Tim Van den Wyngaert

RANK ligand inhibition in bone metastatic cancer and risk of osteonecrosis of the jaw (ONJ): non bis in idem?

PurposeThe purpose of this study was to assess the necessity of post-marketing safety monitoring focused on osteonecrosis of the jaw (ONJ) in patients with bone metastatic cancer treated with denosumab (AMG162).MethodsThe ONJ safety data from three randomized phase III trials were pooled, and risk ratios and power were computed using traditional methods and simulation.ResultsA total of 89 ONJ cases (1.57%; 95% CI, 1.26–1.92) were reported with 52 (1.83%; 95% CI, 1.37–2.39) occurring in the denosumab group (n = 2,841) and 37 (1.30%; 95% CI, 0.92–1.79) in the zoledronic acid group (n = 2,836). Overall, the pooled risk ratio (RR) for ONJ was 1.40 (95% CI, 0.92–2.13; p = 0.11). In the trials reporting superior therapeutic efficacy of denosumab, the RR for ONJ was 1.61 (95% CI, 0.99–2.62; p = 0.052). However, neither separately nor pooled had any trial adequate power (>80%) to detect excess relative risks of ONJ of up to 76%, assuming fixed ONJ rates in the control arms. The joint power of the trials to detect the observed excess relative risk of 40% was only 36%. The rate of mucosal healing in patients with ONJ appeared similar in both groups (RR, 1.28; 95% CI, 0.66–2.45; p = 0.5).ConclusionsAlthough the overall frequency of ONJ was low, post-marketing risk–benefit studies with this novel compound appear warranted focusing specifically on this rare toxicity, which can potentially have a high impact on quality of life.

Bisphosphonates in Oncology: Rising Stars or Fallen Heroes

The introduction of bisphosphonates in oncology has dramatically changed the management of patients with metastatic bone disease. In this manuscript, we thoroughly scrutinize the available body of clinical trials supporting the use of bisphosphonates in this setting and review new and ongoing research. Additionally, we summarize the data showing the benefits of bisphosphonate use in the prevention of treatment-induced bone loss and the intriguing emerging evidence on the antitumor potential of some of these agents when used in the adjuvant setting. Finally, we address the need for a careful consideration of potential benefits of bisphosphonate therapy and the risk for osteonecrosis of the jaw, a recently recognized late-toxicity of their use.

Scintigraphic evaluation of mandibular bone turnover in patients with solid tumors receiving zoledronic acid

Bisphosphonates (BP) have been associated with the occurrence of osteonecrosis of the jaw (ONJ), possibly by causing an excessive bone turnover inhibition. However, little in vivo evidence exists to support this theory. The (99m)Tc-medronate scintigrams of patients with skeletal metastases and BP use (n=40) were individually matched with cancer patients without BP exposure (n=40) and controls with neither malignancy nor BP use (n=40). Patients with established ONJ or intense focal abnormalities in the studied regions were excluded. Mandibular (MBT) bone turnover was quantified relative to the femur by defining regions-of-interest with correction for background activity. The patients with BP exposure (34 female, 6 male) had a median age of 63 years (range 25-81) and received a median number of 11 zoledronic acid administrations (range 1-44). Most patients suffered from breast cancer (n=30). The mean ratio of the MBT in cancer patients with BP use over non-users was 0.88 (95% CI 0.80-0.96; p=0.003), and 0.83 (95% CI 0.73-0.94; p=0.001) when BP using oncological patients were compared with controls without malignancy or BP use. The ratio of MBTs between BP naive patients was 0.95 (95% CI 0.83-1.07; p=0.8). No dose-response effect between the number of BP administrations and MBT could be demonstrated (r=0.02; p=0.9). These findings suggest that, relative to the femur, BP exert a stronger effect on mandibular bone turnover, which strengthens the hypothesis that the inhibition of bone turnover may be important in the pathophysiology of ONJ.

Prognostic value of bone scintigraphy in cancer patients with osteonecrosis of the jaw

Purpose of the Report: Identifying imaging predictors of healing of osteonecrosis of the jaw (ONJ) in cancer patients may assist in better stratification of treatment strategies. Materials and Methods: Patients with ONJ were followed prospectively and underwent bone scintigraphy, both planar and single-photon emission computed tomography (SPECT) imaging. End points were time to healing and the number of recurrences. Studied parameters included lesion visibility, pattern of uptake, and quantification of uptake relative to the unaffected side. Results: A total of 22 patients were recruited (3 men; 19 women) with a stage 1 ONJ lesion in 8, stage 2 in 9, and stage 3 ONJ in 5 patients. Median duration of follow-up was 12 months (range, 6–37). SPECT acquisitions proved superior over planar images in detecting ONJ lesions (P = 0.03). Quantification of tracer uptake in the ONJ lesion relative to the unaffected side showed increasing uptake with higher stages of ONJ: mean, 1.67 (95% confidence interval [CI], 1.17–2.18) in stage 1, 2.72 (95% CI, 2.24–3.20) in stage 2, and 4.62 (95% CI, 3.98–5.26) in stage 3. In addition, this relative ratio of uptake was found to be an independent predictor of ONJ healing (hazard ratio, 0.24; 95% CI, 0.07–0.82; P = 0.02). Neither ONJ stage nor relative ratio of uptake were predictors of the occurrence of ONJ relapses. Conclusions: Bone scintigraphy in patients with ONJ is feasible and SPECT acquisitions are preferred over planar images. Relative quantification of tracer uptake provides prognostic information independent of clinical stage that may assist in identifying patients with a poor prognosis.

Preoperative ultrasound staging of the axilla make’s peroperative examination of the sentinel node redundant in breast cancer: saving tissue, time and money

OBJECTIVE To evaluate the role of preoperative axillary staging with ultrasound (US) and fine needle aspiration cytology (FNAC). Can we avoid intraoperative sentinel lymph node (SLN) examination, with an acceptable revision rate by preoperative staging? DESIGN This study is based on the retrospective data of 336 patients that underwent US evaluation of the axilla as part of their staging. A FNAC biopsy was performed when abnormal lymph nodes were visualized. Patients with normal appearing nodes on US or a benign diagnostic biopsy had removal of the SLNs without intraoperative pathological examination. We calculated the sensitivity, specificity and accuracy of US/FNAC in predicting the necessity of an axillary lymphadenectomy. Subsequently we looked at the total cost and the operating time of 3 models. Model A is our study protocol. Model B is a theoretical protocol based on the findings of the Z0011 trial with only clinical preoperative staging and in Model C preoperative staging and intraoperative pathological examination were both theoretically done. sentinel node, staging, ultrasound, preoperative axillary staging, FNAC, axilla RESULTS: The sensitivity, specificity and accuracy are respectively 0.75 (0.66-0.82), 1.00 (0.99-1.00) and 0.92 (0.88-0.94). Only 26 out of 317 (8.2%) patients that successfully underwent staging needed a revision. The total cost of Model A was 1.58% cheaper than Model C and resulted in a decrease in operation time by 9,46%. The benefits compared with Model B were much smaller. CONCLUSION Preoperative US/FNAC staging of the axillary lymph nodes can avoid intraoperative examination of the sentinel node with an acceptable revision rate. It saves tissue, reduces operating time and decreases healthcare costs in general.

Neoadjuvant systemic therapy in breast cancer: Challenges and uncertainties

The management of locally advanced breast cancer (LABC) remains a major clinical issue, despite progress achieved in diagnosis and therapy. Preoperative or neoadjuvant therapy has gained interest since breast cancer has been regarded as a systemic disease. Comparing adjuvant versus neoadjuvant treatment, the neoadjuvant approach offers the advantage of downstaging the disease and testing the efficacy of therapy administered to patients. A large number of clinical trials have attempted to define the optimal neoadjuvant treatment, but little attention has been paid to the sequence of chemotherapy. Moreover, the integration of antibodies against Human Epidermal Receptor-2 (HER-2) and other biological therapies that may improve the long-term control of breast cancer patients, have a special clinical interest. In this review, we will discuss these topics attempting to answer the questions why, when and which regimen to use for patients with LABC. Especially, the introduction of the platina derivatives in neoadjuvant trials with their exceptional high pathological complete response rates are challenging to rethink the optimal treatment options in early and locally advanced breast cancer.

Bone SPECT/CT in the postoperative spine: a focus on spinal fusion

Low back pain is a global problem affecting one in 10 people. The management of low back pain varies from conservative to more invasive methods with a spectacular increase in the number of patients undergoing spinal fusion surgery during the last decade. Conventional radiological and radionuclide studies are often used in the assessment of persistent or recurring pain after spinal surgery with several advantages and limitations related to each technique. This article reviews the key contribution of integrated bone SPECT/CT in evaluating patients with persistent or recurring pain after spinal surgery, focusing on spinal fusion. Current literature supports the use of bone SPECT/CT as an adjunct imaging modality and problem-solving tool in evaluating patients with suspicion of pseudarthrosis, adjacent segment degeneration, and hardware failure. The role of bone SPECT/CT in post-operative orthopaedic scenarios is evolving, and this review highlights the need for further research on the role of bone SPECT/CT in these patients.

18F-FDG-PET/CT for the detection of disease in patients with head and neck cancer treated with radiotherapy

Objective The aim of this study is to evaluate the diagnostic performance of FDG-PET/CT for the detection of residual disease after (chemo)radiotherapy in patients with head and neck squamous cell carcinoma (HNSCC) and to evaluate the prognostic value of the FDG-PET/CT findings. Methods Patients with HNSCC who underwent FDG-PET/CT after (chemo)radiotherapy were studied retrospectively. Results 104 FDG-PET/CT-scans were performed at a median of 13.2 weeks post-treatment (5.4–19.0 weeks). The diagnostic performance was time dependent with decreasing sensitivity and slightly increasing specificity over time. Sensitivity, specificity, PPV and NPV at 9 months after imaging were 91%, 87%, 77% and 95%, respectively. In a logistic regression model, the odds of a correct FDG-PET/CT increased with 33% every additional week after end of therapy (p = 0.01) and accuracy plateaued after 11 weeks (97%; p<0.001). A complete response on FDG-PET/CT was associated with an overall survival benefit (50.7 versus 10.3 months; p<0.001). Residual disease on FDG-PET/CT increased the risk of death 8-fold (p<0.001). Conclusion FDG-PET/CT is able to detect residual disease after (chemo)radiotherapy, with an optimal time point for scanning between 11–12 weeks after therapy. However, a reevaluation is probably necessary 10–12 months after the FDG-PET/CT to detect late recurrences. In addition, FDG-PET/CT can guide decisions about neck dissection and identifies patients with poor prognosis.

Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography After Concurrent Chemoradiotherapy in Locally Advanced Head-and-Neck Squamous Cell Cancer: The ECLYPS Study

Purpose To assess the standardized implementation and reporting of surveillance [18F]fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan of the neck in locoregionally advanced head-and-neck squamous cell carcinoma (LAHNSCC) after concurrent chemoradiotherapy (CCRT). Patients and Methods We performed a prospective multicenter study of FDG-PET/CT scanning 12 weeks after CCRT in newly diagnosed patients with LAHNSCC (stage IVa/b) that used standardized reconstruction and Hopkins reporting criteria. The reference standard was histology or > 12 months of clinical follow-up. The primary outcome measure was the negative predictive value (NPV) of FDG-PET/CT scans and other supporting diagnostic test characteristics, including time dependency with increasing follow-up time. Results Of 152 patients, 125 had adequate primary tumor control after CCRT and entered follow-up (median, 20.4 months). Twenty-three (18.4%) had residual neck disease. Overall, NPV was 92.1% (95% CI, 86.9% to 95.3%; null hypothesis: NPV = 85%; P = .012) with sensitivity of 65.2% (95% CI, 44.9% to 81.2%), specificity of 91.2% (95% CI, 84.1% to 95.3%), positive predictive value of 62.5% (95% CI, 45.5% to 76.9%), and accuracy of 86.4% (95% CI, 79.3% to 91.3%). Sensitivity was time dependent and high for residual disease manifesting up to 9 months after imaging but lower (59.7%) for disease detected up to 12 months after imaging. Standardized reporting criteria reduced the number of equivocal reports (95% CI for the difference, 2.6% to 15.0%; P = .003). Test characteristics were not improved with the addition of lymph node CT morphology criteria. Conclusion FDG-PET/CT surveillance using Hopkins criteria 12 weeks after CCRT is reliable in LAHNSCC except for late manifesting residual disease, which may require an additional surveillance scan at 1 year after CCRT to be detected.

Introducing TOPMAST, the first double-blind randomized clinical trial specifically dedicated to perioperative maintenance fluid therapy in adults

BACKGROUND Although prescribed to every patient undergoing surgery, maintenance fluid therapy is a poorly researched part of perioperative fluid therapy. The tonicity of the chosen solutions, could be an important cause of morbidity, with hyponatremia being a potential side effect of hypotonic solutions, where isotonic solution could lead to fluid overload. METHODS The TOPMAST-trial is an ongoing prospective single-center double-blind randomized trial comparing an isotonic and a hypotonic maintenance fluid strategy during and after surgery in patients undergoing different types of major thoracic surgery. Patients receive NaCl 0.9% in glucose 5% with an added 40 mmol L-1 of potassium chloride or a premixed solution containing 54 mmol L-1 sodium, 55 mmol L-1 chloride and 26 mmol of potassium at a rate of 27 mL per kg of body weight per day. The primary hypothesis is that isotonic maintenance solutions cause a more positive perioperative fluid balance than hypotonic fluids. Different secondary safety endpoints will be explored, especially the effect of the study treatments on the occurrence electrolyte disturbances (e.g. hyponatremia, hyperchloremia) and a set of clinical endpoints. Efficacy endpoints include the need for resuscitation fluids and assessment of renal and hormonal adaptive mechanisms. An anticipated 68 patients will be included between March 2017 and January 2018. DISCUSSION The study will provide the most comprehensive evaluation of clinically important outcomes associated with the choice of perioperative maintenance fluid therapy.