Marta Fiocco

Chemotherapeutic adjuvant treatment for osteosarcoma: Where do we stand?

AIM Since the introduction of chemotherapy, survival in localised high-grade osteosarcoma has improved considerably. However, there is still no worldwide consensus on a standard chemotherapy approach. In this systematic review evidence for effectiveness of each single drug and the role of response guided salvage treatment of adjuvant chemotherapy are addressed, whereas in a meta-analysis the number of drugs in current protocols is considered. METHODS A systematic literature search for clinical studies in localised high-grade osteosarcoma was undertaken, including both randomised and non-randomised trials. Historical clinical studies from the pre-chemotherapy era were included for comparison purposes. RESULTS Nine historical studies showed a long-term survival of 16% after only local treatment. Fifty single agent phase II studies showed high response rates for adriamycin (A, 43%), ifosfamide (Ifo, 33%), methotrexate (M, 32%), cisplatin (P, 26%) but only 4% for etposide (E). In 19 neo-adjuvant studies the mean 5-year event free survival (EFS) was 48% for 2-drug regimens and 58% for ⩾3 drug regimens, with a 5-year overall survival (OAS) of 62% and 70%, respectively. Meta-analysis showed that ⩾3 drug regimens including methotrexate plus adriamycin plus cisplatin (plus ifosfamide) (MAP(Ifo)) had significant better outcome (EFS: HR=0.701 (95% confidence interval [95% CI]: 0.615-0.799); OAS: HR=0.792 (95% CI: 0.677-0.926) than 2-drug regimens, but there was no significant difference between MAP and MAPIfo (or plus etoposide). Salvage of poor responders by changing drugs, or intensifying treatment postoperatively has not proven to be useful in this analysis. CONCLUSION Meta-analysis in patients with localised high-grade osteosarcoma shows that 3-drug regimens, for example MAP are the most efficacious drug regimens.

Long-term results of Dutch Childhood Oncology Group studies for children with acute lymphoblastic leukemia from 1984 to 2004

The Dutch Childhood Oncology Group (DCOG) has used two treatment strategies for children with acute lymphoblastic leukemia (ALL) based on Pinkels St Jude Total Therapy or the Berlin–Frankfurt–Münster (BFM) backbone. In four successive protocols, 1734 children were treated. Studies ALL-6 and ALL-9 followed the Total Therapy approach; cranial irradiation was replaced by medium-dose methotrexate infusions and prolonged triple intrathecal therapy; dexamethasone was used instead of prednisone. Studies ALL-7 and ALL-8 had a BFM backbone, including more intensive remission induction, early reinduction and maintenance therapy without vincristine and prednisone pulses. The 5-year event-free survival and overall survival increased from 65.4 to 80.6% (P<0.001) and from 78.7 to 86.4% (P=0.07) in ALL-7 and ALL-9, respectively. In ALL-7 and ALL-8 National Cancer Institute (NCI) high-risk criteria, male gender, T-lineage ALL and high white blood cells (WBCs) predict poor outcome. In ALL-9 NCI criteria, gender, WBC >100 × 109/l, and T-lineage ALL have prognostic impact. We conclude that the chemotherapy-only approach in children with ALL in Total Therapy-based strategies and BFM-backbone treatment does not jeopardize survival and preserves cognitive functioning. This experience is implemented in the current DCOG-ALL-10 study using a BFM backbone and minimal residual disease-based stratification.

Early migration of tibial components is associated with late revision: a systematic review and meta-analysis of 21,000 knee arthroplasties.

Purpose We performed two parallel systematic reviews and meta-analyses to determine the association between early migration of tibial components and late aseptic revision. Methods One review comprised early migration data from radiostereometric analysis (RSA) studies, while the other focused on revision rates for aseptic loosening from long-term survival studies. Thresholds for acceptable and unacceptable migration were determined according to that of several national joint registries: < 5% revision at 10 years. Results Following an elaborate literature search, 50 studies (involving 847 total knee prostheses (TKPs)) were included in the RSA review and 56 studies (20,599 TKPs) were included in the survival review. The results showed that for every mm increase in migration there was an 8% increase in revision rate, which remained after correction for age, sex, diagnosis, hospital type, continent, and study quality. Consequently, migration up to 0.5 mm was considered acceptable during the first postoperative year, while migration of 1.6 mm or more was unacceptable. TKPs with migration of between 0.5 and 1.6 mm were considered to be at risk of having revision rates higher than 5% at 10 years. Interpretation There was a clinically relevant association between early migration of TKPs and late revision for loosening. The proposed migration thresholds can be implemented in a phased, evidence-based introduction of new types of knee prostheses, since they allow early detection of high-risk TKPs while exposing only a small number of patients.

Comparison of conditioning regimens of various intensities for allogeneic hematopoietic SCT using HLA-identical sibling donors in AML and MDS with <10% BM blasts: a report from EBMT

In this multicenter retrospective study, the long-term outcomes of 878 adults with AML and refractory anemia with excess blasts (RAEB) with BM blasts <10% who underwent transplantation with an HLA-identical sibling donor between 1998 and 2004 were analyzed according to four regimens of conditioning intensity: reduced-intensity conditioning (RIC) (either intermediate RIC (IntermRIC) or non-myeloablative (NMA) RIC), and myeloablative conditioning (MC) in 718 patients (either conventional MC or hyperintense MC. In multivariate cox analysis, patients undergoing NMA transplantation had lower non-relapse mortality risk in the first 100 days after transplantation (P<0.01), but a higher risk beyond day +100 (P=0.02), as well as higher relapse incidence in the first 12 months (P<0.01), but the risk was similar in all groups beyond 12 months. The probabilities of PFS and OS up to 7 years were significantly lower only in the NMA subgroup (P⩽0.01 for both). The 7-year OS was 53%, 29%, 56% and 51%, respectively. Our data suggest that prospective studies comparing RIC regimens (especially IntermRIC) with MC are appropriate in patients with AML and RAEB who are in a non-advanced disease status.

Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group

PURPOSE Outcome of childhood acute lymphoblastic leukemia (ALL) improved greatly by intensifying chemotherapy for all patients. Minimal residual disease (MRD) levels during the first months predict outcome and may select patients for therapy reduction or intensification. METHODS Patients 1 to 18 years old with ALL were stratified on the basis of MRD levels after the first and second course of chemotherapy. Thereafter, therapy was substantially reduced in patients with undetectable MRD (standard risk) and intensified in patients with intermediate (medium risk) and high (high risk) levels of MRD. Seven hundred seventy-eight consecutive patients were enrolled. The method of analysis was intention-to-treat. Outcome was compared with historical controls. RESULTS In MRD-based standard-risk patients, the 5-year event-free survival (EFS) rate was 93% (SE 2%), the 5-year survival rate was 99% (SE 1%), and the 5-year cumulative incidence of relapse rate was 6% (SE 2%). The safety upper limit of number of observation years was reached and therapy reduction was declared safe.MRD-based medium-risk patients had a significantly higher 5-year EFS rate (88%, SE 2%) with therapy intensification (including 30 weeks of asparaginase exposure and dexamethasone/vincristine pulses) compared with historical controls (76%, SE 6%). Intensive chemotherapy and stem cell transplantation in MRD-based high-risk patients resulted in a significantly better 5-year EFS rate (78%, SE 8% v 16%, SE 8% in controls). Overall outcome improved significantly (5-year EFS rate 87%, 5-year survival rate 92%, and 5-year cumulative incidence of relapse rate 8%) compared with preceding Dutch Childhood Oncology Group protocols. CONCLUSION Chemotherapy was substantially reduced safely in one-quarter of children with ALL who were selected on the basis of undetectable MRD levels, without jeopardizing the survival rate. Outcomes of patients with intermediate and high levels of MRD improved with therapy intensification.

Meta-analysis of internal herniation after gastric bypass surgery.

The aim of this study was to provide a systematic and quantitative summary of the association between laparoscopic Roux‐en‐Y gastric bypass (LRYGB) and the reported incidence of internal herniation (IH). The route of the Roux limb and closure of mesenteric and/or mesocolonic defects are described as factors of influence.

Health-related quality of life 14 years after preoperative short-term radiotherapy and total mesorectal excision for rectal cancer: Report of a multicenter randomised trial

BACKGROUND Preoperative short-term radiotherapy (PRT) in combination with total mesorectal excision (TME) has shown to improve local control in rectal cancer treatment, however without a survival benefit and at the cost of increased morbidity. The current study investigates the long-term health-related quality of life (HRQL) of patients 14 years after treatment in the Dutch TME trial. METHODS In the TME trial (1996-1999) 1530 Dutch patients with rectal cancer were treated with TME and randomly assigned to PRT (5 × 5 Gy). In 2012 HRQL was evaluated in surviving patients (n=606) using a questionnaire combining EORTC QLQ-C30, EORTC QLQ-CR29 and additional questions. FINDINGS Results were obtained from 478 patients (82%), with a median follow up of 14 years. PRT+TME patients without stoma reported more faecal leakage and higher stool frequency, resulting in increased need of pads. Furthermore, irradiated males reported more erection problems. However, radiotherapy did not have negative effects on overall functioning. Compared with Dutch population, patients in both treatment arms reported a small decrease in overall functioning and males reported less sexual activity, interest and enjoyment and more erection difficulties. Irradiated females reported more vaginal dryness and more pain at intercourse compared with Dutch population. INTERPRETATION Long-term HRQL evaluation shows that treatment-related symptoms are still present 14 years after treatment for rectal cancer. Radiotherapy increased bowel dysfunction in patients without stoma. Compared with the Dutch population, both groups reported increased sexual dysfunction. Despite these treatment-related symptoms, there was no difference in overall functioning and global health between TME and PRT+TME.

Patients with severe radiographic osteoarthritis have a better prognosis in physical functioning after hip and knee replacement: a cohort-study.

Introduction Although Total Hip and Knee Replacements (THR/TKR) improve Health-Related Quality of Life (HRQoL) at the group level, up to 30% of patients are dissatisfied after surgery due to unfulfilled expectations. We aimed to assess whether the pre-operative radiographic severity of osteoarthritis (OA) is related to the improvement in HRQoL after THR or TKR, both at the population and individual level. Methods In this multi-center observational cohort study, HRQoL of OA patients requiring THR or TKR was measured 2 weeks before surgery and at 2–5 years follow-up, using the Short-Form 36 (SF36). Additionally, we measured patient satisfaction on a 11-point Numeric Rating Scale (NRSS). The radiographic severity of OA was classified according to Kellgren and Lawrence (KL) by an independent experienced musculoskeletal radiologist, blinded for the outcome. We compared the mean improvement and probability of a relevant improvement (defined as a patients change score≥Minimal Clinically Important Difference) between patients with mild OA (KL Grade 0–2) and severe OA (KL Grade 3+4), whilst adjusting for confounders. Results Severe OA patients improved more and had a higher probability of a relevant improvement in physical functioning after both THR and TKR. For TKR patients with severe OA, larger improvements were found in General Health, Vitality and the Physical Component Summary Scale. The mean NRSS was also higher in severe OA TKR patients. Discussion Patients with severe OA have a better prognosis after THR and TKR than patients with mild OA. These findings might help to prevent dissatisfaction after THR and TKR by means of patient selection or expectation management.

Early proximal migration of cups is associated with late revision in THA: A systematic review and meta-analysis of 26 RSA studies and 49 survival studies

This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the source is credited.Background and purpose The association between excessive early migration of acetabular cups and late aseptic revision has been scantily reported. We therefore performed 2 parallel systematic reviews and meta-analyses to determine the association between early migration of acetabular cups and late aseptic revision. Methods One review covered early migration data from radiostereometric analysis (RSA) studies, while the other focused on revision rates for aseptic loosening from long-term survival studies. Thresholds for acceptable and unacceptable migration were classified according the Swedish Hip Arthroplasty Register and the Australian National Joint Replacement Registry: < 5% revision at 10 years. Results Following an elaborate literature search, 26 studies (involving 700 cups) were included in the RSA review and 49 studies (involving 38,013 cups) were included in the survival review. For every mm increase in 2-year proximal migration, there was a 10% increase in revision rate, which remained after correction for age, sex, diagnosis, hospital type, continent, and study quality. Consequently, proximal migration of up to 0.2 mm was considered acceptable and proximal migration of 1.0 mm or more was considered unacceptable. Cups with proximal migration of between 0.2 and 1.0 mm were considered to be at risk of having revision rates higher than 5% at 10 years. Interpretation There was a clinically relevant association between early migration of acetabular cups and late revision due to loosening. The proposed migration thresholds can be implemented in a phased evidence-based introduction, since they allow early detection of high-risk cups while exposing a small number of patients.

Minimal clinically important differences in health-related quality of life after total hip or knee replacement: A systematic review

Objectives We aimed first to summarise minimal clinically important differences (MCIDs) after total hip (THR) or knee replacement (TKR) in health-related quality of life (HRQoL), measured using the Short-Form 36 (SF-36). Secondly, we aimed to improve the precision of MCID estimates by means of meta-analysis. Methods We conducted a systematic review of English and non-English articles using MEDLINE, the Cochrane Controlled Trials Register (1960–2011), EMBASE (1991–2011), Web of Science, Academic Search Premier and Science Direct. Bibliographies of included studies were searched in order to find additional studies. Search terms included MCID or minimal clinically important change, THR or TKR and Short-Form 36. We included longitudinal studies that estimated MCID of SF-36 after THR or TKR. Results Three studies met our inclusion criteria, describing a distinct study population: primary THR, primary TKR and revision THR. No synthesis of study results can be given. Conclusions Although we found MCIDs in HRQoL after THR or TKR have limited precision and are not validated using external criteria, these are still the best known estimates of MCIDs in HRQoL after THR and TKR to date. We therefore advise these MCIDs to be used as absolute thresholds, but with caution.