remission after primary chemotherapy.

Prognostic factors after relapse in nonmetastatic rhabdomyosarcoma: a nomogram to better define patients who can be salvaged with further therapy.

PURPOSE: Previous studies suggest poor outcome in children with relapsed rhabdomyosarcoma (RMS). A better understanding is needed of which patients can be salvaged after first relapse. PATIENTS AND METHODS: The analysis included children with nonmetastatic RMS and embryonal sarcoma enrolled onto the International Society of Paediatric Oncology (SIOP) Malignant Mesenchymal Tumor (MMT) 84, 89, and 95 studies who relapsed after achieving complete local control with primary therapy. All patients included in the analysis had follow-up for ≥ 3.0 years after the last event. The clinical features, initial treatment characteristics, and features of the relapse were correlated with survival in univariate and multivariate analyses. RESULTS: In all, 474 eligible patients were identified for the study. At ≥ 3.0 years from the last event, 176 (37%) were alive ("cured"). In a full-model multivariate analysis, the factors identified at first relapse that most strongly associated with poor outcome were metastatic relapse (odds ratio [OR], 4.19; 95% CI, 2.0 to 8.5), prior radiotherapy treatment (OR, 3.64; 95% CI, 2.1 to 6.4), initial tumor size > 5 cm (OR, 2.53; 95% CI, 1.5 to 4.1), and time of relapse < 18 months from diagnosis (OR, 2.20; 95% CI, 1.3 to 3.6). Unfavorable primary disease site, nodal involvement at diagnosis, alveolar histology, and previous three- or six-drug chemotherapy were also independently associated with poor outcome. To estimate chance of cure for individual patients, a nomogram was developed, which allowed for weighting of these significant factors. CONCLUSION: Some children with relapsed RMS remain curable. It is now possible to estimate the chance of salvage for individual children to direct therapy appropriately toward cure, use of experimental therapies, and/or palliation.