Correction to: Results of nimotuzumab and vinorelbine, radiation and re-irradiation for diffuse pontine glioma in childhood.

The therapeutic experience reported in the paper was conceived after the use of nimotuzumab and radiotherapy (BSCPED-05 international multicentric trial, EUDRACT 2005-003100-11) in 2009 when we decided to explore the activity of the same combination plus vinorelbine (see the paper for the rationale).

Results of nimotuzumab and vinorelbine, radiation and re-irradiation for diffuse pontine glioma in childhood.

Radiotherapy is the only treatment definitely indicated for diffuse pontine gliomas (DIPG). Findings on the role of EGFR signaling in the onset of childhood DIPG prompted the use of nimotuzumab, an anti-EGFR monoclonal antibody. Assuming a potential synergy with both radiotherapy and vinorelbine, a pilot phase 2 protocol was launched that combined nimotuzumab with concomitant radiation and vinorelbine. An amendment in July 2011 introduced re-irradiation at relapse. The primary endpoint for first-line treatment was objective response rate (CR + PR + SD) according to the RECIST. This report concerns the outcome of this strategy as a whole. Vinorelbine 20 mg/m(2) was administered weekly, with nimotuzumab 150 mg/m(2) in the first 12 weeks of treatment; radiotherapy was delivered from weeks 3 to 9, for a total dose of 54 Gy. Vinorelbine 25 mg/m(2) and nimotuzumab were given every other week thereafter until the tumor progressed or for up to 2 years. Re-irradiation consisted of 19.8 Gy, fractionated over 11 days. Baseline and latest MRIs were assessed blindly by an outside neuroradiologist. Twenty five children (mean age 7.4 years) were enrolled as of August 2009 (median follow-up 29 months). A response was observed in 24/25 patients (96 %). The nimotuzumab/vinorelbine combination was very well tolerated, with no acute side-effects. Eleven of 16 locally-relapsing patients were re-irradiated. One-year PFS and OS rates were 30 ± 10 % and 76 ± 9 %, respectively; 2-year OS was 27 ± 9 %; the median PFS and OS were 8.5 and 15 months, respectively. This strategy generated interesting results and warrants further investigation.

Critical analysis of locoregional failures following intensity-modulated radiotherapy for nasopharyngeal carcinoma.

AIM: To analyze the patterns of locoregional failure following intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) at our institution, as part of an internal quality assurance program. We aimed to investigate the potential existence of a correlation between any part of the IMRT process and clinical outcome. METHODS & MATERIALS: A total of 106 non-metastatic NPC patients consecutively treated with IMRT (with or without chemotherapy) were analyzed. Radiotherapy was administered using a sequential or simultaneous integrated boost approach at the total prescribed dose of 66-70 Gy (2.00-2.12 Gy per fraction). MRI studies of recurrences were recorded with the planning computed tomography studies to identify volume of failure. Recurrence-related characteristics were analyzed with respect to the original treatment. Failures were classified as 'in-field', 'marginal' or 'out-field' if at least 95, 20-95 or less than 20% of the volume of failure, respectively, was within 95% of the total prescription dose. RESULTS: With a median follow-up of 43.4 months, 5-years local control, regional control, locoregional control and overall survival rates were 87.7, 88.0, 83.5 and 81.3% respectively. A total of 21 failures were registered in 15 patients. In particular, ten failures (47.6%) were classified as 'in-field' (seven local failures and three regional failures [RFs]), nine failures (42.9%) as 'marginal' (five local failures and four RFs) and only two failures (9.5%) as 'out-field' (both RFs). The most relevant causes of failures were suboptimal target definition and target coverage as well as a longer than planned overall treatment time. CONCLUSION: IMRT determines excellent outcome in NPC patients. However, great attention in all IMRT steps is necessary to reduce potential causes of failure.

A prospective protocol for nasopharyngeal carcinoma in children and adolescents: the Italian Rare Tumors in Pediatric Age (TREP) project.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is very rare in childhood. It differs from its adult counterpart in the prevalence of the nonkeratinizing, undifferentiated subtype and by an advanced clinical stage at onset and better chances of survival. The risk of long-term treatment-related toxicity also may be a more important issue in younger individuals. METHODS: A prospective chemoradiotherapy protocol for pediatric NPC was started in Italy in 2000 within the framework of the Rare Tumors in Pediatric Age (TREP) project. Three courses of cisplatin/5-fluorouracil induction chemotherapy were followed by radiotherapy (doses up to 65 grays) with concomitant cisplatin. RESULTS: Forty-six patients (ages 9-17 years) were considered eligible for the study over a 10-year period. The ratio of observed to expected cases based on epidemiological data was approximately 1 for both children and adolescents. All but 1 patient had lymph node involvement, and 5 patients had distant metastases. The rate of response to primary chemotherapy was 90%. The 5-year overall and progression-free survival rates were 80.9% and 79.3%, respectively (median follow-up, 62 months). The only statistically significant prognostic variable was the presence or absence of distant metastases. A 65% incidence of late sequelae was reported. CONCLUSIONS: This study demonstrates the feasibility and efficacy of a prospective protocol even for such rare tumors as pediatric NPC. The use of lower radiotherapy doses than those used in adults did not affect locoregional failure rates. Long-term follow-up will be needed to obtain more information on both survival and treatment sequelae. The next objective will be to establish broader, international prospective cooperation schemes.

Long-term results of combined preradiation chemotherapy and age-tailored radiotherapy doses for childhood medulloblastoma.

To reduce the sequelae of craniospinal irradiation (CSI) in children under 10 (≥3) years old and to improve the prognosis for high-risk medulloblastoma in adolescents, we adjusted postoperative chemotherapy and CSI doses to patients' stage and age. From 1986 to 1995, 73 patients entered the study. Children under 10 and adolescents with metastases, residual disease (RD) or stage >T3 received postoperative IV vincristine and high-dose (HD) ± intrathecal (IT) methotrexate, while standard-risk adolescents were given IV vincristine and IT methotrexate. Chemotherapy was followed by CSI (19.8 Gy for children <10; 36 Gy for adolescents), with a 54-Gy posterior fossa boost. Maintenance chemotherapy with lomustine and vincristine was administered for a year afterwards. A total of 39 children were under 10 of whom 20 had metastases. Response to chemotherapy was recorded in 70%, but 5-year EFS and OS were only 48 and 56%, respectively. Results were significantly worse for metastatic cases, patients under 10, those with RD, and those staged without MRI (unavailable early in the study). Efforts to preserve survivors' quality of life did not pay off, and most patients over 30 still depended on their parents' income and had severe cognitive/endocrine disabilities. In conclusion, despite a very high response rate with this preradiation HD methotrexate schedule, the outcome for high-risk medulloblastoma patients did not improve (especially when lower CSI doses were used) and patients still developed severe morbidities.

A lower-dose, lower-toxicity cisplatin-etoposide regimen for childhood progressive low-grade glioma.

After successfully using cisplatin (30 mg/m(2)/day) and etoposide (150 mg/m(2)/day) in ten three-day courses for progressive low-grade gliomas, a subsequent protocol reduced the daily doses of cisplatin (to 25 mg) and etoposide (to 100 mg), with the objective of achieving the same response and three-year PFS rates with lower neurotoxicity and myelotoxicity. We treated 37 patients (median age 6 years); 23 had optochiasmatic tumours and nine were metastatic cases. Diagnoses were clinical in 13 cases and histological in 24, and comprised: pilocytic astrocytoma (17), ganglioglioma (3), pilomyxoid astrocytoma (2), and fibrillary astrocytoma (2). Treatment was prompted by radiological evidence of progression and/or clinical deterioration a median 18 months after the first diagnosis. After initial MRI staging, neurological and clinical examinations were performed before each chemotherapy cycle, with MRI after the first three courses and every three months thereafter. After a median 48 months, a volume reduction was appreciable in 24 cases (65%) and response was maximum 12 months after starting treatment. The three-year EFS and OS rates were 65 and 97%, respectively. Clinical, neurological, or functional improvements were seen in 26/37 cases. No children had a WBC nadir below 2,000/mm(3). Audiological toxicity caused damage in 4/34 cases. The previous protocol had achieved volume reductions in 70% of cases, causing audiological damage (data updated) in 11/31 (P = 0.023), with three-year PFS and OS rates of 70 and 100%, respectively. Lower doses of cisplatin/etoposide are still effective in progressive low-grade glioma, with less acute and persistent morbidity.

Effects of treatment intensification on acute local toxicity during radiotherapy for head and neck cancer: prospective observational study validating CTCAE, version 3.0, scoring system.

PURPOSE: To quantify the incidence and severity of acute local toxicity in head and neck cancer patients treated with radiotherapy (RT), with or without chemotherapy (CHT), using the Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE v3.0), scoring system. METHODS AND MATERIALS: Between 2004 and 2006, 149 patients with head and neck cancer treated with RT at our center were prospectively evaluated for local toxicity during treatment. On a weekly basis, patients were monitored and eight toxicity items were recorded according to the CTCAE v3.0 scoring system. Of the 149 patients, 48 (32%) were treated with RT alone (conventional fractionation), 82 (55%) with concomitant CHT and conventional fractionation RT, and 20 (13%) with accelerated-fractionation RT and CHT. RESULTS: Severe (Grade 3-4) adverse events were recorded in 28% (mucositis), 33% (dysphagia), 40% (pain), and 12% (skin) of patients. Multivariate analysis showed CHT to be the most relevant factor independently predicting for worse toxicity (mucositis, dysphagia, weight loss, salivary changes). In contrast, previous surgery, RT acceleration and older age, female gender, and younger age, respectively, predicted for a worse outcome of mucositis, weight loss, pain, and dermatitis. The T-score method confirmed that conventional RT alone is in the "low-burden" class (T-score = 0.6) and suggests that concurrent CHT and conventional fractionation RT is in the "high-burden" class (T-score = 1.15). Combined CHT and accelerated-fractionation RT had the highest T-score at 1.9. CONCLUSIONS: The CTCAE v3.0 proved to be a reliable tool to quantify acute toxicity in head and neck cancer patients treated with various treatment intensities. The effect of CHT and RT acceleration on the acute toxicity burden was clinically relevant.

A method for dynamic subtraction MR imaging of the liver.

BACKGROUND: Subtraction of Dynamic Contrast-Enhanced 3D Magnetic Resonance (DCE-MR) volumes can result in images that depict and accurately characterize a variety of liver lesions. However, the diagnostic utility of subtraction images depends on the extent of co-registration between non-enhanced and enhanced volumes. Movement of liver structures during acquisition must be corrected prior to subtraction. Currently available methods are computer intensive. We report a new method for the dynamic subtraction of MR liver images that does not require excessive computer time. METHODS: Nineteen consecutive patients (median age 45 years; range 37-67) were evaluated by VIBE T1-weighted sequences (TR 5.2 ms, TE 2.6 ms, flip angle 20 degrees , slice thickness 1.5 mm) acquired before and 45s after contrast injection. Acquisition parameters were optimized for best portal system enhancement. Pre and post-contrast liver volumes were realigned using our 3D registration method which combines: (a) rigid 3D translation using maximization of normalized mutual information (NMI), and (b) fast 2D non-rigid registration which employs a complex discrete wavelet transform algorithm to maximize pixel phase correlation and perform multiresolution analysis. Registration performance was assessed quantitatively by NMI. RESULTS: The new registration procedure was able to realign liver structures in all 19 patients. NMI increased by about 8% after rigid registration (native vs. rigid registration 0.073 +/- 0.031 vs. 0.078 +/- 0.031, n.s., paired t-test) and by a further 23% (0.096 +/- 0.035 vs. 0.078 +/- 0.031, p < 0.001, paired t-test) after non-rigid realignment. The overall average NMI increase was 31%. CONCLUSION: This new method for realigning dynamic contrast-enhanced 3D MR volumes of liver leads to subtraction images that enhance diagnostic possibilities for liver lesions.

Clinical activity of androgen deprivation therapy in patients with metastatic/relapsed androgen receptor-positive salivary gland cancers.

BACKGROUND: Androgen deprivation therapy has some clinical activity in selected salivary gland cancer histotypes, with androgen receptor expression. METHODS: We retrospectively analyzed patients with androgen receptor-expressing recurrent/metastatic salivary gland cancer, treated with androgen deprivation therapy. Protein expression of androgen receptor and ErbB family members was investigated. Progression-free survival (PFS) and overall survival (OS) were the main endpoints. RESULTS: Seventeen patients were identified. No significant toxicities were reported. Overall response rate was 64.7%; 3-year PFS and 5-year OS were 11.8% and 19.3%, respectively. Androgen receptor overexpression may be sustained by gain of chromosome X (58%) and TP53 mutation (44%). No association between response to androgen deprivation therapy and epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)2, HER3 expression, PIK3CA mutations, or phosphatase and tensin homolog (PTEN) deletion was identified. CONCLUSION: We confirm the activity of androgen deprivation therapy in androgen receptor-expressing recurrent/metastatic salivary gland cancers. The hypothesis that an androgen receptor increased gene copy number may represent a possible mechanism of primary resistance should be further investigated.

Improved outcome of nasopharyngeal carcinoma treated with conventional radiotherapy.

PURPOSE: To describe the outcome of patients with nonmetastatic nasopharyngeal carcinoma (NPC) treated with conventional radiotherapy at a single institution. METHODS AND MATERIALS: From 1990 to 1999, 171 consecutive patients with NPC were treated with conventional (two-dimensional) radiotherapy. Tumor histology was undifferentiated in 82% of cases. Tumor-node-metastasis Stage (American Joint Committee on Cancer/International Union Against Cancer 1997 system) was I in 6%, II in 36%, III in 22%, and IV in 36% of patients. Mean total radiation dose was 68.4 Gy. Chemotherapy was given to 62% of the patients. The median follow-up for surviving patients was 6.3 years (range, 3.1-13.1 years). RESULTS: The 5-year overall survival, disease-specific survival, and disease-free survival rates were 72%, 74%, and 62%, respectively. The 5-year local, regional, and distant control rates were 84%, 80%, and 83% respectively. Late effects of radiotherapy were prospectively recorded in 100 patients surviving without relapse; 44% of these patients had Grade 3 xerostomia, 33% had Grade 3 dental damage, and 11% had Grade 3 hearing loss. CONCLUSIONS: This analysis shows an improved outcome for patients treated from 1990 to 1999 compared with earlier retrospective series, despite the use of two-dimensional radiotherapy. Late toxicity, however, was substantial with conventional radiotherapy.

Hyperfractionated radiotherapy and chemotherapy for childhood ependymoma: final results of the first prospective AIEOP (Associazione Italiana di Ematologia-Oncologia Pediatrica) study.

PURPOSE: A postsurgical "stage-based" protocol for ependymoma was designed. METHODS AND MATERIALS: Children were given: (1) focal hyperfractionated radiotherapy (HFRT) if with no evidence of disease (NED), or (2) 4 courses with VEC followed by HFRT for residual disease (ED). HFRT dose was 70.4 Gy (1.1 Gy/fraction b.i.d.); VEC consisted of VCR 1.5 mg/m2 1/w, VP16 100 mg/m2/day x 3, CTX 3 g/m2 d 1. When feasible, second-look surgery was recommended. RESULTS: Sixty-three consecutive children were enrolled: 46 NED, 17 ED; the tumor was infratentorial in 47 and supratentorial in 16, with spinal metastasis in 1. Of NED patients, 35 of 46 have been treated with HFRT; 8 received conventionally fractionated radiotherapy, and 3 received no treatment. Of the 17 ED patients, 9 received VEC + HFRT; violations due to postsurgical morbidity were as follows: HFRT only (2), conventionally fractionated radiotherapy (3) + VEC (2), and no therapy (1). Objective responses to VEC were seen in 54%; objective responses to RT were seen in 75%. Overall survival and progression-free survival at 5 years for all 63 children were 75% and 56%, respectively; for the NED subgroup, 82% and 65%; and for the ED subgroup, 61% and 35%, respectively. All histologies were centrally reviewed. At multivariate analysis, grading, age, and site proved significant for prognosis. CONCLUSIONS: HFRT, despite the high total dose adopted, did not change the prognosis of childhood ependymoma as compared to historical series: New radiotherapeutic approaches are needed to improve local control. Future ependymoma strategies should consider grading when stratifying treatment indications.

Activity of abiraterone in rechallenging two AR-expressing salivary gland adenocarcinomas, resistant to androgen-deprivation therapy.

Androgen-deprivation therapy (ADT) has been reported to be active in androgen receptor (AR)-expressing, relapsed/metastatic (RM), salivary gland cancers (SGCs). Abiraterone, an inhibitor of androgen synthesis, has recently been approved as a second-line treatment in hormone-resistant (HR) prostate cancer (PCa) patients. Two patients with AR-positive HR-RM adenocarcinoma, NOS of the salivary glands have been treated with abiraterone. This is the first time that this agent has been reported to be active in tumors other than HRPCa. Immunohistochemical analysis showed overexpression of EGFR, HER2, and HER3 in both untreated primary tumors. Sequencing analysis revealed a TP53 non-functional mutation in one case and a PIK3CA-activating mutation in the other. In conclusion, second line activity of ADT in AR-expressing, adenocarcinoma, NOS of salivary glands further strengthens the pathogenic and therapeutic role of AR signaling in AR-positive SGCs.

Temozolomide is an active agent in children with recurrent medulloblastoma/primitive neuroectodermal tumor: an Italian multi-institutional phase II trial.

BACKGROUND: The aim of this study was to assess the objective response rate (ORR) of children and young adults with recurrent medulloblastoma/primitive neuroectodermal tumor (MB/PNET) treated with temozolomide (TMZ). The secondary purpose was to analyze the toxicity profile of TMZ when administered orally for 5 days in 3 divided daily doses every 28 days. METHODS: Forty-two patients with recurrent MB/PNET, aged 21 years and younger, were recruited. Patients were treated with oral TMZ. Starting doses ranged from 120 to 200 mg/m(2)/day based on previous treatments. A craniospinal MRI was performed prior to the first cycle of TMZ and following every 2 cycles of treatment. RESULTS: Median age was 10 years (range, 2-21 years). Forty of 42 patients were assessed for response and toxicity. The objective response rate was 42.5%: 6 patients achieved a complete response, 11 had a partial response, and 10 had stable disease. Progression-free survival rates for all patients at 6 and 12 months were 30% and 7.5%, respectively. Their median overall survival rates at 6 and 12 months were 42.5% and 17.5%, respectively. No major extrahematological effects or life-threatening events were reported. The most common grade 3/4 toxicity included thrombocytopenia (17.5%), neutropenia (7.5%), and anemia (2.5%). CONCLUSIONS: TMZ proved to be an effective agent in children and young adults with MB/PNET, heavily pre-treated, with a tolerable toxicity profile.

Tp53 status as guide for the management of ethmoid sinus intestinal-type adenocarcinoma.

OBJECTIVE: Intestinal-type adenocarcinoma (ITAC) of the ethmoid sinus is a rare, occupational-related tumor. Optimal treatment consists of surgery and radiotherapy, while chemotherapy is still investigational. The molecular profile of ITAC is characterized by the occurrence of TP53 mutations associated with genotoxic agents such as wood dust. We investigated the role of p53 functionality in relation to the primary treatment. MATERIALS AND METHODS: We retrospectively reviewed 100 medical charts of consecutive patients with a first diagnosis of ITAC treated at our Institute; 74 patients were evaluable for TP53 analysis. Thirty (41%) were treated from 1991 to 2006 with craniofacial resection followed by radiotherapy (Group A), compared with 44 patients (59%) treated from 1996 to 2006 with cisplatin-based induction chemotherapy (PFL) followed by standard treatment (Group B). RESULTS: Five-year OS in Group A was 42%, while in Group B it was 70% (p = 0.041); 5-year DFS in Group A was 40%, while in Group B it was 66%, (p = 0.009) (p = 0.061 and 0.003 at Cox multivariable OS and DFS analyses). Analyzing each group according to p53 functional status, only for Group B patients (who received preoperative chemotherapy) both OS and DFS were in favor of functional p53 (p = 0.023 and p = 0.010, respectively). No impact of p53 functional status as a biomarker was observed in Group A. CONCLUSIONS: Functional p53 may predict PFL-chemotherapy efficacy, offering a possible increase in survival when induction chemotherapy is given to a selected population. On the other hand, upcoming innovative approaches should be explored in the presence of non-functional p53.

Quantitative characterization and identification of lymph nodes and nasopharingeal carcinoma by coregistered magnetic resonance images.

In this study we developed a technique to improve the identification of carcinoma and pathological lymph nodes in cases of Nasopharingeal Carcinoma (NPC), through a quantitative characterization of the tissues based on MR images: 3D VIBE (Volumetric Interpolated Breath-hold Examination) T1-CE (Contrast Enhanced), T1, T2 and Diffusion Weighted Imaging (DWI) for b-values 0,300,500,700,1000. The procedure included two phases: 1) coregistration of volumes and 2) tissue characterization. Concerning the first phase, the DICOM images were reassembled spatially and resampled with isotropic 0.5mm resolution. Coregistration was performed by two multiresolution rigid transformations, merging head and neck volumes, plus a final multiresolution non rigid transformation. The anatomical 3D CE-VIBE volume was taken as reference. The procedure for tissue characterization is semi automated and it required a radiologist to identify an example of tissue from the primary tumor and a metastatic lymph node. We generated a 8-dimensional membership function to perform a fuzzy-like identification of these tissues. The result of this procedure was the generation of two maps, which showed complementary characterization of lymph nodes and carcinoma. A few example will be shown to evidence the potentiality of this method in identification and characterization of NPC lesions.

Second-look surgery for ependymoma: the Italian experience.

OBJECT: Complete ependymoma resection ensures a better prognosis for children with this tumor, but the complete excision of infratentorial ependymomas involves serious risks. Second-look surgery for tumor remnants may be less harmful and enable complete removal. There is a potential, although still unclear, role for neoadjuvant chemotherapy in preparation for further surgery. METHODS: Since 1994, the authors have adopted two successive protocols for intracranial ependymoma, both including a phase of adjuvant chemotherapy for children with surgical tumor remnants with a plan for potential second-look surgery before radiotherapy. RESULTS: In the first protocol, 9 of 63 children underwent further surgery, and 6 became tumor free with no additional sequelae. Their prognosis for progression-free survival and freedom from local relapse was comparable to that of children who were operated on only once. In the second protocol, efforts were made to achieve complete resection and 29 of 110 patients underwent reoperations: 9 after the first surgery, 17 after chemotherapy, and 3 soon after radiotherapy. Fourteen of the 29 patients became tumor free, 1 of them with worsening neurological symptoms. The outcome of the 66 patients who became tumor free after 1 operation was compared with that of the 14 who became tumor free after reoperation. The 3-year progression-free survival of the 66 patients compared with the 14 other patients was 71.4% ± 6.9% and 90% ± 9.5%, respectively; the 3-year freedom from local relapse was 84.7% ± 5.9% and 90% ± 9.5%, respectively; and the 3-year overall survival was 85.9% ± 5.4% and 87.5% ± 11.7%, respectively. CONCLUSIONS: Second-look surgery proved feasible with no major morbidity, and results improved with time. Local tumor control was comparable in patients undergoing 1 or more resections.

Infant ependymoma in a 10-year AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) experience with omitted or deferred radiotherapy.

PURPOSE: The protocols of the 1990s omitted or delayed irradiation, using upfront chemotherapy to spare the youngest children with ependymoma the sequelae of radiotherapy (RT). We treated 41 children under the age of 3 years with intracranial ependymoma between 1994 and 2003. PATIENTS AND METHODS: After surgery, chemotherapy was given as follows: regimen I with four blocks of vincristine, high-dose methotrexate 5 g/m(2), and cyclophosphamide 1.5 g/m(2) alternating with cisplatin 90 mg/m(2) plus VP16 450 mg/m(2) for 14 months; subsequently, regimen II was used: VEC (VCR, VP16 300 mg/m(2), and cyclophosphamide 3 g/m(2)) for 6 months. Radiotherapy was planned for residual tumor after the completion of chemotherapy or for progression. RESULTS: We treated 23 boys and 18 girls who were a median 22 months old; 14 were given regimen I, 27 were given regimen II; 22 underwent complete resection, 19 had residual tumor. Ependymoma was Grade 2 in 25 patients and Grade 3 in 16; tumors were infratentorial in 37 patients and supratentorial in 4. One child had intracranial metastases; 29 had progressed locally after a median 9 months. Event-free survival was 26% at 3 and 5 years and 23% at 8 years. One child died of sepsis, and another developed a glioblastoma 72 months after RT. Progression-free survival was 27% at 3, 5, and 8 years, and overall survival was 48%, 37%, and 28% at 3, 5, and 8 years, respectively. Of the 13 survivors, 6 never received RT; their intellectual outcome did not differ significantly in those children than in those without RT. CONCLUSIONS: Our results confirm poor rates of event-free survival and overall survival for up-front chemotherapy in infant ependymoma. No better neurocognitive outcome was demonstrated in the few survivors who never received RT.

Further improvement in outcomes of nasopharyngeal carcinoma with optimized radiotherapy and induction plus concomitant chemotherapy: an update of the Milan experience.

PURPOSE: To report the outcome of a consecutive series of patients with nonmetastatic nasopharyngeal carcinoma (NPC), focusing on the impact of treatment-related factors. METHODS AND MATERIALS: Between 2000 and 2006, 87 patients with NPC were treated with either conventional (two- or three-dimensional) radiotherapy (RT) or with intensity-modulated RT (IMRT). Of these patients, 81 (93%) received either concomitant CHT (24%) or both induction and concomitant chemotherapy (CHT) (69%). Stage was III in 36% and IV in 39% of patients. Outcomes in this study population were compared with those in the previous series of 171 patients treated during 1990 to 1999. RESULTS: With a median follow-up of 46 months, actuarial rates at 3 years were the following: local control, 96%; local-regional control, 93%; distant control (DC), 90%; disease-free survival (DFS), 82%; overall survival, 90%. In Stage III to IV patients, distant control at 3 years was 56% in patients treated with concomitant CHT only and 92% in patients treated with both induction and concomitant CHT (p = 0.014). At multivariate analysis, histology, N-stage, RT technique, and total RT dose had the strongest independent impact on DFS (p < 0.05). Induction CHT had a borderline effect on DC (p = 0.07). Most dosimetric statistics were improved in the group of patients treated with IMRT compared with conventional 3D technique. All outcome endpoints were substantially better in the study population compared with those in the previous series. CONCLUSIONS: Outcome of NPC has further improved in the study period compared with the previous decade, with a significant effect of RT technique optimization. The impact of induction CHT remains to be demonstrated in controlled trials.

No salvage using high-dose chemotherapy plus/minus reirradiation for relapsing previously irradiated medulloblastoma.

PURPOSE: Myeloablative regimens were frequently used for medulloblastoma relapsing after craniospinal irradiation (CSI): in 1997-2002, we used repeated surgery, standard-dose and myeloablative chemotherapy, and reirradiation. METHODS AND MATERIALS: In 10 patients, reinduction included sequential high-dose etoposide, high-dose cyclophosphamide/vincristine, and high-dose carboplatin/vincristine, then two myeloablative courses with high-dose thiotepa (+/- carboplatin); 6 other patients received two of four courses of cisplatin/etoposide. Hematopoietic precursor mobilization followed high-dose etoposide or high-dose cyclophosphamide or cisplatin/etoposide therapy. After the overall chemotherapy program, reirradiation was prescribed when possible. RESULTS: Seventeen patients were treated: previous treatment included CSI of 19.5-36 Gy with posterior fossa/tumor boost and chemotherapy in 16 patients. Fifteen patients were in their first and 2 in their second and third relapses, respectively. First progression-free survival had lasted a median of 26 months. Relapse sites included leptomeninges in 9 patients, spine in 4 patients, posterior fossa in 3 patients, and brain in 1 patient. Three patients underwent complete resection of recurrence, and 10 underwent reirradiation. Twelve of 14 patients with assessable tumor had an objective response after reinduction; 2 experienced progression and were not given the myeloablative courses. Remission lasted a median of 16 months. Additional relapses appeared in 13 patients continuing the treatment. Fifteen patients died of progression and 1 died of pneumonia 13 months after relapse. The only survivor at 93 months had a single spinal metastasis that was excised and irradiated. Survival for the series as a whole was 11-93 months, with a median of 41 months. CONCLUSIONS: Despite responses being obtained and ample use of surgery and reirradiation, second-line therapy with myeloablative schedules was not curative, barring a few exceptions. A salvage therapy for medulloblastoma after CSI still needs to be sought.