MANAGEMENT OF NON-SMALL CELL LUNG CANCER

Dr. NilaxiDr. ShraddhaModerator- Dr. Rajiv Sharma

Overview in management of lung cancer:

Intent of treatment depends on: resectability performance status associated co-morbidities.

Two different approaches: curative palliative.

Treatment modalities: surgery (for early stages)

radiotherapy- radical or palliative. Chemotherapy.

RT in Lung Cancer: Issues

NSCLC: a moderately radiosensitive tumor; dose escalation required.

Surrounded by organs which are dose limiting: heart, opposite lung, spinal cord, esophagus.

Respiratory motion: a pertinent factor necessitating motion management in radiation delivery.

Treatment options:

Stage I: surgery (TOC) or radiotherapy.

Stage II: surgery or RT.

Stage III: surgery+RT/ CT+RT

Stage IV: palliative RT/ chemotherapy.

Resectable Early stage ( I, II ) NSCLC::

Surgery is the treatment of choice.

Types of surgery: lobectomy pneumonectomy

sleeve resection wedge resectionsegmentectomyen bloc resection.

Resectable Early stage ( I, II ) NSCLC::

Patients are considered suitable for pneumonectomy if their predicted post-op. FEV1 is > 1.2L; the patient does not suffer from hypercarbia and cor pulmonale is not present.

Standard of care is surgical resection through either a lobectomy or pneumonectomy with mediastinal lymph node dissection.

Lobectomy has been shown to be superior to more limited surgical resections such as wedge resection or segmentectomy (acc to the LCSG trial, which showed improved local control with more extensive resection).

Complete mediastinal lymphadenectomy provides the best possible surgical staging by removing all lymph nodes, which can then be analyzed pathologically for metastatic involvement.

This can help to identify patients who may require post-operative adjuvant radiation therapy.

At minimum, lymph node sampling of all the draining areas should be performed at the time of surgical resection, for accurate final surgical-pathologic staging.

5-year survival rates following surgical resection are:

73% for stage IA 58% for stage IB 46% for stage IIA 36% for stage IIB.

Patients who fail after surgery, present with- extrathoracic disease (70%)

local recurrence (20%)local + distant metastasis (10%).

Adjuvant chemotherapy is accepted as the standard of care for patients with node-positive disease (stages IIA, IIB, IIIA)

Post-op radiotherapy may be beneficial in stage IIIA, but is not indicated in completely resected stage I and II NSCLC.

Thoracoscopic Lobectomy::

Video-assisted thoracoscopic surgery (VATS) or thoracoscopic lobectomy is a minimally invasive surgical treatment currently being investigated in all aspects of lung cancer.

Has several advantages over standard thoracotomy:- Acute and chronic pain is minimal.- Associated with low post-operative morbidity and

mortality.- Minimal risk of intra-operative bleeding.- Minimal loco-regional recurrence.- More rapid return to function than lobectomy by

thoracotomy.

Inoperable Early-stage (I, II) NSCLC::

For patients who cannot undergo surgery, or decline surgical treatment, conventional radiation therapy results in survival rates of approx. 15-30%.

However, conventional RT has inferior local control as compared with surgery.

Hypofractionation, or delivery of high doses of radiation in a few fractions, is a means of increasing the biologic effects of RT. Options now available are:

- SBRT (SABR)/ Cyber Knife- Brachytherapy: endoluminal and interstitial.

SBRT:

SBRT, or Stereotactic Body Radiotherapy ( stereotactic ablative radiotherapy) refers to the delivery of large doses of radiation to a small treatment volume, usually employing multiple beams, using a small number of fractions (5 or less).

Patient selection criteria are:- Medically inoperable or do not want surgery- PS 0-2- Stage T1-3, N0 following PET- Maximum tumor size 5cm- Not adjacent to major structures like great vessels,

heart, esophagus- Able to lie supine for at least an hour.

SBRT systems can either use a frame-based system or it can be frameless.

Frame-based systems have been developed to control lung and tumor motion, including compression devices, breath-hold techniques, automated breathing control or full body moulds.

For frameless systems, gold fiducial markers can be placed to allow tumor localization by the treatment machine, or stereotactic real-time imaging can be performed to localize the tumor visually prior to treatment.

Stereotactic methods of tumor localization decrease the effects of lung and tumor motion, resulting in smaller treatment fields and margins.

SBRT planning involves CT imaging of the patient. To assess the degree of physical excursion of the

tumor during different phases of the respiratory cycle, 4D-CT imaging should be performed; or, maximum inspiratory and expiratory scans will provide some degree of approximation of the degree of motion.

Margins are 1cm in the superior and inferior dimensions and 5mm radially.

Typically, 6-12 convergent, non-co planar beams are used in a linac-based system.

Commonly used doses for SABR:

Total dose No. of fractions

Indications

25-34Gy 1 Peripheral, small (<2cm) tumors, esp. >1cm from the chest wall

45-60Gy 3 Peripheral tumors and >1cm from the chest wall

48-50Gy 4 Central or peripheral tumors <4-5cm, esp. <1cm from chest wall.

50-55Gy 5 Central or peripheral tumors, esp. <1cm from chest wall.

60-70Gy 8-10 Central tumors.

RESULTS:

Timmerman et al reported the results of RTOG 0236, a phase II trial in medically inoperable patients with T1 or T2 tumors treated to 54Gy in three 18Gy fractions.

3-year primary tumor control rate 97.6% Loco-regional control rate 90.6% 3-year distant failure rate 22.1%. Median OS 48.1 months.

Because patients are at risk for a second primary or mediastinal relapse, close follow-up is required. Imaging should be obtained at least 2-3 months after completion of SBRT.

Serial PET scans are not recommended as inflammation can persist for as long as 6 months to 2 years.

Thus SBRT, with its advantage of patient convenience and promising local control results, has largely replaced conventionally fractionated radiotherapy as the standard approach in the medically inoperable patient.

Two international phase III trials for SBRT are underway-

- The Stereotactic Radiotherapy versus Surgery (STARS) Trial, which compares surgery vs. Cyberknife SRT for stage I NSCLC;

- The Radiosurgery or Surgery for Operable Early-Stage NSCLC (ROSEL) study, which compares local control, QOL and treatment costs of surgery versus SBRT.

Brachytherapy in Lung cancer:Brachytherapy in Lung cancer:

is considered a suitable alternate treatment for very early cancers; localized, large unresectable cancers or as a boost in combination with EBRT.

Indications include thoracic symptoms ( dyspnea due to endobronchial tumor or obstructive pneumonia), previous high dose RT to the chest; and endobronchial or endotracheal lesions.

May be administered by permanent iodine-125 interstitial implants performed intra-operatively, removable iridium-192 implants through intra-operative insertion of Teflon catheters in the tumor, or intra-bronchial LDR or HDR iridium 192 implants.

Stage III Non-Small Cell Lung Cancer::

Majority of patients with inoperable locally advanced NSCLC (stage IIIB) receive definitive thoracic RT as part of their treatment strategy, with concurrent chemotherapy (standard of care acc to RTOG 94-10 trial).

Sequential chemoRT or RT alone is appropriate for frail patients unable to tolerate concurrent therapy.

Accelerated RT regimens may be beneficial ( to improve therapeutic ratio and survival rates and to decrease local failures)--- particularly if not concurrent with chemotherapy i.e. in a sequential or RT-only approach.

RT has a role after surgery; however pre-op. RT has no survival benefit in management of marginally resectable or unresectable disease.

Stage III Non-Small Cell Lung Cancer (contd.)

Preoperative concurrent chemoRT is an option for patients with resectable stage IIIA (minimal N2 and treatable with lobectomy) and is also recommended for resectable superior sulcus tumors.

Preoperative chemotherapy and postoperative RT is an alternative for patients with resectable stage IIIA.

In patients with clinical stage I/II upstaged surgically to N2+, PORT is generally administered after post-op chemotherapy. For positive resected margins, PORT with concurrent chemotherapy is recommended.

stage III

Resectable Unresectable

Preop chemo or chemoRT chemoRT

RT only

surgery

PORT + adj. CT

Modalities of RT:

- 2D conventional planning- 3D CRT.- IMRT- 4D gated RT.

RT Techniques:

For 2D planning: 2cm margin around any gross tumor. 1cm margin around regional

lymph node groups.

Upper lobe tumors- I/L supraclav and subcarinal lymph nodes to be included.

Middle and lower lobe tumors- entire mediastinum

from the thoracic inlet to the diaphragm.

Fields: AP-PA portals till spinal cord tolerance (~40Gy).

boost of 20Gy by shrinking field technique after spinal shielding.

Energy: either Cobalt-60 or Linac.

Dose: 60Gy in 30# over 6 weeks (RTOG 73-01 trial).

Diagram:

3D-CRT:: Treatment simulation:Treatment simulation:

- Goal of simulation is to acquire an image-based representation of the patient for the purposes of tumor and normal organ delineation for treatment planning.

- Imaging traditionally performed with CT.

- Slice thickness =< 5mm.

- Anatomic region scanned should include both lungs and extends from level of cricoid cartilage to L2 vertebra.

Management of tumor motion:Management of tumor motion:

- Motion can result in significant distortion of axial or helical CT scans—confounds the ability to contour the target accurately on the planning CT data set.

- Motion management strategies should be considered when range of tumor motion is >5mm in any direction.

- Motion encompassing methods are:- 4D-CT scans, which contain spatial and temporal

information during the CT acquisition process.- Slow CT scans (4 seconds per slice) acquired during

quiet respiration.- Abdominal compression devices- Techniques as deep-inspiration breath hold, automated

breathing control, respiratory gating and tumor tracking.

3D-CRT

GTV: primary tumor and any gross lymph nodes.

CTV: areas thought to harbor micrometastases (hilar/mediastinal LN, margin).

PTV: margin for physiologic organ motion during treatment and setup errors.

Beam energy: 6-10 MV.

Gross Tumor Volume (GTV)

Clinically macroscopic disease, as typically identified on any imaging modality.

Usually derived from a treatment planning CT or a PET-CT obtained during quiet respiration.

Lung windowing should be used for delineation of the primary tumor GTV.

Mediastinal extent : mediastinal windows. Lymph node >1cm in SAD: +ve When feasible, mediastinum should be pathologically

staged and this information should be incorporated into delineating the nodal GTV.

Clinical Target Volume (CTV)

Represents a volumetric expansion of the GTV to encompass microscopic disease.

GTV-to-CTV: 6mm for squamous cell ca and 8mm for adenoca, with 95% accuracy.

For others: 9mm. In the absence of radiographic proof of invasion, CTV of the

primary should not extend into the chest wall or mediastinum. For nodal disease, a 3mm margin encompasses 95% of the

microscopic extranodal extension of disease in LN <2cm. Larger margins required for LN >2cm.

CTv expansion of the LNs should not extend into the major airways or the lung.

In PORT, CTV includes the bronchial stump and high-risk draining lymph node stations.

Internal Target Volume (ITV)

Defined by ICRU 62 as ‘an expansion of the CTV to account for tumor motion’.

Planning Target Volume (PTV)

Volumetric expansion of the CTV to account for setup variability.

Individual assessment is recommended. PTV margin can be decreased by immobilization,

motion management and IGRT techniques. Typical margins are 5-10mm if daily IGRT employed;

otherwise 10-20mm.

Beam arrangements:Beam arrangements:

- Beam arrangements can range from simple two-field, parallel opposed fields to complex, multiple gantry angle, modulated beams for more focal treatments.

- Beams are shaped with MLC, which enables conformation of radiation to the target.

- AP/PA fields are considered when disease is more extensive and located centrally. Off-cord fields are required beyond 40-45 Gy (in 1.8-2Gy per #) because of spinal cord tolerance.

Treatment type

total dose Fraction size Treatment duration

Definitive RT with/without chemo

60-74Gy 2Gy 6-7.5 weeks

Post-op RT- neg margins-ECE or +ve margins-Gross residual tumor

50-54Gy54-60 Gy

60-70Gy

1.8-2Gy1.8-2Gy

2Gy

5-6 weeks6 weeks

6-7 weeks

Doses:

Normal dose-volume constraints for conventionally fractionated RT::organ RT alone ChemoRTSpinal cord 50Gy 45Gylung MLD <20Gy

V20 <40%MLD <20GyV20<35%V10<45%V5<65%

heart V40 <50% V40 <50%esophagus V60 <50% V55 <50%kidney 20Gy (<50% of

combined both kidneys or <75% of one kidney if he other one is not functional)

same

liver 30Gy (40%) same

IMRT::

More suitable than 3D-CRT for advanced-stage disease with a larger GTV.

Median absolute reduction in lung volume irradiated above 10 and 20 Gy are 7% and 10% respectively.

>2Gy less mean total lung dose and 10% decrease in the risk of radiation pneumonitis.

Dose to the heart, esophagus and thoracic tissue also decreased.

Tumors in the superior sulcus or close to the esophagus or spinal cord or patients with +ve lymph nodes may benefit more.

Image-guided radiation therapy (IGRT) is recommended when using SABR and 3D-CRT/IMRT :

- with steep dose gradients around the target- When OARs are in close proximity to high-dose

regions- When using complex motion management techniques.

Chemotherapy regimens used with RT::

Concurrent chemoRT regimens:

- Cisplatin 50mg/m2 days 1, 8, 29 and 36; etoposide 50mg/m2 days 1-5 and 29-33 (preferred).

- Cisplatin 100mg/m2 days 1 and 29; vinblastine 5mg/m2 /weekly; x 5 (preferred).

- Carboplatin AUC 5 day 1; pemetrexed 500mg/m2 on day 1 every 21 days for 4 cycles (non-squamous).

- Cisplatin 75mg/m2 day 1; pemetrexed 500mg/m2 on day 1 every 21 days for 3 cycles (non-squamous).

Sequential chemoRT regimens:

- Cisplatin 100mg/m2 days 1 and 29; vinblastine 5mg/m2/weekly on days 1,8, 15, 22, 29; followed by RT.

- Paclitaxel 200mg/m2 over 3hours on day 1; carboplatin AUC 6 over 60 minutes on day 1 every 3 weeks for 2 cycles followed bt RT.

- Concurrent chemoRT followed by chemotherapy:

- Paclitaxel 45-50mg/m2 weekly; carboplatin AUC 2 with RT f/b 2 cycles of paclitaxel 200mg/m2 and carboplatin AUC 6.

- Cisplatin 50mg/m2 days 1, 8, 29, 36; etoposide 50mg/m2 days 1-5, 29-33 with RT f/b cisplatin 50mg/m2 and etoposide 50mg/m2 x 2 cycles (category 2B).

Chemotherapy regimens for NACT and adjuvant therapy::

Cisplatin 50mg/m2 days 1 and 8; vinorelbine 25mg/m2 days 1, 8, 15, 22, every 28 days for 4 cycles.

Cisplatin 100mg/m2 day 1 ; vinorelbine 30mg/m2 days 1, 8, 15, 22, every 28 days for 4 cycles.

Cisplatin 100mg/m2 day 1; etoposide 100mg/m2 days 1-3, every 28 days for 4 cycles.

Cisplatin 75mg/m2 day 1; gemcitabine 1250mg/m2 days 1 and 8, every 21 days for 4 cycles.

Cisplatin 75mg/m2 day 1; docetaxel 75mg/m2 day 1 every 21 days for 4 cycles.

Cisplatin 75mg/m2 day 1; pemetrexed 500mg/m2 day 1 for adenocarcinoma and large cell carcinoma and NSCLC NOS (without specific histologic subtype) every 21 days for 4 cycles.

For patients with comorbidities or patients not able to tolerate cisplatin---- paclitaxel 200mg/m2 day 1, carboplatin AUC 6 day 1, every 21 days.

Stage IV NSCLC::

Effective palliation is an important objective. It is important to intervene before SVCO, obstructive

pneumonia or lobar collapse develops.

EBRT: Certain symptoms like hemoptysis and pain are more effectively

palliated, whereas dyspnea, hoarseness and poor PS appear to be more refractory.

Isolated symptomatic lesions such as bone metastasis and spinal cord compression are also managed with palliative courses of RT (eg. 30Gy in 10#).

Standard therapy for multiple brain metastases in NSCLC is whole-brain RT ( with dexamethasone 4mg four times daily before and during RT and anticonvulsants only if seizures occur).

Doses:

Palliative RT Total dose Fraction size Treatment duration

Obstructive disease

30-45Gy 3Gy 2-3 weeks

Bone mets with soft tissue mass

20-30Gy 4-3Gy 1-2 weeks

Bone mets without soft tissue mass

8-30Gy 8-3Gy 1 day-2 weeks

Brain mets 30Gy 3Gy 2 weeks

Any mets in patients with poor PS

8-20Gy 8-4Gy 1 day-1 week

Systemic therapy:

Platinum-based chemotherapy prolongs survival, improves symptom control and yields superior QOL compared to BSC.

Agents used are:- Cisplatin - Mitomycin- Carboplatin - Pemetrexed

- Paclitaxel - Erlotinib- Docetaxel - Bevacizumab- Vinorelbine - Cetuximab- Gemcitabine - Albumin-bound paclitaxel- Etoposide - Crizotinib- Irinotecan - Afatinib- Vinblastine - Ceritinib.- ifosfamide

Targeted therapy::

Indicated in patients with advanced NSCLC who have failed platinum/taxane based chemotherapies.

Rationale: EGFR in epithelial tumors gets activated by binding of natural ligands TGF.

- Activation of EGFR leads to:- Increased cell proliferation- Angiogenesis and metastasis.

- Anti-EGFR agents are: a) monoclonal antibodies cetuximab and panitumumab.

- b) TKIs- geftinib, erlotinib.

Geftinib- 250mg OD (oral);

Erlotinib- 150mg OD (oral). rash and diarrhoea are the most common side effects. 10-15% 0f tumors show shrinkage, while 30-40% remain stable.

Bevacizumab:- Is a VEGF monoclonal antibody.- Inhibits angiogenesis and metastasis by blocking VEGF

induced increase in capillary permeability and peritumoral lymph drainage.

- Crizotinib: approved by FDA for patients with locally advanced or metastatic NSCLC who are

positive for ALK gene rearrangement.

First-line therapy:First-line therapy:

Bevacizumab +chemotherapy or chemotherapy alone is indicated in PS 0-1 patients with advanced or recurrent NSCLC. Bevacizumab should be given until disease progression.

Cetuximab + vinorelbine/cisplatin is an option for patients with PS 0-1 (category 2B).

Erlotinib is recommended as a 1st line therapy in patients with sensitizing EGFR mutations and should not be given as 1st line therapy to patients negative for EGFR mutations or with unknown EGFR status.

Crizotinib is indicated for select patients with ALK rearrangements.

First-line therapy:First-line therapy:

Two-drug regimens are preferred; a third cytotoxic drug increases response rate but not survival.

Single agent therapy or platinum based combinations are a reasonable alternative in patients with PS2 or the elderly.

Cisplatin or carboplatin are effective in combination with any of the following agents: paclitaxel, docetaxel, gemcitabine, etoposide, vinblastine, vinorelbine, pemetrexed or albumin-bound paclitaxel.

Maintenance therapy:Maintenance therapy:

Continuous maintenance refers to the use of at least one of the agents given in 1st line, beyond 4-6 cycles, in the absence of disease progression.

Switch maintenance refers to the initiation of a different agent, not included as part of the 1st line regimen, in the absence of disease progression, after 4-6 cycles of initial therapy.

a) Continuation maintenance:

- Continuation of bevacizumab after 4-6 cycles of platinum doublet chemotherapy and bevacizumab.

- Continuation of cetuximab after 4-6 cycles of cisplatin, vinorelbine and cetuximab.

- Continuation of pemetrexed after 4-6 cycles of cisplatin and pemetrexed chemotherapy (non-squamous).

- Continuation of gemcitabine after 4-6 cycles of platinum doublet chemotherapy (category 2B).

b) Switch maintenance:

- Initiation of pemetrexed after 4-6 cycles of 1st line platinum-doublet chemotherapy ( non-squamous ).

- Initiation of erlotinib after 4-6 cycles of 1st line platinum-doublet chemotherapy (category 2B).

- Initiation of docetaxel after 4-6 cycles of 1st line platinum-doublet chemotherapy, in patients with squamous cell ca (category 2B).

- Close surveillance of patients without therapy is a reasonable alternative to maintenance.

Second-line therapy:Second-line therapy:

In patients who have experienced disease progression either during or after 1st line therapy, single agent docetaxel, pemetrexed or erlotinib are established 2nd line agents.

- Docetaxel is superior to vinorelbine or ifosfamide.- Pemetrexed equivalent to docetaxel with less toxicity

in patients with adeno- or large cell ca.- Erlotinib is superior to BSC.

- Third-line therapy:Third-line therapy: if not already given, options are docetaxel, pemetrexed, erlotinib or gemcitabine.

Sequelae of therapy:: Acute sequelae:Acute sequelae:

include esophagitis, cough, skin reaction and fatigue. Acute radiation esophagitis usually begins in the 3rd week of RT, at

approx. 30Gy. Treatment includes mucosal anaesthetics (viscous lidocaine) and

agents that coat the irritated surfaces (suspension or liquid antacids).

Cough is common but usually mild. Anti-tussive therapy with or without codeine phosphate is usually effective.

Treatment of acute phase of radiation pneumonitis includes absolute bed rest, use of bronchodilators and corticosteroid therapy. Antibiotics indicated only if associated secondary infection.

Skin reaction is mild to moderate; topical moisturizing creams or ointments relieve symptoms.

Late sequelae:Late sequelae:

Include pneumonitis and pulmonary fibrosis, esophageal stricture, cardiac sequelae ( pericardial effusion, constrictive pericarditis, cardiomyopathy), spinal cord myelopathy and brachial plexopathy.

Conclusion::

NSCLC accounts for more than 75% of all cases of lung cancer

Accurate staging is critical as t/t options depend on spread of the disease.

Surgery is treatment of choice for early stage NSCLC

Radiation has imp role in all stages, for radical t/t as well as palliation

However its curative potential in stage III is extremely poor with 5-yr survival rates of 3–10%

ThankYou!!!