Clinical variation in the organization of clinical pathways in esophagogastric cancer, a mixed method multiple case study.

BACKGROUND: Among esophagogastric cancer patients, the probability of having undergone treatment with curative intent has been shown to vary, depending on the hospital of diagnosis. However, little is known about the factors that contribute to this variation. In this study, we sought to understand the organization of clinical pathways and their association with variation in practice. METHODS: A mixed-method study using quantitative and qualitative data was conducted. Quantitative data were obtained from the Netherlands Cancer Registry (e.g., outpatient clinic consultations and diagnostic procedures). For qualitative data, thematic content analysis was performed using semi-structured interviews (n = 30), observations of outpatient clinic consultations (n = 26), and multidisciplinary team meetings (MDTM, n = 16) in eight hospitals, to assess clinicians' perspectives regarding the clinical pathways. RESULTS: Quantitative analyses showed that patients more often underwent surgical consultation prior to the MDTM in hospitals associated with a high probability of receiving treatment with curative intent, but more often consulted with a geriatrician in hospitals associated with a low probability of such treatment. The organization of clinical pathways was analyzed quantitatively at three levels: regional, local, and patient levels. At a regional level, hospitals differed in terms of the number of patients discussed during the MDTM. At the local level, the revision of radiological images and restaging after neoadjuvant treatment varied. At the patient level, some hospitals routinely conduct fitness tests, whereas others estimated the patient's physical fitness during an outpatient clinic consultation. Few clinicians performed a standard geriatric consultation in older patients to assess their mental fitness and frailty. CONCLUSION: Surgical consultation prior to MDTM was more often conducted in hospitals associated with a high probability of receiving treatment with curative intent, whereas a geriatrician was consulted more often in hospitals associated with a low probability of receiving such treatment.

Patterns of recurrence following definitive chemoradiation for patients with proximal esophageal cancer.

INTRODUCTION: The aim of this retrospective study was to determine the patterns of recurrence and overall survival (OS) in patients achieving clinical complete response after treatment with definitive chemoradiation (CRT) for proximal esophageal cancer. MATERIALS AND METHODS: Patients with proximal esophageal cancer treated with CRT between 2004 and 2014 in 11 centers in the Netherlands were included. OS and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Cumulative incidence of first recurrence (locoregional or distant) and locoregional recurrence (LRR) were assessed using competing risk analyses. RESULTS: In 197 of the 200 identified patients, response was evaluated, 133 (68%) showed a complete response. In complete responders, median OS, three-year OS, and PFS were 45.0 months (95% CI 34.8-61.5 months), 58% (95% CI 48-66), and 49% (95% CI 40-57), respectively. Three- and five-year risk of recurrence were respectively 40% (95% CI 31-48), and 45% (95% CI 36-54). Three- and five-year risk of LRR were 26% (95% CI 19-33), and 30% (95% CI 22-38). Eight of 32 patients with an isolated LRR underwent salvage surgery, with a median OS of 32.0 months (95% CI 6.8-not reached). CONCLUSION: In patients with a complete response after definitive CRT for proximal esophageal cancer, most recurrences were locoregional and developed within the first three years after CRT. These findings suggest to shorten locoregional follow-up from five to three years.

Impaired Geriatric 8 Score is Associated with Worse Survival after Radiotherapy in Older Patients with Cancer.

AIMS: To investigate whether the Geriatric 8 (G8) score and the Timed Get Up and Go Test (TGUGT), together with clinical and demographic patient characteristics, are associated with survival and late toxicity after (chemo)radiation therapy, administered with curative intent in older patients with cancer. MATERIALS AND METHODS: Four hundred and two patients aged ≥65 years (median age 72 years, range 65-96 years), diagnosed with either breast, non-small cell lung, prostate, head and neck, rectal or oesophageal cancer, and referred for curative (chemo)radiation therapy, took part in a multicentre prospective cohort study in eight radiotherapy centres in the Netherlands. The G8 and TGUGT scores were assessed before starting treatment. Other potential predictors and late toxicity were also recorded. Survival status and date of death, if applicable, were ascertained at the Dutch national death registry. RESULTS: After 2.5 years, the overall survival was 83%. Survival was 87% for patients with high G8 scores and 55% for patients with low G8 scores (Log-rank P value < 0.0001). Survival was 77% for patients with good TGUGT results and 50% for patients with poor TGUGT results (Log-rank P value < 0.001). In multivariable analysis, in addition to age and type of primary tumour, the association of the G8 score with overall survival remained, with a hazard ratio of 2.1 (95% confidence interval 1.2-3.8) for low versus high scores. CONCLUSIONS: G8 was associated with overall survival in older patients with cancer irradiated with curative intent. This association was independent of the predictive value of age and primary tumour.

MRI response rate after short-course radiotherapy on rectal cancer in the elderly comorbid patient: results from a retrospective cohort study.

BACKGROUND: The aim of the present study was to evaluate MRI response rate and clinical outcome of short-course radiotherapy (SCRT) on rectal cancer as an alternative to chemoradiotherapy in patients where downstaging is indicated. METHODS: A retrospective analysis was performed of a patient cohort with rectal carcinoma (cT1-4cN0-2 cM0-1) from a large teaching hospital receiving restaging MRI, deferred surgery or no surgery after SCRT between 2011 and 2017. Patients who received chemotherapy during the interval between SCRT and restaging MRI were excluded. The primary outcome measure was the magnetic resonance tumor regression grade (mrTRG) at restaging MRI after SCRT followed by a long interval. Secondary, pathological tumor stage, complete resection rate and 1-year overall survival were assessed. RESULTS: A total of 47 patients (M:F = 27:20, median age 80 (range 53-88) years), were included. In 33 patients MRI was performed for response assessment 10 weeks after SCRT. A moderate or good response (mrTRG≤3) was observed in 24 of 33 patients (73%). While most patients (85%; n = 28) showed cT3 or cT4 stage on baseline MRI, a ypT3 or ypT4 stage was found in only 20 patients (61%) after SCRT (p <  0.01). A complete radiologic response (mrTRG 1) was seen in 4 patients (12%). Clinical N+ stage was diagnosed in n = 23 (70%) before SCRT compared to n = 8 (30%) post-treatment (p = 0.03). After SCRT, 39 patients underwent deferred surgery (after a median of 14 weeks after start of SCRT) and a resection with complete margins was achieved in 35 (90%) patients. One-year overall survival after surgery was 82%. Complete pathological response was found in 2 patients (5%). CONCLUSIONS: The use of SCRT followed by a long interval to restaging showed a moderate to good response in 73% and therefore can be considered as an alternative to chemoradiotherapy in elderly comorbid patients.

Axial cortical involvement of metastatic lesions to identify impending femoral fractures; a clinical validation study.

BACKGROUND AND PURPOSE: Patients with advanced cancer may develop painful bone metastases, potentially resulting in pathological fractures. Adequate fracture risk assessment is of key importance to prevent fracturing and maintain mobility. This study aims to validate the clinical reliability of axial cortical involvement with a 30 mm threshold on conventional radiographs to assess fracture risk in femoral bone metastases. MATERIALS AND METHODS: All patients with bone metastases who received radiotherapy for pain included in two multicentre prospective studies were selected. Conventional radiographs obtained at a maximum of two months prior to radiotherapy were collected. Three experts independently measured lesions and scored radiographic characteristics. Sensitivity, specificity, positive (PPV) and negative predictive value (NPV) were calculated. RESULTS: Hundred patients were included with a median follow-up of 23.0 months (95%CI: 10.6-35.5). Two fractures occurred in lesions with axial cortical involvement <30 mm, and 12 in lesions ≥30 mm. Sensitivity, specificity, PPV and NPV of axial cortical involvement for predicting femoral fractures were 86%, 50%, 20% and 96%, respectively. Patients with lesions ≥30 mm had a 5.3 times higher fracture risk than patients with smaller lesions. CONCLUSION: Our validation study confirmed the use of 30 mm axial cortical involvement to assess fracture risk in femoral bone metastases. Until a more accurate and practically feasible method has been developed, this clinical parameter remains an easy method to assess femoral fracture risk to aid patients and clinicians to choose the optimal individual treatment modality.

Evaluation of clinical and endoscopic toxicity after external beam radiotherapy and endorectal brachytherapy in elderly patients with rectal cancer treated in the HERBERT study.

INTRODUCTION: The HERBERT study evaluated a high-dose-rate endorectal brachytherapy boost (HDREBT) after EBRT in medically inoperable/elderly patients with rectal cancer. The response-rates are promising but not without risk of toxicity. The current analysis provides a comprehensive overview of patient reported, physician reported and endoscopically observed toxicity. MATERIAL AND METHODS: A brachytherapy dose finding study was performed in 38 inoperable/elderly patients with T2-T4N0-1 rectal cancer. Patients received EBRT (13 × 3 Gy) followed by three weekly HDREBT applications (5-8 Gy). Toxicity was assessed via three methods: patient and physician (CTCAEv3) reported rectal symptoms and endoscopically. Wilcoxon's signed rank test, paired t-test and Spearman's correlation were used. RESULTS: Patient reported bowel symptoms showed a marked increase at the end of EBRT and two weeks after HDREBT. Acute grade 2 and 3 proctitis occurred in 68.4% and 13.2% respectively while late grade 2 and ≥3 proctitis occurred in 48% and 40%. Endoscopic evaluation mainly showed erythema and telangiectasia. In three patients frank haemorrhage or ulceration occurred. Most severe toxicity was observed 12-18 months after treatment. CONCLUSION: For elderly patients with rectal cancer, definitive radiotherapy can provide good tumour response but has a substantial risk of toxicity. The potential benefit and risks of a HDREBT boost above EBRT alone must be further evaluated.

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative.

BACKGROUND: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. MATERIAL AND METHODS: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. RESULTS: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. CONCLUSION: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting.

Histopathologisch onderzoek van mogelijke metastase.

Histopathological examination of possible metastasis; indispensable or diagnostic excess?

Textbook outcome as a composite measure in oesophagogastric cancer surgery.

BACKGROUND: Quality assurance is acknowledged as a crucial factor in the assessment of oncological surgical care. The aim of this study was to develop a composite measure of multiple outcome parameters defined as 'textbook outcome', to assess quality of care for patients undergoing oesophagogastric cancer surgery. METHODS: Patients with oesophagogastric cancer, operated on with the intent of curative resection between 2011 and 2014, were identified from a national database (Dutch Upper Gastrointestinal Cancer Audit). Textbook outcome was defined as the percentage of patients who underwent a complete tumour resection with at least 15 lymph nodes in the resected specimen and an uneventful postoperative course, without hospital readmission. Hospital variation in textbook outcome was analysed after adjustment for case-mix factors. RESULTS: In total, 2748 patients with oesophageal cancer and 1772 with gastric cancer were included in this study. A textbook outcome was achieved in 29·7 per cent of patients with oesophageal cancer and 32·1 per cent of those with gastric cancer. Adjusted textbook outcome rates varied from 8·5 to 52·4 per cent between hospitals. The outcome parameter 'at least 15 lymph nodes examined' had the greatest negative impact on a textbook outcome both for patients with oesophageal cancer and for those with gastric cancer. CONCLUSION: Most patients did not achieve a textbook outcome and there was wide variation between hospitals.

Improvement in survival for patients with synchronous metastatic esophageal cancer in the south of the Netherlands from 1994 to 2013.

BACKGROUND: We assessed the use of external beam radiotherapy, brachytherapy chemoradiotherapy and chemotherapy in patients with metastatic esophageal cancer and evaluated the effect on overall survival. METHODS: We included all patients diagnosed with synchronous metastatic esophageal cancer in the south of the Netherlands between 1 January 1994 and 31 December 2013. Proportions of patients treated with external beam radiotherapy, brachytherapy, chemoradiotherapy and chemotherapy were described with respect to the period of diagnosis, patient and tumor characteristics. Independent risk factors for death were discriminated. RESULTS: A total of 1020 patients were included, 61.5% of these patients received palliative treatment with external beam radiotherapy, chemoradiotherapy, brachytherapy and/or chemotherapy. The use of external beam radiotherapy decreased from 44.5% in 1994 to 22.2% in 2013 (p = 0.0001), whereas the use of chemoradiotherapy increased from 2.9% in 1994 to 19.1% in 2013 (p < 0.0001). The prescription of systemic chemotherapy as single modality increased from 13.9% to 30.5% (p < 0.0001). The use of brachytherapy decreased from 20.9% in 1994 to 7.4% in 2013 (p = 0.0013). The odds of receiving external beam radiotherapy, brachytherapy, chemoradiotherapy and chemotherapy were influenced by different tumor and patient characteristics, such as age, gender, histologic subtype and number of metastatic sites. The median overall survival in patients with metastatic esophageal cancer significantly improved over time from 18 weeks (one-year survival rate 14.4%) in 1994-1998 to 25 weeks (one-year survival rate 22.4%) in 2009-2013. Patients treated with chemoradiotherapy had the most favorable prognosis, followed by patients treated with chemotherapy as a single modality. CONCLUSION: The median overall survival of patients diagnosed with metastatic esophageal cancer improved from 18 weeks in 1994-1998 to 25 weeks in 2009-2013. Although this increase could be attributed to stage migration, our population-based study suggests that major changes in treatment strategies and appropriate patient selection might have played a role as well.

Decision consultations on preoperative radiotherapy for rectal cancer: large variation in benefits and harms that are addressed.

BACKGROUND: For shared decision making to be successful, patients should receive sufficient information on possible benefits and harms of treatment options. The aim of this study was to evaluate what information radiation oncologists provide during the decision consultation about preoperative radiotherapy with rectal cancer patients. METHODS: Decision consultations of 17 radiation oncologists with 81 consecutive primary rectal cancer patients, eligible for short-course radiotherapy followed by a low-anterior resection, were audio taped. Tapes were transcribed and analysed using the ACEPP (Assessing Communication about Evidence and Patient Preferences) coding scheme. RESULTS: A median of seven benefits/harms were addressed per consultation (range, 2-13). This number ranged within and between oncologists and was not clearly associated with the patient's characteristics. A total of 30 different treatment outcomes were addressed. The effect of radiotherapy on local control was addressed in all consultations, the effect on survival in 16%. The most important adverse effects are bowel and sexual dysfunction. These were addressed in 82% and 85% of consultations, respectively; the latter significantly less often in female than in male patients. Four out of five patients did not initiate discussion on any benefits/harms. CONCLUSIONS: Our results showed considerable inconsistency between and within oncologists in information provision, which could not be explained by patient characteristics. This variation indicates a lack of clarity on which benefits/harms of radiotherapy should be discussed with newly-diagnosed patients. This suboptimal patient information hampers the process of shared decision making, in which the decision is based on each individual patients' weighing of benefits and harms.

Preoperative chemoradiotherapy for esophageal or junctional cancer.

BACKGROUND: The role of neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer is not well established. We compared chemoradiotherapy followed by surgery with surgery alone in this patient population. METHODS: We randomly assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin (doses titrated to achieve an area under the curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by surgery. RESULTS: From March 2004 through December 2008, we enrolled 368 patients, 366 of whom were included in the analysis: 275 (75%) had adenocarcinoma, 84 (23%) had squamous-cell carcinoma, and 7 (2%) had large-cell undifferentiated carcinoma. Of the 366 patients, 178 were randomly assigned to chemoradiotherapy followed by surgery, and 188 to surgery alone. The most common major hematologic toxic effects in the chemoradiotherapy-surgery group were leukopenia (6%) and neutropenia (2%); the most common major nonhematologic toxic effects were anorexia (5%) and fatigue (3%). Complete resection with no tumor within 1 mm of the resection margins (R0) was achieved in 92% of patients in the chemoradiotherapy-surgery group versus 69% in the surgery group (P<0.001). A pathological complete response was achieved in 47 of 161 patients (29%) who underwent resection after chemoradiotherapy. Postoperative complications were similar in the two treatment groups, and in-hospital mortality was 4% in both. Median overall survival was 49.4 months in the chemoradiotherapy-surgery group versus 24.0 months in the surgery group. Overall survival was significantly better in the chemoradiotherapy-surgery group (hazard ratio, 0.657; 95% confidence interval, 0.495 to 0.871; P=0.003). CONCLUSIONS: Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer. The regimen was associated with acceptable adverse-event rates. (Funded by the Dutch Cancer Foundation [KWF Kankerbestrijding]; Netherlands Trial Register number, NTR487.).

Small cell carcinoma of the esophagus: a multicentre Rare Cancer Network study.

Small cell carcinoma of the esophagus (SCCE) is a rare and aggressive malignant tumor with a poor prognosis. The aims of this retrospective study were to analyze the epidemiology, clinical characteristics, and treatment outcomes of these patients. Between 1994 and 2004, 24 patients with SCCE from several centers were reviewed for data on demographics, presenting symptoms, diagnosis, disease stage, type of treatment, and outcome. SCCE occurs in the sixth decade: median age (interquartile range [IQR]): 65 (59-69) years with a male predominance (63%). The most common complaining symptoms were rapidly progressive dysphagia (79%), weight loss (54%), and retrosternal/epigastric pain (46%). The tumor arises primarily in the middle (52%) or in the lower (35%) third of the esophagus. History of tobacco and alcohol exposure was present in 90% and 70% of case, respectively. Extensive disease was present in 13 cases (54%) at initial diagnosis. The overall median survival (IQR) was 11 (8-20) months for all 24 patients, and the 2-year overall survival was 25.1%. Four patients were alive more than 2 years after treatment. Chemotherapy increased the survival compared with symptomatic management in extensive disease (median survival [IQR]: 9.5 [6-14] vs. 6 [4-7] months, P= 0.05). In limited disease, concurrent chemo-radiotherapy was more effective than non-concurrent treatment (median survival [IQR]: 36 [14-93] vs. 11 [9-15] months, P= 0.04). Two patients were treated by surgery and chemoradiation therapy with a survival of 35 and 66 months. Chemotherapy is the cornerstone of treatment of SCCE in all stage. For limited disease SCCE, concurrent chemo-radiotherapy is the primary choice compared with sequential approach. The role of surgery was not assessable in our study.