Editing Oesophageal cancer

== '''Epidemiology''' ==

* Highest rates in Eastern     Asia, and south and east Africa
* In Australia - incidence 5.1     per 100,000 in 2023
* More common in men

== '''Pathophysiology''' ==

* Think of it as two separate     disease processes, with separate risk factors
** However, controversial      whether this actually influences treatment approach
** SCC tends to respond more      favourably to chemoradiotherapy
* Check biomarkers:
** dMMR - checkpoint modulator
** PD-L1 - checkpoint modulator
** HER2 for gastric/GOJ      adenocarcinoma - trastuzumab

=== '''Adenocarcinoma     (60%)''' ===

** Risk factors:
*** Modifiable:
**** Smoking
**** Obesity
**** NOT alcohol
*** Non-modifiable:
**** GORD/Barrett's/oesophageal        acid exposure - duration and frequency of symptoms is correlated with        risk
**** There are familial forms        of Barrett's that increase the risk
**** Caucasian men
** Generally found at GOJ and      a/w Barrett's
** Increasing prevalence in      developed countries
** Adenocarcinomas usually      metastasise intra-abdominally

=== '''SCC (40%)''' ===

** Risk factors:
*** Modifiable
**** Smoking and alcohol are        the main risk factors (~90% of cases)
***** Synergistic effect on         risk
**** Dietary factors -        N-nitroso, hot drinks
**** Caustic ingestion
*** Non-modifiable
**** HPV (probably only a small        proportion of cancers)
**** Plummer-Vinson syndrome
**** Achalasia
**** Upper aerodigestive tract        SCC
**** Tylosis
**** Fanconi anaemia
**** 4x more prevalent in men
** Pathophysiology
*** Premalignant lesion is       squamous dysplasia (a.k.a. squamous intra-epithelial neoplasia). Over a       13.5 year follow-up, SCC developed in 24%, 50% and 74% of patients with       mild, moderate and severe dysplasia at baseline, compared to 8% of       patients with normal index histology.
*** Squamous dysplasia can       regress and relapse spontaneously. Can be present anywhere in the       oesophagus. Chromoendoscopy with Lugol's iodine or NBI helps to identify       it.
*** Squamous dysplasia should       be treated with EMR/ESD depending on size


* Generally proximal- or     mid-oesophagus - at or higher than carina
* Decreasing prevalence in     developed countries
* Usually metastasises     intra-thoracic, and metastasises earlier than adenocarcinoma
* Worse prognosis

=== '''Rare     malignant tumours''' ===

** '''Small cell      carcinoma (0.6%)'''
*** Aggressive phenotype,       similar to other poorly-differentiated neuroendocrine cancers
*** Typically present with       lymph node involvement already
*** Overall prognosis poor but       long-term survival is possible with curative resections
** '''Primary      melanoma of the oesophagus (0.1%)'''
*** Generally late stage at       presentation, with poor prognosis
** '''Leiomyosarcoma'''
*** Far less common than       leiomyoma
*** Often erode through mucosa,       appearing as an ulcerated or exophytic mass
*** EUS - irregular borders and       more heterogenous than would be seen with leiomyoma
*** Oesophagectomy with radical       lymphadenectomy is treatment of choice, although prognosis is poor
** '''GIST'''
*** Similar appearance to       leiomyoma, differentiated by CD117 (c-kit) and CD34 stain positivity.       Also tend to be larger than leiomyomas, with uptake of IV contrast on CT       and significant PET avidity.
*** Can be enucleated provided       negative margins can be obtained; if not, formal oesophagectomy will be       required
*** Consider imatinib for any       GIST >3cm or with high-risk factors, or as neoadjuvant therapy for       locally advanced tumours
*** Lymph node metastasis is       unusual
*** Worse prognosis than       gastric GIST


== '''Clinical manifestations''' - really only seen in advanced disease ==
There are two scenarios. Either presenting with dysphagia (late) or picked up on screening (earlier), but the majority are only found once symptomatic.

* Progressive dysphagia - once     lumen <13mm (two-thirds obstructed), generally signifying T3 disease
* Weight loss - mostly due to     dysphagia-related change in diet
* Odynophagia seen in 20%
* GIT blood loss ?anaemia
* Adenocarcinoma - long history     of reflux symptoms
* Fatigue, retrosternal pain
* Resp - aspirations, cough,     hoarse voice (?RLN involvement)
* Late - tracheobronchial     fistulae
* Check for cervical and     supraclavicular lymph nodes

== '''Diagnosis:''' ==

* Gastroscopy and biopsy with     forceps - multiple biopsies should be taken for any suspicious lesions
** Classically appears as      friable, ulcerated masses
** Early stage - ulcerations or      small nodules
** Can present as strictures or      ulcerations
** Location should be noted
** Presence of Barrett's should      be defined according to Prague criteria
* Sometimes seen on barium     swallow
**

== '''Workup''' ==

* CT CAP with IV contrast
** Look for mets, and      locoregional extent
** Not as useful in early stage      disease, and can't distinguish T3 from T4 very well
** Look for lymph nodes >1cm      in short axis
* FDG PET/CT
** Should be done in most cases      to look for distant mets
** Also look for suspicious      local nodes that can be sampled in EUS
* EUS
** Most useful in patients with      M0 disease after CT and PET - unnecessary in patients with M1 disease
** Can provide information on      T-status and evaluation of regional lymph nodes, although not as accurate      for superficial tumours (T1a-T2), where EMR gives better information
** Best use is probably to look      for, and then target with FNA, suspicious nodes that may be outside of      field and thus change management
*** Nodes are suspicious if       they have distinct borders, rounded appearance, hypoechogenic       architecture, and size >1cm
* EMR can stage suspicious     lesions in background of widespread mucosal changes
** Good for T1a-T2 lesions
* Laparoscopy
** Stage tumours around GOJ
* Bronchoscopy
** Useful in proximal and      middle third oesophageal cancers to assess for direct tracheal invasion
* For SCC, flexible     laryngoscopy and exclusion of synchronous head/neck cancer is recommended

== '''Staging:''' depth of invasion, lymph node involvement, distant disease, histologic characteristics ==

* Separate staging for SCC and     adenocarcinoma
* Stage GOJ adenocarcinomas as     oesophageal cancer, except for Siewert III tumours (those 2-5cm below GOJ)     which are classified as gastric cancers
* Oesophageal adenocarcinoma -     nodal disease from coeliac axis up to paratracheal region is considered     regional disease, while nodal disease outside of those boundaries is     considered distant disease
* Oesophageal SCC -     peri-oesophageal cervical lymphadenopathy is still considered regional     disease

* Siewert I: tends to move to     mediastinal lymph nodes - trans-thoracic en-bloc oesophagectomy with     two-field lymphadenectomy
* Siewert II: tends to move to     coeliac nodes - Ivor Lewis
* Siewert III: tends to move to     coeliac ndoes - total gastrectomy with trans-hiatal resection of distal     oesophagus and extended upper abdominal lymphadenectomy

= '''MANAGEMENT''' =

== '''Initial considerations''' ==

* Curative or palliative intent
* Fitness for surgery
* Resectable
* Choice of neoadjuvant     treatment

== '''General stage-based approach''' ==

* As of 2024, no consensus on     whether to treat SCC and AC any differently
* '''Pre-treatment     optimisation is vital'''
** Nutritional assessment and      management, including enteral access if required - NGT through tumour on      diagnosis if unable to tolerate pureed/solids. 60% of newly-diagnosed      upper GI cancer have malnutrition.
** Management of other      comorbidities
* Mucosa-only cancer ('''TisN0M0''' and '''HGD''') - intensive surveillance vs     endoscopic ablation vs oesophagectomy
** See separate topic under      'Barrett's oesophagus'
** Current best option probably      endoscopic in the first instance
* '''T1aN0M0'''
** Only 2% lymph node mets (not      much lymphoid tissue in lamina propria/muscularis mucosae)
** Can usually be treated with      EMR
*** Better with lesions <2cm
*** Indicated in nodular or       raised Barrett's or other findings suspicious of superficial invasive       cancer
*** Resects down to submucosa
*** Does not address the       potential for nodal disease (need to assess risk of nodal mets using       nomogram above)
** Higher-risk T1a lesions      (larger tumours or lymphovascular invasion) or extensive multifocal      lesions/ulcerated tumours could be considered for oesophagectomy
* '''T1bN0M0''' - oesophagectomy generally     best due to abundance of lymphoid tissue in the submucosa
** Up to 20% lymph node      metastasis risk - probably should go back and do oesophagectomy if this      is the final EMR diagnosis
** However low-risk sm1 may be      able to have oesophagus-sparing therapy, with 84% five-year survival rate
*** Needs intense high-dose       PPI, H2 blockers, and sucralfat, with 3-monthly endoscopy for the first       year
** EMR not considered adequate      for sm2 and above due to risk of missing nodal mets
** Generally, give neoadjuvant      therapy
* '''T2-4a''', any N, M0 ('locally     advanced')
** Easy to get locoregional      control with oesophagectomy, but rates of death from distant recurrence      or metastasis continue to be high
** Neoadjuvant CTX followed by      surgery 5-7 weeks later is best strategy
** Restage with CT after CTX
** Clinical T2N0 is somewhat      controversial
*** Many have node-positive       disease in histopathology after oesophagectomy
*** One strategy is to       selectively offer neoadjuvant CTX based on the pretest probability of       upstaging (long tumours >3cm, presence of lymphovascular invasion,       and high-grade tumours indicate likely to upstage)
* '''T4b or any     M1''' - palliative     - consider palliative chemoradiotherapy
** Endoscopic palliation -      self-expanding stents

== '''Neoadjuvant/adjuvant therapy''' ==

* Consider everything >     stage I (non-superficial) cancers for multimodality therapy
** T2-T4
** Nodal involvement with no      mets
* Regime choices/trials
** '''MAGIC''' trial (2006) demonstrated      advantage to neoadjuvant chemotherapy
*** '''NEOAGIS''' didn't show much       difference between MAGIC CTX and CROSS CRT
** '''CROSS''' - chemoradiotherapy -      weekly carboplatin and paclitaxel for five weeks, with concurrent 41.4Gy      radiotherapy in 23 fractions - better tolerated than FLOT, used for      patients with comorbidities or poor performance status
*** Landmark trial was the '''CROSS''' trial - 366 patients, R0       in neoadjuvant CRTx was 92% vs 69% for up-front surgery, and double the       median survival (49 vs 24 months)
** '''FLOT-'''4 trial - chemotherapy      5-fluorouacil, folinic acid, oxaliplatin, and docetaxel for three cycles,      then surgery, then another three cycles - perhaps this is the best      neoadjuvant CTx for adenocarcinoma - can be hard to tolerate for      comorbid/frail patients, with mortality 2%
*** '''ESOPEC''' 2024 trial showed an       advantage to FLOT over CROSS in terms of long-term survival
** '''CHECKMATE577''' - CROSS vs CROSS followed      by adjuvant nivolumab immunotherapy - best results for SCC - give as      adjuvant if did not achieve complete response - especially good for SCC.
*** Should we also be using it       in complete response, to treat microscopic distant disease?
** '''TOPGEAR''' - Australian trial which      showed no benefit to neoadjuvant radiotherapy
**
* It's not really known what to     do with patients who initially have surgery but are then found to have     pathological indications for chemoradiotherapy
** May reduce local recurrence      in patients with T4 or node positive tumours who didn't have CTX/RTX      initially
* Chemotherapy
** Usually downstages      marginally resectable tumours, allowing improved R0 rates
** Decreases the rate of      locoregional recurrence
** Current regimes based      cisplatin/carboplatin and 5-fluorouacil/taxanes
** Both adenocarcinoma and SCC      patients experience a benefit
** Much better survival with      neoadjuvant compared to adjuvant CTX
** Synergistic effect with RTX
* Immunotherapy
** Usually nivolumab which is a      checkpoint inhibitor with anti-PD-L1 activity
** Start adjuvant immunotherapy      12/52 post op, if indicated based on presence of residual disease
** Duration 1 year
** SCC or adenocarcinoma
** Improved median disease-free      survival from 11 to 22 months
* Radiotherapy
** 50.4 Gy of radiation used      concomitantly with CTX is both a neoadjuvant and potentially definitive      dose
* Definitive chemoradiotherapy     can be curative
** Can do RTx + FOLFOX, CROSS      or fluorouracil/cisplatin
** Need surveillance, and      salvage therapy if recurrence is found
** 98% of local recurrences      occur in first 36 months - suggest vigilant surveillance for this period
** Combination of clinical      examination, gastroscopy and CT +/- PET
** SCC is more likely than AC      to achieve complete response based on definitive CRT, but there isn't yet      consensus on indications for CRT vs surgery in those patients. If      complete endoscopic and radiological response has been achieved for      oesophageal SCC after CRT, likely appropriate to observe.

== '''Early cancers''' ==

* Use this diagram to     subclassify depth of invasion of superficial cancers
* M1, M2 and M3 are reasonable     candidates for endoscopic resection, if no evidence of lymphovascular     invasion
** If M3 with lymphovascular      invasion, treat as T1b
** If recurrence/positive      margins, needs oesophagectomy
* All submucosal tumours (T1b)     should have oesophagectomy with therapeutic lymphadenopathy

== '''Recurrent cancers''' ==

* Not much evidence for or     against salvage oesophagectomy after CRT, but can be done in the knowledge     that risks are higher and systemic cure not guaranteed
* Resection of oligometastatic     disease should be carefully considered, taking disease tempo and ECOG     status into account

== '''Palliation''' ==

* Poor performance status or     metastases or unresectable cancers
* Checkpoint inhibitors have     given good results as palliative CTX
* Endoscopic options based on     symptoms

== '''Prognosis:''' ==

* 5-year survival:
** Tis 90%
** pT1 75%
** pT2 45%
** pT3 30%
** pT4 15%
* Overall 5 year survival 23.7%
* Adenocarcinoma
**
* SCC
**


[[Category:UGIS]]