Upper GI Flashcards
Describe the epidemiology of Oesophageal cancer
Incidence (Australian statistics)
- 1649 cases annually
- 11th most common malignancy
Incidence is changing
- SCC rates are decreasing in Western world (reduced smoking)
○ Accounts for ~90% of cases worldwide
- Adenocarcinoma are rapidly increasing in Western world (increased obesity)
○ Europe, north America, some high risk Asian counties
○ 60-75% in high income countries
Male predominance (3:1)
Vast geographical variance overall
- Highest = Asia, Middle East (oesophageal carcinoma belt), Africa
- Lowest = Central America
Mean age is 60 years (lower for adeno ~50)
Usually present at advanced stage. Can perforate = mediastinitis
Young tend to present with more advances stages
What are the risk factors for Oesophageal SCC?
- Half mid, half distal1) Smoking and alcohol (esp SCC)
a. Synergistic effect
b. Field cancerisation –> concomitant risk of H+N and lung cancers
2) Low-socioeconomic status
3) Dietary factors
a. Nitrosamine compounds (pickled/preserved foods) - Asian
b. High-temperature beverages (mucosa trauma –> increased penetration of other carcinogens)
c. Betel leaf
4) ??HPV infection
a. Associated, but much less important than in other sites
5) Benign UGI disease
a. GORD
b. Gastrectomy
c. Achalasia
6) Familial (both diet/lifestyle and genetic)
- Peutz-Jeghers syndrome (PJS - STK11 gene)
- Cowden syndrome (germline PTEN mutation)
7) Previous H+N malignancy
8) Previous radiation
9) Plummer Vinson syndrome (postcticoid dysphagia, iron deficiency anaemia, oesophageal webs)
What are the risk factors for Oesophageal Adenocarcinoma?
1) Smoking (esp SCC)
a. Field cancerisation –> concomitant risk of H+N and lung cancers
2) Gastro-oesophageal reflux (GORD)
a. Barrett’s oesophagus (adenocarcinoma) > associated oesophageal intestinal metaplasia
3) Obesity and metabolic syndrome
4) Dietary factors
a. Nitrosamine compounds (pickled/preserved foods). Diet low in fruit
b. High-temperature beverages (mucosa trauma –> increased penetration of other carcinogens)
5) H. Pylori infection (gastro-oesophageal junction adenocarcinoma)
a. Conflicting data, may be protective
6) Benign UGI disease
a. Gastrectomy
b. Achalasia
c. Acid hypersecretion (e.g. Zollinger-Ellison syndrome)
7) Familial (both diet/lifestyle and genetic)
a. Peutz-Jeghers syndrome (PJS - STK11 gene)
b. Cowden syndrome (germline PTEN mutation)
8) Previous radiation
Describe the pathogenesis for oesophageal SCC and Adenocarcinoma
Adenocarcinoma
- Majority of cases begin with metaplasia and development of Barrett’s oesophagus
○ Barrett’s oesophagus –> columnar metaplasia in the distal oesophagus (TP53 inactivation)
○ 30-50% risk of adenocarcinoma
○ Risk is dependent on length of Barrett’s and the grade of dysplasia
- Stepwise accumulation of genetic and epigenetic changes
○ Early (TSG) = p53 and CDKN2A
○ Late (oncogenes) = EGFR, HER2, MET, Cyclin D, SMAD 4, RB
Squamous Cell Carcinoma
- Accumulation of squamous dysplasia (LG intraepithelial >HG) due to trauma/carcinogens –> carcinoma in-situ
- Stepwise progression
- Molecular pathogenesis is unclear
○ P53 early driver mutation known to occur and be important in the early development stage
○ P16 mutations
○ Amplification/over expression Cyclin D and EGFR
○ Tissue invasion and metastasis: Loss of E cadherin, EMT transformation
List the differential diagnosis for primary oesophageal cancer
Histological Subtypes (prevalence as per Western world)
- Adenocarcinoma (60%) (15% in developing world)
- SCC (>35%)
○ Note in developing world, SCC comprises 90% of cases
- Neuroendocrine
○ G1-3
○ Large cell
- GIST
- Mucosal melanoma
- Adenoid cystic
- Mucoepidermoid
- Adenosquamous
Describe the pathology for Barrett’s Oesophagus.
Barrett oesophagus
- Metaplastic replacement of Squamous cells of distal oesophagus with glandular mucosa (goblet cells or glands)
○ Biopsy must be 10mm above GOJ
- Incidence of 5-10% of people with GORD
- Pathogenesis:
○ Exposure to acid/low pH from stomach GORD induces tissue damage and reprograms cells to express columnar development. Activation of pathways: NF-kB, Hedgehog, SOX 9 CDX1,2,
○ Stepwise accumulations of mutations –p53, Rb, p16, CDKN2a
- Macro: Red / salmon coloured mucosa between pale squamous mucosa of lower esophagus, mayu be in tongues
- Micro:
○ Squamous epithelium replaced by columnar intestinal epithelium with goblet cells
▪ Goblet cells rounded, mucinous cytoplasm
▪ Forms villi/tubules/glands
▪ Low or high grade dysplasia (crowding, loss of polarity, nucleus hyperchromatic
▪ Does not breach basement membrane
- Risk of dysplasia and adenocarcinoma
○ Dysplasia = looks like tubular adenoma -hyperchromatic, crowded nuclei, mitotic figures
§ Low grade: Normal architecture/gland size
§ High grade: complex architecture, small size, nucleus have nucleoli, larger
□ No stromal reaction (from invasion)
- Treated with PPI, endocscopy 3-5 years, high grade dysplasia = endoscopic ablation/resection
- Annual risk of progression with low grade dysplasia (0.7% per year) and high grade dysplasia (7% per year)
Describe the pathology for Oesophageal adenocarcinoma
- Anatomy –> Predominantly distal
- Inferior response to chemoRT (need to push resection harder)
- Macroscopic
○ Typically a distal oesophageal tumour
○ Often appear in advanced stages
○ May be flat patches or nodular masses -similar colour (Stricturing, polypoid, fungating, ulcerative or diffusely infiltrative)
§ Areas of haemorrhage or necrosis. Sometimes big mass
○ Almost always associated with Barrett’s - Microscopic
○ Generally well to moderately differentiated tumours with intestinal type mucinous cells
§ Gland forming cells, Mucus pooling
○ Generally tubular (most common), papillary, mucinous or Signet ring cell (uncommon) growth patterns
§ Papillary pattern may show micropapillary architecture
§ Tubular pattern is most common, with irregular, single or anastomosing tubular glandular structures and a single or stratified layer of malignant epithelium
○ Generally adjacent Barrett oesophagus
○ Grading
§ Well = >95% gland formation
§ Moderate = 50-95% gland formation
§ Poor = <50% gland formation
○ Cytology - Immunohistochemistry (CK7+/CK20-)
○ POS = CK7 (prognostic biomarker), CK19, somatostatin
○ PDL 1 predictive biomarker (gastric or GOJ carcinoma)
○ NEG = CK20 (colon, biliary, HCC), TTF1 (lung), GATA3 & ER (breast)
Describe the pathology for Oesophageal SCC
- Anatomy –> <20% cervical, 50% mid, 30% distal
- Better response to chemoRT
- Macroscopic
○ Most commonly present in mid-oesophagus
○ Fungating exophytic/polypoid lesion is most common
○ May also be ulcerating with deep penetration (trachea, mediastinum)
○ Fibrosis can constrict oesophagus - Microscopic
‘Keratinocyte type cells with intercellular bridges or keratinisation’
○ Generally well to moderately differentiated
§ WD: Frequently keratinising with intercellular bridges and keratin pearls. Minimal cytological atypia, low mitotic rate.
§ MD: Evident cytological atypia, mitotic figures easily identified
§ PD: large hyperchromatic nuclei (10x size), no keratin. Predominant basal cells.
○ May present with clusters distant to main mass (intramural metastases)
○ Stromal desmoplasia is common
○ Variants
§ Basaloid –> oval hyperchromatic nuclei, scant cytoplasm and peripheral palisading - Immunohistochemistry
○ POS = PanCK (Mixture of 2 Anti cytokeratin monoclonal antibodies AE1 and AE3 to detect broad spectrum of cytokeratin’s–>p confirms epithelial origin), p63 , CK5/6, p40
○ NEG= Synaptophysin/chromogranin (rule out neuroendocrine), PAS, mucicarmine (r/o adeno) - Molecular
○ Benefit from PDL1 blockade
Some studies use TPS, others CPS
Describe the different anatomical components of the oesophagus and the Siewert classification
Oesophagus is from hypopharynx (15 cm) to GEJ (40 cm)
○ Cervical esophagus: 15-20 cm. From cricoid cartilage/hypopharynx to sternal notch
○ Upper thoracic esophagus: 20-25 cm. To carina.
○ Mid thoracic esophagus: 25-30 cm. To inferior pulmonary veins
Lower thoracic esophagus: 30-40 cm. To GEJ.
Abdominal esophagus: 40-42cm.
Siewert Classification of GOJ Cancers (where the centre of the tumour is) - Siewert 1 (upper) = 1-5cm above the GOJ ○ ivor-lewis esophagectomy - Siewert 2 (middle) = between 1cm above and 2cm below GOJ ○ total gatrectomy - Siewert 3 (lower) = 2-5cm below the GOJ ○ treat as gastric ca ○ total gastrectomy
List the prognostic factors for Oesophageal cancer
Patient Factors
- Age and co-morbidity (not when adjusted for treatment)
- Weight loss
Tumour Factors
- TNM staging
○ T-stage (depth of invasion) and nodal involvement are each independently prognostic
○ Higher T stage-> higher chance of Nodal met (Tis 0%, T1b 20%, T2 60%, T3 90%, T4 100%)
- Location- Upper 1/3 worse than Lower 1/3
- Histological subtype and grade
○ SCC better than Adenoca
- LVI
- CEA
- Biomarkers
○ Adenocarcinoma: PDL 1 expression, CK 7 (CK 7 overexpression independent prognostic factor for poor OS)
○ SCC: Loss of p63
- Synchronous H&N second primary tumour
Treatment Factors
- pCR following chemoRT
- Treatment in a high-volume centre
- Multi-modality approach
○ Optimal is neoadjuvant chemoRT with surgery
○ Lack of concurrent chemotherapy reduces prognosis
Describe history and examination for Oesophageal cancer.
History
- Local symptoms
○ Dysphagia and odynophagia
○ Weight loss
○ Chest pain
○ Reflux symptoms
○ Haematemesis/melena (UGI bleeding)
- Regional + Distant symptoms
○ Voice change (recurrent laryngeal nerve)
○ Tracheobronchial fistula
○ Abdominal pain or jaundice (liver metastases)
○ Bony pain
- PMHx:
○ Reflux or Barrett’s oesophagus
○ Benign oesophageal disease
○ H+N cancers (metachronous cancers common)
- Family Hx
○ Peutz Jeghers - STK11 (GIT incl pancreas, breast, gynae and lung cancers)
○ Cowden’s - PTEN (hamartomas, breast cancer, thyroid cancer)
- Social
○ Smoking and alcohol
Examination
- Weight and cachexia
- Abdominal palpation
○ Hepatomegaly
- Cervical LN
○ If cervical cancer, all LN at risk
○ If thoracic, then left SCF (Virchow’s node)
Describe the work up for oesophageal cancer
- Bloods
○ FBC (anaemia secondary to losses)
○ EUC and CMP (pre-chemo & nutrition)
○ LFT (liver metastases + pre-chemo)
○ Albumin (nutrition)
○ CEA + Ca19.9 (prognostic and surveillance)- Endoscopy + biopsy
○ Check start/stop length
○ Degree of obstruction/ pediatric scope
○ Consider EUS with biopsy of mediastinal LN (generally not done unless T1a)
○ Add HER2 status to all GOJ and gastric cancers
○ Multiple endoscopic biopsies ideal >=6 to ensure adeqaute representation and sufficient tissue for molecular analysis - Endoscopic USS
○ Can be used for T and N staging
§ Assessment of T4b status with invasion towards airways, pericardium or Ao
§ Nodal masses outside RT field
○ Low accuracy for T1 tumours; Endoscopic resection offers more precise staging in addition to therapeutic benefit
○ If stricture, bronchoscopy may be helpful - Imaging
○ FDG PET-CT (staging)
§ help detect occult mets and define extent of primary tumour
§ Performed in most, should be performed if candidate for oesophagectomy, avoid futile surgery
○ Diagnostic CT CAP (anatomical resolution) - Diagnostic laparoscopy and peritoneal washings
○ For distal tumours
○ Peritoneal mets found in ~15% of patients
All imaging modalites are only 30-50% sensitive for nodal disease - Lung function tests (ideal)
○ Pre-radiotherapy
- Endoscopy + biopsy
Describe the staging for Oesophageal cancer.
Describe the management for cT1aN0 Oesophageal cancer.
All cT1a N0 (pre-submucosal) cancers including HGD
- Endoscopic resection is preferred (Supported by ESMO guidelines) ○ Provides accurate staging ○ If deep margin -ve and low risk features= definitive ▪ High risk factors predict for lymph node mets □ Depth of invasion □ LVI □ High grade □ Large tumour size ○ Low risk features: pT1a, No LVI, G1/2 ▪ Adenocarcinoma: <0.5mm invasion, <20 mm in diameter, no ulceration □ Also superficial submucosal involved T1b (sm1, invasion <0.5mm, no ulceration; ESMO) □ EMR preferred for small lesions □ ESD (endoscopic submucosal dissection) in lesions >15mm, poorly lifting and tumours at risk of submucosal invasion ▪ SCC: Mucosal infiltration grade M1/2, in the squamous epithelium □ LN met risk higher deep intramucosal lesions (m3) need additional treatment if other risk factors present - Esophagectomy is preferred if extensive disease is seen or high risk features for lymph node involvement, aswell as involved margins ○ Chemoradiotherapy can be considered for stage IA SCC with organ preservation - Endoscopic surveillance for local recurrence important
If unfit, chemort 70-90% survival
Brachy boost
- Further management as per histopathology and pTNM staging ○ Proceed as appropriate per below
Describe the management of cT1b-T2N0 (low risk) Oesophageal Cancer
- Two key approaches exist
○ Upfront oesophagectomy
○ Neoadjuvant chemoradiotherapy followed by oesophagectomy- Low-risk cancers can be reasonably managed with upfront oesophagectomy (for non-cervical oesophagus)
○ Low risk = <3cm in size; well differentiated; no LVI - Alternatively, if unable or unwilling to undergo surgery combined chemoRT is superior to RT alone 50.4Gy/28F with cisplatin/5FU
- Controversy re neoadjuvant in T2N0
○ as under-represented population in RCTs and retrospective data shows conflicting results.
○ Randomised Phase III trial ins tage I-II showed NA CRT did not improve R0 rate or OS but increased operative mortality
▪ Criticisim: heterogenous cohort, included cT1-3 tumours - Presence of high-risk factors indicate need for neoadjuvant chemoradiotherapy (>3cm, LVI, Poorly differentiated)
○ High risk of microscopic nodal disease
○ ChemoRT preferred followed by oesophagectomy
▪ ESMO/NCNN guidelines do allow for observation or oesophgeactomy for SCC if completed response to chemoRT - Final histopathology will determine need for adjuvant therapy
○ If pT1b-2 N0 with R0 resection and without risk factors
§ No adjuvant therapy
○ Final histopathology will determine need for adjuvant therapy
○ If pT1b-2 N0 with R0 resection and without risk factors
§ No adjuvant therapy
○ IF pT1-2 N+
§ No evidence for Adj chemo alone based on MA, even if N+
○ If pT3+, N+ or R1/R2 resection
§ Adj Chemoradiotherapy
□ 50.4Gy at 1.8Gy/F with concurrent carboplatin/paclitaxel - If not surgical candidate, or declines:
○ Consider definitive chemoRT (50.4Gy/28F with cisplatin/5FU),
- Low-risk cancers can be reasonably managed with upfront oesophagectomy (for non-cervical oesophagus)
Describe the management of cT2+ or N+ Mid/distal Oesophageal cancer.
- Mid/distal oesophageal SCC/adeno
- Curative options:
○ Neoadjuvant chemoradiotherapy to be followed by oesophagectomy and adjuvant nivolumab (best for SCC)
○ GOJ: Perioperative ie. Preop chemotherapy, followed by surgery, followed by chemotherapy
○ Definitive chemoradiotherapy + close surveillance and salvage surgery
§ The use of salvage oesophagectomy in SCC patients with persistent disease has been shown to be safe and associated with survival rates similar to planned neoadjuvant chemoRT + surgery
○ Neoadjuvant immunotherapy for dMMR tumours–ph2 trial - IF using CROSS protcol, give Adj Nivo after surg
- IF Using FLOT protocol, give Adj FLOT after surg
- Adjuvant RT alone
○ Little evidence, consider if positive margin to decrease local recurrence.
○ Prefer nivo - Adjuvant chemo alone: no benefit
- Adjuvant CRT: (without neoadjuvant) single study oesophagealT3N1 improved survival, also old study supporting adjuvant CRT for GOJ
- Curative options:
Describe the management of cT2+ or N+ GOJ cancer.
○ Treatment depends on Siewert (AJCC8th ed) location:
§ Type I (distal esophagus) - 1-5 cm above GEJ
§ Type II (cardia) - 1-2 cm just distal to GEJ.
§ Type III (sub-cardia) - > 2 cm distal to GEJ. Now, only Type III is considered gastric cancer.
○ Siewert I = manage as oesophageal adenocarcinoma ○ Siewert II = either approach (MDT discussion) § FLOT if fit § CROSS if less fit ○ Siewert III = manage as per gastric
Discuss the evidence for Neoadjuavant chemoradiotherapy for oesophageal cancer
NEOADJUVANT THERAPY:
- Neoadjuvant therapy (either NACT or NA CRT) with resection is the standard of care (irrespective of histopathology; SCC>AC)
○ Increased R0 resections
○ Increased OS
- Neoadjuvant chemoradiotherapy improved OS when compared with
§ Surgery alone (HR 0.75)
§ Neoadjuvant chemotherapy (HR 0.83)
§ Neoadjuvant radiotherapy (HR 0.82)
§ Risk of peri-operative morbidity and mortality is higher
NEOADJUVANT CHEMORADIOTHERAY:
* CROSS protocol- NA CRT improved OS, LRR, DM progression, pCR rate, R0 resection rate (in both SCC and AC) compared to surgery alone
○ 41.4Gy/23F with concurrent carboplatin/paclitaxel
○ Re-stage after completion (4-6 weeks after)
○ If clear, oesophagectomy to follow (aim before 8 weeks)
* Insufficient evidence to allow omission of surgery if cCR achieved (regardless of histopathology)
* If R0 with residual micro disease or partial response (having had CRT then surgery), can consider role of adjuvant nivolumab for 12 months [Checkmate 577] ○ Sigificant improvement in DFS 11 months ○ PDL1 testing not required * Note: NA chemo alone followed by Sx can also be given however MA showed that NA CRT is superior to NA chemo alone
Discuss the evidence for neoadjuvant chemo alone for oesophageal cancer
- Four trials negative (including Intergroup 0113) and five trials positive OS benefit (including MRC OE2, MAGIC, French FNLCC/FFCD)
- Meta-analyses benefit of NACT cw Surgery alone; in one benefit was limited to SCC only
- MRC trial showed OS and pCR improvement with NA chemo. However Intergroup showed no OS benefit, unless there is R0 resection.
- NA therapy for Adenocarcinoma (GOJ)
○ NA chemo an alterative to CROSS, supported by large prospective RCTs (these two trials from GASTRIC cancer, and included GOJ)
§ Phase III MAGIC - 3xpre op and 3x post op epirubicin-cisplatin-5FU (ECF): tumour downstaging, improved R0 resection rate, improved OS
§ Phase II/III FLOT4-AIO trial: perioperative ECF vs. 4x FLOT pre op and 4x post op: OS benefit for FLOT
○ Comparisons between chemo and chemoRT limited
§ Phase III Neo-AEGIS (Lancet, 2023): non-inferiority study comparing chemo to CROSS: MFU. 34 months. No diff OS, higher rates of tuour regresssion, pCR in CRT
□ Majority treated with OLDER (and less effective) ECF rather than FLOT
□ ESOPEC comparing CROSS to FLOT awaited
Discuss the evidence for definitive chemoRT for oesophageal cancer?
- Definitive chemoradiotherapy may be offered if:
○ Medically ineligible for surgery ‘unable’ (unresectable, medically inoperable, pt preference);
§ Or as per ESMO guidelines as an alternative for SCC (with close surveillance and salvage surgery)
○ Patient preference ‘unwilling’ (especially if SCC pathology)
§ can be used for both SCC or Adeno
○ Prescription: 50.4Gy at 1.8Gy/F OR 50Gy/25Fwith concurrent cisplatin/5-FU (or capecitabine)
§ No evidence to support higher doses than 50.4Gy
□ No improvement with LC or OS
□ Doses >55Gy have been associated with increased post op mortality and morbidity
○ Currently no rando evidence to support carbo/taxol however commonly used in clinical setting (as used in CROSS).
§ Honing et al
□ compared RT+cis5FU vs carbo+paclitaxel (16 vs 14 month survival)
® evidence: mOS and mDFS, no difference between adeno vs SCC
◊ Less toxic with carbotaxol
◊ more completed treatment with carbotaxol vs cis5FU
§ Alternative 6 cycles of foliniic acid-5 FU-oxaliplatin (FOLFOX)
Def CRT recommended for cervical localised tumours where surgery would entail a laryngectomy- SCC vs adenocarcinoma
○ Higher pCR rate with SCC following chemoradiotherapy cf to adenoca
○ No sufficient evidence to allow change in gold-standard recommendation (chemoradiotherapy followed by oesophagectomy)
§ Whilst OS is similar with definitive chemoRT, higher rates of local failure are seen
○ However, perhaps definitive RT is a more reasonable alternative for SCC than in adenocarcinoma
E.g. borderline fitness for surgery
- SCC vs adenocarcinoma
Discuss the management of cervical oesophagus cancer.
○ Technically unresectable cancers due to morbidity
○ Classified as disease from cricoid to sternal notch / thoracic inlet
○ Preferred treatment-> Upfront CRT (like HNC); maintains function, similar survival + less morbidity in long-term.
§ [NCCN] Cervical or cervicothoracic esophageal carcinomas <5 cm from the cricopharyngeus should be treated with definitive chemoradiation.
§ [NCCN] Consider treatment of the supraclavicular nodes and treatment of higher echelon cervical nodes, especially if the nodal stage is N1 or greater.
§ With potential role for Sx in partial or poor response post CRT. CRT is less toxic than Sx
○ Definitive chemoradiotherapy is the standard of care
§ Benefit:
□ preservation of function, non invasive, similar LC, OS and PFS cf. surgery and decreased toxicity
□ Sx can be used as salvage
§ Dose: ChemoRT 50/45Gy in 25F with carbo/paclitaxel
□ Multiple studies have looked into sequential boost to 54-60Gy-> no significant LC benefit and increases toxicity
□ 2020 De Vos-Geelen study compared Cis vs Cis/paclitaxel with low vs high dose RT in SCC of prox esophagus
® Comparable median OS 21mo (range 16.9-27m)
® G3-G5 acute tox better in C/P-low dose vs C-high dose RT
® G3-G5 late tox equivalent between treatment groups
® Conclusion: low-dose carboplatin-paclitaxel is the preferred option based on safety/toxicity data.
Some people would treat it like a H&N cancer, dose to 50-66-70Gy with cis/5FU
□ Refer to H&N clinic. 60-66/56y in 2Gy/F with concurrent Cis/5FU; need to treat bilat SCF nodes. Lung DVH not issue but brachial plexus and cord are limiting
® Concurrent carbo/taxol may be preferred given less toxicity
® Often should refer to RO H+N specialist
® No consensus on elective node irradiation
◊ Consider paratracheal (43% +)
◊ Consider SCF and higher echelon cervical nodes > N1
□ GTV primary and node
□ CTV: 2cm sup+inf (no need to go more sup than cricoid) and 1cm radially
□ CTV node: cover bilateral SCF and consider lower cervical nodes
[MJ treat to 60/56Gy in 30F. CTV60= GTV+1cm, CTV56= GTV+3cm sup inf, paraesophageal and SCF node]
Describe the management of advanced Oesophageal cancer
- First-line treatment for advanced oesophageal SCC
○ First-line ChT with a platinum and fluoropyrimidine is recommended as a standard treatment for advanced untreated oesophageal SCC [II, A].
§ Dose-reduced oxaliplatin–capecitabine is an alternative option for patients who are unsuitable for full-dose ChT [I, A].
○ Pembrolizumab–ChT is recommended for advanced, untreated oesophageal SCC. The greatest benefit is seen in patients with a PD-L1 CPS ≥10 [I, A; ESMO-MCBS v1.1 score: 4; European Medicines Agency (EMA) approval is for tumours with PD-L1 CPS ≥10, Food and Drug Administration (FDA) approval is irrespective of PD-L1 expression].
○ Nivolumab–ChT is recommended in patients with tumours expressing PD-L1 with a TPS ≥1% [I, A; ESMO-MCBS v1.1 score: 4]. Nivolumab–ipilimumab can be given, but a lower radiological response rate and increased risk of early progression and death in patients treated without ChT needs to be considered [I, B; ESMO-MCBS v1.1 score: 4].
Describe the palliative management of anastomotic oesophageal cancer recurrence post previous CROSS treatment
Management of local symptoms:
* If bleeding, provide haemostasis with haemospray, endoscopic cautery, pall RT or tranexamic acid
* Manage pain as per WHO analgesia ladder
* optimise nutrition and refer to dietician to improve oral intake. Consider Stent +/- insertion of NGT if suitable
2. Stent
* Rapid relief of dysphagia.
* For patients with poor performance status and limited life expectancy <3-6 months.
* Permanent diet modification to fluid/pureed diet.
* Side effects include retrosternal pain, reflux, stent migration, occlusion and perforation, oseophageal fistula and haemorrhage.
3. Chemotherapy (either as monotherapy or combination)
* Control of distant disease and potentially prolong survival.
* Less effective in providing local control.
* Consideration of addition of checkpoint inhibitor immunotherapy such as pembrolizumab if MSI high or PDL1 expression is high and HER2 targeted therapy such as Trastuzumab for HER2 amplified adenocarcinoma.
4. Endoscopic dilatation
* Provides temporary relief of dysphagia, facilitating stent, RIG/PEG tube insertion.
* Will require repeat procedure every 2-4 weeks.
* Risk of perforation, bleeding.
5. Ablation with photodynamic therapy.
* Provides temporary relief of dysphagia for obstructing endoluminal tumours.
* More definitive response but risk of stricture.
6. Salvage surgery
* usually limited or unlikely
7. Re-irradiation:
* Given previous high dose given with CROSS protocol, not suitable for any further meaningful dose for local control.
* re-irradiation increase acute and latent toxicity
* however, low dose of re-irradiation could be offered for palliation of sx eg haemostasis
* High dose reirradiation for SCC 50Gy/2# CRT –median local control 1 year but 15-20% perforation 30% fistula, 10% g3 pneumonitis
8. Best supportive care.
Describe the palliative management of thoracic oesophageal cancer with chemo or RT
General:
* Poor prognosis if unable to undergo trimodality therapy -> median OS is 6 months
* These patients are:
○ Unable to receive curative treatment
○ Distant metastatic disease
* Aim: palliation (esp. dysphagia), maintain local control.
Options for palliative local treatment:
* RT alone: doses 45/15, 35/15, 30/10, 20/5, (depends on PS)
* Endoscopic stenting
* Dilatation
* Brachytherapy (e.g. recurrence after EBRT)
* Surgical palliation: resection, bypass. But high mortality and morbidity, therefore not std practice
* EMR, laser
Palliative radiotherapy: ○ RT palliates dysphagia in ~70% for average of 6 months; median time to relief is ~2 weeks. ○ Can be EBRT or brachytherapy (EBRT more common) ○ 3x RCTs comparing pall RT vs no RT -> improved symptom control and reduced time for re-intervention ○ Various doses: 39Gy/13F, 35Gy/15F, 30Gy/10F, 20Gy/5#F, [45Gy/15F ML/ MJ] ○ What dose to use? § 2019 Walterbos et al retro- No difference in sx improvement between regimens, however median OS increases with dose and longer time to second intervention in 30 and 39Gy compared to 20Gy ○ Pall ChemoRT or RT alone? § TROG 03.01. (Lancet 2017) RCT. Palliative chemoRT v pall RT alone. [35/15# or 30/10# or CRT with Cisplatin and 5FU] □ No difference in dysphagia or survival. Increased toxicity (N+V) in patients receiving CRT. HENCE Recommend RT alone. □ Criticism – no CTx alone arm Palliation of dysphagia: ○ Consider chemo alone with diet changes ○ Brachy= more durable dysphagia relief, fewer complications vs. stenting § Stents less durable response, can migrate, cause pain, reflux etc § Length should be 10cm or less; 10-14Gy/2Fx, q1w, prescribed as a 1cm radius ○ RT (20Gy/5Fx) decreases dysphagia in 75%, duration of response ~5 months
Describe palliative oesophageal stenting.
○ Indications:
§ Severe dysphagia, needing intervention before CT
§ Inadequate palliation with prior mx
§ Recurrent dysphagia dt locoregional failure
§ Recurrent dysphagia dt XRT induced strictures
§ Palliation in poor candidates for RT or CT
○ Complications: perforation, stent migration, intractable GO reflux (esp. lower stents), foreign body sensation (upper stents), stent related pain
○ If able to swallow a little – prefer RTx short course and then reserve stent for later (avoid Cx of stent); occasionally put in removable fully-covered stent before neoadjuvant treatment.
○ If unable to swallow at all – needs stent.
Evidence: § Trial of palliative stent vs brachytherapy (Dutch trial: Homs 2004). More rapid palliation with stent. More durable palliation with brachy (3 months vs 5 months). □ Dose: 10-12Gy/1# □ 1/3 of patients had stent complications such as pain, GORD, bleeding. QOL better with brachy. § Indian trial (RCT): consolidation with RT post-stent --> Prolongs duration of dysphagia response (7 vs 3 months). Improves OS. 30Gy/10#. § ROCS RCT (Adamson, 2021): 220 patients with incurable oesophageal cancer receiving stent insertion upfront for dysphagia. --> Randomised to RT (20Gy5F or 30Gy/10F) vs standard of care □ Outcomes: ® No difference in dysphagia outcomes ◊ Early dysphagia and pain increase with EBRT ® No difference in survival ® No difference in time to stent complication or re-intervention ® Some benefit in time to first bleeding event (49 wks vs 69 wks)
Discuss the pros and cons of elective nodal irradiation in oesophageal cancer management
Pro ENI:
- Risk mucosal plexus hence High risk of submucosal lymphatic spread. ENI would treat occult nodes
- PETCT sensitivity is limited to the size of nodes hence risk of false negative on staging
- ENI improve nodal coverage and decrease risk of locoregional failure
- Extended surgical nodal resection improve LC and OS, hence ENI would also improve LC and OS
Against ENI:
- Pattern of failure is usually in field or distant mets, < 10% risk of nodal alone LRR
- Increase treatment volume, increasing dose to lung and heart, increasing acute and latent toxicities
- Risk of overtreatment adding unwarranted pneumonitis and esophagitis
- Pattern of nodal spread is not predictable
- Chemotherapy can treat and reduce any nodal micromet
- No significant improvement in LC or OS in evidence
Discuss the management of metastatic oeosophageal cancer.
1st line:
* If PD-L1 low/neg— Platinum & fluoropyrimidine.
Most RCTs is based on AC. SC extrapolated from these (+multiple P2 studies supporting this).
○ Dose reduced oxaliplatin-capecitabine (if not tolerating) GO2 P3 trial—equivalent outcomes & reduced tox.
* If PD-L1 CPS≥10—Pembro-chemo KEYNOTE-590—OS benefit (vs chemo alone).
* If PD-L1 TPS≥1%—Nivo-chemo CheckMate- 648—OS benefit (vs chemo alone).
HER2+ Cancers (gastric and GOJ)
Around 20% of gastric cancer and 33% of GOJ ca are HER2+ as per ToGA
Trastuzumab demonstrates a modest to marginal benefit in this disease. This benefit is driven by IHC 2-3+ positivity, NOT in IHC 1+ and FISH positivity.
Currently, there is no role of adding herceptin to CROSS protocol as per RTOG1010- no DFS or OS benefit
* In the metastatic setting for both gastric/ GOJ ca, HER2 can improve mOS and RR as per TOGA.
* 2018 MA confirmed and showed that adding trastuzumab to a diff doublet chemo has significant OS benefit oxaloplatin +cap or 5FU). No benefit of adding trastuzumab to single or triple chemo regimens
* There is no role in adding pertuzumab to trastuzumab + chemo as per JACOB trial
* Role of pembro + trastuzumab + chemo is still pending but early data from the Keynote studies seems to suggest PFs survival beenfit with improved RR and higher and prolonged response rate
Discuss the general principles with surgical management of oesophageal cancer.
Restaging endoscopy 4-6 weeks after neoadjuvant
Surgery @ 6-10 weeks for all adeno, consider watching SCC with complete repsonse
Longer = more scarring or disease recurrence
Principles of surgery:
* preserve function fo neo-esophagus
* blood supply- right gastoepiploic artery
* tension- can lead to ischeamic stricture
* choose the right conduit- reflux, position (thoracic, retrosternal and substernal)
Surgery options
* Resectable or potentially resectable:
○ Thoracic location (cervical is not resectable)
○ Medically fit for surgery
○ T3 or select T4
○ No presence of bulky mediastinal or SCF nodes
○ No metastatic disease
* Only 30-40% have potentially resectable dx at presentation.
* Goal is R0 resection- as ultimately affects RR + survival
* Total thoracic oesophagectomy with cervical oesophagogastrostomy + LN dissection.
* Total oesophagectomy dt high risk submucosal skip lesions.
Anastomosis done in neck or chest, stomach usually used as conduit.
Describe the surgical options for oesophageal cancer
○ ***Ivor-Lewis (transthoracic)- laparotomy + R thoracotomy. Upper thoracic anastomosis. Used for lesions in any thoracic location, but margins may be inadequate for mid oesophageal lesions. Now 1-5% mortality rate from Ivor Lewis but traditionally much higher. Preferred operation now ‘minimally invasive’ version of Ivor-Lewis (avoids thoracotomy and improved outcomes in every way).
○ Modified IL = left thoracotomy: lower 1/3 gastric cardia lesions. Lower anastomosis.
○ Transhiatal oesophagectomy- laparotomy + Cx incision, can be any location in oesophagus, blunt chest dissection + gastric conduit drawn through mediastinum for neck anastomosis. Issue is not visualizing and does not allow full thoracic nodal dissection as its blind resection.
○ McKeown 3 stage or tri-incisional (cervico,thoracic,abdominal) technique combines aspects of the Ivor Lewis & transhiatal approaches.
§ Adv:
□ Esier MX of leak
□ lower incidence of reflux
□ more extensive proximal margins
□ Allows for safer dissection of the intrathoracic esophagus under direct vision with complete nodal resection, & brings the anastomosis to the neck, allowing for maximal proximal margins and minimizing the risk of an intrathoracic leak.
* Lymph node surgical management:
○ LN dissection can be 2 field (mediastinum + abdo) or 3 field (Japan- cx LN). Lymphadenectomy – peri-oesophageal, subcarinal, parabronchial and mediastinal nodes, thoracic duct, coeliac and L gastric nodes
* For GOJ tumours: need at least partial gastrectomy. For an R0 resection needs 4cm gastric tissue and 5cm oesophageal margin + at least 15 LN.
What is the evidence for management of T1a Oesophageal cancers?
Retrospective data only
- Endoscopic treatment provides similar outcomes to oesophagectomy, with reduced operative morbidity
- Endoscopic resection does not address lymph node risk and once invades the muscularis propria LN risk >30%
Meta-analysis of retrospective data (Zheng, 2021)
- Endoscopic resection fewer major adverse events and procedure related mortality
- Oesophagectomy had a lower recurrence rate and higher R0 resection rate, may be conferred advantage with OS
- Both procedures similar rates of post-procedure stricture
What is the evidence for adjuvant oesophageal cancer treatment post oesophagectomy ?
Adjuvant RT
○ Post op XRT- 3 small studies, 15% ↓in LR but no survival benefit + ↑morbidity.
○ No evidence to clearly support this techniquee
○ No role if node positive
○ Consider if +ve margins to anastomotic site based on a retrospective study to ↑LC (R+O paper). But need v large fields as hard to determine site to target, so get ↑lung doses.
Adjuvant CT ○ MA shows no OS benefit for adjuvant CT. ○ No evidence to support adj chemotherapy alone -> even if N+ still observe § ?Option of perioperative CT (MAGIC trial for gastric + GOJ ca) Adjuvant Chemoradiotherapy Following Up-front Oesophagectomy Data depend on the stage ○ Adj Tx is difficult to administer ○ pT3+ or pN+ --> there is a survival advantage to the use of adjuvant chemoradiotherapy ○ Otherwise, no clear evidence supporting use Chinese Phase III RCT (Ni, 2021) § 172 patients with oesophageal SCC were randomised to three arms □ Surgery alone □ Adjuvant radiotherapy alone (54Gy/27F) □ Adjuvant chemoradiotherapy (50.4Gy/28F with concurrent cisplatin/paclitaxel) § Any adjuvant therapy was associated with improved DFS and OS § ChemoRT was superior to RT alone □ 3 yr OS = 66.5% vs 60.8% □ 3 yr DFS = 57.3% vs 50% - For GOJ adenoca - Option of adjuvant CRT (Intergp MacDonald study for gastric + GOJ ca) MacDonald study, NEJM 01. Postop CRT in stomach + GOJ adenocarcinoma. 20% of 550pts had GOJ tumours. 5FU + leucovorin, 45Gy/25F XRT. CRT gp had a 9% ↑3yr OS, 9m ↑median survival (36 vs. 27m) dt ↑locoregional control. But 2/3pts had G3/4 toxicity (mainly haem, GI) and 3 deaths (1%). Benefit but toxic treatment.
What is the evidence for neoadjuvant chemotherapy in oesophageal treatment and the evidence comparing it to chemoRT?
Neoadjuvant Chemo alone
- Data for NA chemo is more conflicting, as MRC trial showed OS and pCR improvement with NA chemo. However Intergroup showed no OS benefit, unless there is R0 resection.
MRC OE2 UK resectable (AC>SCC>undiff, lower 1/3)-> ± CDDP/5-FU x2c→ Surgery. Positive trial -> NAC improves survival (mOS &OS) in both AC &SCC and R0 resection. Nil diff in complications rates. RTOG/Intergroup resectable (AC=SCC) CDDP/5-FU x3c→ Surgery→ x2c vs. Surgery alone. Negative trial -> Nil diff in survival or pCR rates. ○ Long-term FU-> R0 resection improved long term survival. Issues: larger doses chemo (more toxic), longer time to surg (?dt chemo tox)-> ? negate chemo benefit.
Describe the evidence for neoadjuvant chemoRT in oesophageal cancer.
CROSS Protocol is the SOC- for both Adeno and SCC. (SCC better response than Adeno)
- Meta-analysis level data have demonstrated a OS advantage to tri-modality therapy
- Chemo RT is superior to chemotherapy alone
- Chinese trial compared CRT vs NA chemo –> CRT better pCR and downstaging with trend of OS improvement in LA E SCC
- POET trial compared CRT vs NA chemo –> CRT better pCR and LC with trend of OS improvement in LA E Adeno
- Network meta-analysis (Chan, 2018) ○ 31 RCTs with 5500 patients were included ○ Neoadjuvant chemoradiotherapy improved OS when compared with § Surgery alone (HR 0.75) § Neoadjuvant chemotherapy (HR 0.83) § Neoadjuvant radiotherapy (HR 0.82) ○ Risk of peri-operative morbidity and mortality is higher CROSS trial (Van Hagen, 2012; Eyck, 2021) -> NA CRT improved OS, LRR, DM progression, pCR rate, R0 resection rate ○ 363 patients with resectable oesophageal/GOJ § Majority adenocarcinoma; 75% adeno, 25% SCC. 80% distal or GOJ § 0 patients T4 randomised to CROSS § Up to 8cm long tumours ○ Patients were randomised to surgery +/- neoadjuvant chemoRT § 41.4Gy/23F with concurrent carboplatin/paclitaxel § Surgery within 4-6 weeks of neoadjuvant chemoRT ○ Initial report: § Improved mOS 25-> 50mo and 5yr OS 34-> 47% § Improved R0 resection rate (92% vs 69%) § High pCR rate with chemoRT (29%) □ Subanalysis: 50% for SCC vs 25% for Adenoca § No statistically significant differences in post-operative morbidity/mortality □ Cardiac and pulmonary complications, anastomotic leak, mediastinitis, chylothorax, death ○ 10 year follow-up report: § 10yr OS = 38% CRT vs 25% Sx (Absolute difference 13%) □ 10yr OS Subanalysis based on histo: ® SCC 46% CRT vs 23% Sx (23%) ▪ Higher benefit for SCC histopathology ® Adenoca 35% CRT vs 26% Sx (9%) § 10yr LRR = 22% vs 38% § 10yr DM progression 39% CRT vs 48% Sx
What is the evidence comparing CROSS vs FLOT protocols for gastro-oesophageal cancer?
For GOJ
CROSS vs FLOT (Periop Chemo)
Retrospective study:
Syndey:
No survival difference, R0
CROSS more tolerable, less gr3/4 toxicity
NEOAEGIS –chemo less operative mortality
NEO-AEGIS (Reynolds, 2023) RCT ○ 377 patients with distal/GOJ adenocarcinoma were randomised to: § CROSS chemoRT (41.4Gy/23F with concurrent carboplatin/paclitaxel) § Peri-operative chemo (ECF or FLOT) (majority treated with older, less effective ECF prior to FLOT 4 study) ○ The CROSS regimen leads to superior pathologic response (tumour regression) and R0 resections over MAGIC/FLOT. ○ In regards to OS, CROSS and MAGIC/FLOT are noninferior. § CROSS also has the added benefit of potential nivolumab after chemoradiation and surgery (Checkmate 577, Kelly 2021). ○ 3-yr OS 56-57%, noninferior
What is the evidence for definitive chemoRT in oesophageal cancer?
Data is relative to the benefit of adding oesophagectomy to chemoradiotherapy alone
Most data for SCC
For SCC
- MA, French and German RCT showed that Def CRT has similar OS compared to Trimodality regimen
- However surgery improved LC and FFLP BUT with increase treatment related toxicity and mortality.
- Caveat –> the majority of cancer were SCC and the 2 RCt used diff Chemo regimen.
For Adenocarcinoma
- Retrospective data only
- Most benefit for oesophagectomy in patients with low risk of distant recurrence
Watchful waiting after CRT: reserve Sx for non-responders – addition of surgery reduced LR but at a cost of increase morbidity and no improvement in survival
SANO [Van der Wilk ESMO ‘23]: Phase III non-inferiority. CCRT (41.4/23)→ cCR: AS vs. Esophagectomy.
309 patients with cCR at 6-12 weeks after nCCRT (response assessment at 10-14 weeks via PET and EGD/EUS+biopsy). AS = active surveillance with surgery only when locoregional growth was detected. R1 ~2%. Postoperative 90d mortality ~5%. MDFS 35→ 49 mo, favoring standard surgery (HR 1.35, 95CI 0.9-2.0, p=0.15). 30 mo after CCRT, DM for AS / standard surgery of 43→ 34% (OR 1.5, 95CI 0.9-2.5, p=0.18). HRQOL was better at 6 and 9 mo for AS.
What is the evidence for adjuvant immunotherapy in oesophageal cancer?
CheckMate 577
○ Oesophageal/ GOJ junction ca (70% adenocarcinoma; 60% oesophageal, 40% GOJ) neoadjuvant CRT
○ Reisdual pathological disease at time of surgery
○ Adj nivolumab doubles mDFS in patients with esophageal/EG junction cancer who have completely resected residual disease after neoadjuvant chemoradiation.
- CheckMate 577 [Kelly NEJM '21]: PhIII. NACCRT→ R0 resection→ ± Nivolumab 240 q2w x16w→ 480 q2w up to 1y. 794 pts with R0 stage II-III AC (70%) or SqCC. Residual pathologic disease. PD-L1 < 1% (75%). MFU 2y. ○ Europe (38%). USA/Canada (32%). Asia (13%). Rest of world (16%). ○ mDFS 11→ 22 mo. ○ G3-4 treatment related AE 6→ 13%. ○ Maintenance placebo or nivo discontinued due to AE in 3→ 9%. ○ Benefits across all subgroups (histo, location, pre and post disease stage, PDL1 expression) ○ OS data awaited; mostly G1/2 toxicities, only 9%
What is the evidence to support definitive chemoRT compared to RT alone for oesophageal cancer?
ChemoRT is superior to definitive RT alone (data for SCC only)
RTOG 8501 (Cooper, 1999) ○ 129 patients with oesophageal carcinoma were included § 80+% were SCC § Trial terminated early due to clear advantage ○ Randomisation was to § 64Gy/32F radiotherapy alone § 50Gy/25F with concurrent cisplatin/5-FU ○ Long-term data § 5 year OS = 26% CRT vs 0% RT alone § mOS 14 vs 9mo § Recurrence: DM 12% CRT vs 26%; LR 44% vs 65% Interpretation: CRT is better than RT alone, CRT provide reasonable LC in unresectable cases
What is the evidence for palliative RT vs stent for oesophageal cancer?
No rationale to deliver palliative RT immediately after stenting
- No clear benefit associated
- Only benefit may be if at risk of bleeding
Evidence: ○ Trial of palliative stent vs brachytherapy (Dutch trial: Homs 2004). More rapid palliation with stent. More durable palliation with brachy (3 months vs 5 months). § Dose: 10-12Gy/1# § 1/3 of patients had stent complications such as pain, GORD, bleeding. QOL better with brachy. ○ Indian trial (RCT): consolidation with RT post-stent --> Prolongs duration of dysphagia response (7 vs 3 months). Improves OS. 30Gy/10#. ○ ROCS RCT (Adamson, 2021): 220 patients with incurable oesophageal cancer receiving stent insertion upfront for dysphagia. --> Randomised to RT (20Gy5F or 30Gy/10F) vs standard of care § Outcomes: □ No difference in dysphagia outcomes ® Early dysphagia and pain increase with EBRT □ No difference in survival □ No difference in time to stent complication or re-intervention □ Some benefit in time to first bleeding event (49 wks vs 69 wks) Sortie trial rct 20gy vs stent - Stent quicker rt more durable and better qol - Use stent for fistula or severe dysphagia
RT alone -75% reduction in dysphagia 20/5, 30/10, 39/13
Trog trial randomised: CRT 35gy/15# -increased toxicity, no clinical benefit
Is there evidence to support dose escalation in oesophageal cancer?
No better tumor control over 50.4 Gy. There was numerical improvement in LRC after SIB, but increased toxicity was noted without improved OS. There appears to be no increased toxicity with [MDACC SIB] or [sequential boost].
- For 2xMA—dose escalation to >60Gy improved OS, PFS and LRFS-> need RCT to confirm. - INT0123 Minsky—crt 50 vs 64gy - no locoregional or survival benefit of dose escalation. - ARTDECO 2021 PhIII. CCRT 50.4/28 ± 61.6/28 SIB (2.2 Gy). 260 pts. cT2-4 cN0-3 M0. SqCC 60%. Primary endpoint LPFS with 80% power to detect differences of 15%. MFU 4y. § CCRT with Carboplatin AUC 2 + paclitaxel 50 q1w x6c. § RT: 50.4/28 to ± 3 cm CC (2 cm into stomach). SIB to 1 cm isotropic margin. CTVn + 0.5 cm. PTV + 1 cm. § Not isotoxic dose-escalation: For example, Heart V45 < 50% while NCCN recs V30 < 20-30% and Mean 20-30. ○ RT completed in 94% of patients, 85% had at least 5 courses of chemotherapy. ○ 3y LPFS ~71→ 73% (p=0.62). 3y LPFS for SqCC of ~75→ 79% (p=0.59), 3y LPFS for AC of ~61% ○ 3y LRPFS ~53→ 59% (p=0.24). § Site of LR-progression: Primary only (62%), primary and in-field nodes (17%), in-field nodes only (9%), OOF nodes (12%). ○ 3y PFS ~33→ 25% (p=0.31). 3y PFS for AC / SqCC of 23→ 35%. ○ 3y OS ~40%. ○ G4 toxicity ~13%, G5 toxicity ~5→ 10% (p=0.15). ARTDECO failed to show that dose escalation improve survival free from local recurrence, perhaps due to a worrisome number of treatment-related deaths. This is contrary to the two trials above, which suggest dose escalation is safe. ○ Conclusion: dose escalation using a SIB from 50.4→ 61.6 Gy does not improve local control or survival. Majority of LR is still primary site
Describe the neoadjuvant radiotherapy technique for oesophagus/GOJ/proximal cardia cancer with CROSS protocol.
Patients
All eligible patients with oesophagus/GOJ/proximal cardia cancer
Pre-simulation
MDT discussion
Dietician input
Lung function tests
Consider DMSA scan
Endoscopy report
EUS – for lymph node detection
Simulation
Supine in vacbag
- Knee block and ankle stocks
- Arms above head (wing-board)
If distal oesophagus, fasting for 2 hours prior
Generous CT (2mm with IV contrast)
- Mid neck to below diaphragm
- Include entire lung and kidney
- oral contrast if distal tumour
Consider 4DCT if distal oesophagus
Fusion
FDG-PET
Dose prescription
Single Dose Level
- 41.4Gy/23F prescribed to PTV as per ICRU 83
Concurrent chemotherapy weekly
- Carboplatin (AUC 2)
- Paclitaxel (50mg/m2)
Prophylactic ondansetron
VMAT technique
10 days per fortnight
Volumes
* GTV
○ Gross disease and involved nodes on imaging modalities (CT and PET)
* CTVp
○ GTVp + 30mm craniocaudal & 10mm radial clip to boundary
* CTVn
○ GTVn + 7mm
○ NO ELECTIVE NODAL REGIONS
* ITV (optional)
○ CTV on each phase of the respiratory cycle
- PTV
○ If ITV = CTV + 5mm
○ If not = CTV + 10mm
Special Cases
- Distal oesophageal
* Consider electively include coeliac axis LN
- Cervical oesophageal
* Cover SCF
Target Verification
Daily CBCT
OARs
- Heart
* V40 < 30%
- Kidneys
* Bilateral mean < 15Gy
* V20 < 30%
- Liver
* Mean < 26Gy
* V30 <33%
- Bilateral Lung
* V20 < 30%
* Mean < 18Gy (Mark Lee Aim less then 14-15 GY due to cardiopulmonary toxicity with surgery)
* V5 < 60%
- Bowel
* V45 <195 cc
- Spinal Cord
* Dmax < 45Gy
Describe your definitive chemo radiotherapy technique for oesophageal cancer
Patients 1) Medically ineligible for oesophagectomy
2) Patient preference
Pre-simulation
MDT discussion
Dietician input
Lung function tests
Consider DMSA scan
EUS – for lymph node detection
Simulation
Supine in vacbag
- Knee block and ankle stocks
- Arms above head (wing-board)
If distal oesophagus, fasting for 2 hours prior
Generous CT (2mm with IV contrast)
- Mid neck to below diaphragm
- Include entire lung and kidney
Consider 4DCT if distal oesophagus
Fusion
FDG-PET
Dose prescription
Single dose level
- 50.4Gy/28F prescribed to the PTV as per ICRU 83
Concurrent chemotherapy
- Cisplatin (75mg/m2 on D1 and D29)
- 5-FU infusional over 4 days (4000mg/m2 on D1 and D29)
- Or Carboplatin/paclitaxel considered equivelant
Prophylactic ondansetron VMAT technique 10 days per fortnight (MON to FRI)
Volumes
* GTV
○ Gross disease and involved nodes on imaging modalities (CT and PET)
* CTVp
○ GTVp + 30mm craniocaudal & 5mm radial
* CTVn
○ GTVn + 7mm
○ NO ELECTIVE NODAL REGIONS
* ITV (optional)
○ CTV on each phase of the respiratory cycle
* PTV
○ If ITV = CTV + 5mm
○ If not = CTV + 10mm
Special Cases - Distal oesophageal
* Consider electively include coeliac axis LN
- Cervical oesophageal
* Cover SCF
Target Verification
Daily CBCT
OARs - Heart
* V40 < 30%
- Kidneys
* Bilateral mean < 15Gy
* V20 < 30%
- Liver
* Mean < 26Gy
* V30 <33%
- Bilateral Lung
* V20 < 30%
* Mean < 18Gy
* V5 < 60%
- Bowel
* V45 <195 cc
- Spinal Cord
* Dmax < 45Gy
Describe the acute and late toxicity from Oesophageal radiotherapy.
Describe the prognosis post neoadjuvant and definitive treatment for oesophageal cancer and a suitable follow up plan.
Stage I 70-80%, cut in half for each upgrade in stage
If pCR for any stage, then equal to stage I
CROSS trial –> locations of relapse
- 40% distant relapse
- 20% locoregional relapse –may need more CTV margin
Definitive CRT:
Distal oesophagus
Pattern of failure
Local failure 50% -90% in GTV, 30% in CTV -high infield failure so elective coverage less important
Coeliac nodes 7-10% failure
Distant 48%
GOJ tumours: High rates of microscopic nodal involvement 20-50%
Consider Elective coverage more strongly.
But dose >45Gy to stomach 4cm distal to tumour increases surgical complications
Cervical oesophagus
Up to 90% locoregional control
Failure –10% failure regional –elective nodal SCF radiation recommended
Follow-Up
- Clinical review every three months for the first two years -no guidelines or survival difference ○ Bloods (FBC, EUC, CMP, LFT) § Ca19.9 and CEA only if elevated at diagnosis ○ CT CAP - Clinical review every six months for years 3-5 ○ Bloods (FBC, EUC, CMP, LFT) § Ca19.9 and CEA only if elevated at diagnosis ○ CT CAP - Endoscopy should be conducted as required only ○ If definitive chemoRT, consider endoscopy every six months (salvageable) ○ If oesophagectomy, no benefit to surveillance endoscopy
What is the epidemiology for Gastric cancer?
Incidence (Australian statistics)
- 2392 cases annually
- 11th most common malignancy
Overall, the incidence is declining
- Likely related to refrigeration (less salted/preserved
- H. Pylori also explains some difference
Incidence of GOJ tumours is rising
- Likely related to obesity and GORD
Male predominance (2:1)
Strong geographic differences in distribution
- Highest in Asia (esp Japan), Eastern Europe and South America
- Lowest in North America and parts of Africa
Median age 55 years
Typically presents late unless pt having screening
List the risk factors for gastric cancer.
1) H. Pylori infection = non-cardia gastric ca
a. Very significant risk factor (>80% of cases are linked)
b. Only for distal/body cancers
2) Diet
a. Intake of smoked/preserved/salted foods (incl nitrosamine compounds)
b. Low fruit/vegetable intake
3) Obesity
a. Most significant for gastric cardia
4) Smoking
5) Socioeconomic status
6) Benign gastric issues
a. Gastric ulcers
b. Pernicious anaemia (autoimmune)
7) Occupational exposures
a. Mining, metal smelting, rubber manufacturing
8) EBV infection (uncommon)
a. Pathogen is often found in malignant cells of gastric carcinoma with lymphoid stroma
b. Fundus or body
9) Family history (up to 10%, with identified inherited genetic predisposition in 1-3%)
3 major heritable syndromes that affect primarily the stomach
a. Hereditary diffuse gastric cancer (HDGC)
i. Germline mutation CDH1/E-cadherin (also association with lobular breast cancer) and CTNNA1
b. Proximal polyposis of the stomach (GAPPS)
i. FAP (APC promoter 1B gene)
ii. Peutz-Jehers syndrome (STK11)
iii. Li-Fraumeni (p53)
c. Familial Intestinal Gastric Cancer (FIGC)
i. Unknown gene
10) Previous abdominal radiotherapy
11) Pernicious aneamia
12) Previous partial gastrectomy (reflux of bile/pancreatic enzymes)
Describe the macroscopic classifications for gastric cancer.
Gastric adenocarcinoma macroscopically classified by:
- Location: Gastric (Non cardia) or GOJ
- Histological type: Intestinal or diffuse type (Laurens classification)
- Early: Paris classification: 0-I (protruded); 0-II (superficial); and 0-III (excavated).
- Advanced: Borrmans: polypoid/fungating without ulceration (type I), ulcerated with elevated borders and sharp margins (type II), ulcerated with diffuse infiltration at the base (type III) and diffusely infiltrative with thickening of the wall (type IV)
Describe the two pathways for pathogenesis of gastric cancer.
1) Intestinal type gastric adenocarcinoma (Incidence decreasing, associated with H.Pylori)
a. Cascade of precancerous lesions: chronic gastritis (atrophic or not) → intestinal metaplasia (complete or not) → low grade dysplasia → high grade dysplasia (in situ carcinoma) → invasive carcinoma
b. Pathway is as per classical colorectal cancer –> stepwise progression
1) Inactivation of APC (somatic/germline mutation or epigenetic change)
a. APC usually promotes degradation of β-catenin
b. When APC is inactivated –> β-catenin accumulates –> activation of Wnt signalling pathway
c. Acts as a transcription factor (e.g. MYC and cyclin D)
2) Allows early adenoma formation
3) Activating mutations in KRAS develop –> allow progression in adenoma
4) Additional mutations (or epigenetic silencing) may complete carcinogenesis
a. SMAD2 & SMAD4 –> TGF-β pathway inactivation
b. P53 mutation
c. BAX mutation (pro-apoptotic molecule)
2) Diffuse type gastric adenocarcinoma (Incidence increasing, not associated with H.pylori) a. Either familial or sporadic/somatic loss-of-function mutation of CDH1 gene (codes for E-Cadherin) 1) If CDH1 gene is preserved, then hypermethylation may result in decreased transcription of E-Cadherin b. E-Cadherin is responsible for cell adhesion Without E-Cadherin, cancer cells tend to infiltrate in small nests or individual cells
List the histological subtypes of primary gastric cancer.
1) Adenocarcinoma (>90%)
a. Intestinal type 70%
1) Papillary, tubualr, mucinous
b. Diffuse type 30%
1) Signet ring
2) Poorly cohesive
c. Lymphoepithelioid-like (EBV-related)
d. Other:
2) Lymphoma (5%)
a. DLBCL
b. Extra-nodal marginal zone (MALT)
3) GIST (<1%)
4) Neuroendocrine tumour (still malignant but different treatment)
5) Neuroendocrine carcinoma
6) SCC
7) adenoacanthoma
Describe the effects of H.Pylori on the stomach and the mechanism of carcinogenesis.
Chronic inflammation
* direct invasion of the gastric mucosa triggers chronic inflammation and gastritis which trigger immune reaction and inflammation- increase inflammatory response and release of cytokine contribute to increase cellular damage, atypia, metaplasia, dysplasia and carcinogenesis
Indirect effect of Chronic inflammation causes DNA methylation abnormalities
* H Pylori infection-> stimulate T cell and B cell immunity response-> increase pro-inflammatory expression of TNF, IL1, Nos2-> causes increase inflammation, tissue injury, and CpG islands methylations in specific promoter region of TSG.
Field cancerisation and DNA damage
* H pylori contribute to carcinogenesis and field cancerisation by causing point mutation and DNA methylation abnormalities in the gastric mucosa
○ H pylori produces various virulence factors (eg CagA, cagPAI, Vac A) -> dysregulate host intracellular signalling pathways-> abnormal proliferation, apoptosis, promotion of cell migration, disruption of construction of gastric mucosa, and DNA damage-> abnormal proliferation of gastric cells
○ H pylori releases enzyme which causes cellular damage
* Urease:
▪ enzyme produce to colonise the stomach- produced ammonia which neutralises the gastric acid, form compounds that directly damages the epithelial cells, and directly activate the immune system and indirectly produced injury by stimulating inflammatory cells
* Bacterial phospholipases
▪ alter the phospholipid content of the gastric mucosa barrier, changing the surface tension, hydrophobicity, and permeability-> causes cell injury, and disrupt the structure and integrity of the gastric mucosa
* Catalase
▪ protect the bacteria from toxic ROS liberated by neutrophils, and allow bacteria to survive and proliferate in inflamed and damaged mucosa
Describe the pathology for intestinal type gastric adenocarcinoma.
- Associated with APC pathway of carcinogenesis, or gastritis
- Declining incidence over 30 years
- Includes multiple subtypes
○ Papillary
○ Tubular
○ Mucinous - Macroscopic
○ Tends towards bulky polypoid or exophytic tumours
○ Tendency to ulcerate and bleed (crater) - Microscopic
○ Neoplastic cells forming intestinal glands resembling colonic adenocarcinoma
§ WD = columnar cells which secrete mucin
§ PD = solid pattern of neoplastic cells
○ Contains apical mucin vacuoles - Immunohistochemistry
○ POS = E-Cadherin, variable expression CK7 and CK20
○ NEG =
Describe the pathology of diffuse type gastric adenocarcinoma.
- Associated with E-Cadherin inactivation
- Aggressive natural history and very poor prognosis
○ Early nodal metastasis - More common in younger patients than intestinal-type
- Macroscopic
○ Infiltrative growth pattern ‘linitis plastica’/’leather bottle stomach’
§ Tends to invade longitudinally within submucosa, rather than into stomach lumen
▪ May result in mural ulceration
▪ Can’t see margin - Microscopic (Loss of E cadherin)
○ Poorly cohesive neoplastic cells which are either isolated or arranged in small nests
§ No well-formed glands
○ Can be signet-ring cell or non-signet ring cell (poorly diff)
§ Signet-ring cell = intra-cytoplasmic mucin with a displaced nucleus –> lace-like/microtrabelcular pattern
○ Marked stroma desmoplasia - Immunohistochemistry
○ POS = PAS (mucin), AE1/AE3, CEA, PanCK, CK7, CK20 (variable), CDX2
○ NEG = E-Cadherin, TTF, ER/PR, sox 10, CD45 (MALT),
○ Need to do HER-2 testing if metastatic (20%)–> Herceptin
- Aggressive natural history and very poor prognosis
Describe the pathology of GIST.
- Most common mesenchymal tumour of the GIT
○ Most common in stomach 50%, small bowel, colon- Arises from the interstitial cells of Cajal (myenteric plexus for peristalsis)
- Mean age 60years. slight male predominance
Younger age of onset associated with syndrome - Carney triad (Gastric GIST, paraganlgioma, pulmonary chondroma), NF1, Familial GISTS KIT - Pathogenesis –> cKIT mutation
® TK activation and growth
○ Or PDGFR pathway - Macroscopic
○ Well-circumscribed intramural lesion (centred on muscularis propria)
○ Cut surface –> fleshy tan-pink tissue with haemorrhage +/- cystic degeneration - Microscopic
○ Smooth muscle tumours with spinfle or epethelioid cells
○ Three types:
§ Spindle –> bland spindle cells in a syncytial pattern
§ Epithelioid –> round cells in sheets or nests (looks like PD carcinoma)
§ Mixed
§ Signet ring
§ Giant cell
○ Risk stratification
§ Location
§ Size 0-2, 2-5, 5-10, 10cm
§ Mitotic count >5/hpf
§ necrosis - Immunohistochemistry
○ POS = DOG1 (GIST specific, positive in 80%), CD117 (product of the cKIT gene), CD34, SMA
○ NEG = S100, CKs, GFAP negative (differentiating from gastrointestinal schwannoma)
○ Ddx Leiomyoma negative for CKIT
Describe the four types of gastric cancer by the cancer genome atlas
○ EBV (9%) - PICK3CA, PDL1/2.
○ MSI (22%) - MLH1 .
○ Genomically stable (20%) - diffuse histology.
Chromosomal instability – CIN (50%) - intestinal, TP53.
What would be the history and examination for gastric cancer?
History
- Often asymptomatic in early stages> vague symptoms >late presentation with advanced disease, often not curable
- Local symptoms
○ Dysphagia , nausea and early satiety
○ Weight loss
○ Reflux symptoms
○ Abdominal pain/discomfort
○ Haematemesis
○ Malaena
- Regional + Distant symptoms
○ Abdominal pain or jaundice (liver metastases)
○ Bony pain
- PMHx:
○ H. Pylori infection
○ Benign gastric disease (pernicious anaemia - autoimmunity)
- Family Hx
○ CDH/E-cadherin –> lobular breast
○ APC/FAP –> colorectal, pancreatic, CNS (glioma + medulloblastoma), desmoid
○ Lynch/dMMR –> bowel, gynaecological, genitourinary
- Social
○ Smoking
Examination
- Weight and cachexia
- Abdominal palpation
○ Hepatomegaly
- Cervical LN
○ Left SCF node (Virchow’s node)
List the prognostic factors for gastric cancer
Patient Factors
- Age and performance status
- BMI
Tumour Factors
- TNM stage
○ Depth of invasion (T-stage)
○ Nodes and mets
- Histological subtype (controversial)
○ Some low level evidence that diffuse type has worse prognosis
○ Difusse/signet worse with propoensity for intraperitoneal mets compared to intestinal
- Anatomical location
○ Distal better than proximal/cardia
- distal is worse; also proximal/cardia (as opposed to body)
- LVI & PNI
- HER2 status –more aggressive
- Ca19.9 level
- MSI is associated with better prognosis
Treatment Factors
- Quality of resection
○ R0 vs R1/2
○ Extent of nodal dissection (D1 vs D2)
- Treatment within a high volume unit
What would be the work up for gastric cancer?
- Bloods
○ FBC (anaemia secondary to losses)
○ EUC and CMP (pre-chemo & nutrition)
○ LFT (liver metastases + pre-chemo)
○ Albumin (nutrition)
○ Iron studies (chronic losses)
○ CEA + Ca19.9 (prognostic and surveillance)- Endoscopy + biopsy
○ EUS is most accurate way to perform T- and N-staging
○ Multiple biopsies >5 for accurate histological dx and molecular studies; especially in setting of ulceration
○ Can use EMR and EDS
○ Histopath
§ Perform H. Pylori testing
§ Add HER2 status to all GOJ and gastric cancers - Imaging
○ Diagnostic CT CAP
○ FDG PET-CT (not medicare funded)
§ Intestinal type has uptake, but not diffuse type or mucinous tumours - Paracentesis (if ascites present)
- Staging laparoscopy (if non-invasive staging is clear) + peritoneal washings
○ For all stage Ib-III gastric cancers considered potentially resectable. The benefit is greater for T3/T4 disease
○ Sensitivity 85%, specificity 100%
○ Document Peritoneal carcinoma index (PCI) score = low may be candiddates for peritonectomy + HIPEC
○ Prognosis for positive lavage cytology without gross peritoneal dissemination is poor
- Endoscopy + biopsy
Describe the management of cT1aN0 (mucosal only) gastric cancer.
- Preference is for endoscopic resection (organ preserving) in very early stages
○ Criteria
§ Clearly defined to mucosa
§ <20mm diameter mucosal tumour without ulceration
§ Well differentiated G1-2
§ No LVI
§ N0 disease
§ Technically suitable for en-bloc resection- Surgical approaches
○ Endoscopic mucosal resection
§ Suitable if lesion <10mm -15mm only
§ Often piecemeal resection of larger lesions (higher risk of recurrrence)
○ Endoscopic mucosal dissection
§ Recommended as treatment of choice in European guidelines
§ Allows en-bloc resection of larger lesions (allows for complete histological evaluatioon of lateral and basal resection margins)
§ Includes the submucosa with the mucosa
○ May be carried out for diagnostic purposes and aimed with R0 resection - If does not meet the relevant criteria (including on final pathology), should be managed as per new stage
○ Typically a gastrectomy
§ Intestinal can do Subtotal -lower/middle 2/3 stomach, L gastric artery. Has less dumping
§ Total gastrectomy
§ Lymph node dissection for T1 tumours may be confined to D1+ (perigastric LNs and include local N2 nodes with variation in nodal groups dissected according to site of cancer)
○ Note that the likely OS associated with no further treatment is reasonable in the short term
§ 3yr OS = 83%
§ 5yr OS = 77% - No adjuvant therapy is required (even if pT1b on pathology –> presuming clear margins)
○ Consistent with NCCN, ESMO and japanese guidelines
- Surgical approaches
What would be the differential diagnosis for a gastric lesion?
Benign
- Peptic ulcer
- Gastritis
- Extrinsic gastric wall changes from pancreatitis
- Menetrier disease (AKA giant hypertrophic gastritis)
Malignant
- Gastric adenocarcinoma
- Gastric lymphoma
- Gastric metastasis
- GIST
Describe the staging for gastric cancer.
What are the possible patterns of spread for gastric cancer?
- Direct invasion→ omentum, pancreas, duo, diaphragm, trans colon + ant abdo wall.
- Lymphatic spread- (depends on location of primary)
○ All →perigastric LN on lesser + greater curvature
○ Proximal → peri-oesophageal (mediastinal), coeliac, splenic LN
○ Distal → portahepatic (liver), pancreaticoduodenal, paraAo LN
○ Virchow’s node= L SCF
○ Irish node= axillary LN
○ Sister Mary Joseph nodule= periumbilical - Peritoneal spread (transcoelemic)→ ascites, Kruckenburg’s tumour (ovarian met)
- Distant mets in 30%- usually liver, also lung
- Patterns of failure post-op: 60% pts w LN+ or extension through serosa fail in tumour bed, regional LN, stump or anastomosis.
- Lymphatic spread- (depends on location of primary)
Describe the management of Ib -III Gastric cancer
STAGE IB-III = perioperative therapy + radical gastrectomy recommended
- Surgical resection is potentially curative, however most patients relapse following resection
- Combined modalities are standard for ≥ IB disease
- RCTs and MA demonstrate OS benefit for combined modality vs. surgery alone for pt with potentially resectable disease
- Still not clear which approach is best. No evidence for superiority of approach
- Adj CRT, perioperative chemotherapy, adj chemo, neoadjuvant CRT (TOPGEAR)
○ Adjuvant treatments are difficult to deliver
- Radical gastrectomy is indicated
○ Proximal margin of ≥3cm recommended for tumours with expansive growth pattern (including intestinal histology) and ≥5cm for those with an infiltrative growth pattern)
Describe the management of cT1bN0 (submucosal) gastric cancer
All patients
- Need to eradicate H. Pylori infection ○ Triple therapy (daily for 7 days) § Pantoprazole 40mg BD § Amoxycillin 1g BD § Clarithromycin 500mg BD ○ Associated with development of metachronous gastric cancers § Most relevant for early cancers where the stomach will be preserved - Early dietician involvement - Essentially all require MDT discussion
cT1b N0 (submucosal) gastric cancer
- Reasonably to proceed directly to upfront gastrectomy + LN dissection ○ Note that distal/antral tumours may be managed with partial gastrectomy ○ D1 vs D2 resection - If pT2 or pN+ disease found on pathology, proceed with adjuvant therapy Details below
Describe perioperative chemotherapy in gastric cancer.
Perioperative chemotherapy:
- Standard of care is peri-operative chemotherapy followed by total gastrectomy + LN dissection
- Improves pCR, OS, DFS, R0 rate and treatment delivery (FLOT more tolerable than ECF)
○ FLOT chemotherapy
§ 4 cycles pre-op & 4 cycles post-op
○ Alternative is ECF chemotherapy (worse OS & tolerability)
§ 3 cycles pre-op & 3 cycles post-op
○ If unlikely to tolerate FLOT or ECF
§ 5FU + LV + oxaliplatin (FOLFOX)
§ Capecitabine + oxaliplatin (CAPOX)
○ Better survival than surgery alone.
- In all trials post op chemo was the same as preop chemo; unclear whether different regimen should be used in the case of poor response.
Describe the advantages and disadvantages for neoadjuvant chemotherapy in gastric cancer.
Advantages:
- Downstage tumour
- Increase R0 resection
- Achieve complete pathological response
- Treat micro metastatic disease
- Improve OS
Disadvantages: - Interval progression may lead to unresectable disease (although this likely indicates tumour biological behaviour) - Treatment toxicity may lead to delay in definitive therapy - Increased risk of surgical complications - Overtreatment in some patients
Discuss the indications and recommendations for adjuvant therapy in gastric cancer.
- Rationale for any adjuvant therapy: 40-60% LRR after surgery alone
- Beware that need for adjuvant Rx is somewhat controversial as Stage IB included in the Mcdonald trial was only small proportion
- many adjuvant CRT only had Stg II-III while some included IB
- Extent of node resection may influence benefit from Adj CRT
○ <15nodes, OS benefit for adj CRT vs non for >15no examined (based on retrospective data in et al, Ann Sur Oncol 2016) - Options include chemotherapy with or without chemoradiotherapy
○ If inadequate dissection (ie <D2, with 16 or more nodes), node positive, or R1/2 favour chemo + CRT
○ If adequate LN dissection (D2) and pN0 then chemo alone
○ If no preop chemo; then post op chemo
○ Surgery with clear margins (R0) - nil added benefit to post op RT (chemo only). Additionally, the Korean ARTIST and ARTIST II studies did not demonstrate a survival benefit for the addition of RT to adjuvant ChT in patients who had undergone gastrectomy with D2 lymphadenectomy
○ If periop chemo or post op chemo - nil added benefit to post op RT
○ No preop chemo and <D2 lymphadenectomy consider adj CRT (45/25 w/ concurrent fluoropyrimidine)
○ R1/R2 > consider adj RT or CRT (however not routine, as with R0 resection the main risk of relapse is distal. Discuss in MDT and consider P/T/T factors)○ Adequate sx & high-risk relapse (e.g. N+)--> adj chemo. § Dutch registry study—marginal survival benefit of adj CRT (vs obs) w/ R1 resection. § R1 resection= high risk of distant relapse. § No specific and ev § Consider P/T/T
Describe the evidence for neoadjuvant chemoRT in gastric cancer.
Neoadjuvant Chemoradiotherapy –GOJ siewart 1,2
- 12-17% develop DM during preop CCRT - pCR 20-30% for adenocarcinoma - Bridging after CCRT with more chemo may allow for ○ Dose escalation with less formation of scar tissue ○ Longer interval to surgery to allow for higher pathological complete response - Mainly only gastric cardia data - Benefit has been demonstrated for GOJ/proximal cardia ○ POET trial & NEO-AEGIS trial ○ CROSS protocol --> 41.4Gy/23F with concurrent carboplatin/paclitaxel ○ RTOG 9904 Phase II: Cis/5FUx2 -> CCRT 45Gy with 5FU and weekly Taxol-> Sx § D2 in 50% of patients § 26% pCR, 1 yr OS better if pCR - Despite this, there is no clearly established role for neoadjuvant chemoradiotherapy for gastric body cancers ○ TOPGEAR showed no OS advantage. Ongoing trials -->CRITICS-II, ESOPEC - Surgery 8 weeks post chemo
Discuss optimal lymph node dissection for gastric cancer.
- Extent of nodal dissection is controversial
- No RCTs for D1 vs. D2 in context of RT
○ Patients do better when surgery performed in a high-volume specialist centre
○ D2 is better than D1 (improved staging and possible OS advantage without morbidity detriment)
§ Cochrane review 15 year FU better cancer specific survival
§ Dutch trial: D2 lower LRR and better CSS, however higher morbidity/mortality/reoperation; No OS benefit (?related to operative mortality)
□ No OS diff in N0 vs. N+… need to do D2?
○ D3 is no better than D2 (increased morbidity without OS benefit) on metanalysis
- No RCTs for D1 vs. D2 in context of RT
nimum number of nodes for reasonable D2 dissection = 16 LN
Describe the systemic management of advanced/ metastatic gastric cancer.
factors to consider:
* performance status
* histology
* PDL1
○ TPS (tumour proportion score)
○ CPS (combined proportion score)
○ Cutoff
○ Differential assays
○ temporal heterogeneity (40% TPs+ and reg on rebiopsy)
* Biomarkers
○ MSI
○ HER2
First line chemo
- Platinum-fluoropyrimidine doublet
○ Platinum: oxaliplatin or cisplatin
§ Equal efficiacy in RCTs; better for older (superior safety profile, possible improved OS)
○ Fluoro: 5FU or capeciabine or S1
§ Oral cape at least as effective as infusion 5-FU
§ Infusional 5-FU may be favoured if dysphagia
§ S1 common in asia; non-asian = different pharmaogenetics, requires dosage alteration
○ Addition of taxane explored, however increased toxicity ++
§ JCOG1013 cis-S1 vs cis-S1-docetaxel: no diff in local response rate, PFS or OS
- HER 2 positive
○ Recommend adding trastuzumab based on phase III ToGA study: inc response rates and longer OS compared to chemo alone. Tox low and managable.
- Immunotherpay: Nivo first line
○ Checkmate 649: Nivo + chemo (cape/oxali or 5FU/leucovorin/oxali) = inc OS and PFS
○ KEYNOTE 062: pembro mono non-inferior to chemo for OS in PDL1 CPS>= ; but lower response rates and inferior PFS; recommneded for AC of oesophagus and GOJ CPS>=10 (KEYNOTE 590), however included relatively few pt with AC
○ high response rates and long term outcomes in MSI-H with anti-PD1 monotherapy
What is the prognosis for gastric cancer patients, by stage? Provide a suitable follow up plan.
Without treatment
- 63 % will provess to advanced stage disease within 5 years
SEER: 5 year OS ~30% largely due to most pt presenting with locally advanced disease
5yr OS ~60% for localised, 30% for node + and 3.7% for DM+
Recurrence:
-
- 60% T2-4 or N+ fail locoregionally (especially with no RT), 20% without evidence of DM
- Distant -peritoneal, bones, liver
Follow-Up
- Clinical review every 3 months for the first two years ○ Bloods (FBC, EUC, CMP, LFT) § Fe and B12 panels if gastrectomy § CEA or CA19.9 if elevated at baseline ○ CT CAP every six months - Clinical review every six months for years 3-5 ○ Bloods (FBC, EUC, CMP, LFT) § Fe and B12 panels if gastrectomy § CEA or CA19.9 if elevated at baseline ○ CT CAP every twelve months - Endoscopy should be performed as indicated only
Discuss the management of localised and metastatic GIST. Include the expected prognosis.
Localised disease
Resectable
* Resection may be indicated if haemorrhage, tumour rupture or risk of bowel perforation
* Resection of localised disease >2 cm (no consensus on tumours <2cm ?resection vs surveillance)
* Evaluate for adjuvant therapy imatinib for 3 years (very low risk can consider surveillance)
Locally advanced/Unresectable/ Anorectal Primary * Evaluate for neoadjuvant therapy with imatinib (in patients with KIT mutation) * Advanced unresectable GIST * Systemic therapy imantanib
Metastatic disease
* Imantanib
* Possible methods of overcoming imantanib resistance–> resection or ablation of metastases to remove resistant clones
Second line TKI sunitinib
Imanitib MOA
* Competitive inhibitor with ATP-binding site of target kinase and inhibits down stream signaling * Relatively selective ○ ABL tyrosine kinases (CML and Philadelphia chromosome) ○ Transmembrane KIT ○ Platelet derived growth factor receptors * 400mg daily 3 years (Increased to 800 mg in treatment resistance or in patients with KIT exon 9 mitation)
Describe the pathogenesis of pancreatic cancer
Invasive pancreatic malignancies arise from pancreatic intraepithelial neoplasia (PanIN)
- Low-grade PanIN –> often observed
- High-grade PanIN –> always managed
The genetic mutations in PanIN are identical to those in invasive malignancy
Key genetic changes
- Ductal epithelial cells: Telomere shortening allows accumulation of DNA damage
- KRAS mutation –> allows constitutive activation of Ras/Raf/MEK/Erk pathway (>90% of PaCa)
- Tp53 (70%)
- CDKN2A mutation (in 30%)- inactivation of p16 and p14-> uncontrolled cell proliferation
SMAD4 inactivation (in 55%)–> modulates signal transduction for TGF-b + P53 inactivation –> impaired cell cycle arrest and apoptosis
What is the staging for Pancreatic cancer?
Describe management for unresectable pancreatic cancer.
- 30-40% of patients at presentation
- Can attempt to downstage
- Induction therapy increases chance of R0 and OS prolonged
- Very few randomised trials
- Unresectable Definition
○ >180 deg contact with SMA or coeliac artery
○ Unreconstructable portal vein or SMV
○ Tumour thrombus in SMV or portal vein - Prognosis 9-13months
- Should proceed onto chemotherapy alone
○ FOLFIRINOX preferred as per LANCET systematic review
○ Gemcitabine-based as an alternative Japanese study (Gem-Abraxane)
○ Gem monotherapy (if poor PS)
Definitive chemoradiotherapy - No OS advantage associated with definitive treatment
○ Local control benefit only - Reserve radiotherapy for palliation as required
- Some benefit associated with dose escalation (retrospective data)
○ Consider enrolment in a clinical trial
SBRT
* Limited but emerging data, under investigation, currently MASTERPLAN
* Rationale: dose escalation to improve LC. rate of 50% LR with standard RT
* Multiple Ph2 trials - many used modern NA chemo before SBRT
○ Mellon et al. has the highest conversion rate for surgery 51%, R0 resection 96% (highest of any of the current trials)
* Benefit:
○ Dose escalation- reduce dose to OAR and higher BEDs
○ less fractions, more convenient for pt and less machine time
○ higher rate of conversion to surgery based on phase 2 studies
○ Shorter treatment time
○ improved LC as per institutional data
○ Improved acute toxicities
* Disav:
○ increase geographical miss
* CRISP systematic review showed improved 2yr OS and improved acute G3/4 toxicities with SBRT cf conventional RT
* Variable dose fractionation: 24Gy/1F, 24-36Gy/4F, 25-50Gy/5F
Palliative proceudres
* Stenting
○ Preoperative: for jaundice if bili >60 or cholangitis
Plastic last 3-4 months
Metal -cover ampulla but not block cystic duct -risk of cholecystitis
○ jaundice increases peroop complication
○ high risk of renal failure with surgery and bili >250
○ consider if v high bili >300, cholangitis, surg delayed by 2 weeks
* Obstructed ampulla: Radiological PTC
○ Pass though wire/stent then ERCP pass stent
* Surgical bypass
Describe the resectability criteria for pancreatic cancer.
Upfront Resectable
- NO neoadjuvant RT
- Rarely consider adjuvant RT (if R1/R2 only)
- Adjuvant chemo
- 45Gy/25F (boost to 50.4Gy/28F if positive margin)
Concurrent capecitabine
Borderline Resectable
* All should have neoadjuvant RT (Updated PREOPANC study) or neoadjuvant FOLFIRINOX
* Alternatively murphys
* PREOPANC Protocol
* 36Gy/15F with concurrent gemcitabine
Murphys 8x FOLFORINOX > 50.4Gy/28Fx with Cap
Unresectable
* NO definitive RT (LAP-07 study)
* Palliative RT only
* CCRT 54Gy/30F with Gem
Palliative doses of between 30Gy/10F to 40Gy/15F
What is the management for resectable pancreatic cancer?
- Surgery = only potentially curative option
- Able to achieve R0 resection, defined as no cancer cells within 1mm at all margins
- Patients should proceed directly to a resection
- Neoadjuvant therapy not recommended due to limited phase III evidence, except in context of clinical trial
○ Typically a Whipple’s pancreaticoduodenectomy
§ Can preserve pylorus or not -may have less dumping
§ Adequate venous inflow+outflow
§ Risk of leak (fistula, bleeding, leak)
§ Cut through jejunum, bild ducts, pancreas, distal stomach (duodenum removed)
□ Bile duct, pancreas and jejunnum connected
□ Stomach and jejnum connected
○ Nodes: hepatoduodenal, L gastric, Common hepatic, GDA, SMA - Post-operative investigations
○ Restaging post-operatively to ensure freedom from interval metastatic disease
○ Repeat Ca19.9 to use as a guide during adjuvant chemotherapy
Describe the management for Borderline resectable pancreatic cancer.
- Borderline Resectable Definition
○ Contact with IVC, hepatic artery or SMA (<180 deg) allowing for vessel reconstruction
○ Contact with the coeliac plexus (<180 deg)
○ Encasement of SMV or portal vein (>180 deg) with sufficient normal vessel to allow reconstruction- If medically operable, should consider neoadjuvant therapy
○ Aim is to convert to operable state
○ Need to ensure treatment is sufficient for definitive (if surgery is not feasible)
○ MA = improvement in OS - Neoadjuvant chemotherapy alone in the first instance
○ FOLFIRINOX is optimal
○ Gemcitabine + capecitabine is a reasonable alternative - Other approaches include: (PREOPANC 1 & 2)
○ Neoadjuvant chemoradiotherapay is not inferior and has trend to better toxicity profile
- If medically operable, should consider neoadjuvant therapy
Neoadjuvant chemoradiotherapy
- Only 15-20% of pt are suitable for primary surgery - 40% of pts have borderline or unresectable disease ○ 30-50% of these may proceed to resection after NA Rx § of these 75% will have R0 resection - Several case series and MA suggest benefit of NA Rx vs upfront surgery - Should now be considered the standard of care (late PREOPANC data) ○ Need to be fit patients - When treating, would deliver PREOPANC protocol (36Gy/15F with 3 cycles of concurrent gemcitabine) ○ Upfront induction chemotherapy should be considered required prior to chemoRT (improved OS compared with chemoRT alone) ○ SABR is alternative as per MASTERPLAN trial (40Gy/5F)
Discuss surgery for pancreatic cancer
- Goals: Oncologic resection of primary tumour and regional lymph nodes, aim for R0 resection (margin-positive specimen is associated with poor long term survival)
- Indications:
○ Surgery is the only chance of cure
○ Offer if resectable disease and fit for surgery - Intraoperative staging:
○ Careful intraoperative staging should rule out peritoneal, liver and distant LN metastases
○ Resection of the primary tumour should only be performed in the absence of distant disease - Selection of procedure:
○ Cancers of head and uncinate process: Pancreatoduodenectomy (Whipple procedure)
○ Cancers of body and tail (rarely resectable due to late presentation): Distal pancreatectomy with en-block splenectomy
○ Cancers of the neck: Especially difficult to manage; depending on the extent of involvement,
§ Pancreaticoduodenectomy extending to the left of the SMV (extended pancreaticoduodenectomy),
§ Distal pancreatectomy extending to the right of the SMV (extended distal pancreatectomy); or
§ Total pancreatectomy
Decision often must be made intraoperatively - Pancreatoduodenectomy (Whipple technique)
○ Structures removed (conventional operation):
§ Pancreatic head
§ Duodenum
§ First 15cm of the jejunum
§ Common bile duct
§ Gallbladder (does not function without hormones from duodenum)
§ Partial gastrectomy
○ Reconstruction:
§ Leaves three tubes that need re-connecting to the jejunum:
□ Distal pancreas
□ Bile duct
□ Stomach
§ These are reconnected in the above order from proximal jejunum to distal jejunum
○ Modified operations
§ Pylorus-preserving pancreaticoduodenectomy
□ Preserves gastric antrum, pylorus, proximal 3-6cm of duodenum
□ Residual duodenum anastomosed to jejunum to restore GIT continuity
§ Subtotal stomach-preserving pancreaticoduodenectomy
□ Aims to preserve as much stomach as possible
○ Vascular resection and reconstruction
§ Of portal vein or superior mesenteric vein
§ Controversial
□ Adds complexity to operative procedure
□ Poor quality published data
○ Outcomes:
§ After surgery alone:
□ Local recurrence >20%
□ Systemic recurrence >80%
§ Median survival 10-20 months
§ 5 yr OS 10-25%
□ Node negative: ~30%
□ Node positive: ~10%
Lymphadenectomy
Standard lymphadenectomy should involve>= 16 nodes
- Indications:
Discuss management for metastatic pancreatic cancer and symptomatic disease
Describe the evidence for Neoadjuvant chemoradiotherapy in pancreatic cancer.
Recently, OS has been demonstrated
- Patient should be very fit to tolerate the protocol
Alternative is neoadjuvant chemotherapy alone which is typically standard of care (FOLFIRINOX or gemcitabine/capecitabine)
Better for improving margins, improved tolerability, earlier treatment of micrometastatic disease
PREOPANC trial (Versteijne, 2020 & 2022) - Phase III ○ 246 patients with resectable/ borderline resectable pancreatic cancer were randomised to § 3x gemcitabine + chemoradiotherapy (36Gy/15F) + resection + 4x adjuvant gemcitabine § Vs Upfront resection + 6x adjuvant gemcitabine (no neoadjuvant chemo or CRT) § 10% of neoadjuvant didn't make to surgery, 30% more chemo in neoadv ○ Initial analysis (2020) § No median OS advantage associated with chemoRT (16mo vs 14.3mo; p=0.096) □ OS benefit was seen in subgroup who completed chemoRT, underwent surgery and commenced adjuvant CT, from 18month onwards □ More benefit in borderline resectable, no resectable, larger tumours □ No difference in surgical complications § Improved R0 resection (71% vs 40%) § Improved DFS and LRC (30 vs 13%) ○ New Analysis (2022) § Improved 5-year OS with chemoRT (20% vs 6%; HR 0.76) and mOS 15.7 CRT vs 14.3 sux □ OS effect seen across subgroups regardless of resectability, age, sex, PS, tumour size and CA19.9 □ No diff in adverse effect, postop complication or mortality rate ○ Limitation: § adj gem monotherapy is out of date § control arm if surg alone rather than NA chemo+sx KROG (Jang, 2018) [Jang Ann Surg '18]: ○ Phase II/III. Neoadjuvant vs adjuvant CRT § [(Surgery→ 54gy/30/Gem) vs. (54gy/30/Gem→ Surgery)]→ Gemcitabine. ○ Study was terminated due to mOS advantage in the pre-op CCRT arm. There were high cancer-related deaths in the surgery-first arm. Radiation dose of 54 Gy is higher than the typical 50.4 Gy used at most centers. ○ 50 pts. BRPC. RT: 45Gy/25+ 9Gy/5 with gemcitabine 400 mg/m2. In the preoperative arm, most (n=26/27) completed CCRT (1 had progression) and 24 underwent surgery. ○ 2y OS 34%. MS 16 mo. ○ ITT 2y OS 26→ 41%. ITT mOS 12→ 21 mo. ○ ITT R0 26→ 52%. Resected R0 33→ 82%. ○ Positive LNs 1.9 ± 1.6→ 0.5 ± 0.9. ○ Recurrences ~88%, systemic recurrences 67→ 41%.
Describe the prognosis for pancreas cancer and recommended follow up
Poor OS – 95% dead w/in 1yr
20% resectable at present: 5yr OS: 20% (R0 resection, LN neg, small size = better)
30% unresectable: MS 12mo
50% metastatic: MS 2-6mo
Follow-Up
- Clinical review every three months for two years ○ Bloods (FBC, EUC, CMP, LFT, Ca19.9) ○ CT CAP - Clinical review every six months for years 3-5 ○ Bloods (FBC, EUC, CMP, LFT, Ca19.9) ○ CT CAP
Conditional survival: if survive 3 year then 70% survival
For HCC discuss the TNM Staging system
No single staging system is appropriate for all patients
* AJCC/TNM appropriate for patients undergoing liver resection - more for patients treated by resection or transplantations
○ Includes microvascular invasion - can only be assessed on pathology = less useful in clinical practice before decision making
○ Heterogeneity of T2 cancers
○ Lack of vascular invasion as a prognostic factor in T3 group
* BCLC system appropriate for patients with advanced liver disease who are not candidates for resection
○ Some stage B & C might be candidates for resection/transpalnt
Microvasc invasion is present in
* 20% if 2cm
* 30-60% 2-5cm
* 60-90% >5cm
portal vein invasion is a prognostic factor for LR
For HCC discuss the BCLC Staging system
- Developed on basis of results of RCTs and cohort studies
○ Links tumour stage, liver function, cancer-related symptoms and PS to an evidence based algorithm
○ Incorporates liver function, performance status as well as tumour extent
○ Associated treatment algorithm and prognosis- Identifies patients
○ with early HCC who may benefit from ablative treatment (stage 0 &A)
○ Those at intermediate stage (B)
○ Advanced stage (C) - Includes:
- Assessment of tumour extent
- AFP level
- Liver function
- Portal pressure
- Clinical PS
- Significant disagreement including
○ All single nodules, including large (>5cm) combined in stage A
§ In conflict with widely accepted Milan criteria for liver transplant (solitary tumour up to 5cm or three tumours <=3cm)
○ Some patients that would benefit from resection would not receive resection by BCLC algorithm
○ Stage C is heteroegnous, some of whom would benefit from local treatments rather than systemic therapy - BCLC-0 HCC - recommended to undergo ablation as the preferred option; alternatives include resection or transplantation.
- Single BCLC-A HCC - resection is favored over ablation owing to lower recurrence especially treating tumors >2 cm.
- Multifocal BCLC-A HCC (three or more nodules, each ≤ 3 cm) - Do not recommend resection; rather, recommended ablation for non-LT candidates, while LT is suggested for acceptable LT candidates
○ Note: In general, resection and ablation have been demonstrated to provide comparable long-term outcomes among individuals with HCC ≤ 2 cm. - BCLC-B HCC
○ IF meeting extended LT criteria or meet criteria after downstaging with TACE- then consider LT
○ IF well-defined nodules, preserved portal flow, and selective access to tumor feeding arteries- then consider TACE
○ IF diffuse or extensive bilobar disease- then consider systemic therapy - BCLC-C HCC - recommend systemic therapy
BCLC-D HCC- recommend palliative or best supportive care
- Identifies patients
Discuss assessment of HCC patients for liver transplantation
Medically fit for a major operation
Meets Milan criteria, used more commonly in sydney (also adopted by UNOS - United Network for Organ Sharing)
○ Single lesion <=5cm;
○ or 2-3 lesions <=3 cm
○ No regional nodal or distant mets (extrahepatic)
○ No vascular invasion
Other criteria include
- USCSF
- Metroicket
Discuss the management of HCC with resection
Surgical assessment (note - may be resectable and not transplant eligible or vice versa)
Assess resectability
- Liver and tumour factors
○ CP-A, no portal hypertension
○ Suitable tumour location (able to achieve R0 resection)
○ Adequate liver reserve, suitable liver remnant
§ Able to be carried out without causing postop liver failure due to insufficient reserve of liver remnant
○ Carefully selected CP-B and/or portal HTN may be candidates for minor surgical resection (ESMO)
§ Based on MA; not absolute contraindication
○ CP-C not suitable
○ In cirrhosis should be laparoscopic
§ Reduced blood loss, faster post op recovery, no impairment on oncological outcome
- Patient factors
○ Operable by performance status and comorbidity
- Treatment
○ Able to achieve R0 resection
- Assessment
○ Of liver function
○ Future liver remnant volume
Discuss portal vein ligation and portal vein embolization in HCC
Hypertrophy of contralateral lobe after embolisation due to increased blood flow and trophic factors
Describe a radiotherapy technique for Liver SABR
- Presim:
○ Consider fiducial markers in appropriate patients.
○ Lipiodol and/or surgical clips may serve as fiducial markers.
○ Alternatively, a fiducial-less approach could be considered using anatomical boundaries if the motion management set up is stable.
○ DTPA if close to kidney for differential renal function- CT Sim
○ Advanced motion management should be considered.
Options :
○ Breath hold
□ EEBH is prefer than DIBH, as it is more stable, less motion
□ DIBH could be variable in term of the diaphragm position
○ Next: gating or abdo compression
○ Free breathing- Mock session with advanced motion management
- Supine, arms above head, neck/knee/ ankle support
- customised Immobilisation eg full body vacuum device (SABR immobilisation)
- 2mm 4DCT from aortic arch/carina to below the kidneys with oral + IV contrast (triple phase)
- Fuse MRI liver (normally done in EBH)/ PETCT/ diagnostic multiphase CT
- Contrast: oral (stomach/duo), IV - preferably triple phase (anterial, PV, delayed/washout)
- Organ preparation: NBM 2-4 hours, gas reducing diet, PPI, antiemetics
- Wide range of dose fractionation schedules used 24-60Gy over 3-6 fractions
○ Generally 27.5-50Gy/5Fx, second daily
§ 50Gy/5 but reduce to achieve MLD <13Gy, 800cc of liver receiving low dose (<15Gy)
§ Consider 45Gy/5# for bridging treatment -aims just to ‘hold tumour’
○ to 100% of the isodose line as per ICRU 91, VMAT, 6-10MV FFF, 2F per week, 36hrs apart
Can consider 3 Fx in small peripheral lesions, well away from OARs with well compensated liver function
IF CPA: 40-50Gy/3-5F Eg. 48Gy/3F
IF CPB: 30-40Gy/5F. Eg. 40Gy/5F
○ Dose scaled back to keep mean liver dose 15-17Gy
○ Aim for BED10>= 100 (“Ablative”) - All treatments generally over 2 weeks, 2nd daily
○ Can consider mid treatment bloods to assess CP score, potentially cease - Dose based on mean liver minus GTV (MLD)
- CT Sim
Treatment
- Dose coverage/Target Volume Objectives
· All doses prescribed to 90% isodose level, as per ICRU 91
· Target volume objectives
§ GTV/ITV - D100% > 95 prescribed dose, ideally ≥100% of PD
§ PTV Dmax 120-150%, D95% aim > 100% of PD
§ V100% ≥ 99% PTV volume
- During treatment
· Consider pre-treatment anti-emetics
· Hexapod couch
· RPM system for monitoring breathing
· CBCT and exactrac
- Image verification:
· Daily 4D CBCT
· Match to fiducials, if not then match to surrogate eg. Diaphragm or liver contour
match soft tissue + fiducials
Discuss the Liver as an OAR in HCC treatment.
Liver minus GTV (must be at least 700cc, preferably 800cc)
Childs Pugh B7
-Exercise caution and ideally aim to keep mean dose <6-8 Gy.
Discuss the expected prognosis in HCC and a suitable follow up schedule.
Outcomes
* Poor prognosis overall
○ Overall: 5yr OS 10%; median survival 6 months
* Curative intent treatments (20% of patients)
○ Resection:
§ 5yr OS up to 90%
§ Long term relapse free survival >40%
○ Transplant: 4yr OS 70-80%
○ RFA:
* Palliative intent treatments (median survival 11-20 months) (50% of patients)
○ TACE (palliative): 2yr OS 30-60%
○ Sorafenib (palliative): Improves median survival 3 months cf. placebo
* Child Pugh C / ECOG 3-4 (20% of patients)
○ Median survival 3 months
Follow up
- Imaging (multiphase CE CT or MRI liver +/- chest) every 3-6 months for 2 years, then 6-12 months
○ Viable tumour assessed on contrast enhanced CT or MRI
○ mRECIST for assessment of response/progression
○ As long as tumour is shrinking with no progression than continue to observe after SBRT despite residual enhnacement
- 3 monthly assessment of liver decompensation
- AFP every 3-6 months
- Refer to hepatologist for discussion of antiviral therapy for carriers of hepatitis virus
Recurrence
Re-assess and manage as per de novo disease
Describe the staging for cholangiocarcinoma
- Extrahepatic
- dCCA common bile duct BELOW the cystic duct insertion
- pCCA common bile duct ABOVE the cystic duct insertion and second order bile ducts (Right and Left hepatic ducts)
- Intrahepatic
iCCA are proximal to the right and left hepatic ducts, in the liver parenchyma
Peri-hilar cholangiocarcinoma
-Bismuth Corlett classification
Discuss adjuvant management after resected cholangiocarcinoma.
- High 3 year recurrence rates, up to 80% after curative intent surgery
○ Locoregional and distant- Adj Chemo for all resected disease (including R0)
○ Capecitabine for 6 mo as er BILCAP improve mOS 36-> 51mo
○ Alternative regimen Gem or 5FU, improved mOS in ESPAC3
○ Horan MA: benefit especially in pt with N1 and R1 disease - If R1 or N+ –> Adj CRT with Cap (after Adj Chemo is given )
○ as per MA Ren, MA Horgan and SWOG improve 2yr OS, mOS and LC for R1 and N+.
○ In R0, OS detriment noted with Adj RT in the MA Horgan.
○ 2x Gem/Cap followed by CCRT with Cap
○ Tumour bed: 55Gy/25F (R1) or 52.5Gy/25F (R0)
○ ENI: 45Gy/25F - If R2 –> manage as unresectable
- Adj Chemo for all resected disease (including R0)
Discuss management of inoperable cholangiocarcinoma.
- RT based on retrospective Ph1/2 data. Signal high dose= increased control
- Majority of IHCC will die from liver failure due to vascular compromise or biliary obstruction- rationale for local control
Unresectable IHCC
* General; approach is to proceed first with Systemic therapy
○ Can be either chemo alone or in combination with radiotherapy (both have shown improvement in PFS and OS
○ Pall Doublet Gem+Cis for 6mo as per UK ABC trial improve PFS and OS
○ (chemo) Can be used as induction therapy prior to consideration of high dose radiotherapy (see below)
* IF not progressive, then Consider consolidation RT . [Dose escalate if IHCC (Mark Lee)]
○ Fractionated RT (37.5-67.5Gy/15F) concurrent with Cap as per Kim et al, CRT improve LC and OS. Dose escalation BED >76-80Gy improve LC and OS as per Tao and SABR study .
OR ○ SBRT (27.5-50Gy/5F) for IHCC and EHCC * Ablation ○ Mostly evaluated in pt unresectable due to cirrhosis or recurrence from previous resection ○ Consider in iCCA≤3cm who have contraindications to surgery * SBRT ○ High local control rates § Pooled 1 year LC 83% § Pooled 1 year OS 58.3% ○ Consider in case of contraindications to surgery for liver-limited disease * Intra-arterial therapies * RT for symptoms
Discuss management of advanced and metastatic cholangiocarcinoma
Firstline
- Chemotherapy current SoC
- Any combination of inoperable chemo regimens
- OS improved when compared to BSC
- Cisplatin-Gemcitabine double OS benefit overt Gem alone (UK ABC-02 phase 3 RCT study, Japanese BT22 study)
○ cis 25 gem 1000 8 cycles 3 weekly
○ Median OS 13.0 months when limited to ECOG 0-1 vs. 3 months (10 month
○ PFS 8.4m vs. 6.5m
- Insufficient evidence to recommend maintenance beyond 6 months
○ Should be based on tox, tolerability, tumour repsonse
- Gem-S1 non inferior in Japanese patients
- Oxaliplatin can be substituted if concern re renal function
- Gem mono if PS≥2
- TOPAZ-1 demonstrated improved OS, response rate and PFS with addition of PDL1 ICI (Durva)
○ Cisplatin-gem-durva firstline SoC (ESMO, not PBS funded)
○ response rate 70%, especially for high pdl1
○ Pfs 18-24 months
○ Objective response 26%
○ OS 1 month (13 vs. 12)
Targeted therapies (none are PBS funded)
- ~40% biliary tract cancers have targetable mutations
- Most common IDH1 & 2
○ Present in 10-20% of iCCA
○ Ivosidenib - inhibitor of mutant IDH1 enzyme (affects methylation and thus growth)
§ ClaIDHy study - improved PFS in pt who had progressed on first line therapy (by 1 month…)
§ Improvement in OS, even when accounting for cross over
§ FDA approved
- FGFR inhibitors recommended for FGFR2 fusions who have progressed after ≥1 prior line of therapy
○ 30-40% repsonse rate
- Pembro in MSI-H/dMMR
○ Phase 2 - response 40%, 30% survive 3 years
- Dabrafenib-Trametinib if BRAF
- BRCA1/2 or PALB2 - PARP inhibitors
- NTRK inhibitors if NTRK fusions
- HER2 directed therapies (3+ or amp on NGS FISH)
○ Pertuzumab and trastuzumab
§ 23% response, control 50%, PFS 4 months
Discuss the staging for gallbladder carcinoma
- Surgery only curative option
- Often advanced at diagnosis
15-60% pt candidates for resection at time of diagnosis
- Often advanced at diagnosis
