Superior Long-Term Outcome of Patients With Early Transformation of Non-Hodgkin Lymphoma Undergoing Stem Cell Transplantation

BackgroundTransformed non-Hodgkin's lymphoma arising from follicular lymphoma (TL) carries a poor prognosis with a median survival time after transformation reported to be approximately 1 year.Patients and MethodsFifty-one consecutive patients with TL received SCT between January 2000 and December 2010 (autologous SCT, n = 44, allogeneic SCT, n = 7).ResultsThirty-six (70.5%) patients had an early transformation, defined as histologic evidence of transformation at the time of initial diagnosis or transformation within 1 year of follicular lymphoma. Fifteen patients had early stage disease (29%) and 36 (71%) had advanced stage disease on presentation. At the time of analysis, 37 patients were alive with an estimated 5-year overall survival (OS) and event free survival (EFS) of 61.8% and 45%, respectively. OS and EFS were not significantly different between types of transplant procedure. The major cause of transplant failure was disease recurrence, with estimated 2-year relapse rate of 37.4%. Importantly, early transformation was independently associated with improved OS (hazard ratio [HR] 3.29; P = .028) and EFS (HR 2.49; P = .029).ConclusionOur results indicate that an aggressive transplant approach should be considered first in patients with TL and emphasize the need to incorporate novel strategies (eg, immunomodulation) early post-SCT to prevent relapses as disease recurrence remains the major cause of failure in heavily pretreated patients.     

Neurosurgical morbidity in pediatric supratentorial midline low-grade glioma: Results from the German LGG studies

Surgical resection is a mainstay of treatment for pediatric low-grade glioma (LGG) within all current therapy algorithms, yet associated morbidity is scarcely reported. As supratentorial midline (SML) interventions are particularly challenging, we investigated the frequency of neurosurgical complications/new impairments aiming to identify their risk factors. Records were retrospectively analyzed from 318 patients with SML-LGG from successive German multicenter LGG studies, undergoing surgery between May 1998 and June 2020. Exactly 537 operations (230 resections, 167 biopsies, 140 nontumor procedures) were performed in 318 patients (54% male, median age: 7.6 years at diagnosis, 9.5 years at operation, 11% NF1, 42.5% optic pathway glioma). Surgical mortality rate was 0.93%. Applying the Drake classification, postoperative surgical morbidity was observed following 254/537 (47.3%) and medical morbidity following 97/537 (18.1%) patients with a 40.1% 30-day persistence rate for newly developed neurological deficits (65/162). Neuroendocrine impairment affected 53/318 patients (16.7%), visual deterioration 34/318 (10.7%). Postsurgical morbidity was associated with patient age <3 years at operation, tumor volume ≥80 cm³, presence of hydrocephalus, complete resection, surgery in centers with less than median reported tumor-related procedures and during the earlier study period between 1998 and 2006, while the neurosurgical approach, tumor location, NF1 status or previous nonsurgical treatment were not. Neurosurgery-associated morbidity was frequent in pediatric patients with SML-LGG undergoing surgery in the German LGG-studies. We identified patient- and institution-associated factors that may increase the risk for complications. We advocate that local multidisciplinary teams consider the planned extent of resection and surgical skills.     

Treatment of Ph-Negative Acute Lymphoblastic Leukemia in Adolescents and Young Adults with an Affordable Outpatient Pediatric Regimen

BackgroundB-cell acute lymphoblastic leukemia is frequent in Hispanic adolescents and young adults. Outcomes of implementation of pediatric-inspired regimens in low-and middle-income countries are not well known.MethodsIn this study we treated 94 adolescents and young adults with a local BFM regimen designed to be affordable with the use of native L-asparaginase and mitoxantrone administered in an outpatient fashion, and the of BCR/ABL and measurable residual disease (MRD) determined by high sensitivity flow cytometry for risk stratification.ResultsInduction mortality was 11%; 25% of patients had to abandon treatment or be transferred to another health system. Two-year overall (OS) and event free survival (EFS) were 61.5% and 49.8%, MRD-negative patients had a 24-month OS of 85.6% vs. 69.6% (p = .024) and EFS of 76% vs. 45.5% (p = .004). Patients older than 40 years and those who abandoned treatment had worse EFS. Overall drug costs in our regimen were 52% lower than those of CALGB10403.Conclusion The treatment of AYAs with ALL with an outpatient focus was implemented successfully at a reduced cost. Genetic risk assessment, treatment abandonment and lack of access to novel therapies remain major barriers for improving outcomes.     

Autologous Stem Cell Transplantation for Multiple Myeloma: Identification of Prognostic Factors

IntroductionThe purpose of this study was to evaluate the effect of prognostic factors on the outcome of patients with MM after ASCT.Patients and MethodsWe analyzed results of 170 consecutive patients (121 male and 49 female) of MM who underwent ASCT. Patients' median age was 52 years (range, 26-68 years). High dose melphalan (200 mg/m²) was used for conditioning. One hundred thirty-two patients (77.6%) had evidence of chemosensitive disease before transplant. Response was assessed using European Group for Blood and Bone Marrow Transplantation criteria.ResultsPost ASCT 44.7% of patients achieved CR, 24.7% had very good partial response (VGPR), and 21.2% had partial response (PR). Presence of pretransplant chemosensitive disease (CR, VGPR, and PR) and transplant within 12 months of diagnosis for years before 2006 were associated with higher response rates on multivariate analysis. At a median follow-up of 84 months, median overall (OS) and event-free survival (EFS) is 85.5 and 41 months, respectively. Estimated OS and EFS at 60 months is 62 ± 0.04% and 41 ± 0.04%, respectively. Patients who responded to transplant (CR, VGPR, and PR) had a longer OS (P < .001) and EFS (P < .001). Additionally, patients who achieved CR post transplant had a longer OS (P < .001) and EFS (P < .001). Patients who received novel agents for induction pretransplant had a longer OS (P < .001) and EFS (P < .002).ConclusionOutcome after ASCT is better for myeloma patients with pretransplant chemosensitive disease and those who achieve CR after transplant.     

Intensified alemtuzumab–CHOP therapy for peripheral T-cell lymphoma

BackgroundThe prognosis of T-cell lymphoma is poor. To explore the addition of the monoclonal antibody alemtuzumab, we studied the efficacy and tolerability of an intensified alemtuzumab–chemotherapy combination for aggressive T-cell lymphoma in a phase II study by Dutch-Belgian Hemato-Oncology Group (HOVON).Patients and methodsPatients (≤65 years) with newly diagnosed T-cell lymphoma received eight CHOP cycles (cyclophosphamide, doxorubicin, vincristine, prednisone) 2-weekly, each cycle with three doses of 30 mg alemtuzumab. Prophylaxis consisted of cotrimoxazole, fluconazole and valaciclovir. Cytomegalovirus (CMV) monitoring took place at least every fortnight.ResultsTwenty patients from 10 centers, median age 50 years, were included. Eighty-five percent received six or more cycles. The overall response was 90% [12 complete remissions (CRs), 1 CR unconfirmed, 5 partial remissions]. Median duration of follow-up of patients still alive was 29 months (range 19–41 months). Median overall survival (OS) and event-free survival (EFS) were 27 and 10 months, with 55%/27% OS/EFS at 2 years. Adverse events consisted of neutropenic fever (n = 8) and CMV reactivation (n = 7), with one CMV disease. Three patients developed secondary Epstein-Barr virus (EBV)-related lymphoma, all after end of treatment.ConclusionsAlthough intensified alemtuzumab–CHOP induces high responses, many patients relapse, and the scheme is associated with serious infection-related adverse events. EBV monitoring after end of treatment is required.     

Pseudoprogression in pediatric low-grade glioma after irradiation

This study aimed to assess the incidence and management of pseudoprogression after radiation therapy (RT) in patients with pediatric low-grade glioma (LGG). This retrospective review included patients aged 21 years or younger with intracranial LGG treated with curative-intent RT. Pseudoprogression was defined as an increase in tumor size by ≥10% in at least two dimensions between two and three consecutive MR imaging studies. Overall survival (OS) and event-free survival (EFS) were measured from the first day of RT. EFS was defined as survival without true progression or secondary high-grade glioma. Sixty-two of 221 patients developed pseudoprogression, with a 10-year cumulative incidence of 29.0% (95% CI 23.0–35.2). Median time to pseudoprogression was 6.1 months after RT. Symptomatic pseudoprogression was managed with subtotal resection, shunt/Ommaya reservoir placement, or corticosteroids in 11 (18%), 7 (11%), and 2 patients (3%), respectively. The remaining tumors were observed (68%). Patients with pilocytic astrocytoma (PA) had 5.4-fold greater odds of developing pseudoprogression relative to tumors of other histology (odds ratio 95% CI 2.5–11.4, P?<?0.0001). Among patients with PA (n?=?127), the 10-year cumulative incidence of pseudoprogression was 42.9%. In this group, pseudoprogression was associated with improved 10-year EFS (84.5% vs. 58.5%, P?=?0.008) and OS (98.0% vs. 91.2%, P?=?0.03). Pseudoprogression after irradiation was common, especially in patients with pilocytic astrocytoma, and was associated with improved survival. Knowledge of the incidence and temporal course of pseudoprogression may help avoid unnecessary salvage therapy.     

High-dose therapy followed by autologous stem-cell transplantation with and without rituximab for primary treatment of high-risk diffuse large B-cell lymphoma

BackgroundWe aimed to determine safety and efficacy of rituximab (R) in combination with repetitive high-dose therapy (HDT) as primary treatment for diffuse large B-cell lymphoma (DLBCL).Patients and methodsPatients aged 18–60 years and elevated lactate dehydrogenase were treated with four cycles of MegaCHOEP and transplantation of autologous stem cells after cycles 2, 3 and 4. Rituximab (375 mg/m²) was given before each cycle and 12 and 33 days after start of the last cycle of chemotherapy. Sixty-four patients given R-MegaCHOEP were compared with 29 patients who had received identical treatment without rituximab.ResultsOverall survival (OS) and event-free survival (EFS) after 3 years were significantly improved in patients treated with R-MegaCHOEP (OS: 78.7% versus 55.0%, P = 0.045; EFS: 72.7% versus 47.2%, P = 0.013). In a Cox regression model adjusted for performance status and stage, relative risk of treatment failure was lower (relative risk 0.5, P = 0.041) and OS was better (relative risk 0.4, P = 0.054) for patients given R-MegaCHOEP. Grade 3/4 infections were more frequent in the R-MegaCHOEP group (18.5% versus 6.0%, P = 0.003).ConclusionsThe addition of rituximab to MegaCHOEP significantly improved outcome in young patients with high-risk DLBCL. The higher incidence of grade 3/4 infections needs consideration when rituximab and HDT regimens are combined.     

Does the extent of surgery have an impact on the survival of patients who receive postoperative radiation therapy for supratentorial low‐grade gliomas?

We evaluate the impact of extent of surgery (EOS) on survival of patients with supratentorial nonpilocytic low‐grade gliomas (LGG) treated with postoperative radiation therapy (PORT). Sixty‐five patients with pathologically confirmed supratentorial nonpilocytic LGG (36 astrocytomas and 29 oligodendrogliomas) were treated with PORT after different extents of surgery: 12 gross total resections (GTR), 27 minimal or subtotal resections (MR/SR), and 26 biopsies (B). EOS was confirmed with postoperative imaging. The median radiation dose delivered was 5,940 cGy (range, 4,950–6,620 cGy). One of 12 patients (8%) in the GTR group and 12 of 53 patients (23%) in the less than GTR group demonstrated contrast enhancement. The median follow‐up was 61 months (range 5–194 month). The 10‐year overall survival (OS) was 82.5% and 32% for the GTR and the less than GTR groups, respectively (P = 0.0008). The corresponding 10‐year disease‐specific survival (DSS) was 90% and 41.4%%, respectively (P = 0.001). Multivariate analysis showed that only contrast enhancement and EOS were predictors for OS and DSS. Our data suggest that EOS correlates with OS and DSS in patients who have PORT. GTR should be the goal if technically achievable without causing significant morbidity, and its combination with PORT is compatible with long‐term survival. © 2002 Wiley‐Liss, Inc.     

Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes: a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial

BackgroundPathological complete response (pCR) following chemotherapy is strongly associated with both breast cancer subtype and long-term survival. Within a phase III neoadjuvant chemotherapy trial, we sought to determine whether the prognostic implications of pCR, TP53 status and treatment arm (taxane versus non-taxane) differed between intrinsic subtypes.Patients and methodsPatients were randomized to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel then three cycles of eprirubicin/docetaxel (T-ET). pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in primary tumour and lymph nodes. We used a simplified intrinsic subtypes classification, as suggested by the 2011 St Gallen consensus. Interactions between pCR, TP53 status, treatment arm and intrinsic subtype on event-free survival (EFS), distant metastasis-free survival (DMFS) and overall survival (OS) were studied using a landmark and a two-step approach multivariate analyses.ResultsSufficient data for pCR analyses were available in 1212 (65%) of 1856 patients randomized. pCR occurred in 222 of 1212 (18%) patients: 37 of 496 (7.5%) luminal A, 22 of 147 (15%) luminal B/HER2 negative, 51 of 230 (22%) luminal B/HER2 positive, 43 of 118 (36%) HER2 positive/non-luminal, 69 of 221(31%) triple negative (TN). The prognostic effect of pCR on EFS did not differ between subtypes and was an independent predictor for better EFS [hazard ratio (HR) = 0.40, P < 0.001 in favour of pCR], DMFS (HR = 0.32, P < 0.001) and OS (HR = 0.32, P < 0.001). Chemotherapy arm was an independent predictor only for EFS (HR = 0.73, P = 0.004 in favour of T-ET). The interaction between TP53, intrinsic subtypes and survival outcomes only approached statistical significance for EFS (P = 0.1).ConclusionspCR is an independent predictor of favourable clinical outcomes in all molecular subtypes in a two-step multivariate analysis.ClinicalTrials.govEORTC 10994/BIG 1-00 Trial registration number NCT00017095.     

The contribution of chest CT-scan at diagnosis in children with unilateral Wilms' tumour. Results of the SIOP 2001 study

BackgroundThe SIOP 2001 nephroblastoma study hypothesised that patients with ‘CT-only’ pulmonary nodules would have the same outcome as patients with localised disease of same stage and histology.PatientsUnilateral Wilms’ tumour (WT) patients, who had chest CT scans at diagnosis showing any sized pulmonary nodules undetected on chest X-ray, between November 2001 and November 2009, were selected from the SIOP 2001 database.ResultsAmong 2532 WT patients, 103 unilateral nephroblastoma patients with CT-only lung lesions were found. Thirty-seven patients received preoperative treatment according to the localised-disease protocol, and 66 according to the metastatic-disease protocol. The 3-year event-free survival (EFS) was 70% (95% CI: 55–89%) and 77% (95% CI: 66–89%), respectively. Corresponding 3-year overall survival (OS) was 89% (95% CI: 77–100%) and 85% (95% CI: 75–96%), respectively (p-value not significant). EFS and OS of all 2071 patients with true localised disease were 87% (95% CI: 86–89%) and 96% (95% CI: 94–97%), respectively. Patients with metastatic disease (n = 358) had 3-year EFS and OS estimates of 68% (95% CI: 63–74%) and 77% (95% CI: 72–82%), respectively.ConclusionsEFS and OS of patients with CT-only lung lesions were inferior to that of true localised-disease patients and superior to that of patients with metastatic disease. However, no significant difference was found in EFS and OS between CT-only patients treated for localised or metastatic disease. The clinician’s preference to treat patients with CT-only pulmonary nodules as metastatic disease is not evidence-based. Chest CT at diagnosis does not improve outcome but presents paediatric oncologists with a difficult dilemma.     

Treatment outcomes for older patients with relapsed/refractory aggressive lymphoma receiving salvage chemotherapy and autologous stem cell transplantation are similar to younger patients: a subgroup analysis from the phase III CCTG LY.12 trial

BackgroundHigh-dose therapy and autologous stem cell transplantation (ASCT) is often considered for older patients (age >60 years) with relapsed/refractory aggressive lymphomas. Although registry data support the safety and potential efficacy of this approach, there are no prospective trials evaluating outcomes of ASCT in older patients. We evaluated the result of second-line chemotherapy and ASCT in older versus younger patients in the CCTG randomized LY.12 trial.Patients and methodsFrom August 2003 to November 2011, 619 patients with relapsed/refractory aggressive lymphoma were randomized to gemcitabine, dexamethasone, cisplatin (GDP) or dexamethasone, cytarabine, cisplatin (DHAP); 177 patients (28.6%) enrolled were >60.0 years of age (range, 60–74) and 442 were ≤60.0 years of age. After two to three cycles, responding patients proceeded to ASCT. Intention-to-treat analysis was used to compare response rate, transplantation rate, event-free survival (EFS) and overall survival (OS) between patients aged ≤60.0 and >60.0 years.ResultsPatient characteristics were comparable between the two cohorts, except a larger proportion of older patients had high International Prognostic Index risk scores. Response to salvage therapy was 48.6% for patients aged >60.0 versus 43.0% for those aged ≤60.0 (P = 0.21). Transplantation rates were also similar: 50.3% versus 49.8% (P = 0.87) for older versus younger patients. Rates of febrile neutropenia and adverse events requiring hospitalization were comparable for older and younger patients (30.5% versus 22.9% and 37.9% versus 32.1%, respectively). With a median follow-up of 53 months, there was no difference in 4-year OS (36% and 40% for patients aged >60.0 and ≤60.0 years,P = 0.42), or 4-year EFS (20% versus 28%,P = 0.43). Mortality from salvage therapy was 8/174 (4.60%) and 5/436 (1.15%), and 100-day mortality post-ASCT was 7/88 (8.06%) and 4/219 (1.85%).ConclusionThis subgroup analysis suggests that older patients derive similar benefit from salvage therapy and ASCT to younger patients, with acceptable toxicity.ClinicalTrials.gov IdentifierNCT00078949.     

Risk factors in germ cell tumour patients with relapse or progressive disease after first-line chemotherapy: evaluation of a prognostic score for survival after high-dose chemotherapy

PurposeTo retrospectively re-evaluate a published prognostic score for response to salvage treatment in patients with germ-cell tumours relapsing or progressing after cisplatin-based first-line chemotherapy.Patients and methodsFrom a database of 257 germ cell tumour (GCT) patients treated with salvage high-dose chemotherapy (HDCT) we identified 176 patients (67%) with relapse or progression after first-line conventional-dose chemotherapy (CDCT). Patients were retrospectively grouped according to a published prognostic score defined by Fossa and colleagues [Fossa SD, Stenning SP, Gerl A, et al. Prognostic factors in patients progressing after cisplatin-based chemotherapy for malignant non-seminomatous germ cell tumors. Br J Cancer 1999; 80:1392–9]. Overall survival (OS) and event free survival (EFS) after HDCT were retrospectively evaluated in each prognostic group.ResultsAfter a median follow-up of 9 years the OS probability for all 176 patients was 38% and the EFS probability was 35%. The respective survival probability at 5 years in 100/176 (57%) good prognosis patients and 76/176 (43%) poor prognosis patients were 47% versus 28% for OS (p < 0.001) and 41% versus 26% for EFS (p < 0.005). Whereas survival probabilities did not differ in good prognosis patients, OS and EFS in poor prognosis patients were substantially better in the current series of patients treated with HDCT compared to the ones reported by Fossa treated with CDCT.ConclusionThis retrospective analysis confirms the impact of prognostic factors on the results of salvage treatment in patients with GCT and suggests a clinical benefit for patients with poor prognosis features receiving a single course of HDCT.     

Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression

BackgroundTaxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO epiribicine and cyclophosphamide (EC)-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1–3 positive lymph nodes (LNs) only.Patients and methodsA total of 2011 BC patients (18–65 years, pN1) were entered into a randomized phase III trial comparing 4 × E₉₀C₆₀₀ q3w followed by 4 × docetaxel₁₀₀ q3w (n = 1008) with the current standard: 6 × F₅₀₀E₁₀₀C₅₀₀ q3w (n = 828) or C₆₀₀M₄₀F₆₀₀ d1, 8× q4w (n = 175). Primary end point was event-free survival (EFS); secondary end points were overall survival (OS), toxicity, translational research, and quality of life. Central tumor bank samples were evaluable in a representative collective (n = 772; 40%). Ki-67 was assessed centrally in hormone receptor-positive disease as a surrogate marker for the distinction of luminal A/B-like tumors.ResultsBaseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59-month median follow-up, superior efficacy of EC-Doc [versus FEC (a combination of 5-fluorouracil, epirubicin, and cyclophosphamide)] was seen in EFS and OS: 5-year EFS: 89.8% versus 87.3% (P = 0.038); 5-year OS: 94.5% versus 92.8% (P = 0.034); both tests one-tailed. EC-Doc caused more toxicity. In hormone receptor-positive (HR)+ disease, only high-Ki-67 tumors (≥20%) derived significant benefit from taxane-based therapy: hazard ratio = 0.39 (95% CI 0.18–0.82) for EC-Doc versus FEC (test for interaction; P = 0.01).ConclusionEC-Doc significantly improved EFS and OS versus FEC in intermediate-risk BC (1–3 LNs) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy.Clinical Trial numberClinicalTrials.gov, NCT02115204.     

Final results from the prospective phase III WSG-ARA trial: impact of adjuvant darbepoetin alfa on event-free survival in early breast cancer

BackgroundWSG-ARA plus trial evaluated the effect of adjuvant darbepoetin alfa (DA) on outcome in node positive primary breast cancer (BC).Patients and methodsOne thousand two hundred thirty-four patients were randomized to chemotherapy either with DA (DA+; n = 615) or without DA (DA−; n = 619). DA (500 µg q3w) was started at hemoglobin (Hb) levels <13.0 g/dl (<12 g/dl after DA label amendment) and stopped at Hb levels ≥14.0 g/dl (12 g/dl after label amendment). Primary efficacy end point was event-free survival (EFS); secondary end points were toxicity, quality of life (QoL) and overall survival (OS).ResultsVenous thrombosis (DA+: 3.0%, DA−: 1.0%; P = 0.013) was significantly higher for DA+, but not pulmonary embolism (0.3% in both arms). Median Hb levels were stable in DA+ (12.6 g/dl) and decreased in DA− (11.7 g/dl). Hb levels >15 g/dl were reported in 0.8% of cycles. QoL parameters did not significantly differ between arms. At 39 months, DA had no significant impact on EFS (DA+: 89.3%, DA−: 87.5%; P_log-rank = 0.55) or OS (DA+: 95.5%, DA−: 95.4%; P_log-rank = 0.77).ConclusionsDA treatment did not impact EFS or OS in routine adjuvant BC treatment.     

Clinical outcomes in a large pediatric cohort of patients with ependymoma treated with proton radiotherapy

BackgroundTreatment for pediatric ependymoma includes surgical resection followed by local radiotherapy (RT). Proton RT (PRT) enables superior sparing of critical structures compared with photons, with potential to reduce late effects. We report mature outcomes, patterns of failure, and predictors of outcomes in patients treated with PRT.MethodsOne hundred fifty patients (<22 y) with World Health Organization grades II/III ependymoma were treated with PRT between January 2001 and January 2019 at Massachusetts General Hospital. Demographic, tumor, and treatment-related characteristics were analyzed. Event-free survival (EFS), overall survival (OS), and local control (LC) were assessed.ResultsMedian follow-up was 6.5 years. EFS, OS, and LC for the intracranial cohort (n = 145) at 7 years were 63.4%, 82.6%, and 76.1%. Fifty-one patients recurred: 26 (51.0%) local failures, 19 (37.3%) distant failures, and 6 (11.8%) synchronous failures. One hundred sixteen patients (77.3%) underwent gross total resection (GTR), 5 (3.3%) underwent near total resection (NTR), and 29 (19.3%) underwent subtotal resection (STR). EFS for the intracranial cohort at 7 years for GTR/NTR and STR was 70.3% and 35.2%. With multivariate analysis, the effect of tumor excision persisted after controlling for tumor location. There was no adverse effect on disease control if surgery to RT interval was within 9 weeks of GTR/NTR.ConclusionPRT is effective and safe in pediatric ependymoma. Similar to previous studies, GTR/NTR was the most important prognostic factor. Intervals up to 9 weeks from surgery to PRT did not compromise disease outcomes. There was no LC benefit between patients treated with >54 Gray relative biological effectiveness (Gy_RBE) versus ≤54 Gy_RBE.     

Surgical outcomes and prognostic factors of non-metastatic radiation-induced sarcoma of bone

BackgroundThe survival and prognostic factors in non-metastatic, radiation-induced bone sarcomas of bone have not been described. Moreover, the quantitative data about surgical outcomes and complications after limb-salvage surgery versus amputation are quite limited.MethodsTwenty-five patients with non-metastatic, radiation-induced sarcoma of bone who underwent definitive surgery were analysed. Histological diagnosis was osteosarcoma in 19 and undifferentiated pleomorphic sarcoma in six. The definitive surgery was limb-salvage surgery in 15 patients and an amputation in 10.ResultsThe 5-year overall survival rate (OS) and the 5-year event-free survival rate (EFS) were 53% (95% CI 31%–70%) and 40% (21%–59%), respectively. Patients with wide or radical surgical margins (n = 13) showed significantly better OS compared with those with marginal (n = 8) or intralesional (n = 2) margins (5-year OS, radical or wide = 74%, marginal = 17%, intralesional = 0%, p = 0.044). The risk of local recurrence was significantly higher in the limb-salvage group compared to the amputation group (49% vs 0%, p = 0.011). OS and EFS were not significantly different between limb-salvage group and an amputation group (p = 0.188 and 0.912, respectively).ConclusionsWe believe non-metastatic, radiation-induced sarcoma of bone should be resected with the aim of achieving wide or radical margins. Although limb-salvage surgery was related to higher rates of local recurrence compared with those of the amputation group, OS and EFS were not different among two groups. Surgeons need to discuss the higher risk of local recurrence in limb-salvage surgery.     

Metastatic medulloblastoma in adults: Outcome of patients treated according to the HIT2000 protocol

BackgroundDue to the rarity of metastatic medulloblastoma in adults, knowledge about the efficacy and toxicity of intensified chemotherapy and radiotherapy is limited.Patients and methodsAdults with disseminated medulloblastoma registered in the HIT2000 trial as observational patients and treated according to one of two different treatment regimens were analysed. The sandwich strategy MET-HIT2000AB4 consists of postoperative chemotherapy, hyperfractionated craniospinal radiotherapy, and maintenance chemotherapy; while the HIT′91 maintenance strategy consists of postoperative craniospinal radiotherapy, and maintenance chemotherapy.ResultsTwenty-three patients (median age: 30.7 years), diagnosed from November 2001 to July 2009, and treated in 18 institutions in Germany and Austria, were eligible. The median follow-up of surviving patients was 3.99 years. The 4-year event-free survival (EFS) and overall survival (OS) ± standard error (SE) were 52% ± 12% and 91% ± 6%, respectively. The survival was similar in both treatment groups (HIT′91 maintenance strategy, n = 9; MET-HIT2000AB4 sandwich strategy, n = 14). Patients with large cell/anaplastic medulloblastoma relapsed and died (n = 2; 4-year EFS/OS: 0%) and OS differed compared to patients with classic (n = 11; 4-year EFS/OS: 71%/91%) and desmoplastic medulloblastoma (n = 10; 4-year EFS/OS: 48%/100%), respectively (p = 0.161 for EFS and p = 0.033 for OS).Treatment-induced toxicities consisted mainly of neurotoxicity (50% of patients, ⩾ °II), followed by haematotoxicity and nephrotoxicity/ototoxicity. The professional outcome appeared to be negatively affected in the majority of evaluable patients (9/10).ConclusionsTreatment of adults with metastatic medulloblastoma according to the intensified paediatric HIT2000 protocol was feasible with acceptable toxicities. EFS rates achieved by both chemotherapeutic protocols were favourable and appear to be inferior to those obtained in older children/adolescents with metastatic disease.     

Treatment of embryonal tumors with multilayered rosettes with carboplatin/etoposide induction and high-dose chemotherapy within the prospective P-HIT trial

BackgroundEmbryonal tumors with multilayered rosettes (ETMR) are highly aggressive tumors occurring in early childhood. Published clinical data refer to retrospective, heterogeneously treated cohorts. Here, we describe the outcome of patients treated according to the prospective P-HIT trial and subsequent HIT2000-interim-registry.Patients and methodsAge-stratified treatment included carboplatin/etoposide induction, tandem high-dose chemotherapy (“CARBO/ETO + HDCT”), and response-stratified radiotherapy. Patients with centrally reviewed neuropathological and molecularly confirmed diagnosis of ETMR recruited within the P-HIT trial (2001-2011; n = 19), the HIT2000-interim-registry (2012-2014; n = 12), and earlier HIT trials (n = 4) were selected for analysis.ResultsAge-adjusted incidence rate was 1.35 per 1 million children (aged 1-4 years) in the years 2012-2014. Median age at diagnosis for 35 patients was 2.9 years. Metastases at diagnosis were detected in 9 patients. One patient died due to postoperative complications. For 30 patients with non-brainstem tumor location, 5-year progression-free survival (PFS) and overall survival (OS) were 35% and 47% after treatment with CARBO/ETO + HDCT (n = 17), compared to 0% and 8% with other treatments (n = 13, P[OS] = .011). All 4 patients with brainstem tumor died within 10 months after diagnosis. By multivariable analysis, supratentorial location: (HR [PFS]: 0.07 [95%CI: 0.01-0.38], P = .003), localized disease (M0): (HR [OS] M0, no residual tumor: 0.30 [95%CI: 0.009-1.09], P = .068; M0, residual tumor: 0.18 [95%CI: 0.04-0.76], P = .020), and CARBO/ETO + HDCT treatment (HR [OS]: 0.16 [95%CI: 0.05-054], P = .003) were identified as independent prognostic factors. Of 9 survivors, 6 were treated with radiotherapy (craniospinal 4; local 2).ConclusionsOur data indicate improved survival with intensified chemotherapy (CARBO/ETO + HDCT). However, despite intensive treatment, the outcome was poor. Thus, innovative therapies need to be evaluated urgently in an upfront setting.     

Ovarian and peritoneal psammocarcinoma: Results of a multicenter study on 25 patients

PurposePsammocarcinoma (PK) is a rare disease of unknown origin. We aimed to report the characteristics, management and survival of patients operated on for PK within the French Network for Rare Peritoneal Malignancies (RENAPE) expert centers.Patients and methodsAll consecutive cases of PK operated within all 26 RENAPE centers between 1997 and 2018 were retrospectively analyzed.ResultsTwenty-five patients were identified. The median age was 53 years [range 17–78]. None of the patients had extra peritoneal metastases at diagnosis. A median of 6 cycles of carboplatin-based systemic chemotherapy was delivered in 52% preoperatively (n = 13) and 56% postoperatively (n = 14); associated with placlitaxel for 12 patients. All patients were operated on. The median PCI was 23 [0–33]. Eighty-four percent had a complete cytoreductive surgery through digestive (n = 7), spleen (n = 3), pancreas (n = 1) resections and/or multiple peritonectomies (n = 11). Five patients (20%) had intraperitoneal chemotherapy. Morbidity (Dindo-Clavien ≥3) was 12%. No postoperative death occurred. After a median follow-up of 42 months (range [2–194]), the median overall (OS) and progression-free (DFS) survival times were respectively 128 months and 31 months. Eighteen patients recurred (72%), mainly in the peritoneum (n = 16). Four of them (22%) were reoperated. The 5 and 10-year DFS rates were both 20.3%. The 5 and 10-year OS rates were 62% and 51.7%, respectively. A complete cytoreductive surgery was associated with a better OS and DFS in a univariate analysis.ConclusionComplete cytoreductive surgery is the cornerstone of the PK's management as a primary treatment. Recurrence remains common and new adjuvant strategies seem needed.     

Evaluation of predictive variables in locally advanced pancreatic adenocarcinoma patients receiving definitive chemoradiation

PurposeTo analyze a single-center experience with locally advanced pancreatic cancer (LAPC) patients treated with chemoradiation (CRT) and to evaluate predictive variables of outcome.Methods and MaterialsLAPC patients at our institution between 1997 and 2009 were identified (n = 109). Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier analysis. Cox proportional hazard models were used to evaluate predictive factors for survival. Patterns of failure were characterized, and associations between local progression and distant metastasis were explored.ResultsMedian OS was 12.1 months (2.5-34.7 months) and median PFS was 6.7 months (1.1-34.7 months). Poor prognostic factors for OS include Karnofsky performance status ≤80 (P = .0062), treatment interruption (P = .0474), and locally progressive disease at time of first post-therapy imaging (P = .0078). Karnofsky performance status ≤80 (P = .0128), pretreatment CA19-9 >1000 U/mL (P = .0224), and treatment interruption (P = .0009) were poor prognostic factors for PFS. Both local progression (36%) and distant failure (62%) were common. Local progression was associated with a higher incidence of metastasis (P < .0001) and decreased time to metastasis (P < .0001).ConclusionsLAPC patients who suffer local progression following definitive CRT may experience inferior OS and increased risk of metastasis, warranting efforts to improve control of local disease. However, patients with poor pretreatment performance status, elevated CA19-9 levels, and treatment interruptions may experience poor outcomes despite aggressive management with CRT, and may optimally be treated with induction chemotherapy or supportive care. Novel therapies aimed at controlling both local and systemic progression are needed for patients with LAPC.