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Question 1

INCIDENCE AND EPIDEMIOLOGY

Answer 1

1. seventh most common cancer worldwide
2. sixth most common cause of cancer-related mortality
3. Approximately 70% of oesophageal cancer diagnoses occur in men
4. Eastern Asia exhibits the highest regional incidence, followed by Southern Africa, Eastern Africa, Northern Europe and South Central Asia
5. an increased incidence of oesophageal adenocarcinoma (AC) in patients aged <50 years
6. young patients > more advanced stages.
7. Although SCC accounts for w90% of cases of oesophageal cancer worldwide, the incidence of AC is rising
8. Heavy alcohol consumption, smoking and their synergis- tic effects are the major risk factors for oesophageal SCC in Western populations
9. AC represents roughly two-thirds of oesophageal cancer cases in high-income countries, with excess body weight, gastroesophageal reflux disease and oesophageal intestinal metaplasia among the key risk factors

Question 2

DIAGNOSIS, PATHOLOGY AND MOLECULAR BIOLOGY

Answer 2

1. PET CT, if available Staging of tumour to detect local/ distant lymphadenopathy and
   metastatic disease
2. Laparoscopy washings Exclude occult metastatic disease involving peritoneum/diaphragm, especially in locally advanced (T3/T4) ACs of the OGJ infiltrating the anatomical cardia
3. Immunohistochemical (IHC) staining is recommended in poorly differentiated and undifferentiated cancers
4. Patients with oesophageal SCC have been shown to benefit from programmed cell death protein 1 (PD-1) blockade
5. PD-L1 positivity is defined as TPS > 1% in the case of first-line treatment with nivolumab and nivolumab-eipilimumab

Question 3

STAGING AND RISK ASSESSMENT

Answer 3

1.Staging should include a complete clinical examination, endoscopy and computed tomography (CT) or positron emission tomography (PET) with [18F]2-fluoro-2-deoxy-D-glucose (FDG). Endoscopic ultrasound (EUS)
2. EUS is particularly useful to determine the therapeutic strategy in two ways: (i) for assessment of T4b status with invasion towards the airways, pericardium or aorta, and (ii) for identification and biopsy of suspected lymph node metastases outside the regular radiation field or beyond the planned resection limits
3. bronchoscopy with endobronchial ultrasonography
4. FDGe PET should therefore be carried out in patients who are candidates for oesophagectomy
5. In locally advanced (T3/T4) ACs of the OGJ infiltrating the anatomical cardia, laparoscopy should be carried out to rule out peritoneal metastases, which are found in w15% of patients
6. enfermedad temprana ct1n0m0, localmente avanzada ct2-4, n1-3, m0

Question 4

MANAGEMENT OF LOCAL AND LOCOREGIONAL DISEASES

Answer 4

• Occasionally, enteral feeding is necessary, either via feeding jejunostomy or via nasogastric tube. Endo- scopic stenting should be avoided in patients undergoing treatment with curative intent as this may worsen prognosis

Question 5

managment of early stages (cT1 N0 M0):

Answer 5

• Endoscopic en bloc resection, using either endoscopic mucosal resection (EMR) or endoscopic submucosal dissec- tion (ESD), is the treatment of choice for lesions with intra- epithelial high-grade dysplasia and most T1 tumours.
• The strongest risk factors for lymph node metastasis are depth of invasion, lymphovascular invasion, low differentiation grade, ulceration and large tumour size
• for AC endoscopic resection can usually be considered curative in all T1a cancers and, in the absence of other risk factors for lymph node metastasis, also in the most superficial submucosally involved T1b cancers (sm1, invasion depth <500 mm, no ulceration)
• EMR should normally be preferred in small lesions, while ESD should be considered in lesions >15 mm, poorly lifting tumours and tumours at risk of submucosal invasion
• The risk of lymph node metastasis is generally higher with oesophageal SCC than with AC

Question 6

Locally advanced resectable disease (cT2-T4 or cN1-3 M0)

Answer 6

• curative-intent treatment for both histological subtypes
• definitive CRT with surveillance and salvage oeso- phagectomy when needed for local tumour control is also a recommended option
• Radical oesophagectomy with en bloc two-field lymphadenectomy» For distal tumours-(Ivor Lewis procedure»»For mid and upper oesophageal tumours,McKeown procedure
• lower post-operative morbidity, quicker functional recovery and better QoL up to 1 year after surgery with Minimal ivasive surgery
• oncological end- points such as free resection margins, lymph node yield and survival, the outcomes seem at least noninferior to open oesophagectomy

Question 7

Pre- and perioperative treatment

Answer 7

• ChT or CRT has been shown to increase rates of resection with no tumour at the margin (R0) and survival rates in oesophageal cancer, and should be considered in all patients with locally advanced resectable disease
• There is currently insufficient evidence to make firm recommendations regarding the use of preoperative treatment in cT2 N0 tumours
• cross esqueme CRT can be recommended as a standard of care for SCC of the oesophagus, the 5-year OS rate of >60% for SCC
• Given the high response rates of oesophageal SCC to CRT, an alternative curative-intent treatment is definitive CRT with the option of salvage oesophagectomy in selected cases
• CRT incorporating modern techniques of RT planning and delivery has reported encouraging results with a 3-year OS rate of 47.8% and median OS of 35.9 months in patients with oesophageal SC
• definitive CRT showed equivalent OS following definitive CRT without surgery compared with preoperative CRT followed by sur- gery, although the non-operative strategy was associated with higher local recurrence rates
• The use of salvage oesophagectomy in patients with persistent disease has been shown to be safe and associated with survival rates similar to those observed with preoperative CRT and planned surgery.
• Based on the results of CROSS preoperative CRT can be recommended as one standard of care for locally advanced AC of the oesophagus and OGJ
• for AC MAGIC trial using a regimen of three preoperative and three post-operative cycles of epirubicine-cisplatine5-FU (ECF), which resulted in tumour downstaging, improved R0 resection rate and improved survival
• FLOT4-AIO trial: ECF vs FLOT and showed an OS benefit for FLOT
• Neo-AEGIS»»CRT (CROSS regimen) or perioperative ChT (MAGIC trial ECF regimen or FLOT), higher rates of tumour regression and pathological complete response in the CRT arm. No OS difference, but the majority of patients in the ChT arm were treated with the older ECF
• ESOPEC trial, which is comparing the CROSS CRT regimen with FLOT, are awaited

Question 8

Adjuvant nivolumab following trimodality therapy

Answer 8

• CheckMate 577 trial evaluated the addition of 1 year of adjuvant treatment with the anti-PD-1 antibody nivolumab after surgery in patients with SCC or AC, with CRT preoperative, and evidence of residual pathological disease in the resection specimen (ypT1 and/or ypN1)
• disease-free survival for patients treated with adjuvant nivolumab (22.4 months) compared with placebo [11.0 months; hazard ratio (HR) for disease recurrence or death 0.69; 96.4% confidence interval (CI) 0.56-0.86; P < 0.001

Question 9

Definitive CRT

Answer 9

1. definitive CRT (with close surveillance and salvage surgery) is a recommended option for resectable oesophageal SCC or AC and are unable or unwilling to undergo surgery
2. definitive CRT is four cycles of cisplatine 5-FU (or capecitabine) combined with RT to a dose of 50.4 Gy in 28 fractions (or 50 Gy in 25 fractions), six cycles of folinic acide5-FUeoxaliplatin (FOLFOX) can be considered, weekly carboplatine-paclitaxel, as used in the CROSS regimen, has been combined with RT as definitive treatment
3. dose escalation have not demonstrated improved local control or survival with RT doses >50.4 Gy.

Question 10

MANAGEMENT OF ADVANCED AND METASTATIC DISEASE

Answer 10

1. oesophageal cancer that is metastatic or unresectable, poor prognosis»>clinical trials has historically been <1 year
2. Standard first-line ChT for oesophageal SCC is a platinume fluoropyrimidine doublet
3. trials in locoregionally advanced oeso- phageal SCC suggest equivalence for cisplatin- and oxaliplatin-based regimens
4. benefit from ICI therapy is enhanced in both oesophageal SCC and AC tumours with elevated levels of PD-L1 expression using the CPS
5. The phase III KEYNOTE-590 trial»» pembrolizumab to cisplatine5-FU in patients with untreated, advanced oesophageal or OGJ (Siewert type I) cancer, OS gain was observed in patients with SCC and elevated PD-L1 expression (CPS >10; HR 0.57, 95% CI 0.43- 0.75; P < 0.0001), A post hoc analysis suggested no benefit in patients with a PD-L1 CPS <10.

Question 11

FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP

Answer 11

1. 90% of relapses occur within the first 2 years after completion of local therapy, potentially treatable relapses have been reported >5 years after local therapy
2. Except for those patients who may be potential candi- dates for an endoscopic reintervention or early ‘salvage surgery’ after (failing) endoscopic resection or definitive CRT, there is no evidence that regular follow-up after initial therapy has an impact on survival.
3. In case of complete response to definitive CRT, a 3-month follow-up based on endoscopy, biopsies and CT scan may be recommended to detect early recurrence, for which salvage surgery may be carried out