A B S T R AC T 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.)

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Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

Background Uncontrolled studies suggest that a combination of chemotherapy and radiotherapy improves the survival of patients with esophageal adenocarcinoma. We conducted a prospective, randomized trial comparing surgery alone with combined chemotherapy, radiotherapy, and surgery. Methods Patients assigned to multimodal therapy received two courses of chemotherapy in weeks 1 and 6 (fluorouracil, 15 mg per kilogram of body weight daily for five days, and cisplatin, 75 mg per square meter of body-surface area on day 7) and a course of radiotherapy (40 Gy, administered in 15 fractions over a three-week period, beginning concurrently with the first course of chemotherapy), followed by surgery. The patients assigned to surgery had no preoperative therapy. Results Of the 58 patients assigned to multimodal therapy and the 55 assigned to surgery, 10 and 1, respectively, were withdrawn for protocol violations. At the time of surgery, 23 of 55 patients (42 percent) treated with preoperative multimodal therapy who c...

/pdf/a-comparison-of-multimodal-therapy-and-surgery-for-3cbymnzr3y.pdf

A comparison of multimodal therapy and surgery for esophageal adenocarcinoma.

ContextCarcinoma of the esophagus traditionally has been
treated by surgery or radiation therapy (RT), but 5-year overall
survival rates have been only 5% to 10%. We previously reported
results of a study conducted from January 1986 to April 1990 of
combined chemotherapy and RT vs RT alone when an interim analysis
revealed significant benefit for combined therapy.ObjectiveTo report the long-term outcomes of a previously
reported trial designed to determine if adding chemotherapy during RT
improves the survival rate of patients with esophageal carcinoma.DesignRandomized controlled trial conducted 1985 to 1990 with
follow-up of at least 5 years, followed by a prospective cohort study
conducted between May 1990 and April 1991.SettingMulti-institution participation, ranging from tertiary
academic referral centers to general community practices.PatientsPatients had squamous cell or adenocarcinoma of the
esophagus, T1-3 N0-1 M0, adequate renal and bone marrow reserve, and a
Karnofsky score of at least 50.InterventionsCombined modality therapy (n=134):
50 Gy in 25 fractions over 5 weeks, plus cisplatin intravenously on the
first day of weeks 1, 5, 8, and 11, and fluorouracil, 1
g/m2 per day by continuous infusion on the first 4 days of
weeks 1, 5, 8, and 11. In the randomized study, combined therapy was
compared with RT only (n=62): 64 Gy in 32 fractions
over 6.4 weeks.Main Outcome MeasuresOverall survival, patterns of failure, and
toxic effects.ResultsCombined therapy significantly increased overall survival
compared with RT alone. In the randomized part of the trial, at 5 years
of follow-up the overall survival for combined therapy was 26% (95%
confidence interval [CI], 15%-37%) compared with 0% following RT.
In the succeeding nonrandomized part, combined therapy produced a
5-year overall survival of 14% (95% CI, 6%-23%). Persistence of
disease (despite therapy) was the most common mode of treatment
failure; however, it was less common in the groups receiving combined
therapy (34/130 [26%]) than in the group treated with RT only (23/62
[37%]). Severe acute toxic effects also were greater in the combined
therapy groups. There were no significant differences in severe late
toxic effects between the groups. However, chemotherapy could be
administered as planned in only 89 (68%) of 130 patients (10% had
life-threatening toxic effects with combined therapy vs 2% in the RT
only group).ConclusionCombined therapy increases the survival of
patients who have squamous cell or adenocarcinoma of the esophagus,
T1-3 N0-1 M0, compared with RT alone.

https://jamanetwork.com/journals/jama/articlepdf/189737/JOC81619.pdf

Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group.

The use of various transgenic mouse models and analysis of human tumour biopsies has shown that bone marrow-derived myeloid cells, such as macrophages, neutrophils, eosinophils, mast cells and dendritic cells, have an important role in regulating the formation and maintenance of blood vessels in tumours. In this Review the evidence for each of these cell types driving tumour angiogenesis is outlined, along with the mechanisms regulating their recruitment and activation by the tumour microenvironment. We also discuss the therapeutic implications of recent findings that specific myeloid cell populations modulate the responses of tumours to agents such as chemotherapy and some anti-angiogenic therapies.

The role of myeloid cells in the promotion of tumour angiogenesis

Background Sarcopenia is associated with increased morbidity and mortality in oncologic and transplant surgery. It has a high incidence in chronic inflammatory states including inflammatory bowel disease (IBD). The validity of existing data in IBD and of sarcopenia's correlation with surgical outcomes is limited. Methods We performed a systematic review to assess the correlation of sarcopenia with the requirement for surgery and surgical outcomes in patients with IBD. Observational studies of patients with IBD in whom an assessment of sarcopenic status/skeletal muscle index was undertaken, a proportion of whom proceeded to surgical management, were selected. Results A total of 5 studies with a combined 658 IBD patients met the inclusion criteria. The majority (70%) had a diagnosis of Crohn's disease. Median (range) body mass index and skeletal muscle index were reported in 4 studies and were 16.58 (13.66-22.50) kg/m2 and 44.52 (42.90-50.64) cm2/m2, respectively. Forty-two percent of IBD patients had sarcopenia. Notably, none of the studies assessed both the anatomical and functional component required for a correct assessment of sarcopenia. Three studies noted that sarcopenic IBD patients had a higher probability of requiring surgery. The rate of major complications (Clavien-Dindo grade ≥IIIa) was significantly higher in patients with sarcopenia. Improved perioperative nutrition management may mitigate the risk of complications. Conclusion Many IBD patients are young, may be malnourished, and commonly require emergent surgery. There is considerable heterogeneity in the assessment of sarcopenia. Sarcopenia is common in the IBD population and can predict the need for surgical intervention. Sarcopenia correlates with an increased rate of major postoperative complications. Improved perioperative intervention may diminish this risk. A formal assessment, screening by a dedicated IBD dietician, and preoperative physical therapy may facilitate early intervention.

Sarcopenia and Inflammatory Bowel Disease: A Systematic Review.

In patients with severe abdominal pain, of pancreatic origin, there are a few with minimal or equivocal findings on pancreatic investigation and in whom the aetiology of their pancreatic disease is elusive. The findings and outcome in 16 of these patients (four men and 12 women) who underwent resection are reported. Pancreatic imaging showed minimal or equivocal findings in all 16; pancreas divisum was present in five. All were managed conservatively at first but resection was required for progression of symptoms. A drainage procedure was performed initially in five patients but relief of pain was at best transitory before further surgery was required. Partial resection was needed in 12, of whom eight required subsequent completion pancreatectomy and four had a one stage total resection. Nine patients are currently pain free after resection or are very much improved, while six are no better and one patient has died from an unrelated cause. Histology of resected specimens showed chronic inflammatory changes accompanied by subtle non-inflammatory changes in all but one. These changes include duct proliferation, duct complex formation, adenomatous nodules, and acinar cell atrophy, the significance of which is unclear. These findings suggest a syndrome of minimal macroscopic and radiological change chronic pancreatitis with pain as its chief clinical feature and a distinct histology, the aetiology of which is unclear. It seems that there is a distinct syndrome of minimal change pancreatitis, among the group of patients which presents with the clinical features of chronic pancreatitis.

https://gut.bmj.com/content/gutjnl/33/11/1566.full.pdf

Minimal change chronic pancreatitis.

Background. Multimodality therapy with chemotherapy and radiotherapy followed by surgery may improve survival in patients with esophageal squamous cell carcinoma compared with each of the individual treatment options. Histologic assessment of resected tumors after chemoradiotherapy shows that some patients have a complete response with no residual tumor, whereas other patients derive no benefit. The ability to predict response to chemoradiotherapy would allow treatment to be planned accordingly.



Methods. Expression of the tumor growth and proliferation proteins epidermal growth factor receptor (EGFR) and proliferating cell nuclear antigen (PCNA) was determined using immunohistochemical staining of pretreatment endoscopic biopsies from patients with esophageal squamous cell carcinoma who were randomized to chemoradiotherapy before surgery. Response to chemoradiotherapy was assessed by histologic examination of the resected specimens. Response to chemoradiotherapy and survival were correlated with EGFR and PCNA expression individually and with both markers combined as EGFR/PCNA.



Results. Of 14 patients available for study, 6 had a complete histologic response (CR) to chemoradiotherapy with no residual tumor in the resected specimen, 3 had a partial response (PR) to chemoradiotherapy, and the remaining 5 had minimal response (MR). Of the nine patients with a CR or PR, tumors of eight patients were negative for one or both markers. Of the five patients with an MR, four tumors were positive for both EGFR and PCNA (P < 0.05, Fisher's exact test). Comparison of survival from the date of randomization shows that patients with tumors negative for one or both markers had a signiticant survival advantage (P = 0.0003, log-rank test).



Conclusions. Evaluation of PCNA and EGFR status of pretreatment biopsies may identify a group of patients likely to derive the greatest benefit from chemoradiotherapy before surgery in terms of histologic response and long term survival.

Expression of epidermal growth factor receptor and proliferating cell nuclear antigen predicts response of esophageal squamous cell carcinoma to chemoradiotherapy

Bile reflux has been implicated in the pathogenesis of Barrett's oesophagus but evaluation remains difficult. Bilitec 2000 is an ambulatory system that detects bilirubin based on its spectrophotometric properties. Oesophageal bile exposure was evaluated in three groups of patients. Group 1 (n = 11) were normal controls, group 2 (n = 13) were patients with uncomplicated gastro-oesophageal reflux and group 3 (n = 12) were patients with Barrett's oesophagus. Bile reflux was greater in patients with Barrett's mucosa than in controls or those with uncomplicated reflux. This difference was seen in the supine and interdigestive periods. The percentage of time at which gastric pH was greater than 4 and oesophageal pH was above 7 did not differ between the groups. Bilitec 2000 detects greater bile reflux in patients with Barrett's oesophagus. No corresponding gastric or oesophageal alkaline shift is found. This ambulatory bile reflux monitoring system may be a useful tool in clinical practice.

https://bjssjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/bjs.1800830350

Thomas N. Walsh

Papers

Sarcopenia and Inflammatory Bowel Disease: A Systematic Review.

Minimal change chronic pancreatitis.

Expression of epidermal growth factor receptor and proliferating cell nuclear antigen predicts response of esophageal squamous cell carcinoma to chemoradiotherapy

Ambulatory oesophageal bile reflux monitoring in Barrett's oesophagus.

Mechanisms of columnar metaplasia and squamous regeneration in experimental Barrett's esophagus.