Thoracic Flashcards
What is the aetiology for NSCLC?
1) Smoking
a. Strong link with dose-response relationship
i. Stonger link to SCC
b. Associated with 80+% cases of NSCLC
c. Lifetime risk of 30% in smokers
d. Increased risk with increased pack years
e. Risk decreases with time since quitting, approaches but never equals risk in non-smoker
f. Small increased risk with passive nosmokers
2) Environmental exposures a. Heavy metals b. Asbestos (in addition to mesothelioma risk) i. X5 fold risk of lung cancer ii. Synergistic with smoking to give x50 fold risk iii. Latent period of 10-30years c. Air pollution i. Eg wood smoke. Developing countries 3) Ionising radiation a. Therapeutic/diagnostic radiotherapy i. Younger patient population at risk b. Radon gas eg. uranium miners 4) Familial/genetic a. First degree relative increases risk (RR ~1.8) b. Likely complex with multiple susceptibility loci c. No clear single inherited gene
Note that the biological, molecular and clinical characteristics of NSCLC in non-smokers is markedly different to that of smokers
What are the Differentials for a lung lesion (including histological subtypes)?
Adenocarcinoma (50%); LAMPS
○ Favourable = Lepidic,
○ Intermediate = Papillary, Acinar
○ Poor = Micropapillary, Solid
○ Other: Minimally invasive adenocarcinoma, Pre invasive (Adenocarcinoma insitu, Atypical adenomatous hyperplasia), mucinous, colloid, fetal
* Squamous cell carcinoma (20%)
○ Keratinising
○ Non-keratinising
○ Basaloid
○ Pre-invasive: SCC in situ
* Large cell carcinoma (5%)
○ Sarcomatoid
○ Pleomorphic
* Neuroendocrine
○ SCLC
○ LCNEC
○ Carcinoid
▪ Typical
▪ Atypical
* Other:
* Adenosquamous carcinoma
* Mesenchymal tumours – sarcoma
* Mesothelioma
* Salivary gland – mucoepidermoid, adenoid cystic
* Lymphoproliferative tumours – MALT, DLBCL
* Melanoma
* Germ cell tumours
* Metastatic Tumours
* Benign Epithelial Tumours
▪ - Adenoma
▪ - Papillomas
▪ - Harmatomas
Desccribe the pathology of lung adenocarcinoma.
Adenocarcinoma
- Most common subtype of NSCLC (40%)
○ Increasing incidence
- Slightly higher prevalence in females
- Presentation
○ More common in peripheral regions of lung, upper lobe> lower lobe
○ Most common metastases (brain –> bone –> liver –> adrenal), metastasise early
- Macroscopic
○ Well defined but unencapsulated lesion
○ White-tan cut surface
○ May have central scar or necrosis
○ Pleural invasion common
- Microscopic
○ Characterised by glandular formation and presence of intracytoplasmic mucin
○ Architecture can be one of (LAMPS):
- Lepidic = neoplastic cells resemble type 2 pneumocytes and proliferate to line alveolar wall (without stromal invasion)
- Acinar = gland forming cells which invade stroma
- Papillary = malignant cuboidal cells replace alveolar lining; papillary projections (fronds) with fibrovascular core
- Micropapillary = ill-defined projections which lack fibrovascular core
- Solid = sheets of neoplastic cells
○ Regardless of subtype, tend to have lepidic growth at margin
- Immunohistochemistry
○ POS = TTF1 (positive Adenocarcinonma), Napsin A, CK7, AE1/AE3 (anti-cytokeratin antibiodies)
○ NEG = CK20 (only positive in non-lung adenocarcinoma), p40 (positive squamous carcinoma
), p63
Describe the pathology for lung SCC and basosquamous cell carcinoma
Squamous Cell Carcinoma
- Second most-common subtype (30%)
○ Decreasing incidence (previously most common) –> reduction in smoking
- More common in men and is highly associated with smoking
- Well-defined pre-cursor lesions (dysplasia –> in-situ carcinoma)
- Tends to have central growth (bronchial/peri-hilar)
- Macroscopic ○ Hard, white-gray tumours with central necrosis, endobronchial growth - Microscopic ○ Usually defined by presence of keratin ○ Histological grade determined by degree of keratinisation ○ Non-keratinising SCC requires IHC for diagnosis ○ Intracellular bridges if well differentiated ○ Graded keratin pearls ○ Large polygonal malignant cells - Immunohistochemistry ○ POS = CK5/6, p40, p63 ○ NEG = TTF1 & Napsin A (usually), p16, CK7, CK20 Basaloid-squamous Cell Carcinoma - Rare subtype of SCC - Unfavourable prognosis - Microscopic ○ Typically has features of both non-keratinising SCC and BCC § BCC = peripheral palisading of nuclei, organoid/lobular structures ○ High grade cytology - IHC (as per non-keratinising SCC) ○ POS = p40, p63 NEG = CK20, TTF1, Napsin A
Describe the pathology for lung large cell carcinoma.
Large cell –Diagnosis of exclusion
Sarcomatoid Carcinoma
○ Rare subtype involving mixed epithelial and spindle cell populations
○ May be termed carcinosarcoma or pleomorphic sarcomatoid carcinoma
○ Poorer prognosis in general
○ Macroscopic - As per other large cell carcinomas - Necrosis +/- haemorrhage is common ○ Microscopic - Component with epithelial cells is unchanged * Carcinosarcoma may have heterologous sarcoma components (e.g. osteo, chondro, rhabdomyosarcoma) - Frequent mitoses, extensive necrosis Pleomorphic carcinoma - Presumed epithelial origin - Contains at least 10% with spindle or giant cells * Spindle cells generally resemble fibrosarcoma or peripheral nerve sheath tumour ○ IHC: * POS = Surfactant protein A (in 30%), CK7 , TTF1 NEG= CK20, Chomogranin A
Describe the features of Lung cancer driver mutations.
PD-L1 expression (30% NSCLC)
- Ligand for the PD1 receptor on immune cells
○ Overexpressed by cancer cells
○ Results in T-cell exhaustion –> immune evasion
- More likely to be over-expressed in smokers
○ More complex mutational burdens
- Proportion of cells over-expressing PDL1 is prognostic and predictive
○ Higher scores (i.e. >50%) indicate higher chance of success for immunotherapy (ICIs)
- 30% NSCLC have 1% or more PD-L1
EGFR (10-15% adenocarcinoma)
- Cell-membrane receptor which triggers RAS-RAF-MEK-ERK pathway for cell cycle stimulation
- 10-20% of adenocarcinomas (esp non-smokers, 50% in Asians, females)
- Mutations can include copy number gain, autonomous activation ○ Increased downstream transcription - Key mutations ○ Favourable EGFR-TKI response - Exon 19 deletion - Exon 21 missense mutation (L858R) ○ Unfavourable EGFR-TKI response - Most exon 20 mutations = T790M (can develop on treatment)
ALK (5%)
- Uncommon mutation (incidence is 5%) –> Fusion of the EML4 and ALK
○ Occur in younger patients who are non-smokers/ light smokers
- Tend to be exclusive of EGFR/KRAS mutations
- ALK TKIs such as crizotinib/alectinib are active
ROS1 (<2%)
- Rare mutation/fusion (<2% of all adenocarcinomas) –> multiple fusion partners
○ Tends to occur in non-smokers
- Tends to respond to first-generation ALK TKIs (e.g. crizotinib)
RAS (20% adenocarcinoma)
- KRAS is the most frequently mutated (20% of adenocarcinomas)
○ Mutually exclusive of EGFR or ALK re-arrangement
○ Most common mutation is KRAS G12C
- Impart poorer prognosis
○ Sotorasib (selective KRAS G12C inhibitor) is now available for use
○ Results in inefficacy of EGFR TKIs (mutation further downstream)
BRAF (<5% lung adenocarcinomas)
- Activator of downstream MAPK signalling
- Present in <5% of lung adenocarcinomas
- May involve mutation of the V600 locus or others
If V600E, can use dabrafenib and trametinib doublet therapy (as per melanoma)
What are th prognostic factors for NSCLC?
Key Prognostic Factors
Patient Factors
- Age >65, male, and performance status >1
- Weight loss >5%, Anorexia
- Ongoing smoking
- Lung function/co-morbidity
- High neutrophil/lymphocyte ratio>4
Tumour Factors
- TNM stage
○ Larger size
○ Oligometastatic disease does better than extensive metastases
○ Pleural effusion is adverse
- Histological subtype
○ Unfavourable = sarcomatoid, basaloid, micropapillary
- Mutation status
○ EGFR mutation have better prognosis (irrespective of TKI therapy)
○ EGFR ≅ ALK > KRAS > Wild type.
- LVI - High SUV on PET-CT - Hb, Albumin, LDH - Pancoast (better prognosis)
Treatment Factors
- Complete resection (if early stage)
- Concurrent chemoradiotherapy
- Suitable for immunotherapy
- High volume centre
- Access to treatment
How does NSCLC and SCLC present?
Asymptomatic and incidental finding on imaging.
* Finger clubbing
○ 35% of NSCLC and 5% SCLC
○ Lung cancer one of the most common cause of finger nail clubbing
* Vocal cord paralysis
○ Secondary to recurrent laryngeal nerve injury
○ Assessed on laryngoscopy
* SVC obstruction
○ Chest pain, cough, dyspnoea, blurred vision, plethora, headache, confusion
* Lobar collapse
○ Follows obstruction of bronchus
○ Acute presentations- dyspnoea, hypoxia, chest pain
○ Chronic collapse- may be asymptomatic, chronic cough, weight loss
○ Radiologically volume loss and displacement of fissure towards collapsed lobe, collapsed lobe is triangular or pyramidal shape
* Pleural effusion
○ Dyspnoea, hypoxia, cough, pleuritic chest pain
○ Transudate (CCF, cirrhosis): Low protein and low LDH
○ Exudate (Carcinoma, PE, Pneumonia): High protein, high LDH
* Pericardial effusion ○ Clinical presentation relates to rate at which the fluid accumulates, gradual accumulation allows the pericardium to stretch ○ Dyspnoea on exertion, chest pain , syncope ○ Beck's triad: Low BP, distension of jugular veins, muffled heart sounds/pericardial rub
What features on history are important for someone with a lung lesion?
Consultation
History
- Symptoms related to primary
○ Dyspnoea
○ Cough
○ Haemoptysis
○ Chest Pain
○ Weight loss
○ Voice hoarseness (RLN palsy)
- SVCO
- Pancoast
○ Brachial plexopathy
§ Should/ arm pain/ paresthesia/ weakness
○ Horner’s syndrome (due to involvement of paravertebral sympathetic chain/ inferior cervical ganglion)
§ Ptosis, miosis and anhidrosis
- Paraneoplastic
○ Hypercalcaemia (PTHrP) –> SCC (squamous)
○ SIADH -Small cell
- PMHx - ○ Interstitial lung disease § ILD-GAP score -predicts mortality of ILD at 1,2,3 years * Score 0-1: 3yr mortality of 10% * Score >5: 3yr mortality of 75% ○ COPD - Social History ○ Smoking -> council on smoking cessation ○ Occupational exposures (e.g. asbestos) ○ Functional status ○ Exercise tolerance
Examination
- Observations (including saturations)
- Chest auscultation
- UL neurology exam (if suspicious for brachial plexopathy)
What investigations are important for someone with a lung lesion?
Tissue diagnosis
○ Primary tumour:
- Sputum cytology - esp. central, large tumours, +ve in 70% central airway tumours, only 5% peripheral
- Bronchoscopy (to 2nd/3rd segmental divisions) + biopsy, brushings or lavage. Bronchial findings of proximity to carina relevant to staging.
- CT-guided percutaneous biopsy (core or FNA): 1/3 develop pneumothorax, 5% need ICU. ↑risk if bullous emphysema.
- Thoracoscopy- in rare cases where difficulty in establishing histological diagnosis by other means. Usually due to inflammation associated with small focus of ca.
○ Mediastinal LNs
- EBUS-TBNA (endobronchial US-guided transbronchial needle aspiration) guided bx- good for sampling mediastinal LN too.
* Can access 2R/2L, 4R/4L, 7, 10R/10L
- EUS-FNA (oesophageal endoscopic US-guided FNA)
* Can access 5, 7, 8 and 9
- Mediastinoscopy - Bx LN, can determine whether surgery is an option. Not superseded by PET.
○ Nodal Sampling
- PET/CT has a ~5% false negative rate for peripheral disease, while upwards of 25% for central disease.
○ Peripheral tumours with negative PET/CT in N2 may not require EBUS if frail or elderly.
○ Realistic to avoid mediastinal sampling if ≤ 2 cm peripherally located lesion with negative PET.
○ Peripheral tumours with positive PET/CT in N2 are encouraged to have EBUS for confirmation given false positives.
○ Central tumours with negative PET/CT in N2 or hilar are encouraged to have confirmatory EBUS.
○ Sample at least 3 stations.
○ Sample all abnormal LN.
- Cervical mediastinoscopy: Gold standard (Sn 44-92%, Sp 100%) but risk of complication and operator dependent. Incision 1 cm above suprasternal notch. ?can only be done once due to scarring. ○ Molecular panel for Adenocarcinoma ○ Metastatic disease - Pleural tap (+Bx) cytology- low yield (recommended if a pleural effusion is present in patients who would otherwise have curable disease) - Imaging-guided biopsy of other metastatic sites ○ Important to biopsy any equivocal LN on PET-CT ○ VATS - Video assisted thoracic surgery - Bloods (pre-chemotherapy) ○ FBC, EUC, CMP, LFT ○ Current evidence suggests that neutrophil to lymphocyte ratio may be a biomarker for poor prognosis in lung cancer. Values >4 in a metanalysis found to have associated poorer prognosis ○ Coags ○ HepB sAg, sAb and cAb ○ Hep C serology ○ HIV serology ○ TSH, T4, cortisol (immunotherapy) - Lung Function Tests ○ FEV1 - Correlates well with the degree of respiratory impairment in patients with COPD, and it provides an indirect measure of pulmonary reserve. - FEV1 <60% predicted was the strongest predictor of postop complications. - Suggested thresholds: * Lobectomy: >0.8L (or >40% predicted); * Pneumonectomy: >2L (>60% pred) for pneumonectomy. * Radical radiotherapy (esp. stage III): 1.5L (or >50% predicted) ○ DLCO (diffusing capacity for carbon monoxide) - Indirect assessment of gas exchange capacity of the lung. - Need * >40% of predicted for surgery or XRT (as DLCO drops during XRT). * >60% low risk for post-op complications.
What’s the differential diagnosis for a lung lesion?
Benign
○ Infection: pneumonia, abscess, TB
○ Lung hamartoma (overgrowth of mature lung tissue)
○ Benign mesenchymal tumour (eg fibroma, lipoma, haemangioma)
Malignant
○ Primary lung cancer
○ Metastasis
○ Carcinoid
○ Lymphoma
○ Malignant mesenchymal tumour (eg sarcoma)
What’s the TNM staging for lung cancer?
What is the general management for Stage I and Stage II NSCLC?
- Standard of care is a lobectomy with mediastinal sampling in medically operable
○ (lobectomy >segmentectomy>wedge)
○ Advantages: mediastinal nodal staging, complete histopath/margins
○ Disadvantage: GA and surgical risks, loss of lung volume- Reasonable alternative is SABR in patients who are medically inoperable/declines surgery
○ No comparative RCT
○ Local control data are similar - If SABR is not feasible for whatever reason (e.g. ultracentral), consider EBRT alone
○ Definitive hypofractionated RT alone (55Gy/20F without chemo)
○ No concurrent chemoRT - Medically inoperable/declines surgery:
○ N0
- Peripheral, <5cm: SBRT 48Gy/4# or 54Gy/3# CHISEL (improved LC/OS cf. conventional - CHISEL)
- Central, <5cm: Consider SBRT 50Gy/5# vs. conventional RT
- Ultra-central / >5cm: Conventional/hypofractionated RT (60Gy/15#, 55Gy/20# or 60Gy/30#) Single institution data – excessive toxicity (0-22% gr5 toxicity) with SBRT, esp if on blood thinners
○ N1:
- 60Gy/30# with concurrent chemotherapy, adjuvant durvalumab Extrapolation from data for concurrent CRT for stage III disease - Adjuvant treatment
○ Stage IA, R0 resection: observation
○ Stage II (+/- stage IB): benefit from adjuvant cisplatin double chemotherapy (5 yr OS benefit 5%) LACE MA, MA Collaborative group MA (5yr OS benefit 5%)
- Cisplatin-based regimen
□ +Adenocarcinoma = pemetrexed
□ + Squamous = gemcitabine
○ pN2: chemo > PORT 50-54Gy/25-27Fx - PORT MA (LC), ANITA analysis (OS), NCDB population studies (OS)
○ R1: PORT 60Gy/30Fx - NCDB studies (OS)
○ R2: concurrent chemoRT 60Gy/30Fx - NCDB studies (OS)
- Reasonable alternative is SABR in patients who are medically inoperable/declines surgery
Discuss indications for surgical management for Stage IIIa NSCLC and adjuvant radiotherapy/adjuvant chemotherapy.
Surgery
- Should carefully consider establishing pathological mediastinal nodal status
○ Only single station, non-bulky N2
- Two main options
○ Lobectomy with hilar dissection and mediastinal sampling
○ Definitive chemoradiotherapy
Adjuvant RT
- Adjuvant radiotherapy is indicated after surgery if:
○ Positive surgical margin (usually bronchial)
- Adjuvant RT for incidental pN2 disease is controversial
○ Post-operative finding of pN2 disease is common (20% of surgical specimens are upstaged)
○ No clear benefit seen, with possible survival disadvantage demonstrated
- LungART & PORT-C trials were negative
- Dose is 54Gy/27F
Adjuvant chemotherapy
- Adjuvant cisplatin-based chemotherapy is standard of care for all stage II-III patients
○ Cisplatin-based regimen
- Adenocarcinoma = pemetrexed
- Squamous = Gemcitabine
What is the general management for Stage III NSCLC?
- Standard of care is definitive chemoradiotherapy
○ 60Gy/30F to primary and involved nodal disease (no ENI)
○ ○ Concurrent cisplatin/etoposide
§ Carboplatin/paclitaxel may be an alternative
○ Concurrent CT/XRT has superior survival.
XRT alone: median survival 1yr, 2yr OS 10-20%, 5yr OS 5%.- Two options if chemotherapy is to be omitted
○ Boost to 66Gy/33F
○ Hypofractionation (55Gy/20F) - Adjuvant durvalumab to be given for 12 months
○ PACIFIC trial
○ Following definitive chemoradiotherapy, adjuvant durvalumab 10mg/kg every 2 weeks for up to 12 months, started within 6 weeks of completing chemoradiotherapy improves overall survival by 10% at 2 years (66% vs. 56%)
- Two options if chemotherapy is to be omitted
What is the general management for a Pancoast tumour?
- Two key options
○ Neoadjuvant chemoradiotherapy followed by resection (standard of care) swog and jcog ph2 trials 5year overall survival 50%
- 45Gy/25F with concurrent cisplatin/etoposide
- Surgical resection
- Adjuvant chemotherapy (adjuvant cisplatin/etoposide)
○ Definitive chemoradiotherapy alone
- 60Gy/30F with concurrent cisplatin/etoposideUnresectable tumour.
* Proposed criteria for unresectability may include:
○ the involvement of ipsilateral or contralateral mediastinal nodes (N2/N3)
○ involvement of the brachial plexus above the T1 nerve root
○ involvement of more than 50% vertebral bodies
○ invasion of the oesophagus and/or trachea
○ metastatic disease.- Note the difference in radiotherapy dose (difficult to compensate at the end of treatment)
○ Ideally decide surgical or non-surgical pathway at the beginning of treatment paradigm
- Note the difference in radiotherapy dose (difficult to compensate at the end of treatment)
What is the evidence for SABR in early stage NSCLC?
SABR
For medically inoperable peripheral lung tumours with a maximum diameter less than 5 cm, SABR with BED >100 Gy should be considered as standard therapy, and achieves 5-year local control rates of >90% and 3-year overall survival (OS) rates of 60%-70%.
· RTOG 0236 (Phase II, Timmerman, 2010, 2014, 2018 )
o SABR in medically inoperable early stage (T1-3,N0) non- central <5cm ,
o 54Gy/3Fx,
o 3y OS > 50% with most ppl dying of other comorbidities. MS 48 mo.
o 3y LC 98%, involved lobar control 91%, 3y DM 22%, 3y DFS 48%. 3y LRR 13%, 3y OS 56%. MS 48 mo.
o 5y DFS only 26%.
o 5y LR 7%, 5y involved lobar recurrence 20%, 5y LRF 26%, 5y DM 24%, 5y DFS 25%. 5y OS 40%.
o Grade 3+ toxicity of 30%, twice as high as RTOG 06-18 (operable pt) likely due to non-operable candidates in this study.
· CHISEL TROG 09.02 trial (Phase 3 RCT, Ball, 2019)
o 101 patients with Stage I (T1-T2a) NSCLC were randomised to SABR vs conventional RT
- PET-CT mandated
- SABR (54Gy/3F, 48Gy/4F - if <2cm from CW) or EBRT-3DCRT (66Gy/33F or 50Gy/20F)
- Inoperable pt or refusing surgery
o At 2 years SABR had less local recurrence (65% vs 89%, HR 0.32) and improved OS (77% vs 59%).
o Similar toxicity between groups (low, only 1 grade 4 tox)
· LUSTRE (Canada)(Phase 3 RCT, Clin Lung Ca, Swaminath, 2017; Astro 2022)
o 60/15 (BED = 84) vs. SBRT 48/4 or 60/8 (for central).
o Underpowered non-significant trend to improved LC with SABR.
o LC was numerically better with SBRT w/ no difference in toxicity compared to HFRT
o 324 pts expected to detect 3y LC improvement from 75% with CRT to 87.5% with SBRT. 233 patients with ≤ 5 cm stage I NSCLC or a suspicious growing PET avid lesion were accrued from 2014-2020. MFU 3y.
o 3y LC ~81→ 88% (p=0.15).
o Only one patient in each arm experienced acute G3 toxicity, no G4-5 toxicities were observed.
o Late G3-4 in 7 patients: SABR central (7%), peripheral (2%). Moderate hypofrac central (5%), peripheral (2%).
o One patient who received 60/8 for a central NSCLC experienced possible G5 toxicity (haemoptysis).
· SEER 2001-2001 (Shirvani, Red Journal, 2012)
o 10923pts, age ≥66, stage Ia-Ib NSCLC: lobectomy, sublobar resection, conventional RT, SABR, observe
- Lobectomy:59%, sublobar resect: 12%, conventional RT: 15%, SABR: 1%, observe: 13%
- Median f/up: 3.2yrs
o SABR: lowest risk of death w/in 6mo of dx (HR = 0.48)
o After 6mo: lobectomy assoc w/ best OS, DFS
o In propensity score matched analysis: OS after SABR similar to lobectomy (no stat diff)
o Worst outcomes: conventional RT, observe
SABR vs surgery
- Multiple small randomised trials, but all closed early due to accrual
- Pooled analysis of STARS and ROSEL trials (Chang, 2015)
○ 58 patients in total
○ 3 year OS was better with SABR (95% vs 79%; p=0.037)
○ Toxicity better with SABR
- Retrospective VA database study (Bryant, 2018) ○ 4000 patients identified ○ CSS mortality is worse with SABR compared with lobectomy (HR 1.45) ○ Immediate short-term mortality is worse with surgery ○ Conclusion: - Lobectomy remains the standard of care, but SABR is a reasonable alternative if * Not medically or technically fit for surgery * Patient preference
What is the evidence for adjuavant RT in NSCLC with positive margins?
- Retrospective NCDB data (Wang, 2015)
Increased median OS (33.5mo vs 23.7mo; mvHR 0.8; 95% CI 0.70-0.92) when patients with positive surgical margins following resection of stage II/III NSCLC are given PORT to 50-74Gy
What is the evidence for adjuavant RT in NSCLC with incidental pN2?
PORT for incidental N2 should not be routinely given
- LungART RCT (Le Pechoux, 2022)
○ 501 patients with pN2 positive disease after surgery (had to be cN0-1 at diagnosis)
- FDG-PET staging (91%)
- 3D-CRT mandated, but IMRT allowed (only 11%)
○ Randomised to PORT or observation
- 54Gy/27F
○ 3 year disease free-survival was unchanged (HR 0.86; p=0.18)
○ No difference in OS (HR 0.97)
- PORT-C (2021). Phase III. Single institution. R0N2→ CTX x4c→ ± PORT 50/25. ○ 3y OS ~83 obs→ 78% PORT (p=0.93). ○ mDFS 18.6mo Obst vs 22mo PORT ○ 3y LR-only 18% obs→ 10% PORT. ○ 3y LRFS 60→ 67% (HR 0.71; 95% CI 0.51-.097). ○ 3y DMFS 38→ 42%. ○ Conclusion: For resected, pN2 NSCLC, PORT halves the rate of locoregional recurrence, but that does not appear to significantly improve survival outcomes. Although PORT halves the rate of mediastinal relapse for resected N2 NSCLC, the benefit is insufficient to overcome the effect of metastatic progression and the potential adverse cardiopulmonary effects on overall survival. - ANITA trial (Douillard, 2008) ○ A randomised trial of cisplatin + vinorelbine vs observation in completely resected NSCLC ○ Post-hoc analysis of those who received PORT (non-randomised) demonstrated a reduction in OS in the overall cohort - pN2 disease subgroup had improved OS with PORT in both chemotherapy and observation arms - The survival detriments were isolated to the pN1 cohort who received chemotherapy - SEER analysis (Lally, 2006) ○ 7465 patients from the SEER database ○ For pN2 disease, improved OS (HR 0.85; p=0.007) OS detriment for pN0 (HR 1.176; p=0.04) and pN1 disease (HR 1.097; p=0.019)
What is the evidence for adjuavant chemotherapy in NSCLC, post surgery?
- LACE meta-analysis (Pignon, 2008)
○ Meta-analysis of 5 trials and 4600 patients
○ Cisplatin-based chemotherapy was associated with improved OS (HR 0.89; p=0.005)
○ Subgroup analyses found benefit was isolated to stage II/III patients- Cochrane MA NSCLC collaborative group (Burdett, 2015)
○ MA 47 trials (trials surg vs. surg + adj chemo; and surg +RT vs. Surg +RT +chemo)
Improvement in recurrence and 4% absolute OS benefit
- Cochrane MA NSCLC collaborative group (Burdett, 2015)
What is the evidence for neoadjuvant ChemoRT in NSCLC, with resectable disease?
Resectable N2 disease
- Phase III randomised trial (Albain, 2009)
○ 396 patients with T1-3 pN2 NSCLC were given 2x cisplatin/etoposide + radiotherapy 45Gy/25F
§ If no progression, randomisation to surgical resection OR ongoing radiotherapy to 61Gy (uninterrupted)
○ There was no difference in median OS (HR 0.87; p=0.24)
Surgery provided a PFS benefit (HR 0.77; p=0.017)
NA Chemo-> Sx vs NA ChemoRT -> Sx?
- No diff in EFS or OS between NA Chemo vs NA CRT, hence, no benefit to the addition of neoadjuvant radiotherapy to neoadjuvant chemotherapy, except for increase pCR and mediastinal downstaging
○ The Swiss SAKK16/00 (Lancet, 2015) provides the most straightforward answer to this question. In patients with stage IIIA (N2) NSCLC, sequential induction chemotherapy then radiotherapy (to 44Gy/22#) followed by surgery was compared to induction chemotherapy followed by surgery. There was no difference in event free survival or overall survival.
○ The German GLCCG RCT (Lancet Oncol, 2008) answers a similar question. Neoadjuvant chemotherapy -> radiotherapy -> surgery was compared to neoadjuvant chemotherapy -> surgery -> adjuvant radiotherapy. Neoadjuvant RT improved pathological response and mediastinal down-staging. However, there was no difference in PFS between the two groups (5-year PFS 16% vs. 14%).
What is the evidence for efficacy and timaing of definitive chemoradiotherapy in stage III NSCLC?
Definitive Chemoradiotherapy - Efficacy
- Phase III randomised trial (EORTC 08941, van Meerbeeck, 2007) ○ 579 enrolled and 321 proceeded to randomisation following clinical response from 3x platinum-based induction chemotherapy - If clinical response, randomised to RT 60-62.5Gy/30-32F or surgical resection ○ 5yr OS did not differ between surgery or RT (HR 1.06; 95% CI 0.84 – 1.35)
Definitive Chemoradiotherapy - Timing
- Sequential vs concurrent definitive chemoradiotherapy ○ Auperin meta-analysis (2010) - 1205 patients across six trials comparing concurrent vs sequential chemotherapy □ Key trials included (CALGB 8831, WJLCG, RTOG 94-10) - Concurrent therapy improved OS (HR 0.84; p=0.004) and LRC (HR 0.77; p=0.01) - Increased G3-4 oesophageal toxicity (RR 4.9; p<0.001)
What is the evidence not supporting elective nodal irradiation in Stage III NSCLC?
- PET-PLAN (Nestle, 2020)
○ RT to PET avid sites + 50Gy elective nodal irradiation vs RT to PET avid sites only
○ Concurrent chemo in both
○ Treating avid disease only resulted in improved LRR (14% vs 29%).
○ Slightly higher average dose (~2Gy) able to be given in PET only (less strain on OARs)
Elective nodal irradiation leads to impaired LRR which is mirrored in Jinan, China Trial (2007)
What evidence does not supporting dose escalation in Stage III NSCLC?
- Dose-escalation to 60Gy provides OS benefit
○ RTOG 73-01 trial (Perez, 1987)
- 551 patients with unresectable NSCLC were given definitive RT alone
□ Randomised to 40Gy, 50Gy or 60Gy
- Intrathoracic failure rates were improved with increasing doses (27% with 60Gy vs 48% with 40Gy)- Dose-escalation to 74Gy reduces OS
○ RTOG 06-17 trial (Bradley, 2015)
- 544 patients with unresectable NSCLC were randomised in a 2x2 trial design
□ 60Gy vs 74Gy with concurrent carboplatin/paclitaxel and +/- concurrent cetuximab
- Median OS was inferior in the 74Gy arm (28.7mo vs 20.3mo; p=0.004)
Cetuximab did not improve OS and increased toxicity
- Dose-escalation to 74Gy reduces OS
What is the evidence for immunotherapy post chemoRT, in Stage III NSCLC?
- New standard of care for locally advanced NSCLC
○ PACIFIC trial (Phase 3, Antonia, 2017, 2022)
- ChemoRT (60-66Gy in 30-33#, platinum based chemo)
□ Consolidation Durvalumab q2w for 1 year vs placebo
- Improved OS, PFS, RR and DM.
- 5yr OS 43% vs 33%. Median OS 47.5months vs 29.1months
- Effective in all PDL1 ≥1%
Grade 3-4 toxicity 30% vs 26%
What is the evidence for management of pancoast tumours?
- Phase II Intergroup 0160 trial (Rusch, 2007)
○ 111 patients with T3-4 N0-1 NSCLC underwent 2x cisplatin/etoposide with concurrent 45Gy/25F of radiotherapy
- If disease response, proceeded to thoracotomy (3-5 weeks post chemoRT) 2x cisplatin/etoposide
○ 80% of patients proceeded to surgery
- 92% of patients proceeding to surgery had R0 resection, with 65% showing pCR
○ 5-year OS was 54% if R0 resection (44% for whole cohort)
pCR was associated with improved OS (p=0.02)
Describe a radiotherapy technique for NSCLC concurrent chemoRT
Patients
Stage III NSCLC
Good performance status
Pre-simulation
MDT discussion
Lung function tests
Smoking cessation
Simulation
Supine in vacbag with arms up
- Knee supports and ankle stocks
CT from mid neck to below diaphragm
- 2mm with IV contrast
- 4D-CT
Fusion
FDG-PET
Dose prescription
60Gy/30F (prescribed to PTV as per ICRU 83)
- If no chemo, consider boost to 66Gy/33F
VMAT technique
10 days per fortnight
Concurrent chemotherapy
- Cisplatin (50mg/m2 on D1, D8 & D29, D36)
- Etoposide (50mg/m2 on D1-5 & D29-33)
Alternatively:
- Carboplatin (2 AUC)
- Paclitaxel (45mg/m2)
Volumes
GTVp = lung disease on CT/PET
iGTVp = GTV on all respiratory phases
ITVp = iGTV + 7mm
PTVp = ITV + 7mm
GTVn = nodal disease on CT/PET
iGTVn = GTV on all respiratory phases
ITVn = iGTV + 5mm
PTVn = ITV + 7mm
Target Verification
Daily CBCT
OARs
- Bilat Lung (minus iGTV)
○ Mean < 20Gy
○ V20 < 35%
○ V5 < 60%
- Spinal Cord
○ Dmax < 45Gy
- Oesophagus
○ Mean < 28Gy
○ Avoid hotspots
- Heart
○ Mean < 20Gy
○ V50 < 25%
Describe a radiotherapy technique for NSCLC hypofractionated lung RT
Stage III NSCLC
Reasonable performance status
Ineligible for concurrent chemoRT
Pre-SIM
MDT discussion
Lung function tests
Smoking cessation
SIM
Supine in vacbag with arms up
- Knee supports and ankle stocks
CT from mid neck to below diaphragm
- 2mm with IV contrast
- 4D-CT with respiratory motion management
Fusion
FDG-PET
Prescription
55Gy/20F (prescribed to PTV as per ICRU 83)
VMAT technique
10 days per fortnight
Volumes
GTVp = lung disease on CT/PET
iGTVp = GTV on all respiratory phases
ITVp = iGTV + 7mm
PTVp = ITV + 7mm
GTVn = nodal disease on CT/PET
iGTVn = GTV on all respiratory phases
ITVn = iGTV + 5mm
PTVn = ITV + 7mm
Target varification
Daily CBCT
OARs
- Bilat Lung (minus iGTV)
○ Mean < 16Gy
○ V20 < 30%
○ V5 < 60%
- Spinal Cord
○ Dmax < 44Gy
- Oesophagus
○ Avoid hotspots
- Heart
○ Mean < 18Gy
○ V46 < 25%
Describe a radiotherapy technique for NSCLC with SABR
Stage I-II (cN0) NSCLC
- <5cm dimension
Not suitable for lobectomy (or patient preference)
Not appropriate for ultracentral tumours (PTV overlaps central structures)
Pre-SIM
MDT discussion
Lung function tests
Smoking cessation
SIM
Supine on a SBRT board, on a vacbag with arms up
CT from mid neck to below diaphragm
- 2mm with IV contrast
- Motion management
* 4D-CT with respiratory motion management (gating)
* Breath hold (insp/exp)
* Abdominal compression
Fusion
FDG-PET
Prescription
Prescribed as per ICRU 91 (D95-99% ≥100% of prescribed dose)
Peripheral tumours
- 54Gy/3F
- 48Gy/4F (when GTV <1cm from CW)
- 30Gy/1#
Central tumours
- 50Gy/5F
- 60Gy/8Fx
VMAT-based SABR technique
Alternate days
Motion management is mandatory
Volumes
GTV = lung disease on CT
iGTV/ITV = GTV on all respiratory phases
PTV = iGTV + 5mm
NOTE: no CTV expansion
Target varification
Daily CBCT
- RO present for day 1
OARs
For 48Gy/4F (SABR)
- Bilat Lung (minus iGTV)
○ Mean < 6Gy
- Heart
○ Dmax = 34Gy
- Oesophagus
○ Dmax = 30Gy
- Spinal Cord
○ Dmax = 20.8Gy
- Brachial Plexus
○ Dmax = 24Gy
- Chest wall
- D30cc < 30Gy
- Great vessels
- Dmax < 49Gy
- Trachea + PBT
- D0.5cc < 30Gy
Plan objectives
PTV: Ensure that 98% of the PTV receives ≥100% of the prescription dose
- D99% = >90% PD
- Dmax = 125-143% PD
R100= Conformity index (Vol 100% PD / Vol PTV)
- Aim <1.2 (<1.5 acceptable)
R50= Gradient Index (Vol 50% PD / Vol PTV)
- AKA intermediate dose spillage
- Tumour size dependent 6-12
D2cm = maximum dose 2cm from the PTV / prescription dose
When treating metastatic NSCLC, what factors should be taken into account?
- Patient
○ Age, performance status
○ Comorbidities inclluding contraindications to systemic therapy, radiotherapy
○ Preference & goals
○ Symptoms- Tumour
○ Histopathology/molecular
- Squamous vs. non-squamous histopathology
- PDL1 status
- Driver mutation eg. EGFR, ALK, ROS1 BRAF for which a specific targeted therapy is available
○ Burden of disease
- Number and sites of mets
- Presence of symptoms - Treatment
○ Geographical location
- Tumour
Molecular testing
- Lung panel - tumour assessment for presence of a driver mutation
- Routine PDL1 in all pt with newly diagnosed met for consideration of immunotherapy
Symptom management
For a patient with oligometastatic NSCLC, how would you manage?
- If definitive therapy for thoracic disease is feasible
○ Systemic therapy and restaging to confirm non-progression (ESTRO/ASTRO = 3 months)
○ Treat thoracic disease as per T/N stage
- Surgery
-SBRT
- Or conventional/hypofx +/- concurrent chemo
Then maintenance therapy or observation
What is the systemic management of metastatic NSCLC?
- No driver mutation present, or unknown
○ PDL1 >50%: pembro or atezo monotherapy
- Improvement in OS compared with double chemo alone in this population
- Combination chemoimmunotherapy preferred in rapidly progressive disease
- CI to immunotherapy: connective disease, rheumatological, ILD
○ PDL1 <50%
- Non-squamous:
□ Doublet chemotherpay + pembro
□ Chemo: no singler optimal combination
□ Cisplatin>carboplatin
□ Pemetrexed only in non-squamous histo
- Squamous:
□ Carboplatin + paclitaxel or nab paclitaxel + pembro
□ OS benefit over chemo alone
○ 4-6 cycles, then consider maintenance- Driver mutation present
○ EGFR positive
- Treatment with EGFR TKI: osemertinib, erlotinib, geritinib, afatinib as single agents
- Preferred over chemo and immuno
- Improved outcomes compared to standard platinum basedchemo
- Impact on OS less evident, as frequently used as second line therapy after chemo in trials
- Osemertinib > erlotinib, gefitinib
- Continued until progression, or toxicity
□ Oligo progressive disease > consider MDT
○ ALK
- Treatment with ALK TKI preferred- Alectinib first line
- Continued until disease progression or tox
- Ceritinib
○ Others:
c-ROS oncogene 1 (ROS1), BRAF, RET, TRK, MET, and Kirsten rat sarcoma viral oncogene homolog (KRAS).
- Alectinib first line
- Driver mutation present
What is the evidence for agressive treatment of oligometastic NSCLC?
o Gomez et al lancet oncol 2016, 2019
Phase II, Gomez, 2016, 2019
74pts, ≤ 3mets, after 1st line sytemics w/o progress: aggressive therapy vs chemo
mPFS: 12mo (aggressive) vs 4mo
MS: 41mo (aggressive) vs 17mo
- Design: Phase II RCT (multicentre)
- Population (n=74): Stage IV NSCLC, <=3 metastases, ECOG PS <=2, no disease progression with standard first line systemic therapy
- Initial systemic therapy (all patients):
- 4 or more cycles of platinum dowblet chemotherapy, OR
- 3 or more months of EGFR or ALK TKI
- Arm 1: Local consolidative therapy (chemoRT or resection of all lesions) +/- subsequent maintenance systemic therapy
- Arm 2: Maintenance treatment alone (which could include observation only)
- Outcomes:
- Consolidative local therapy improved PFS (primary endpoint) 12 months vs. 4 months (SS)
- Updated results presented at ASCO 2018 additionally demonstrated improved median OS 41 vs. 17 months (SS)
- Commentary:
- First randomised trial to find a survival benefit for local consolidative therapy
- Limitations:
- Limited sample size (n=76)
- Molecular heterogeneity (including EGFR and ALK patients)
- Definition of oligometastatic disease (which was defined after systemic therapy)
o Lyengar et al. JAMA oncology 2018
- Design: Phase II RCT (single centre)
- Population (n=29): Stage IV NSCLC, <=5 metastases without driver mutation, PR or SD after induction chemotherapy
- Arm 1: SABR to all sites of gross disease (including SABR or hypofractionated RT to the primary) followed by maintenance chemotherapy
- Arm 2: Maintenance chemotherapy
- Outcomes:
- Consolidative SABR associated with improved PFS (10 months vs. 4 months)
- Toxicity similar between arms
What patient factors affect lung surgery?
○ Age. Perioperative mortality increases with age.
- Age is not a contraindication alone for lobectomy or wedge resection. But age should stronlgly be considered when deciding fitness of pneumonectomy
○ Pulmonary reserve
- FEV 1 >1.5 L for lobectomy and >2L for pneumonectomy for
- Predict post-op FEV1 and DLCO and if <40% considered high risk
○ Cardiovascular fitness
- Optimise IHD risk factors + stents prior to being considered for lung resection
○ Weight loss, PFS and nutrition
- Pre-op weight loss >10% or ECOG 2 are more likely to have advanced disease and poorer post op outcomes
WHat are the options for lung surgery and their indications?
○ Operations available
- Sublobar resection (wedge resection)
□ May be suitable for peripheral tumours <1cm
□ Useful for patients with impaired pulmonary reserve - higher local recurrence rate than a full lobectomy
- Lobectomy
□ Standard of care compared with wedge resection (1995 trial)
□ Mortality rates for surgeon after a surgical lobectomy should be <4% as per BMJ
- Pneumectomy
□ If cancer involved >1 lobe, the pleura/pericardium or diaphragm (as portions if this can be dissected with the procedure
□ Mortality rates for a surgeon after pneumectomy should be <8% as per BMJ
- Systematic lymph node dissection at time of lung resection is essential for lung resection to achieve accurate staging
What are the indications for Bronchoscopic laser resection and stents?
Brochoscope (rigid or flexible) to laser resect endobronchial lesions
○ Primary indication: Obstructive lesions of the trachea, main bronchi and bronchus intermedius
- Contraindication: Extrinsic compression
- Relative contraindications: Broncho-oesophageal fistula, coagulopathy, hypoxaemia
○ Laser resection of segmental bronchi does not significantly improve ventillation
○ Goal is often palliation with endobronchial manifestations of inoperable lung cancer
○ If used for curative intent- needs to be combined with other treatment modalities such as endobronchial brachytherapy
Stents
Stents are devices for internal splinting of luminal structures
4 major indications
1) Extrinsic compression from tumour or nodes
2) Stabilising airway patency after endoscopic intraluminal resection of a tumour or prior to EBRT
3) Sealing malignant fistulas
4) Benign strictures
Describe the management options for pleural effusion.
- Thoracentesis
○ Drainage of pleural effusion with local anaesethetic, often performed on the ward
○ May need an indwelling pleural catheter- VATs
○ Video assisted thorascopic surgery is done under moderate or GA
○ Triangular placement of ports in the chest wall, considered minimally invasive.
○ Pleurodesis by either chemical or mechanical methods
- Chemical: Sterile talc in the pleural space to cause if to adhere
- Mechanical: Brushing with dry gauze and mechanical irritaion - Pleurodesis
- Sterile talc powder in the plerual space, causing the layers to adhere together and prevent accumulation of pleural fluid/effusion
- VATs
Discuss the evidence for neoadjuvant chemo/immuno in resectable NSCLC
- Evidence CHECKMATE
○ Phase 2 Stage Ib-IIIa resectable NSCLC randomised to nivolumab + platinum based chemotherapy and resection or platinum based chemotherapy alone and resection
○ Primary end point event-free survival, pathological response
○ Median event free survival 31.6 months vs 20.8 months and pathological response favoured for most subgroups with nivolumab
The addition of nivolumab did not increased grade 3-4 toxcities
Discuss the evidence for adjuvant chemotherapy in NSCLC
Cisplatin and pemetrexed
* Stage ll or lllA Adenocarcinoma - non small cell lung cancer following complete resection, in patients with performance status 0 or 1
○ JIPANG study only randomised pateints with non squamous NSCLC and hence cisplatin/pemetrexed remains standard of care for adenocarcinoma
* LACE MA (JCO 2008) (Lung Adjuvant Cisplatin Evaluation) - MA of 4584 patients. Individual patient data from 5 large RCTs: - International adjuvnat lung trial (IALT) - NEJM 2004 - JBR.10 (NEJM 2005, JCO 2010) - ANITA (Lancet Oncol 2005) - Big Lung Trial - Adjuvant Lung Project Italy - Included patients with completely resected stage I-III disease - All-comers: Postop chemotherapy improved 5 yr OS by 5.4% (absolute benefit) - Subgroup analysis by stage: - IA - no benefit, trend to detriment - IB - HR for death 0.92 (95% CI 0.8-1.1) - Greatest benefit in patietns with stage II and III disease (particularly if good PS) - Beneficial for ECOG 0-1, may be detrimental for ECOG 2 - Conclusion: Adjuvant chemotherapy indicated for stage II, III with good PS (0-1), improves OS by 5% at 5 years - Controversial for Stage IB - Not indicated for stage IA * MA collaborative group MA (Lancet 2015) - MA of 26 RCTs, 8450 patients - Adjuvant chemotherapy associated with 4% improvement in OS at 5 years - Largest benefit (5%) for stage II and III - Benefit not SS for stage IA - Stage IB benefit 3% at 5 years - Conclusion: consider adjuvant chemotherapy for stage IB, II and III
List the common side effects for NSCLC chemotherapy, immunotherapy and targeted therapy.
Chemotherapy:
* Haematological (Neutropenia, thrombocytopenia, anemia)
* Electrolyte derangement
* Peripheral neuropathy
* Ototoxcitiy
* Mucositis
* Nausea and vomiting
* Fatigue
* Hair loss
Immunotherapy
Immune related events:
* GI toxcitiy (Colitis, oesophagitis, hepatits, pancreatitis)
* Cardiotoxcitiy (Myocarditis)
* Haematological (AIHA, TTP, Aplastic anaemia, acquired haemophilia
* Hepatotoxcitiy (Bilirubin elevation and transaminitis)
* MSK (Arthralgia, inflammatory arthritis)
* Neurological (Encephalitis, meningitis, GBS, myasthenia gravis)
* Ocular (Eye pain, uveitis/blepharitis, watery eyes)
* Pulmonary (Pneumonitits)
* Renal
* Skin (rash, blisters)
* Thyroid (Thyroid toxicity common with immune check point inhibitors. Typically HYPER in acute state and then progress to HYPO thyroidism)
* Endocrinology (Diabetes)
Non immune related events
* Nausea and vomiting
* Fatigue
Targeted Therapy
* Acneiform rash to face and upper body
* Anorexia
* Diarrhoea
* Fatigue
* Occular changes
* Oral mucositis
* QT prolongation
* Paronychia
* Pulomonary toxicity
Describe radiation induced lung injury
- Risk factors:
○ Lung comorbidities e.g ILD
○ prior lung RT, mean lung dose, and V20 are important predictors of symptomatic pneumonitis after lung SBRT, higher w/ chemo- Pathogenesis
Immediate phase (Hours to days – Asymptomatic)
· Driven by cascade of damage associated molecular patterns (DAMPs), pro-inflammatory cytokines (TGFb, TNFa, PDGF, IL1, IL6) and chemokines released from dying cells.
· Pulmonary oedema
o Hyperaemic congested mucosa with leukocyte infiltration
o Increased capillary permeability
· Exudative alveolitis
· Tracheal bronchial hypersecretion
· Degenerative changes in the alveolar epithelium/endothelium
· Type 1 pneumocytes are sloughed and surfactant levels are increased.
Latent phase (Weeks – cough/ poor sputum clearance)
· Thick secretions
o Increased number of goblet cells
· Ciliary dysfunction
Acute exudative phase (6 weeks to 6 months – Dyspnoea, cough – from impaired gas exchange)
· Sloughing of endothelial and epithelial cells, with capillary narrowing
· Hyaline membrane formation – due to alveolar pneumocyte desquamation
· Fibrin rich exudate leakage into alveoli.
· Type 2 pneumocytes become hyperplastic, with marked atypia
o Alveoli collapse
Intermediate phase
· Resolution of alveolar exudate and dissolution of hyaline membranes
· Collagen deposition by fibroblasts
ii. radiation fibrosis.
Fibrosis (6 months to years – Dyspnoea) – Driven by TGF-b produced by activated immune cells as well as by alveolar pneumocytes and fibroblasts.
· Increase in the number of Myofibroblasts within interstitium and alveolar spaces
· Increase collagen deposition
· Anatomic narrowing of alveolar spaces, resulting in diminished lung volume
o Vascular subintimal fibrosis causes loss of capillaries
o Traction bronchiectasis - Incidence:
○ Lung cancer - conventional
- V20 >22-31 = 7%
- V20>31-40 = 13%
○ Breast
- 1-9%
- Pathogenesis
What is the 5yr OS for NSCLC, stage I, Stage II, Stage III, Stage IV
5 year OS
Stage I 65%
Stage II 50%
Stage III 43%
Stage IV 10%
Local control with SABR (2 years)
- T1 = 80%
- T2 = 70%
What is the epidemiology of SCLC?
Incidence (Australian statistics) –> lung cancer overall
- 13800 cases annually
- 5th most common malignancy
- Leading cause of cancer death
Small cell lung cancer represents about 15-20% of all lung cancers
- (adeno 40%, SCC 30%, SCLC 20%, ULCC 10%)
- Therefore, incidence is approx 2000 cases annually in Australia
- Incidence declining
Male predominance (1.2:1)
Reduction in incidence secondary to reduction in smoking
- Very strong link
- 99% smokers
- <1% in non-smokers
Natural History
- Most aggressive form of lung ca- rapid progression, early dissemination, often advanced disease at presentation.
- 67% of patients present with metastatic disease outside of chest (extensive stage).
- Local, regional (lymphatic) or distant (haematogenous) spread, usually to lung, liver, adrenal, brain and bone.
- Median survival time without treatment 2-4 months.
- Treated with CT, median survival 10-16 months.
- 2 year survival 10%; 5 year survival 5%
- Local relapse following CT alone 60%, CT+RT 30%.
- Commonly relapses <2years.
Aetiology/Risk Factors
1) Cigarette smoking (dominant risk - very strong link) a. Suggestion of no cases arising in men who are never-smokers 2) Environmental exposures a. Heavy metals b. Asbestos (in addition to mesothelioma risk) c. Air pollution esp industrialised countries 3) Ionising radiation a. Therapeutic radiotherapy b. Radon gas c. Uranium (in miners)
Describe the pathology of SCLC
Histological Subtypes
Typically arise from the neuroendocrine cells of the lung/bronchus epithelium
Neuroendocrine carcinomas of lung have 3 key subtypes
1) Small cell lung carcinoma (SCLC) (aggressive end of spectrum)
2) Large cell neuroendocrine carcinoma (LCNEC)
3) Carcinoid (benign end of spectrum)
Small Cell Lung Carcinoma
- Accounts for 15% of all lung cancers
- Exclusively related to smoking
- Highly aggressive nature
○ Tends to have early metastases (may present with bulky nodes and reasonably small primary) 20% of patients present de novo metastatic disease
○ Paraneoplastic syndromes common (SIADH, Lambert-Eaton)
- Macroscopic ○ Typically a centrally-located or hilar mass ○ White-tan soft and friable tumour ○ Necrosis is common - Microscopic 'sheets small round blue cells, with little cytoplasm, no distinct nucleoli and high mitotic rates' ○ Small blue round cells with minimal "scanty" cytoplasm (high N:C ratio, 2x size of lymphocyte) - Cells may grow in sheets, clusters or rosettes, ribbons, peripheral palisading - Delicate fibrovascular stroma often separates clusters - Neither glandular nor squamous organisation ○ Cells may demonstrate finely dispersed chromatin (chromatin pattern: salt & pepper) without discrete nucleoli ○ Frequent mitoses/High mitotic rate and accordingly, marked necrosis/apoptosis seen ○ Nuclear moulding prominent feature - Immunohistochemistry - KEY: Positive TTF1, synaptophysin and chromogranin A ○ POS = - For at least one NE marker: chromogranin A, synaptophysin, INSM1, CD56 (NE markers), NSE - CK7 (low molecular weight cytokeratin), - Adeno markers: TTF1 ( neg in 15-20%), - p53, EMA (positive in most carcinomas) ○ NEG = CK20 (high molecular weight cytokeratin), PAX8, p63, - Adeno marker: Napsin A (positive in most Lung Adeno, neg in non-lung adeno mets & SCC) - Squamous markers Neg : p40, p63
Describe the pathology for Large cell neuroendocrine carcinoma (LCNEC)
- Quite uncommon (~3% of all lung cancers)
○ More common as a mixed pattern rather than pure- Large cell variant of SCLC
- Remains aggressive with poor prognosis
- Macroscopic
○ Well-circumscribed mass with necrosis and a tan-red colour - Microscopic
○ Appears similar to NSCLC, IHC stains positive for NE
○ Larger cells (3x the size of SCLC) with:
- Abundant cytoplasm
- Coarse granular chromatin, nuclear pleomorphism and prominent nucleoli
○ Necrosis and mitoses frequent (>10 per 10hpf)
○ Multiple patterns (organoid, nesting, solid) - Immunohistochemistry
○ POS = chromogranin A, synaptophysin, CD56, CK7, TTF1, AE1/AE3
NEG = CK20, p40, p63, Napsin A
Describe the pathology for lung carcinoid
Carcinoid (well-differentiated neuroendocrine tumours)
- Exists on a spectrum of neuroendocrine tumours (i.e. LCNEC are poorly-differentiated)
○ Typical = well-differentiated
○ Atypical = moderately-differentiated, poorer prognosis
- Uncommon tumour (1% of all lung cancers)
- Not related to smoking, unclear aetiology
○ Related to MEN1 syndrome
- Highly curable (usually surgery alone)
- Macroscopic ○ Well-circumscribed polypoid tan coloured tumours ○ Typically located centrally (frequently in bronchial lumen with obstruction) - Microscopic ○ Can be arranged as organoid, trabecular, rosette ○ Typical - Cytologically bland large cells with round nuclei, finely dispersed chromatin and inconspicuous nucleoli - Moderate to abundant cytoplasm - Few mitoses (<2 per 10hpf) and necrosis is absent ○ Atypical - More mitoses (2-10 per 10hpf) or presence of necrosis - Generally begin to have more cytological atypia ○ Delicate fibrovascular stroma ○ Ki67 <20% - Immunohistochemistry ○ POS = chromogranin A, synaptophysin, CD56, TTF1, AE1/AE3 ○ NEG = CDX2
Describe the prognostic features for SCLC
Patient Factors
- Age and performance status (tolerability of treatment)
- Ongoing smoking during treatment
- Weight loss
- Females have better survival (unclear cause)
Tumour Factors
- Stage (typically LS vs ES)
○ TNM is also prognostic however
○ Number of metastatic sites
○ CNS, marrow and liver mets (unfavourable cf. other sites)
- Paraneoplastic syndromes are unfavourable (e.g. SIADH) ie. ¯Na
- Elevated LDH
Treatment Factors
- Overall treatment time for RT: Start of chemo > end of RT (OS decreases by 2% for every 1
week of prolonged treatment time)
- Early chemotherapy
Early radiotherapy (cycle 2 at latest)
Describe the features to check on history for SCLC
History
- Primary lesion
○ Dyspnoea
○ Chest pain
○ Cough
○ Haemoptysis
○ Hoarse voice - recurrent laryngeal n involvement
○ Dysphagia
○ Weight loss
- Symptoms of SVCO
○ Mediastinal lesion grow to obstruct blood flow from SVC
▪ Either extrinsic compression or direct tumour invasion
○ Facial plethora
○ Arm swelling
○ Dyspnoea and headaches
○ Collateral vessels on skin
- Paraneoplastic syndromes
○ Lambert-Eaton (proximal muscle weakness, anti voltage-gated ca channel Ab)
▪ Classic association
▪ <5% of patients SCLC
▪ Proximal weakness leading to difficulty walking/difficult to perform ADLs
▪ Develop antibodies to the pre-synaptic calcium channels in the neuromuscular junction leading to weakness. Characteristically improves with repeated contraction (unlike myasthenia gravis)
○ SIADH (5-10%)
- Malaise, weakness, confusion, volume depletion, nausea
- Hyponatremia, euvolemia, low serum osmolality, inappropriately concentrated (high) urine osmolality
○ Cushing Sx
- Weight gain, moon facies, HTN, hyperglycemia, generalised weakness
- High serum cortisol and ACTH, hypernatremia, hypokalaemia, alkalosos
○ Hypercalcaemia (calcitonin)
- Constitutional symptoms
- Other
○ Oesophageal obstruction
○ CNS metastases (seizures, ICP symptoms)
○ Leptomeningeal disease, adrenal mets, liver mets, bone mets and associated sx
- PMHx
- Social History
○ Smoking –Counsel on cessation
Examination
- Observations (including saturations)
- Chest auscultation
- Pemberton’s sign
What investigations are needed to work up SCLC?
- Bloods (pre-chemotherapy)
○ FBC, EUC, CMP, LFT, LDH (LDH non-specific marker, elevated levels in SCLC associated with greater disease burden and worse OS)
○ Coags
○ HepB sAg, sAb and cAb
○ Hep C serology
○ HIV serology
○ TSH, T4, cortisol (immunotherapy)- Histopathology
○ Percutaneous core-biopsy lung/node
○ EBUS + core biopsy (often endobronchial approach)
○ Sputum cytology - Staging imaging
○ CT CAP + WBBS
§ Alternative is FDG-PET-CT (recently funded)
□ Stage change in 5-10% of patients
○ MR Brain (↑ sensitivity, particularly if Sx and neg CT)
§ BM positive in 15% at Dx, 5-8% asymptomatic - Lung function testing
- Other (as indicated)
○ Pleural cytology
○ Lumbar puncture
○ BMAT if features suggestive of marrow infiltration (cytopenias, nucleated RBCs on smear)
- Histopathology
Describe the surgical option for management of Limited stage SCLC.
- A potential option for cT1-2 N0M0 disease
○ SCLC is rarely diagnosed so early (can be an incidental finding in resection for a lung nodule/ open biopsy)
○ <5% of patients- Requires histological mediastinal staging prior to proceeding
- Lobectomy with mediastinal lymphadenectomy
- Should proceed to adjuvant chemotherapy with 4x cisplatin/etoposide
- +/- mediastinal RT (sequential or concurrent if incidentally node positive)
- If refusing surgery then this group could also be managed with SABR + adjuvant chemotherapy or Concurrent chemoRT
Can consider omission of PCI in stage 1, especially for elderly patients (ASTRO)
Describe the general management of Limited stage SCLC.
Chemoradiotherapy
- Patients: Good performance status (ECOG 0-2) or poor performance status due to SCLC - Chemo and RT to commence ASAP - Ideally aim for concurrent chemoradiotherapy ○ Concurrent is superior to sequential ○ Evidence shows that early radiotherapy is better (With C1 or C2) - Commencing with C2 is usually more feasible and may be preferred if bulky disease pre-chemo ○ Can consider sequential in poor performance status (ECOG 3-4) due to SCLC - Aim for four cycles of cisplatin/etoposide (preferred) ○ Carboplatin (poor kidney function) can be swapped if toxicity is a concern ○ Aim 2 cycles with concurrent RT, 2 cycles post ○ Cisplatin 60mg/m2 IV infusion, day 1 (carbo in ES-SCLC) ○ Etoposide 120mg/m2 IV infusion, days 1-3 - Higher response rates with cisplatin/etoposide (therefore preferred for limited stage) - Better toxicity profile with carboplatin/etoposide (therefore preferred for extensive stage) □ Less risk of nephrotoxicity, neuropathy, neurotoxicity and emesis □ Higher risk of mucosal toxicity, interstitial pneumonitis and haematologic toxicity ○ Toxicity: - Immediate: hypersen, N/V, taste/ smell - Early: neutropenia, TCP, hypo Mg, Ca, K; mucosiits, oesophagitiis, anorexia, fatigue, peripheral neuropathy (platinum), nephrotoxiciry, ototoxicity - Late: anaemia, alopecia, infertility - Thoracic radiotherapy should commence ASAP ○ Liaise with med onc: ideally concurrent with C1; often not feasible (planning), so aim for C2 - Options for thoracic radiotherapy; optimal not established ○ Turrisi --> 45Gy/30F/1.5GY BD over 3 weeks preferred - Preferred, but logistically difficult - NEJM 1999 accelerated RT 45Gy in 1.5 fractions BID (6 hours apart) to take advantage of rapid turnover/high mitotic rate. ○ CONVERT --> 66Gy/33F daily - Phase 3 trial unsuccessful at demonstrating superiority compared with Turrisi ○ EviQ - allows a range if concerns re tolerability, preference for higher doses when achievable - 50Gy/25Fx - 40Gy/15Fx
Describe PCI in the SCLC LS setting
- PCI is associated with OS improvement and reduction in symptomatic brain metastases in LS-SCLC
○ Commenced in all pt with LS-SCLC (with complete or partial response) with good performance status
○ Dose = 25Gy/10F
○ Higher doses increase risk of neurotoxicity
○ Rationale: IC mets occur in >50% of pt with SCLC; sanctuary site- Patients should be restaged after completion of chemotherapy prior to proceeding
- Administer after resolution of acute toxicities
- Consider adding memantine (not PBS funded, off label)
○ Improve neurocognitive toxicity with WBRT
○ Schedule
- Commence on D1 of WBRT
- 5mg mane for 1 week, then escalate to 5mg BD for 1 week
- Continue weekly escalation until 10mg BD
- Continue for 6 months - At this stage, use of HA-WBRT should be considered experimental
○ Only one trial, with previous contradictory data
Describe the initial general management of ES SCLC
MDT discussion
–> Upfront systemic treatment is priority
-Radiotherapy can be used initially for symptomatic brain mets
-> radiation for symptomatic bone mets if not respond to upfront chemotherapy or in rare cases of concern for impending cord compression with no response to systemic therapy.
Upfront chemotherapy + immunotherapy
- For Good PS patients (ECOG 0 -2) or poor PS due to SCLC
- 4-6 cycles of carboplatin/etoposide/atezolizumab (IMpower133)
○ Number of cycles depending on tolerability
- Carboplatin AUC 5 IV infusion day 1 (as opposed to cisplatin with limited stage, although both are reasonable - no combination has established superiority)
□ Both combinations were equally effective in tumour response and survival (EviQ)
- Etoposide 100mg/m2 infusion days 1-3
○ Common toxicities: (Carbo/Etop has better toxicity profile compared to Cis/Etop)
- Immediate: hypersensitivity, N/V, taste and smell alteration
- Early: neutropenia, thrombocytopenia, oral mucosiits, anorexia, fatigue
- Late: anaemia, alopecia
- Alternative options ○ Platinum/etoposide + durvalumab x 4 cycles until progression/toxicity (CASPIAN) ○ Carboplatin/etoposide x 4-6 cycles ○ Cisplatin/etoposide x 4-6 cycles - Complete restaging upon completion of chemotherapy ○ CT CAP ○ MR Brain - Maintenance immunotherapy to continue until disease progression/toxicity
What is the role of Radiotherapy in ES SCLC?
Consolidation Thoracic Radiotherapy
- Consider in patients with a good partial response (NCCN guidelines; CREST)
○ Residual thoracic disease
○ Minimal residual extrathoracic disease
○ No benefit if no residual disease
○ Volumes similar to LS-SCLC
○ Treat post chemotherapy volume, but include all mediastinal nodal stations that were invovled prechemo
- Thoracic RT has been shown to improve overall survival
○ NOTE: these trials did not allow immunotherapy (uncertain if benefit persists)
- Typical dose would be 30Gy/10F (CREST)
○ Withhold immunotherapy for this period (concerns for thoracic toxicity)
Symptomatic Lesions
- Consider upfront management of symptomatic lesions prior to systemic therapy
○ SVC obstruction
- For most patients, intiially chemo is treatment of choice, as chemosensitive and response is usually rapid
- Consider endovascular or RT if potentially life threatening, or in those who don’t respond to chemo
○ Significant bronchial obstruction
○ Significant pain/bone metastases
- Stablisation/fixation > RT
○ Cord compression
- Initiate steroids + RT before systemic therapy, unless immediate systemic therapy required
- Brain metastases as a special case ○ If asymptomatic, can consider upfront systemic therapy - Need close MR surveillance during chemotherapy □ Brain MRI every 2 cycles and for RT if progression before finishing systemic treatment - Then WBRT following completion of induction chemo ○ If symptomatic, but be treated with surgery/RT upfront - Steroids + WBRT first - Systemic therapy following ○ Recommended dose: - 30Gy/10Fx ○ WBRT vs. SRS - NCCN guidelines: WBRT rather than SRS □ If recur, SRS preferred; re-WBRT can be consider - Rationale: patients tend to develop multiple CNS mets
Discuss PCI in ES SCLC
PCI
- May be considered if excellent response (complete or partial) to chemoimmunotherapy (and good performance status) ○ No clear OS benefit ○ Reduce incidence of symptomatic brain metastases - Note that close MR surveillance is an appropriate alternative in patients suitable ○ 3 monthly for year 1 and then 6 monthly there after ○ In pt with no brain mets on MRI, PCI reduces incidence of BM (40 vs. 65% at 18 months), but does not improve OS cf MRI surveillance - Dose is typically 25Gy/10F (though 20Gy/5F is reasonable given poor prognosis) ○ Consider withholding immunotherapy for this period
What is the evidence for efficacy of chemoradiotherapy in LS-SCLC?
Efficacy in LS-SCLC
- Thoracic RT improves (below)
- Local relapse following Chemo alone 60%, CRT 30%
- Demonstrated in 2 x Meta-analysis
- (Pignon, 1992)
○ 13 trials and 2140 patients with LS-SCLC
○ Population LS-SCLC
○ Comparison of chemoradiotherapy vs chemotherapy alone
○ Improved OS with chemoradiotherapy (HR 0.86; p=0.001)
- 14% mortality reduction
- + (Warde, JCO 1992)
○ MA 11 RCTs
○ 5% improvement in OS at 2 years
○ Improvement in 2-year LC by 23 % (47% vs. 24%)
What are the primary causes for SVCO?
Describe the grading for SVCO
If Grade 3-4 –> Emergency management and stenting
If not suitable for stenting steroids and RT is reasonable alternative
Then aim for work up and tissue diagnosis once patient is stabilised
What is the TNM staging for pleural mesothelioma?
What are the advantages and disadvantages for management options of pleural effusions?
What is the OS by stage and histology, for mesothelioma?
Describe the staging system for Thymic tumours
Describe the advantages and disadvantages of the different methods of obtaining a tissue diagnosis for lung cancer
How would you manage M1b NSCLC?
M1b (solitary extrathoracic metastasis)
* Brain metastasis (manage brain met first):
○ See management of brain metastases- see below
○ May involve surgical resection +/- cavity FSRS or SRS +/- WBRT
* If definitive therapy for thoracic disease feasible:
○ Systemic therapy and restaging to confirm non-progression
(OR proceed directly to definitive therapy) in NCCN guidelines, but not done in the phase II trials
○ Treat thoracic disease as per T and N stage
2x Phase II RCTS Gomez 2016 (n=76), Lyengar 2018 (n=29); improved PFS (12 vs 4mo) and median OS (41 vs 17mo) cf. maintenance systemic therapy alone
SARON Phase III RCT in progress
○ Then maintenance systemic therapy or observation
* Duration of therapy and maintenance therapy (for patients without a driver mutation)
▪ For patients treated with TKIs - generally continue until progression or significant toxicity
▪ For patients initially treated with combination chemotherapy, treatment is generally limited to 4-6 cycles
▪ In the absence of disease progression, subsequent maintenance systemic therapy has been shown to prolong PFS and OS (the alternative is close observation)
▪ Options for maintenance therapy are in the table below
* If definitive treatment of thoracic disease not feasible, treat as per M1c (systemic therapy)
In general, discuss the advantages and disadvantages of radical surgery compared with SABR in early stage non-small cell lung cancer. (2 marks)
