CL3 - Radiotherapy and Lung Cancer

Lung Cancer stats

35% of patients were diagnosed via emergency

48% of patients present with stage IV

Most common cause of cancer death

Causes of lung cancer

smoking

• causes 80-90% of cases

environmental - passive smoke, asbestos, radon

family history

fibrotic lung disease

Clinical features of lung cancer

• persistent cough which lasts 3-4 weeks or more

• breathlessness

• reoeat chest infections

• chest and/or shoulder pain - referred pain from diaphragm

• loss of appetite and/or unexplained weight loss

• change in long term cough/ cough that gets worse

• coughing up blood - red flag symptoms always

• unexplained fatigue or lack of energy

• hoarseness - cancer could be affecting the laringeal nerves

• finger clubbing

• blood clots

Red flag → management pathway

GP suspected cancer referral - pt usually seen within 2 weeks for CT

Obtain biopsy/tissue diagnosis with imaging to determine extent/distribution (staging)

MDT discuss patients and create management plan for them

treatment to begin within 62 days (aimin to reduce to 49 days)

Diagnostic tests for lung cancer

If central - bronchoscopy

If peripheral then CT guided lung biopsy

Endobronchial ultrasound (EBUS) - sample central lymph nodes

Surgical Biopsy - if not otherwise accessible

Other method used if:

• needle not an option due to air getting into lung and collapsing it

• if chronic smoker and cant breathe properly

PET-CT scan trace used

18F-flurodeoxyglucose is the trace used

• anything that uses lots of glucose take up the tracer and becomes white in picture

• pt stays still after admin to reduce muscle uptake

shows us a picture if lumps there that shouldnt

Two main groups of lung cancer

SCLC - small cell lung cancer

• 10-15%

• usually caused by smoking

• aggressive, often metastatic at presentation

• treated with chemo

• high response rate but relapse quickly too

NSCLC - non-small cell lung cancer

• 85-90%

• Three types:

  • adenocarcinoma

  • squamous

  • large cell carcinoma

SCLC

small cell lung cancer

• surgery has a limited role (only if biopsy is not possible so used as diagnostic)

• limited stage - encompassed by radiotherapy

  • optimal treatment is 4 cycles of chemo combined with radiotherapy

  • median survival is 2 years

• extensive stage - most common

  • without treatment the expected survival is ~ 4 months

  • chemo ~ 10 months

  • chemo-immunotherapy (atezolizumab) for ~12 months

    • improves survival by around 3 months

  • 40% risk of brain metastases

Factors to consider for operability of NSCLC

Factors to consider for operability:

• Tumour factors

  • N0 or N1 (hilar)

  • Not T4 (invasion)

• Patient factors

  • Lung function

  • Co-morbidities (smokers)

• Technique:

  • Open

  • Laparoscopic (‘key-hole’)

Treatment of NSCLC: Perioperative treatment

Neoadjuvant chemotherapy

• Before surgery

• make surgery more difficult?

• less patients fit if complications of SACT (systemic anti-cancer therapy)

• Potentially treating microscopic seedlings sooner

• Fitter to start treatment

Adjuvant:

• After surgery

• Less patients fit enough to receive SACT as recovering from surgery

• Delay in treating microscopic seedlings

Adjuvant cancer

4-5% improvement in overall survival at 5 years

4 cycles of chemo

start within 12 weeks of surgery - some patients havent recovered enough for it

Multiple Chemotherapy options

Neoadjuvant chemotherapy with (check point inhibitor) nivolumab for 3 cycles

• event free survival of 32 months instead of 21

• complete pathological response of 24% vs 4%

• more pt fit after surgery

• no increase in surgical complications

Adjuvant immunotherapy with atezolizumab

• high PD-L1 group

• 57% less likely to relapse

Adjuvant targeted therapy e.g. osimertinib in EGFR mutated cancers

• 3rd gen Tyrosine Kinase inhibitor

SABR

Sterotactic Ablative Body Radiotherapy

very high dose radiotherapy in few fractions (3 or 5)

indications:

• peripheral lung cancer (<5cm) without nodal involvement

• patients not fit (medically inoperable) or decline surgery

outcomes:

• very good local control (>85%)

• minimal toxicities

Adjuvant immunotherapy with durvalumab after chemoradio combo

if given for 12 months then the chances of being alive at every single timepoint is increased by about 10%

SACT

Systemic anti-cancer therapy

• cytotoxic chemo

• targeted agents (tyrosine kinase inhibitors)

• immunotherapy

• antibody drug conjugate (ADC) - many in trial but not yet funded in UK

Indications:

• neo-adjuvant

• adjuvant post op

• adjuvant post chemoradio combo

• palliative

Treatments for MET exon 14 skipping alteration

Tepotinib

Pemetrexed

orgininal chemo was standard cisplatin + gemcitabine

cisplatin combined with pemetrexed was discovered

• used to tackle folate pathway

• better overal survival for adenocarcinoma to 12.9months from 10.6 months

Oncogenic drivers

• rare cause not routinely screened

• a genetic mutation or alteration that directly causes cancer

• should test all adenocarcinomas for drivers

• don’t respond well to immunotherapy

Oncogenic drivers in metastatic NSCLC

• EGFR

• ALK

• BRAV V600E

• ROS-1

• MET exon 14 skipping alteration

• RET

• KRAS G12C

• NTRK

• EGFR (exon 20 mutation)

• HER2 activating mutation

Treatments for EGFR common mutations

Osimertinib

gefitinib

erlotinib

dacomitinib

afatinib

Treatments for EGFR exon 12 insertion

Mobocertinib 

Amivantimab 

Treatments for BRAF oncodrivers

Dabrafenub

Trametinib

Treatments for KRAS oncodrivers

Sotorasib

Treatments for ROS-1 oncodrivers

Crizotinib

entrectinib

Treatments for RET oncodrivers

Selpercatinib

Treatments for NTRK oncodrivers

Entrectinib

Tyrosine kinase inhibitors

• targeted treatment

• next generation drugs are more selective → less off target toxicities

• expect high response rate and long progression free survival

• resistance mechanisms

EGFR mutations

• ~10% in Uk populations

• 1st generation drugs

  • gefitinib

  • erlotinib

• 2nd generation

  • afatinib

• Response rates ~60%

• disease control rates of ~80%

Side effects of EGFR inhibitors

• diarrhoea

• acne like rash

• stomatitis - sore mouth due to ulcers

• paronychia - infected nails

• hepatitis

Oseimertinib

3rd generation EGFRi

better brain penetration

better tolerated

less SE

increased PFS and OS

Oral ALK inhibitors

Tyrosine kinase inhibitors

block the activity of the ALK fusion protein, which drives cancer cell growth and survival

e.g. crizotinib - 1st gen

SE associated with ALK TKI

• visual problems

• N+V

• diarrhoea

• oedema

• rash

• QT prolongation

• bradycardia

• interstitial lung disease

Immunotherapy

PD-1 - oembrolizumab and nivolumab

PD-L1 - atezolizumab and durvalumab

Used in lung cancer as mono or chemo-immuno combo

Checkpoint inhibitors

PD1/PDL1 inhibitors

• given IV over 30-60min

• every 3-6 weeks

PDL1 is used as biomarker to give tumour proportion score to see prognostic and see effectiveness of chemo

Immunotherapy

• autoimmune driven

• onset at anytime even after stopping

• manageable

  • low grade toxicity - treated with oral pred

  • high grade toxicity - treated with iv methylprednisolone

• occasional need for additional treatment

  • colitis

  • mycophenolate

  • colectomy

PD score to determine imunotherapy

Adenocarcinoma - look for oncogenic driver and use tki

PDL1 >50% we give immunotherapy (with no history of autoimmune disease)

PDL1 0-49% we use chemo + immuno combo (with no history of autoimmune disease)

Supportive measures for patients who are unfit for SACT

radiotherapy for symptom relief

• cough

• bone pain

• bleeding

stereotactic radio surgery for brain mets

denosumab and zoledronic acid

• reduce skeletal events, cord compression and improve prognosis

Radiotherapy

• the next most important method of curing cancer

• curative treatments for:

  • inoperable disease

  • organ preservation

• mainly considered for palliation (cord compression and bone pain)

How does radiotherapy work?

• generation of photons

• point in direction of tumours

• hits target and exits in straight line

• free radical formation causing ds DNA damage

• failed cell division

• apoptosis

Two treatment intentions for radiotherapy

Palliative

• symptomatic relief

• duration:

  • single fraction

  • 5 fractions over 1 week

  • 10 fractions over 2 weeks

• not concurrent to chemo

Radical

• to attempt a cure

• duration:

  • conventional

  • 20-37 fractions over 4-7.5 weeks

  • 1-5 fractions on alternate days

• sometimes concurrent to chemo

PRINCIPLES OF RT

• Tumoricidal dose of radiation to tumour with relative sparing of surrounding tissues

• Gray (Gy) – unit of absorbed dose

• Normal tissue tolerance limits total dose (organs at risk – OAR)

• Fractionation

  • Small dose delivered daily allows recovery of normal tissues (conventional)

  • Large dose delivered to small target (stereotactic ablative body radiotherapy)

• DNA damage causes cell death during replication

Radiosensitisers

to improve benefit of radiotherapy when used in combo e.g. fluropyrimidine which dysregulates the S-cycle of the cell cycle and is used in rectal cancer

or platinum combos used in lung cancer

Tumour hypoxia

• hypoxia can cause resistance to radiotherapy

• as tumours grow, they outstrip their blood supply causing hypoxia

How is tumour hypoxia dealt with?

BCON - bladder carbogen and nicotinamide

• carbogen - 98% oxygen and 2% co2

• help reduce the hypoxia associated resistance

• alternative to chemo+radio combo

Planning and treatment of radiotherapy

• clinical mark up of spot - for easy treatment

• Immobolisation

  • clipped to bed using plastic to hold them down

  • needs no movement for accuracy

• reference marks/tattoos to make sure they’re in the same position before treatment

Side effects of radiotherapy

• fatigue

• loss of apptite

localised so only within the irradiated field

dose dependent and predictable

Acute toxicity in radiotherapy

• damage of rapidly cycling cell such as

  • skin

  • mucous membranes

  • gut

  • bone marrow

• onset within 10-14 days

• heals within 2-4 weeks

Late Toxicity due to radiotherapy

• Dose Limiting

• Predictable but not inevitable

• Aim for incidence <5%

• Onset from ~6/12 post RT

• Progressive vessel damage/fibrosis

• Carcinogenesis rare (0.1%)

  • Incidence may be higher but death from 1^st cancer or co-morbidity keep figure low

  • > 7 years post RT, may be much longer

  • Classical picture is sarcoma and breast cancer in HD

Early and Late toxicity: Skin

Early:

• alopecia

• erythema - redness of skin

• desquamation - blisering of skin

Late

• Pigmentation

• Atrophy

• Telangiectasia - fine blood vessels around the nose

• Necrosis

Early and Late toxicity: Lung

Early:

• Dyspnoea

• Cough

Late:

• fibrosis

Early and Late toxicity: Bowel

Early:

• Diarrhoea

• Colic

Late:

• Fibrosis/strictures

• Bleeding

• Fistulae

Early and Late toxicity: Mucosa

Early:

• mucositis

Late:

• Atrophy

• Dryness (head and neck)

• Scarring

Early and Late toxicity: CNS

Early:

• oedema

• l’hermittes

Late:

• cognitive and memory impairment - early dementia

• necrosis

• myelitis

Early and Late toxicity: Gonads

Late:

• Amenorrhoea

• Infertility

• Testosterone failure

Supportive measures during/after radiotherapy

Oral mucositis

• gelclair

• caphosol - prevent ulceration

• analgesia

• modified diet/PEG tube

Skin

• avoid flamazine (used for burns - so radiotherapy symptoms - but can affect the beam due to silver contained) and has during treatment

• topical opiates

Oesophagitis

• analgesia

• modified diet

• antacid + oxetacaine suspension

Bowel

• laxatives/enemas

• loperamide