Non Small Cell Lung Cancer

Background

Epidemiology

There are 222,000 new diagnosis per year and 160,000 deaths attributed to lung cancer. Overall 5yr survival rates are poor ~15%.

Risk Factors

The main risk factors for developing lung cancer besides smoking are radon exposure, occupational exposure including asbestos.

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The RR of a smoker is 20x nonsmokers for development of lung cancers. The risk in former smokers is around half (9x vs 20x) of current smokers. Second hand smoke has a RR of 1.2 to 1.3.

Screening

In SCC the 10 yr survival of 93% vs 82% when screening CT scans are implemented.

Diagnosis

Symptoms

• The most common presenting symptoms are dyspnea, cough and weight loss.
• The most common presentation is metastatic disease. The most common sites of distant metastatsis include: bone, adrenal glands and brain.
• 30% present at stage III at diagnosis and following surgery 25% have occult N2 nodal disease.

Location

• Central location are primarily SCC
• Peripheral lesions are often adenocarcinoma

Syndromes

• Pancoast: Parasthesias, Shoulder, Pain, Horner, Hoarseness, SVC syndrome. Caused by apical invasion into throacic inlet,
• Horners: Ptosis, Miosis, Anhydrosis

Workup

Investigation

Imaging Biopsy Functional MRI Brain PET CT EBUS assisted, Mediastinoscopy, Thoracocenesis, trans-thoracic FNA Pulmonary function testing Indicated if stage II+ CT Chest Sputum Cytology Smoking cessation counselling

\###Sensitivity / Specificity

Criteria Cytology PET Scan CT Scan Sensitivity < 70% 83% 64% Specificity > 90% 91% 74%

The estimated rate of false positive N2 nodes on pet is about 10%. It has a PPV of 80%. PET can determine metastasis in 6–18% of cases. A bone scan does not be ordered if a PET CT scan is ordered

Lung Function

PFT and fitness is important for considering appropriate treatment modalituies. If the FEV 1 is < 80% and DLCO is <80% predicted then patient requires quantitative lung scans/excercise testing to carefully predict postop pulmonary function.

Anatomy

Lung Anatomy

Lung Lobes

• 3 on the right and 2 on the left: RUL, RML, RLL
• Left: LUL, and LLL.
• The Lingula is the anatomic equivalent of LML, and is part of the LUL.

Mediastinum

Nodal Stations

Nodal Zone Nodal Stations N Number Upper Zone 1. Highest Mediastinal 2 2. Upper Paratracheal 2 3. Prevascular 2 4. Lower Paratracheal 2 Aortopulomary Zone 5. Subaortic 2 6. Para-aortic 2 7. Sub-carinal 2 Lower Zone 8. Paraesophageal 2 9. Pulmonary Ligament 2 Hilar Zone 10. Hilar 1 11. Interlobar 1 Peripheral 12. Lobar 1 13. Segmental 1 14. Sub-segmental 1

Intrapulmonary nodes are nodes along the secondary bronchi, whereas hilar nodes are those along the main stem bronchi. These are all considered N1 nodes.

\###Nodal Evaluation

Pre-treatment nodal assessement is done to confirm PET or CT posititvie lymph nodes prior to definitve therapy. It is also indicated for all superior sulcus tumors and central T3 lesions or T1-T2 lesions.

Mediastinoscopy EBUS VATS Station 2, 4 and 7 2, 3, 4, 7, and 10 Stations 5 and 6

Pathology

Adenocarcinoma (50%)

Adenocarcinoma is the least associated with smoking history. Three variants of adenocarcinoma include bronchoalveolar, acinar and papillary. Adenocarcinoma has a worse prognosis stage-for-stage beause of earlier propensity to metastasize (specifically to brain)

EGFR Positivity

Exon 19 and 21 are positive in 10% of cases only. EGFR mutation predicts for a high response rate (80%) to tyrosine kinase inhibitors (erlotinib, gefitinib). EGFR by FISH is the best method

KRAS Mutation

Kras predicts for resistance to platinum

Squamous (35%)

Most associated with smoking history. These primarily present as central lesions and can be associated with hemoptysis at presentation.

Staging

T Staging T1a < 2cm T1b 2–3 cm

T1a  </= 2cm

T1b  2–3cm

T2  3–7cm; or involves main bronchus within 2cm of carina/ invades visceral pleura, associated with atelectasis/obstructive pneumonitis that extends to hilum T2a  3–5cm T2b  5–7cm T3  >7cm; or directly invades chest wall/diaphragm/phrenic nerve/mediastinal pleura/parietal pericardium/<2cm carina; or atelectasis of entire lung; or separate nodules in same lobe T4  invades mediastinum, heart, great vessels, tracheal, recurrent laryngeal nerve, esophagus, vertebral body, carina, nodules in different ipsilateral lobe N1  ipsilateral peribronchial/hilar/intrapulmonary LNs N2  ipsilateral medistinal/subcarinal LNs N3  contralateral mediastinal/hilar/scalene LNs; supraclavicular LNs M1a  nodules in contralateral lung; pleural nodules; malignant pleural/pericardial effusion M1b  distant mets

Early Stage includes stage I and II outlined below.

IA IB IIA IIB T1aN0, T1bN0 T2aN0 T2bN0, T1–2aN1 T2bN1, T3N0

Early Stage

Overview

Surgical Resection

Lobectomy or pneumonectomy + mediastinal lymph node dissection or sampling. Wedge resection is done only if physiologically compromised (not recommended).

Inoperable

The rates of local control for different radiotherapy modalities. SBRT is superior to fractionated RT. — SBRT — Local control of 80–90 % — 48 Gy in 4 fractions

• Fractionated RT
• Local control of 40–50 % l
• 66 Gy in 33 fractions
• CHART
• 55 Gy in 22 fractions
• Prognostic Factors
• The most important prognostic factors are:
• Stage
• e-Treatment KPS
• Weight Loss

Radiotherapy

Constraints

Lung Heart Brachial Plexus Esophagus V20 < 37% V45 < 67% < 66 Gy Mean dose < 34 Gy MLD < 20 Gy V60 < 33% < 26 Gy if SBRT Minimize V60 ❤3% Minimize V55 <66%

SBRT

Biological Equivalent Dose

The maximum BED wanted for centrally located tumors is 180–210 Gy which results in grade 3 pulmonary complication. Keeping the BED > 100 Gy is sufficient for local control and may avert toxicities in central lesions.

The percentage of grade III toxicity in early stage lung cancer treated with SBRT is 15% based on several studies. In RTOG 0236 16.3% of patients experienced grade 3–4 toxicity.

Factors Predicting Toxicity

1. Location (46% hilar vs 17% peripheral)
2. Tumor Size (GTV > 10cc had 8x the risk of Grade 3–5 toxicity)

Toxicity

• PFT Changes are very minimal based on institutional reviews. Mean FEV1 and DLCO only changed about 3% of predicted with no association based on location or dose given.

Management

Overview

Medically Operable Medically Inoperable Lobectomy + Mediastinal LND 1. SBRT +/- Adjuvant chemotherapy 2. Conventional RT

Early Stage

Surgery

Lobectomy is preferred when feasible. Wedge resection has 82% local control while lobectomy has 94% local control. Pneumonectomy can also be preformed but is less desirable.

There is potentially a benefit for mediastinal dissection vs nodal sample in early patients undergoing resection. Mediastinal dissection involves resection of: 2R, 4R, 7, 8R, 9R and left 5, 6, 7, 8L, 9L.

Outcomes

• The 5yr OS with no adjuvant chemo:
• T1N0–80%
• T2N0–68%.
• T1N0 outcomes with no treatment
• 5 year OS 6%
• MS is 13 months.
• Incidence of secondary primary after resection
• Up to 30% recur as second primary

Adjuvant Chemotherapy

The OS benefit of chemotherapy is 5% at 5 years based on the LACE meta-analysis (JCO 2008). Indications for adjuvant chemotherapy include:

1. Stage II — IIIA disease after resection
2. N1 disease
3. T2N0, especially if >4cm as per CALGB 9633

There is no role for preoperative chemotherapy. Based on meta analysis the survival gain is the same as for adjuvant chemotherapy. The largest randomized trial (MRC LU22/EORTC 08012) found no survival benefit to prep chemotherapy but downstaging was seen (31%).

PORT

The indications for mediastinal RT (PORT) after definitive radiotehrapy for easly stage I — II NSCLC is:

• Positive margins
• Extra capsular extension
• Unexpected N2 disease

Per NCCN 2010: Give concurrent CRT for positvie margin and sequential CRT for N2 Disease (chemotherapy followed by radiotherapy). Although not specified, chemo followed by RT is also recommended for extra-capsular extension.

Benefit of PORT Study — Italian Study (Rad Onc 2002) showed improved local control and survival after surgical resection for postoperative RT (1a and 1b) via better local control rates (2% vs 23%) with a trend towards improved survival. Minimal toxicity and no worstend pulmonary function.

The max RT dose used in definitve PORT alone was up to 84 Gy in standard fractionation if lung constraints were respected.

RT alone

Principles of radiotherapy alone:

• No elective nodal volume treatment — (RTOG 9311 the elective failure was <10%). In most series treated with hypofractionated SBRT the regional failure rate is between 5–10%.
• Max LC based on BED — Should be a BED > 100 Gy will yeild a 5yr LC rate of 92% and 5yr OS rate of 72%. However, if BED is <100 Gy the 5 yr LC rate is 57% and 5 yr SO rate is 50%.

Contraindications to SBRT

• Central, within 2cm of the bronchial tree are not good candidates for 20 Gy in 3 fractions due to risk of high grade 3 -5 toxicity.
• BCCA uses:

Outcomes

• The 2yr LR for RT alone is 50–70% (RTOG 9311)
• The 3–5 yr LR and OS — Hypofractionated SBRT for stage I patients the 3yr LC ranges from 85–95% and 5 yr LC ranges from 55–91%.
• 5 YR distant metastasis — 15–25% which is close to surgical resection rates

What SBRT Technique was evaluated in RTOG 0236? — SBRT using 20 Gy x 3 (without homogeneity correction) given in 1.5–2 weeks. Dose was 18 Gy x 3 with homogeneity correction. The 5 yr local control rate was 91%. DFS was 48% and OS was 55%.

Stage III

Criteria

Medically Operable adad

• T4 Nany
• T3 N1–2
• T1–2 N2
• Tany N3

Background

The cure rate in stage III is 20%. Chemotherapy adds 10% benefit so it is a must! The overall management includes:

1. Bimodality: Chemo-Radiotherapy
2. Trimodality: Chemo-Radiotherapy followed by lobectomy
3. RT alone: Palliative or Radical

Bimodality — CRT

Radiotherapy includes 60Gy in 30 fractions with Cisplatin and Etoposide given weeks 1 and 5.

Trimodality — CRT + Surgery

Trimodality approach is taken for superior sulcus tumours, younger patients, no comorbidities, etc. Indications are not well defined. Trimodality approach involves: — Neoadjuvant CRT follow by Surgical Resection — Preoperative RT: 45 Gy in 25 fractions — Cisplatin + Etoposide — Surgery in 3–5 weeks if no progression

Palliative

• Patient factors include:
• Medical inoperability
• ECOG >1
• WT loss greater than 10%
• Disease Factors:
• N3 disease (large volume)
• Dose constraints not met

Prognosis

Outcomes

Stage IA  5yr OS 60–70%

Stage IA: T1a/b N0

Stage IB-IIB 5yr OS 30–40% Stage IB: T2a N0 Stage IIA: T2b N0; T1a-T2a N1 Stage IIB: T3 N0; T2b N1

Stage IIIA/B 5yr OS 10–20% Stage IIIA: T4 N0–1; T3 N1–2; T1a-T2b N2 Stage IIIB: T4 N2; T any N3

Stage IV  5yr OS 5% Stage IV: T any N any M1a/b

Relapse

• 15–30% of NSCLC patients develop brain mets as a site of first relapse

Follow Up

• The overall 5 yr survival rate is 15% for NSCLC
• After 2 yrs a recurrent cancer is likely actualy a second primary

Toxicity

• Pneumonitis
• Grade II — symptomatic with need for steroids
• Grade III — dyspnea at rest and O2 supplementation needed
• Grade IV — hospitalized and intubated
• Grade V — death
• Brachial Plexopathy
• SBRT Risk
• If <26 Gy in 3–4 fractions — 20%
• If >26 Gy in 3–4 fractions — 46%
• Lung fibrosis
• Cough
• Dermatitis
• Chest wall pain
• Esophagitis
• Hemoptysis