Clinically decisive (dis)agreement in multidisciplinary team assessment of esophageal squamous cell carcinoma; a prospective, national, multicenter study.

BACKGROUND: Decisions regarding tumor staging, operability, resectability, and treatment strategy in patients with esophageal cancer are made at multidisciplinary team (MDT) conferences. We aimed to assess interobserver agreement from four national MDT conferences and whether this would have a clinical impact. METHODS: A total of 20 patients with esophageal cancer were included across all four upper gastrointestinal (GI) cancer centers. Fully anonymized patient data were distributed among the MDT conferences which decided on TNM category, resectability, operability, curability, and treatment strategy blinded to each other's decisions. The interobserver agreement was expressed as both the raw observer agreement and with Krippendorff's α values. Finally, a case-by-case evaluation was performed to determine if disagreement would have had a clinical impact. RESULTS: A total of 80 MDT evaluations were available for analysis. A moderate to near-perfect observer agreement of 79.2%, 55.8%, and 82.5% for TNM category was observed, respectively. Substantial agreement for resectability and moderate agreement for curability were found. However, an only fair agreement was observed for the operability category. The treatment strategies had a slight agreement which corresponded to disagreement having a clinical impact in 12 patients. CONCLUSIONS: Esophageal cancer MDT conferences had an acceptable interobserver agreement on resectability and TM categories; however, the operability assessment had a high level of disagreement. Consequently, the agreement on treatment strategy was reduced with a potential clinical impact. In future MDT conferences, emphasis should be on prioritizing the relevant information being readily available (operability, T & M categories) to minimize the risk of disagreement in the assessments and treatment strategies, and thus, delayed or suboptimal treatment.

Recurrence following curative intended surgery for an adenocarcinoma in the gastroesophageal junction: a retrospective study.

Recurrence following a resection for an adenocarcinoma of the gastroesophageal junction leads to reduced long-term survival. This study aims to identify risk factors associated with recurrence, recurrence localization, time to recurrence, and long-term survival. All patients undergoing curative intended resection for an adenocarcinoma of the gastroesophageal junction at Rigshospitalet between June 2003 and December 2011 were identified through a prospectively maintained nationwide database and enrolled in this study. Only histologically verified recurrence was considered eligible. Recurrence within six months, microscopically incomplete resection margins, and death within eight weeks were excluded. A total of 348 patients were included in this study. Biopsy-verified recurrence occurred in 120 patients (34.5%), with 32 local (9.2%), and 88 distant (25.3%) recurrences. Lymph node metastases was associated with an increased risk of recurrence (hazard ratio; [95% confidence interval]: HR = 2.7; [1.7-4.3], P < 0.001). Median time to local versus distant recurrence was 18 months (interquartile range (IQR): 9-37 months) versus 17 months (IQR: 11-27 months), P = 0.96, respectively. A trend toward local recurrence was identified if patients had anastomotic leakage (HR = 2.64; [0.89-7.86], P = 0.08). Survival was inversely associated with recurrence, but a survival comparison between local and distant recurrences showed no significant difference: median survival time was 28 months (IQR: 17-43 months) versus 24 months (IQR: 16-36 months), P = 0.45, respectively. A trend toward local recurrence was seen if the patient had an anastomotic leakage event. However, no factors were associated with site-specific recurrence (local vs. distant).

ICORG 10-14: NEOadjuvant trial in Adenocarcinoma of the oEsophagus and oesophagoGastric junction International Study (Neo-AEGIS).

BACKGROUND: Neoadjuvant therapy is increasingly the standard of care in the management of locally advanced adenocarcinoma of the oesophagus and junction (AEG). In randomised controlled trials (RCTs), the MAGIC regimen of pre- and postoperative chemotherapy, and the CROSS regimen of preoperative chemotherapy combined with radiation, were superior to surgery only in RCTs that included AEG but were not powered on this cohort. No completed RCT has directly compared neoadjuvant or perioperative chemotherapy and neoadjuvant chemoradiation. The Neo-AEGIS trial, uniquely powered on AEG, and including comprehensive modern staging, compares both these regimens. METHODS: This open label, multicentre, phase III RCT randomises patients (cT2-3, N0-3, M0) in a 1:1 fashion to receive CROSS protocol (Carboplatin and Paclitaxel with concurrent radiotherapy, 41.4Gy/23Fr, over 5 weeks). The power calculation is a 10% difference in favour of CROSS, powered at 80%, two-sided alpha level of 0.05, requiring 540 patients to be evaluable, 594 to be recruited if a 10% dropout is included (297 in each group). The primary endpoint is overall survival, with a minimum 3-year follow up. Secondary endpoints include: disease free survival, recurrence rates, clinical and pathological response rates, toxicities of induction regimens, post-operative pathology and tumour regression grade, operative in-hospital complications, and health-related quality of life. The trial also affords opportunities for establishing a bio-resource of pre-treatment and resected tumour, and translational research. DISCUSSION: This RCT directly compares two established treatment regimens, and addresses whether radiation therapy positively impacts on overall survival compared with a standard perioperative chemotherapy regimen Sponsor: Irish Clinical Research Group (ICORG). TRIAL REGISTRATION: NCT01726452 . Protocol 10-14. Date of registration 06/11/2012.

Dysphagia is not a Valuable Indicator of Tumor Response after Preoperative Chemotherapy for R0 Resected Patients with Adenocarcinoma of the Gastroesophageal Junction.

BACKGROUND: Monitoring treatment response to preoperative chemotherapy is of utmost importance to avoid treatment toxicity, especially in non-responding patients. Currently, no reliable methods exist for tumor response assessment after preoperative chemotherapy. Therefore, the aim of this study was to evaluate dysphagia as a predictor of tumor response after preoperative chemotherapy and as a predictor of recurrence and survival. METHODS: Patients with adenocarcinoma of the gastroesophageal junction, treated between 2010 and 2012, were retrospectively reviewed. Dysphagia scores (Mellow-Pinkas) were obtained before and after three cycles of perioperative chemotherapy together with clinicopathological patient characteristics. A clinical response was defined as improvement of dysphagia by at least 1 score from the baseline. The tumor response was defined as down staging of T-stage from initial computer tomography (CT) scan (cT-stage) to pathologic staging of surgical specimen (pT-stage). Patients were followed until death or censored on June 27th, 2014. RESULTS: Of the 110 included patients, 59.1% had improvement of dysphagia after three cycles of perioperative chemotherapy, and 31.8% had a chemotherapy-induced tumor response after radical resection of tumor. Improvement of dysphagia was not correlated with the tumor response in the multivariate analysis (p = 0.23). Moreover, the presence of dysphagia was not correlated with recurrence (p = 0.92) or survival (p = 0.94) in the multivariate analysis. CONCLUSION: In our study, improvement of dysphagia was not valid for tumor response evaluation after preoperative chemotherapy and was not correlated with the tumor response. The presence of dysphagia does not seem to be a predictor of recurrence or survival.

Survival after adjuvant chemoradiotherapy or surgery alone in resectable adenocarcinoma at the gastro-esophageal junction.

BACKGROUND AND AIMS: Longterm survival after curative resection for adenocarcinoma at the gastro-esophageal junction (GEJ) range between 18% and 50%. In the pivotal Intergroup-0116 Phase III trial by Macdonald et all, adjuvant chemoradiotherapy improved both disease-free and overall survival in curatively resected patients with mainly gastric adenocarcinoma. We compared survival data for curatively resected patients with adeno-carcinoma solely at the gastro-esophageal junction (GEJ), treated with surgery alone or surgery and adjuvant chemoradio-therapy. METHODS: From 2003 to 2009, 211 patients underwent curative resection. Surgery alone was performed in 95 pa-tients and 116 patients received adjuvant therapy after resection. All patients underwent Lewis-Tanner operation with D1 node resection including coliac nodes (D1+). Informations about recurrence and death were collected from the Danish Cancer Register and the Central Death Register. Patients who died after experiencing severe complications after surgery were excluded from the survival analysis. Patients with T0N0 or T1N0 were also excluded because patients of this category were not given adjuvant therapy according to the Macdonald protocol. RESULTS: Patients with positive node status in the resected specimen, the 3-year disease-free survival after adjuvant chemoradiotherapy (n = 91) or surgery alone (n = 43) was 24% and 37%, respectively. Median time of survival was prolonged by 10 month in favour of those who received chemoradiotherapy. However, after controlling for the confounding effect of age and node status, only positive node status in the resected specimen had significant partial effect on survival. CONCLUSION: Chemoradiotherapy according to the Intergroup-0116 protocol might still be a reasonable option after curative resection in patients with GEJ adenocarcinomas and positive lymph node status, who did not receive neoadjuvant chemotherapy.

Acute tumor lysis syndrome in solid tumors--a case report and review of the literature.

PURPOSE: Tumor lysis syndrome (TLS) is a potential complication in cancer therapy. It may occur in highly sensitive tumors, especially in childhood cancers and acute leukemias, whereas it is rare in the treatment of adult solid tumors. TLS is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia following massive lysis of malignant cells. Complications include acute renal failure and metabolic acidosis. We report the first case of TLS during chemotherapy in a patient with metastatic medulloblastoma, together with a review of the literature regarding the occurrence of TLS in patients with solid tumors. METHODS: Data regarding clinical and biochemical parameters were extracted from the actual patients' files. Reports of TLS in the English language literature up to 2002 were identified by searching Medline. RESULTS: A 23-year old male with metastatic medulloblastoma received chemotherapy with cisplatin and etoposide due to massive extracerebral manifestations including metastases to the liver, mediastinal lymph nodes and bone marrow metastases. The patient developed classical signs of TLS on the second day of chemotherapy, including acute renal failure. A 17-fold increase in plasma LDH up to 87608 U/l was observed together with a 4-fold increase in plasma creatinine. The patient was treated with aggressive hydration, allopurinol and repeated hemodialysis. During the following days the patient improved and the biochemical markers all returned to normal. REVIEW. Reviewing the literature, a total of 45 patients with solid tumors who developed TLS have been reported. Most of the patients presented with metastatic, therapy-sensitive disease. Although preventable in practically 100% of patients, TLS is a potentially fatal complication, and in this material the mortality rate was one in three. Risk factors included increased LDH, hyperuricemia and pretreatment azotemia. CONCLUSIONS: TLS is only rarely associated with treatment of solid tumors. Precautions should be taken to avoid this potentially fatal complication in (chemo)therapy of solid tumors, especially in therapy-sensitive tumors presenting with bulky, metastatic disease and preexisting risk factors, including azotemia, elevated LDH and hyperuricemia. Prophylactic treatment to avoid TLS includes allopurinol, hydration prior to treatment and alkalization of the urine. Urate oxidase (rasburicase) is now beginning to replace allopurinol as a more effective way of reducing hyperuricemia and thereby the risk of TLS.

Response of cortical bone to antiresorptive treatment.

A total of 113 postmenopausal women (69 controls, 33 using hormone replacement therapy (HRT), and 11 using bisphosphonate) were evaluated twice over 2 years with a new noninvasive, radiogrammetry-based technique called digital X-ray radiogrammetry (DXR) and conventional bone densitometry of the spine, hip, and forearm. Longitudinal changes in bone densitometry were compared with changes captured by DXR: BMD evaluated by DXR (BMDDXR), cortical thickness of the second metacarpal (CTMC2), and porosity of cortical bone. The expected annual postmenopausal reduction in BMD in the control group was detected by BMDspine (-0.8%, P < 0.01), BMDhip (-1.6%, P < 0.001), BMDforearm (-1.5%, P < 0.001), DXR-BMD (-0.8%, P < 0.001), and CTMC2 (-1.1%, P < 0.001). In the HRT group, smaller reductions were seen in BMDDXA, but only significant at the hip (-1.0%, P < 0.01) and distal forearm (-1.0%, P < 0.02). In the bisphosphonate group, cortical porosity was significantly reduced (P < 0.025). Comparing longitudinal changes in age-matched subsamples of controls and bisphosphonate treated, BMDDXR, CTMC2, and porosity of cortical bone all differed significantly (P < 0.01, P < 0.05, P < 0.05, respectively), whereas the BMDDXA measurements did not. In conclusion, DXR provides a densitometry equivalent measurement of the distal forearm and hand and seems to offer new information on the porosity of cortical bone. This may prove useful in the evaluation of bone loss and offer new insight into the effects of different antiresorptive treatment regimens used in the prevention of osteoporosis.

Calcium and vitamin D supplementation increases spinal BMD in healthy, postmenopausal women.

We undertook a double-masked, randomized, placebo-controlled trial to evaluate the effect of a calcium and vitamin D supplement and a calcium supplement plus multivitamins on bone loss at the hip, spine and forearm. The study was performed in 240 healthy women, 58-67 years of age. Duration of treatment was 2 years. Bone mineral density (BMD) was measured at the lumbar spine, hip and forearm. A dietary questionnaire was administered twice during the study and revealed a fairly good calcium and vitamin D intake (919 mg calcium/day; 3.8 micrograms vitamin D/day). An increase in lumbar spine BMD of 1.6% was observed in the treatment group after 2 years (p < 0.002). In the placebo group no significant changes were observed during the 2 years. Lumbar spine BMD was significantly higher in the treatment group at both 1 (p < 0.01) and 2 years (p < 0.05) compared with the placebo group. Though not significant, the same trend was seen at the hip. No significant changes from baseline values were observed at the distal forearm in either the treatment or the placebo group. In conclusion, we found a significant increase in urinary calcium excretion in the treatment group compared with the placebo group. Together with significant changes in serum calcium and serum parathyroid hormone, this indicates that a long-term calcium and vitamin supplement of 1 g elementary calcium (calcium carbonate) and 14 micrograms vitamin D3 increases intestinal calcium absorption. A positive effect on BMD was demonstrated, even in a group of early postmenopausal age, with a fairly good initial calcium and vitamin D status.

Body composition analysis by DEXA by using dynamically changing samarium filtration.

Dual-energy X-ray absorptiometry (DEXA) has a high accuracy for body composition analysis but is influenced by beam hardening and other error sources in the extremes of measurement. To compensate for beam hardening, the Norland XR-36 introduces a dynamically changing samarium filtration system, which depends on the current-absorber thickness. With this system we found a good agreement (r = 0.99) between reference and measured amounts of tissue or fat percentages in a plastic phantom and in smaller (approximately 0.5-4 kg) and larger (approximately 5-20 kg) piles of tissue (ox muscle and lard). Scans of six healthy volunteers covered with combinations of beef and lard (approximately 5-15 kg) showed a good agreement (r = 0.99) between reference and DEXA values of added soft tissue mass and fat percentage. We conclude that the DEXA method (and, in particular, the Norland XR-36 using dynamic filtration) has a high accuracy for body composition analysis. It has a potential for gaining status as a reference method in the future and may presently be used as a supplement to the traditional methods for body composition analysis.